|
1
|
Ghosh U, Samanta A. Monogenic inflammatory bowel disease: An unfolding enigma. World J Clin Pediatr 2025; 14:107165. [DOI: 10.5409/wjcp.v14.i3.107165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 04/10/2025] [Accepted: 05/07/2025] [Indexed: 06/16/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract (GIT). It results either from gene-environment interactions or as a monogenic disease resulting from pathogenic mutations causing impairment in the protective mechanism of the GIT. Around 10%-15% of patients with very early onset IBDs may have an underlying monogenic condition. Monogenic IBD is very different from complex forms of polygenic IBD in the underlying molecular basis of uncontrolled intestinal inflammation, age of onset, extraintestinal comorbidities as well as treatment modality. An in-depth understanding of this distinct form of IBD is essential for deciding an appropriate therapeutic approach as well as prognostication. In this review, we aim to discuss about the epidemiology, clinical presentation, diagnostic approach, therapeutic challenges and latest advances in patients with monogenic IBD.
Collapse
Affiliation(s)
- Upasana Ghosh
- Department of Pediatric Gastroenterology, Post Graduate Institute of Child Health, Noida 201303, Uttar Pradesh, India
| | - Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| |
Collapse
|
|
2
|
Baccarella A, Patel T, Conrad MA, Macchi M, Boyer B, Pickering O, Borodyanskaya Y, Gaddipati S, Cohen M, Cubero A, Dawany N, Heimall J, Bunin N, Sullivan KE, Kelsen JR. Outcomes of Allogeneic Hematopoietic Stem Cell Transplant in Monogenic Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2025:S1542-3565(25)00404-5. [PMID: 40378986 DOI: 10.1016/j.cgh.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/09/2025] [Accepted: 03/11/2025] [Indexed: 05/19/2025]
Abstract
BACKGROUND & AIMS Monogenic inflammatory bowel disease (IBD) can result in inborn errors of immunity and intestinal epithelial cell dysfunction, more commonly seen in patients with very early onset IBD (VEO-IBD). Hematopoietic stem cell transplant (HSCT) has emerged as an effective treatment for a subset of patients with monogenic IBD. We sought to evaluate the efficacy and safety of HSCT in these patients. We hypothesized that HSCT will lead to IBD medication-free remission or significant improvement of disease. METHODS This was a single-center, retrospective study of children with monogenic IBD who underwent HSCT at The Children's Hospital of Philadelphia from 2012 to 2022. The primary outcome was IBD medication-free sustained remission, measured by disease activity index. Secondary outcomes included all-cause mortality, growth, hospitalizations, infections, and HSCT-associated complications. RESULTS Thirty-eight patients with monogenic IBD were identified as eligible for HSCT, with 25 undergoing HSCT as therapy for IBD during the study period. There was 100% survival at a median follow-up of 3 years. Prior to transplant, 76% of patients received immunosuppression, and 20% underwent IBD-related surgery. At most recent follow-up, 92% of patients achieved sustained medication-free remission of IBD and 60% with prior ostomy underwent re-anastomosis. There was significant improvement in growth, hospital days, and severe infections. CONCLUSION HSCT resulted in IBD medication-free remission and reduction in disease-associated complications. This highlights the strength of genetic evaluation in patients with VEO-IBD or refractory IBD and consideration of HSCT, which can be curative and lifesaving in patients with monogenic defects involving immune dysfunction.
Collapse
Affiliation(s)
- Alyssa Baccarella
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Trusha Patel
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Maire A Conrad
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Marina Macchi
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Brooke Boyer
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Oliver Pickering
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Yelizaveta Borodyanskaya
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Shreya Gaddipati
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Maya Cohen
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Andrea Cubero
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Noor Dawany
- Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jennifer Heimall
- Division of Allergy Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Nancy Bunin
- Cellular Therapy and Transplant Section, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kathleen E Sullivan
- Division of Allergy Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Judith R Kelsen
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
| |
Collapse
|
|
3
|
Liao J, Yang Y, Li J, Liu Z, Song S, Zeng Y, Wang Y. Regulatory B cells, the key regulator to induce immune tolerance in organ transplantation. Front Immunol 2025; 16:1561171. [PMID: 40264774 PMCID: PMC12011811 DOI: 10.3389/fimmu.2025.1561171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/24/2025] [Indexed: 04/24/2025] Open
Abstract
In solid organ transplantation, especially renal transplantation, for the induction of immune tolerance, accumulating evidence has revealed that Regulatory B cells (Breg) play a crucial role in stimulating immune tolerance, alleviating immune responses, and improving graft survival. We describe the heterogeneous nature of Bregs, focusing on their defining surface markers and regulatory functions. Meanwhile, the major cytokine secretion function and the correlation between Breg and Treg or other immune checkpoints to balance the immune responses are addressed. Furthermore, we summarized the intrinsic and extrinsic pathways or costimulatory stimuli for the differentiation from naïve B cells. More importantly, we summarized the progression of the immune tolerance induction role of Breg in solid organ (kidney, liver, heart, lung, and islet) transplantation. This is an up-to-date review from the origin of Breg to the function of Breg in solid organ transplantation and how it induces immune tolerance in both murine models and human solid organ transplantation.
Collapse
Affiliation(s)
- Jinfeng Liao
- Department of Dermatology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yixin Yang
- Department of Clinical Medicine, The First Clinical Medical College of Norman Bethune University of Medical Sciences, Jilin, China
| | - Jisong Li
- Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Zheng Liu
- Department of Pathology, MD Anderson Cancer Center, Houston, TX, United States
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Yu Zeng
- Department of Hyperbaric Oxygen, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Translational Clinical Immunology Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China
| |
Collapse
|
|
4
|
Borkhataria CH, Sharma S, Vaja P, Tank C, Mori D, Patel K, Kyada A. Quality management, ethical considerations, and emerging challenges in genomics and biobanking: A comprehensive review. Clin Chim Acta 2025; 569:120161. [PMID: 39864572 DOI: 10.1016/j.cca.2025.120161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 01/28/2025]
Abstract
The integration of genomics into personalized medicine has the potential to transform healthcare by customizing treatments according to individual genetic profiles. This paper examines the diverse applications of genomics, including the identification of disease susceptibility, improvement of diagnostic methods, optimization of drug therapies, and monitoring of treatment responses. It also explores the expanding global market for genetic testing and the increasing implementation of whole-genome sequencing in clinical practice, with a focus on pilot programs that are advancing comprehensive genomic analysis. Despite challenges such as high costs, data interpretation complexities, and ethical concerns, significant efforts are being made to address these issues. Additionally, the creation of biobanks as vital resources for preserving high-quality biosamples and supporting research highlights the critical need for infrastructure development in genomics. By fostering interdisciplinary collaboration and establishing robust ethical and regulatory frameworks, personalized medicine can ensure equitable access to tailored therapies and enhance health outcomes for everyone. This abstract provides an overview of the transformative potential of genomics and personalized medicine in ushering in a new era of precision healthcare.
Collapse
Affiliation(s)
| | - Shweta Sharma
- B K Mody Government Pharmacy College Rajkot Gujarat India
| | - Payal Vaja
- School of Pharmacy, Dr. Subhash University Junagadh Gujarat India
| | | | - Dhaval Mori
- B K Mody Government Pharmacy College Rajkot Gujarat India
| | | | - Ashishkumar Kyada
- Department of Pharmaceutical Sciences, Marwadi University Rajkot Gujarat India
| |
Collapse
|
|
5
|
Tai TS, Hsu DW, Yang YS, Tsai CY, Shi JW, Wu CH, Hsu SC. IL-10RA governor the expression of IDO in the instruction of lymphocyte immunity. Br J Cancer 2025; 132:126-136. [PMID: 39592739 PMCID: PMC11723913 DOI: 10.1038/s41416-024-02893-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 10/17/2024] [Accepted: 10/22/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Indoleamine 2,3-dioxygenase (IDO) impairs anti-pathogen and anti-tumour immunity. Mesenchymal stem cells (MSCs) modulate immunity via IDO but also suppress IFN-γ. While MSC IDO induction by IFN-γ is established, other drivers in this immunosuppressive setting remain unknown. METHODS Human bone marrow mesenchymal stem cells (MSCs) with IDO or IL-10RA knockdown were co-cultured with healthy donor T cells to assess immunosuppression. PDAC organoid anticancer activity was also tested in these co-cultures. RESULTS Co-culturing MSCs with T cells in an IL-10RA-enriched environment enhances IDO expression, resulting in T cell suppression. Moreover, IL-10RA-positive MSCs collected from co-cultures with IL-10 supplementation show increased IDO expression. Conversely, MSCs with IL-10RA knockdown exhibit a significant reduction in IDO RNA and protein expression, as well as STAT3 phosphorylation status, which is a known upstream signalling pathway in IDO gene regulation, in T cell co-cultures. Down-regulation of IL-10RA also inhibits IDO activity in MSCs, resulting in reduced T cell suppression, and enabling the co-cultured T cells to kill PDAC organoids. CONCLUSION Our research reveals IL-10RA as a pharmacological target in stromal cells for enhancing T cell-mediated PDAC eradication by downregulating IDO via blocked IL-10/IL-10RA signalling in MSCs. This advances IL-10RA interference in the tumour microenvironment (TME) to restore T cell cytotoxicity against cancers.
Collapse
Affiliation(s)
- Tzong-Shyuan Tai
- Department of Medical Research and Development, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Duen-Wei Hsu
- Department of Biotechnology, National Kaohsiung Normal University, Kaohsiung City, Taiwan
| | - Yu-Shao Yang
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Ching-Yen Tsai
- Transgenic Core Facility, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
| | - Jai-Wen Shi
- Department of Biotechnology, National Kaohsiung Normal University, Kaohsiung City, Taiwan
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
| | - Chien-Hui Wu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Shu-Ching Hsu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan.
- Graduate Institute of Biomedical Science, Immunology Research and Development Center, China Medical University, Taichung City, Taiwan.
- Department of Biomedical Sciences and Engineering, Tzu Chi University, Hualien, Taiwan.
- Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung City, Taiwan.
| |
Collapse
|
|
6
|
Grotra R, Karri PS, Gupta A, Malik R, Gupta AK, Meena JP, Seth R. Matched Unrelated Donor Hematopoietic Stem Cell Transplant as Successful Curative Therapy for IL10RB Mutation-Associated Very Early Onset IBD. Pediatr Transplant 2024; 28:e14891. [PMID: 39539152 DOI: 10.1111/petr.14891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/17/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Inflammatory bowel diseases are complex chronic disorders with a relapsing-remitting course that affect the gut due to dysregulated immune response. The incidence of these disorders is increasing globally along with an increase in the incidence in pediatric population. Very early onset inflammatory bowel diseases are seen in children with age less than 6 years, where monogenic causes predominate. With the advent of next-generation sequencing methods, these disorders are being diagnosed more. Interleukin-10 receptor mutation-associated inflammatory bowel diseases is one such monogenic disorder where immunosuppression shows poor response. METHODS We report the case of an 8-month-old child of Indian origin who presented with severe enterocolitis and rectovaginal fistulas. She was evaluated on lines of a very early onset inflammatory bowel disease. She was found to have a mutation in the interleukin-10 receptor causing severe enterocolitis. She underwent a diversion colostomy. She was admitted at 25 months of age for the hematopoietic-stem-cell-transplant (HSCT). The conditioning regimen used consisted of busulfan, fludarabine, and anti-thymocyte-globulin (ATG). The child received a 10/10 human leukocyte antigen (HLA) matched from a matched-unrelated adult female donor with bone marrow stem cell product at a dose of 5.6 million CD34+ cells per kg. RESULTS She was treated successfully by a matched unrelated donor HSCT. At present, she is 2 years and 4 months posttransplant and is cured. CONCLUSIONS Early recognition and prompt genetic testing can help in diagnosing and establishing the cause of a very early onset inflammatory bowel disease. Very early onset inflammatory bowel disease caused due to interleukin-10 receptor mutations can be cured by HSCT.
Collapse
Affiliation(s)
- Rohan Grotra
- Division of Pediatric Gastroenterology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Padma Sagarika Karri
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Aditya Gupta
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Rohan Malik
- Division of Pediatric Gastroenterology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Aditya Kumar Gupta
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Jagdish Prasad Meena
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Rachna Seth
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
7
|
Vuijk SA, Camman AE, de Ridder L. Considerations in Paediatric and Adolescent Inflammatory Bowel Disease. J Crohns Colitis 2024; 18:ii31-ii45. [PMID: 39475081 PMCID: PMC11523044 DOI: 10.1093/ecco-jcc/jjae087] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/03/2024] [Accepted: 06/11/2024] [Indexed: 11/02/2024]
Abstract
The incidence of inflammatory bowel disease [IBD] is rising most rapidly among children and adolescents. Paediatric-onset IBD is associated with a more extensive and severe disease course compared to adult-onset IBD. At a young age, screening for underlying genetic and immunological disorders is important and may impact treatment management. Early and effective treatment is crucial to reach disease remission and prevent complications of ongoing active disease. In children with Crohn's disease, exclusive enteral nutrition is an effective induction therapy. Other promising dietary therapies, such as the Crohn's disease exclusion diet, are emerging. Within paediatric IBD, anti-tumour necrosis factor therapy is the only approved biological thus far and additional treatment options are crucially needed. Other biological therapies, such as vedolizumab and ustekinumab, are currently prescribed off-label in this population. A specific challenge in paediatric IBD is the unacceptable and major delay in approval of drugs for children with IBD. A guided transfer period of paediatric patients to adult care is associated with improved disease outcomes and is required. Major knowledge gaps and challenges within paediatric IBD include the aetiology, diagnostics, and monitoring of disease, tailoring of treatment, and both understanding and coping with the physical and psychological consequences of living with IBD. Challenges and research gaps in paediatrics should be addressed without any delay in comparison with the adult field, in order to ensure a high quality of care for all patients with IBD, irrespective of the age of onset.
Collapse
Affiliation(s)
- Stephanie A Vuijk
- Department of Paediatric Gastroenterology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Anouk E Camman
- Department of Paediatric Gastroenterology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Lissy de Ridder
- Department of Paediatric Gastroenterology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands
| |
Collapse
|
|
8
|
Tomomasa D, Suzuki T, Takeuchi I, Goto K, Hagiwara SI, Keino D, Saida S, Ishige T, Kudo T, Eguchi K, Ishimura M, Matsuda Y, Wada T, Ito Y, Kato M, Sasahara Y, Morio T, Arai K, Uhlig HH, Kanegane H. Successful Allogeneic Hematopoietic Cell Transplantation for Patients with IL10RA Deficiency in Japan. J Clin Immunol 2024; 45:6. [PMID: 39264505 DOI: 10.1007/s10875-024-01795-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 08/28/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUND IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes. METHODS We retrospectively analyzed patients with IL10RA deficiency in Japan. RESULTS Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT; one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status. CONCLUSION In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250).
Collapse
Affiliation(s)
- Dan Tomomasa
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tasuku Suzuki
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Ichiro Takeuchi
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Kimitoshi Goto
- Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan
- Department of Virology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shin-Ichiro Hagiwara
- Department of Pediatric Gastroenterology, Nutrition and Endocrinology, Osaka Women's and Children's Hospital, Osaka, Japan
| | - Dai Keino
- Division of Hematology/Oncology, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Satoshi Saida
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Takashi Ishige
- Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Takahiro Kudo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Katsuhide Eguchi
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masataka Ishimura
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yusuke Matsuda
- Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Taizo Wada
- Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Yoshiya Ito
- Division of Clinical Medicine, The Japanese Red Cross Hokkaido College of Nursing, Hokkaido, Japan
| | - Motohiro Kato
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Yoji Sasahara
- Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
| | - Tomohiro Morio
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Katsuhiro Arai
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Holm H Uhlig
- Translational Gastroenterology Unit, Experimental Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
- Department of Pediatrics, University of Oxford, Oxford, UK
- Biomedical Research Center, University of Oxford, Oxford, UK
| | - Hirokazu Kanegane
- Deparment of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
| |
Collapse
|
|
9
|
Tanwar H, Gnanasekaran JM, Allison D, Chuang LS, He X, Aimetti M, Baima G, Costalonga M, Cross RK, Sears C, Mehandru S, Cho J, Colombel JF, Raufman JP, Thumbigere-Math V. Unravelling the Oral-Gut Axis: Interconnection Between Periodontitis and Inflammatory Bowel Disease, Current Challenges, and Future Perspective. J Crohns Colitis 2024; 18:1319-1341. [PMID: 38417137 PMCID: PMC11324343 DOI: 10.1093/ecco-jcc/jjae028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 12/04/2023] [Accepted: 02/27/2024] [Indexed: 03/01/2024]
Abstract
As the opposite ends of the orodigestive tract, the oral cavity and the intestine share anatomical, microbial, and immunological ties that have bidirectional health implications. A growing body of evidence suggests an interconnection between oral pathologies and inflammatory bowel disease [IBD], implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an 'oral-gut' axis, marked by a higher prevalence of periodontitis and other oral conditions in IBD patients and vice versa. We present an in-depth examination of the interconnection between oral pathologies and IBD, highlighting the shared microbiological and immunological pathways, and proposing a 'multi-hit' hypothesis in the pathogenesis of periodontitis-mediated intestinal inflammation. Furthermore, the review underscores the critical need for a collaborative approach between dentists and gastroenterologists to provide holistic oral-systemic healthcare.
Collapse
Affiliation(s)
- Himanshi Tanwar
- Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA
| | | | - Devon Allison
- Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA
| | - Ling-shiang Chuang
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Xuesong He
- Department of Microbiology, The Forsyth Institute, Cambridge, MA, USA
| | - Mario Aimetti
- Department of Surgical Sciences, C.I.R. Dental School, University of Turin, Turin, Italy
| | - Giacomo Baima
- Department of Surgical Sciences, C.I.R. Dental School, University of Turin, Turin, Italy
| | - Massimo Costalonga
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
| | - Raymond K Cross
- Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Cynthia Sears
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Saurabh Mehandru
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Judy Cho
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Pierre Raufman
- Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Vivek Thumbigere-Math
- Division of Periodontology, University of Maryland School of Dentistry, Baltimore, MD, USA
- National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA
| |
Collapse
|
|
10
|
Isobe K, Saida S, Honda Y, Nihira H, Hiejima E, Izawa K, Kubota H, Kato I, Umeda K, Hiramatsu H, Yasumi T, Takita J. Successful cord blood transplantation using reduced intensity conditioning in a 5-month-old patient with IL-10RA deficiency. Pediatr Blood Cancer 2024; 71:e31056. [PMID: 38721857 DOI: 10.1002/pbc.31056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 06/27/2024]
Affiliation(s)
- Kiyotaka Isobe
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
- Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Satoshi Saida
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Yoshitaka Honda
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Hiroshi Nihira
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Eitaro Hiejima
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Kazushi Izawa
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Hirohito Kubota
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Itaru Kato
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Katsutsugu Umeda
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Hidefumi Hiramatsu
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
- Department of Pediatrics, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takahiro Yasumi
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| | - Junko Takita
- Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan
| |
Collapse
|
|
11
|
Hardtke-Wolenski M, Landwehr-Kenzel S. Tipping the balance in autoimmunity: are regulatory t cells the cause, the cure, or both? Mol Cell Pediatr 2024; 11:3. [PMID: 38507159 PMCID: PMC10954601 DOI: 10.1186/s40348-024-00176-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 03/07/2024] [Indexed: 03/22/2024] Open
Abstract
Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options.
Collapse
Affiliation(s)
- Matthias Hardtke-Wolenski
- Hannover Medical School, Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
- University Hospital Essen, Institute of Medical Microbiology, University Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Department of Pediatric Pneumology, Allergology and Neonatology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
| |
Collapse
|
|
12
|
Soomann M, Gilmour K, Güngör T, Pachlopnik Schmid J, Spyropoulou V, Trück J, Prader S. Fevers and ulcers in a newborn-Think genetics and act quickly. Pediatr Allergy Immunol 2024; 35:e14102. [PMID: 38445565 DOI: 10.1111/pai.14102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/31/2024] [Accepted: 02/06/2024] [Indexed: 03/07/2024]
Affiliation(s)
- Maarja Soomann
- Division of Immunology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Kimberly Gilmour
- Immunology Department, Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, NIHR, London, UK
| | - Tayfun Güngör
- Division of Stem Cell Transplantation and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Jana Pachlopnik Schmid
- Division of Immunology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Vasiliki Spyropoulou
- Division of Gastroenterology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Johannes Trück
- Division of Immunology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Seraina Prader
- Division of Immunology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
| |
Collapse
|
|
13
|
Wang P, Qian X, Jiang W, Wang H, Wang Y, Zhou Y, Zhang Y, Huang Y, Zhai X. Cord Blood Transplantation for Very Early-Onset Inflammatory Bowel Disease Caused by Interleukin-10 Receptor Deficiency. J Clin Immunol 2024; 44:67. [PMID: 38372823 DOI: 10.1007/s10875-024-01669-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 02/06/2024] [Indexed: 02/20/2024]
Abstract
PURPOSE Interleukin-10 receptor (IL-10R) deficiency can result in life-threatening very early-onset inflammatory bowel disease (VEO-IBD). Umbilical cord blood transplantation (UCBT) is a curative therapy for patients with IL-10R deficiency. This study aimed to investigate the efficacy of UCBT in treating IL-10R deficiency and develop a predictive model based on pre-transplant factors. METHODS Eighty patients with IL-10R deficiency who underwent UCBT between July 2015 and April 2023 were retrospectively analyzed. Cox proportional hazards regression and random survival forest were used to develop a predictive model. RESULTS Median age at transplant was 13.0 months (interquartile range [IQR], 8.8-25.3 months). With a median follow-up time of 29.4 months (IQR, 3.2-57.1 months), the overall survival (OS) rate was 65.0% (95% confidence interval [CI], 55.3%-76.3%). The engraftment rate was 85% (95% CI, 77%-93%). The cumulative incidences of acute and chronic graft-versus-host disease were 48.2% (95% CI, 37.1%-59.4%) and 12.2% (95% CI, 4.7%-19.8%), respectively. VEO-IBD-associated clinical symptoms were resolved in all survivors. The multivariate analysis showed that IL-6 and stool occult blood were independent prognostic risk factors. The multivariate Cox proportional hazards regression model with stool occult blood, length- or height-for-age Z-score, medical history of sepsis, and cord blood total nucleated cells showed good discrimination ability, with a bootstrap concordance index of 0.767-0.775 in predicting OS. CONCLUSION Better inflammation control before transplantation and higher cord blood total nucleated cell levels can improve patient prognosis. The nomogram can successfully predict OS in patients with IL-10R deficiency undergoing UCBT.
Collapse
Affiliation(s)
- Ping Wang
- Department of Hematology/Oncology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China
| | - Xiaowen Qian
- Department of Hematology/Oncology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China
| | - Wenjin Jiang
- Department of Hematology/Oncology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China
| | - Hongsheng Wang
- Department of Hematology/Oncology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China
| | - Yuhuan Wang
- Department of Gastroenterology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China
| | - Ying Zhou
- Department of Gastroenterology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China
| | - Ye Zhang
- Department of Gastroenterology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China
| | - Ying Huang
- Department of Gastroenterology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China
| | - Xiaowen Zhai
- Department of Hematology/Oncology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, China.
| |
Collapse
|
|
14
|
Farmand S, Sender V, Karlsson J, Merkl P, Normark S, Henriques-Normark B. STAT3 Deficiency Alters the Macrophage Activation Pattern and Enhances Matrix Metalloproteinase 9 Expression during Staphylococcal Pneumonia. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:69-80. [PMID: 37982695 PMCID: PMC10733582 DOI: 10.4049/jimmunol.2300151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 10/19/2023] [Indexed: 11/21/2023]
Abstract
Staphylococcus aureus is a significant cause of morbidity and mortality in pulmonary infections. Patients with autosomal-dominant hyper-IgE syndrome due to STAT3 deficiency are particularly susceptible to acquiring staphylococcal pneumonia associated with lung tissue destruction. Because macrophages are involved in both pathogen defense and inflammation, we investigated the impact of murine myeloid STAT3 deficiency on the macrophage phenotype in vitro and on pathogen clearance and inflammation during murine staphylococcal pneumonia. Murine bone marrow-derived macrophages (BMDM) from STAT3 LysMCre+ knockout or Cre- wild-type littermate controls were challenged with S. aureus, LPS, IL-4, or vehicle control in vitro. Pro- and anti-inflammatory responses as well as polarization and activation markers were analyzed. Mice were infected intratracheally with S. aureus, bronchoalveolar lavage and lungs were harvested, and immunohistofluorescence was performed on lung sections. S. aureus infection of STAT3-deficient BMDM led to an increased proinflammatory cytokine release and to enhanced upregulation of costimulatory MHC class II and CD86. Murine myeloid STAT3 deficiency did not affect pathogen clearance in vitro or in vivo. Matrix metalloproteinase 9 was upregulated in Staphylococcus-treated STAT3-deficient BMDM and in lung tissues of STAT3 knockout mice infected with S. aureus. Moreover, the expression of miR-155 was increased. The enhanced inflammatory responses and upregulation of matrix metalloproteinase 9 and miR-155 expression in murine STAT3-deficient as compared with wild-type macrophages during S. aureus infections may contribute to tissue damage as observed in STAT3-deficient patients during staphylococcal pneumonia.
Collapse
Affiliation(s)
- Susan Farmand
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Division of Pediatric Stem Cell Transplantation and Immunology, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Vicky Sender
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Clinical Microbiology, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Jens Karlsson
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Clinical Microbiology, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Padryk Merkl
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Staffan Normark
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Birgitta Henriques-Normark
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- Clinical Microbiology, Karolinska University Hospital Solna, Stockholm, Sweden
| |
Collapse
|
|
15
|
Abstract
Inflammatory bowel disease (IBD) represents a spectrum of disease, which is characterized by chronic gastrointestinal inflammation. Monogenic mutations driving IBD pathogenesis are more highly represented in early-onset compared to adult-onset disease. The pathogenic genes which dysregulate host immune responses in monogenic IBD affect both the innate (ie, intestinal barrier, phagocytes) and adaptive immune systems (ie, T cells, B cells). Advanced genomic and targeted functional testing can improve clinical decision making and present increased opportunities for precision medicine approaches in this important patient population.
Collapse
Affiliation(s)
- Atiye Olcay Bilgic Dagci
- Division of Pediatric Rheumatology, University of Michigan, C.S Mott Children's Hospital, 1500 East Medical Center Drive Medical Professional Building Floor 2, Ann Arbor, MI 48109-5718, USA.
| | - Kelly Colleen Cushing
- Division of Gastroenterology, U-M Inflammatory Bowel Disease Program, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, SPC 5362, Ann Arbor, MI 48109-5362, USA
| |
Collapse
|
|
16
|
Jagirdhar GSK, Perez JA, Perez AB, Surani S. Integration and implementation of precision medicine in the multifaceted inflammatory bowel disease. World J Gastroenterol 2023; 29:5211-5225. [PMID: 37901450 PMCID: PMC10600960 DOI: 10.3748/wjg.v29.i36.5211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/31/2023] [Accepted: 09/06/2023] [Indexed: 09/20/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex disease with variability in genetic, environmental, and lifestyle factors affecting disease presentation and course. Precision medicine has the potential to play a crucial role in managing IBD by tailoring treatment plans based on the heterogeneity of clinical and temporal variability of patients. Precision medicine is a population-based approach to managing IBD by integrating environmental, genomic, epigenomic, transcriptomic, proteomic, and metabolomic factors. It is a recent and rapidly developing medicine. The widespread adoption of precision medicine worldwide has the potential to result in the early detection of diseases, optimal utilization of healthcare resources, enhanced patient outcomes, and, ultimately, improved quality of life for individuals with IBD. Though precision medicine is promising in terms of better quality of patient care, inadequacies exist in the ongoing research. There is discordance in study conduct, and data collection, utilization, interpretation, and analysis. This review aims to describe the current literature on precision medicine, its multiomics approach, and future directions for its application in IBD.
Collapse
Affiliation(s)
| | - Jose Andres Perez
- Department of Medicine, Saint Francis Health Systems, Tulsa, OK 74133, United States
| | - Andrea Belen Perez
- Department of Research, Columbia University, New York, NY 10027, United States
| | - Salim Surani
- Department of Medicine and Pharmacology, Texas A&M University, College Station, TX 77413, United States
| |
Collapse
|
|
17
|
Gray PE, David C. Inborn Errors of Immunity and Autoimmune Disease. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1602-1622. [PMID: 37119983 DOI: 10.1016/j.jaip.2023.04.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 04/01/2023] [Accepted: 04/21/2023] [Indexed: 05/01/2023]
Abstract
Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory disorders. However, although making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes, and inheritance of autoimmunity associated with primary immune regulatory disorders, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunologic features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. In addition, there will be a review of autoimmunity in non-genetically defined primary immunodeficiency such as common variable immunodeficiency, and of instances where primary autoimmunity can result in clinical phenocopies of inborn errors of immunity.
Collapse
Affiliation(s)
- Paul Edgar Gray
- Sydney Children's Hospital, Randwick, NSW, Australia; Western Sydney University, Penrith, NSW, Australia.
| | - Clementine David
- Sydney Children's Hospital, Randwick, NSW, Australia; The School of Women's & Children's Health, University of New South Wales, Randwick, NSW, Australia
| |
Collapse
|
|
18
|
Lee WI, Chen CC, Chen SH, Lai WT, Jaing TH, Ou LS, Liang CJ, Kang CC, Huang JL. Clinical Features and Genetic Analysis of Taiwanese Primary Immunodeficiency Patients with Prolonged Diarrhea and Monogenetic Inflammatory Bowel Disease. J Clin Immunol 2023:10.1007/s10875-023-01503-w. [PMID: 37202577 DOI: 10.1007/s10875-023-01503-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 04/26/2023] [Indexed: 05/20/2023]
Abstract
PURPOSE Diarrhea lasting longer than 14 days which fails to respond to conventional management is defined as severe and protracted diarrhea and might overlap with inflammatory bowel disease (IBD). METHODS The prevalence, associated pathogens, and prognosis of severe and protracted diarrhea without IBD (SD) and with monogenetic IBD (mono-IBD) in primary immunodeficiency patients (PID) were investigated in Taiwan. RESULTS A total of 301 patients were enrolled between 2003 and 2022, with predominantly pediatric-onset PID. Of these, 24 PID patients developed the SD phenotype before prophylactic treatment, including Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG1 (one each), CVID (two), and SCID (one) without identified mutations. The most detectable pathogens were pseudomonas and salmonella (six each), and all patients improved after approximately 2 weeks of antibiotic and/or IVIG treatments. Six (25.0%) mortalities without HSCT implementation were due to respiratory failure from interstitial pneumonia (3 SCID and 1 CGD), intracranial hemorrhage (WAS), and lymphoma (HIGM). In the mono-IBD group, seventeen patients with mutant TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), LRBA (1), TTC37 (3), IL10RA (1), STAT1 (1), ZAP70 (1), PIK3CD (1), and PIK3R1 (1) genes failed to respond to aggressive treatments. Nine mono-IBD patients with TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), and LRBA (1) mutations were fatal in the absence of HSCT. The mono-IBD group had a significantly earlier age of diarrhea onset (1.7 vs 33.3 months, p = 0.0056), a longer TPN duration (34.2 vs 7.0 months, p < 0.0001), a shorter follow-up period (41.6 vs 132.6 months, p = 0.007), and a higher mortality rate (58.9 vs 25.0%, p = 0.012) compared with the SD group. CONCLUSION When compared to those with the SD phenotype, the mono-IBD patients had significant early-onset and poor responses to empiric antibiotics, IVIG, and steroids. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.
Collapse
Affiliation(s)
- Wen-I Lee
- Primary Immunodeficiency Care and Research (PICAR) Institute, College of Medicine, Chang Gung Memorial University and Hospital, Kwei-Shan, #5 Fu-Shing St. (Pediatric Office 12 L), Taoyuan, Taiwan.
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
| | - Chien-Chang Chen
- Division of Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Shih-Hsiang Chen
- Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wan-Tz Lai
- Division of Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Tang-Her Jaing
- Primary Immunodeficiency Care and Research (PICAR) Institute, College of Medicine, Chang Gung Memorial University and Hospital, Kwei-Shan, #5 Fu-Shing St. (Pediatric Office 12 L), Taoyuan, Taiwan
- Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Liang-Shiou Ou
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chi-Jou Liang
- Primary Immunodeficiency Care and Research (PICAR) Institute, College of Medicine, Chang Gung Memorial University and Hospital, Kwei-Shan, #5 Fu-Shing St. (Pediatric Office 12 L), Taoyuan, Taiwan
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chen-Chen Kang
- Primary Immunodeficiency Care and Research (PICAR) Institute, College of Medicine, Chang Gung Memorial University and Hospital, Kwei-Shan, #5 Fu-Shing St. (Pediatric Office 12 L), Taoyuan, Taiwan
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Jing-Long Huang
- Primary Immunodeficiency Care and Research (PICAR) Institute, College of Medicine, Chang Gung Memorial University and Hospital, Kwei-Shan, #5 Fu-Shing St. (Pediatric Office 12 L), Taoyuan, Taiwan.
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
- Department of Pediatrics, New Taipei Municipal TuChen Hospital, New Taipei, Taiwan.
| |
Collapse
|
|
19
|
Behera J, Pitchiah Kumar M, Ireen Femela A, Senguttuvan G, Ramasamy MS. miRNA-15/IL-10Rα axis promotes Kabasura Kudineer (Indian traditional Siddha formulation) induced immunomodulation by suppressing oxidative stress. JOURNAL OF ETHNOPHARMACOLOGY 2023; 305:116032. [PMID: 36587882 DOI: 10.1016/j.jep.2022.116032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/18/2022] [Accepted: 12/03/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Kabasura Kudineer (KK), the traditional Indian medicine of Siddha, effectively manages common respiratory symptoms such as flu, cold, and fever. However, there is no evidence of the immunomodulatory capacity of KK in the cultured Jurkat T-lymphocytes under the LPS insult studied. AIM OF THE STUDY Assess the effect of the traditional Indian medicine of Siddha, Kabasura Kudineer (KK) on immunomodulation by suppressing oxidative damage in cultured Jurkat T cells in vitro. The miRNA activity on anti-inflammatory gene receptors and cellular nitric oxide levels also was studied. MATERIALS AND METHODS Jurkat T cells were exposed to LPS treatment in the presence or absence of KK. Cell viability and nitric oxide (NO) were measured with MTT and Griess assay. Cellular antioxidant systems (glutathione and SOD) were determined using glutathione and SOD assay. Lipid peroxidation was measured using an MDA assay. MiRNA-15a-5p expression was performed using microRNA qPCR Assays. Both inflammatory and anti-inflammatory genes (IL-6, IL-1, IL-10, IL-13) were performed using a qPCR and ELISA assay. RESULTS The data showed that reduced cell proliferation and exaggerated NO production was observed in LPS treated condition compared to the control condition. Further, LPS treatment increased lipid peroxidation and reduced antioxidant enzyme activities (SOD and glutathione) in cultured Jurkat T cells. However, treatment with KK or N-acetyl cysteine (NAC; antioxidant) treatment mitigates the above effect. Mechanistically, LPS-induced oxidative stress upregulated miR- 15-5p expression and suppressed IL-10 Receptor alpha (IL-10Rα) by binding to its 3'-UTR region. The deregulated expression of IL-10Rα expression leads to increased IL-6 and IL-1β expression in LPS-induced Jurkat T cells; however, treatment with KK or NAC reversed the above effects. CONCLUSION Collectively, our study revealed the previously undefined mechanistic role of Kabasura Kudineer (KK) that alleviates the LPS-induced oxidative damage associated with inflammation by inhibiting the miRNA-15-5p/IL-10Rα axis.
Collapse
Affiliation(s)
- Jyotirmaya Behera
- Department of Cell and Molecular Biology, Sanjeev Biomedical Research Centre, 1/15, Kumaran Nagar, Keelkattalai, Chennai, 600117, Tamilnadu, India
| | - M Pitchiah Kumar
- State Licensing Authority, Directorate of Indian Medicine (Govt. of Tamilnadu), State Licensing Authority (IM), Chennai, 600106, Tamilnadu, India
| | - A Ireen Femela
- Department of Cell and Molecular Biology, Sanjeev Biomedical Research Centre, 1/15, Kumaran Nagar, Keelkattalai, Chennai, 600117, Tamilnadu, India
| | - Govindan Senguttuvan
- Department of Physics, University College of Engineering BIT Campus, Anna University, Tiruchirappalli, 620 024, Tamilnadu, India
| | - M S Ramasamy
- Head, Research & Development, Sanjeev Biomedical Research Centre, 1/15, Kumaran Nagar, Keelkattalai, Chennai, 600117, Tamilnadu, India.
| |
Collapse
|
|
20
|
Ma CS. T-helper-2 cells and atopic disease: lessons learnt from inborn errors of immunity. Curr Opin Immunol 2023; 81:102298. [PMID: 36870225 DOI: 10.1016/j.coi.2023.102298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 03/06/2023]
Abstract
Inborn errors of immunity (IEI) are caused by monogenic variants that affect the host response to bacterial, viral, and fungal pathogens. As such, individuals with IEI often present with severe, recurrent, and life-threatening infections. However, the spectrum of disease due to IEI is very broad and extends to include autoimmunity, malignancy, and atopic diseases such as eczema, atopic dermatitis, and food and environmental allergies. Here, I review IEI that affect cytokine signaling pathways that dysregulate CD4+ T-cell differentiation, resulting in increased T-helper-2 (Th2) cell development, function, and pathogenicity. These are elegant examples of how rare IEI can provide unique insights into more common pathologies such as allergic disease that are impacting the general population at increased frequency.
Collapse
Affiliation(s)
- Cindy S Ma
- Garvan Institute of Medical Research, Sydney, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia; Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Australia.
| |
Collapse
|
|
21
|
Mohammadi F, Yadegar A, Mardani M, Ayati A, Abolhassani H, Rezaei N. Organ-based clues for diagnosis of inborn errors of immunity: A practical guide for clinicians. Immun Inflamm Dis 2023; 11:e833. [PMID: 37102642 PMCID: PMC10091206 DOI: 10.1002/iid3.833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 03/24/2023] [Indexed: 04/28/2023] Open
Abstract
Inborn errors of immunity (IEI) comprise a group of about 490 genetic disorders that lead to aberrant functioning or the development of distinct immune system components. So far, a broad spectrum of IEI-related manifestations has been noted in the literature. Due to overlapping signs and symptoms of IEI, physicians face challenges in appropriately diagnosing and managing affected individuals. The last decade has witnesses improving in the molecular diagnosis of IEI patients. As a result, it can be the mainstay of diagnostic algorithms, prognosis, and possibly therapeutic interventions in patients with IEI. Furthermore, reviewing IEI clinical complications demonstrates that the manifestations and severity of the symptoms depend on the involved gene that causes the disease and its penetrance. Although several diagnostic criteria have been used for IEI, not every patient can be explored in the same way. As a result of the failure to consider IEI diagnosis and the variety of diagnostic capabilities and laboratory facilities in different regions, undiagnosed patients are increasing. On the other hand, early diagnosis is an almost essential element in improving the quality of life in IEI patients. Since there is no appropriate guideline for IEI diagnosis in different organs, focusing on the clues in the patient's chief complaint and physical exams can help physicians narrow their differential diagnosis. This article aims to provide a practical guide for IEI diagnosis based on the involved organ. We hope to assist clinicians in keeping IEI diagnosis in mind and minimizing possible related complications due to delayed diagnosis.
Collapse
Affiliation(s)
- Fatemeh Mohammadi
- School of MedicineTehran University of Medical SciencesTehranIran
- Universal Scientific Education and Research Network (USERN)Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA)TehranIran
| | - Amirhossein Yadegar
- School of MedicineTehran University of Medical SciencesTehranIran
- Universal Scientific Education and Research Network (USERN)Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA)TehranIran
| | - Mahta Mardani
- School of MedicineTehran University of Medical SciencesTehranIran
- Universal Scientific Education and Research Network (USERN)Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA)TehranIran
| | - Aryan Ayati
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart CenterTehran University of Medical ScienceTehranIran
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical CenterTehran University of Medical SciencesTehranIran
| | - Nima Rezaei
- Universal Scientific Education and Research Network (USERN)Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA)TehranIran
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical CenterTehran University of Medical SciencesTehranIran
- Primary Immunodeficiency Diseases Network (PIDNet)TehranIran
- Children's Medical CenterTehranIran
| |
Collapse
|
|
22
|
Moser LM, Fekadu J, Willasch A, Rettinger E, Sörensen J, Jarisch A, Kirwil M, Lieb A, Holzinger D, Calaminus G, Bader P, Bakhtiar S. Treatment of inborn errors of immunity patients with inflammatory bowel disease phenotype by allogeneic stem cell transplantation. Br J Haematol 2023; 200:595-607. [PMID: 36214981 DOI: 10.1111/bjh.18497] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 09/14/2022] [Accepted: 09/21/2022] [Indexed: 12/12/2022]
Abstract
Patients with inborn errors of immunity (IEI) can suffer from treatment-refractory inflammatory bowel disease (IBD) causing failure to thrive and consequences of long-term multiple immunosuppressive treatments. Allogeneic haematopoietic stem cell transplantation (alloHSCT) can serve as a curative treatment option. In this single-centre retrospective cohort study we report on 11 paediatric and young adult IEI patients with IBD and failure to thrive, who had exhausted symptomatic treatment options and received alloHSCT. The cohort included chronic granulomatous disease (CGD), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency, STAT3 gain-of-function (GOF), Wiskott-Aldrich syndrome (WAS), dedicator of cytokinesis 8 (DOCK8) deficiency and one patient without genetic diagnosis. All patients achieved stable engraftment and immune reconstitution, and gastrointestinal symptoms were resolved after alloHSCT. The overall survival was 11/11 over a median follow-up of 34.7 months. Graft-versus-host disease (GVHD) was limited to grade I-II acute GVHD (n = 5), one case of grade IV acute GVHD and one case of limited chronic GVHD. Since treatment recommendations are limited, this work provides a centre-specific approach to treatment prior to transplant as well as conditioning in IEI patients with severe IBD.
Collapse
Affiliation(s)
- Laura M Moser
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Julia Fekadu
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - André Willasch
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Eva Rettinger
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Jan Sörensen
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Andrea Jarisch
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Marta Kirwil
- Division for Pediatric Gastroenterology, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Adrian Lieb
- Division for Pediatric Gastroenterology, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Dirk Holzinger
- Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany.,Department of Applied Health Sciences, University of Applied Sciences Bochum, Bochum, Germany
| | - Gabriele Calaminus
- Department for Children and Adolescents, University Hospital Bonn, Bonn, Germany
| | - Peter Bader
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Shahrzad Bakhtiar
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| |
Collapse
|
|
23
|
Kammermeier J, Lamb CA, Jones KDJ, Anderson CA, Baple EL, Bolton C, Braggins H, Coulter TI, Gilmour KC, Gregory V, Hambleton S, Hartley D, Hawthorne AB, Hearn S, Laurence A, Parkes M, Russell RK, Speight RA, Travis S, Wilson DC, Uhlig HH. Genomic diagnosis and care co-ordination for monogenic inflammatory bowel disease in children and adults: consensus guideline on behalf of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition. Lancet Gastroenterol Hepatol 2023; 8:271-286. [PMID: 36634696 DOI: 10.1016/s2468-1253(22)00337-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 01/11/2023]
Abstract
Genomic medicine enables the identification of patients with rare or ultra-rare monogenic forms of inflammatory bowel disease (IBD) and supports clinical decision making. Patients with monogenic IBD frequently experience extremely early onset of treatment-refractory disease, with complex extraintestinal disease typical of immunodeficiency. Since more than 100 monogenic disorders can present with IBD, new genetic disorders and variants are being discovered every year, and as phenotypic expression of the gene defects is variable, adaptive genomic technologies are required. Monogenic IBD has become a key area to establish the concept of precision medicine. Clear guidance and standardised, affordable applications of genomic technologies are needed to implement exome or genome sequencing in clinical practice. This joint British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition guideline aims to ensure that testing resources are appropriately applied to maximise the benefit to patients on a national scale, minimise health-care disparities in accessing genomic technologies, and optimise resource use. We set out the structural requirements for genomic medicine as part of a multidisciplinary team approach. Initiation of genomic diagnostics should be guided by diagnostic criteria for the individual patient, in particular the age of IBD onset and the patient's history, and potential implications for future therapies. We outline the diagnostic care pathway for paediatric and adult patients. This guideline considers how to handle clinically actionable findings in research studies and the impact of consumer-based genomics for monogenic IBD. This document was developed by multiple stakeholders, including UK paediatric and adult gastroenterology physicians, immunologists, transplant specialists, clinical geneticists, scientists, and research leads of UK genetic programmes, in partnership with patient representatives of several IBD and rare disease charities.
Collapse
Affiliation(s)
- Jochen Kammermeier
- Department of Paediatric Gastroenterology, Evelina London Children's Hospital, London, UK
| | - Christopher A Lamb
- Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Kelsey D J Jones
- Department of Gastroenterology, Great Ormond Street Hospital for Children, London, UK; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, University of Oxford, Oxford, UK
| | | | - Emma L Baple
- University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, UK
| | - Chrissy Bolton
- Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Helen Braggins
- Department of Immunology, Great Ormond Street Hospital of Children NHS Foundation Trust and NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK; Chronic Granulomatous Disorder Society, Dartford, UK
| | - Tanya I Coulter
- Regional Immunology Service for Northern Ireland, Belfast, UK
| | - Kimberly C Gilmour
- Clinical Immunology Laboratory, Great Ormond Street Hospital of Children NHS Foundation Trust and NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK
| | | | - Sophie Hambleton
- Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Department of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne, UK
| | | | - A Barney Hawthorne
- Department of Gastroenterology, University Hospital of Wales, Cardiff, UK
| | - Sarah Hearn
- Translational Gastroenterology Unit and Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Arian Laurence
- Department of Clinical Immunology, Royal Free Hospital, London, UK; Department of Haematology and Bone Marrow Transplantation, University College Hospital, London, UK
| | - Miles Parkes
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge, UK
| | - Richard K Russell
- Child Life and Health, University of Edinburgh, The Royal Hospital for Children & Young People, Edinburgh, UK; Department of Paediatric Gastroenterology, The Royal Hospital for Children & Young People, Edinburgh, UK; Department of Paediatric Gastroenterology, The Royal Hospital for Children & Young People, Edinburgh, UK
| | - R Alexander Speight
- Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Simon Travis
- Translational Gastroenterology Unit and Biomedical Research Centre, University of Oxford, Oxford, UK
| | - David C Wilson
- Child Life and Health, University of Edinburgh, The Royal Hospital for Children & Young People, Edinburgh, UK; Department of Paediatric Gastroenterology, The Royal Hospital for Children & Young People, Edinburgh, UK; Department of Paediatric Gastroenterology, The Royal Hospital for Children & Young People, Edinburgh, UK
| | - Holm H Uhlig
- Translational Gastroenterology Unit and Biomedical Research Centre, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK.
| |
Collapse
|
|
24
|
Kołtun-Jasion M, Sawulska P, Patyra A, Woźniak M, Dudek MK, Filipek A, Kiss AK. Bio-Guided Isolation of Compounds from Fraxinus excelsior Leaves with Anti-Inflammatory Activity. Int J Mol Sci 2023; 24:ijms24043750. [PMID: 36835169 PMCID: PMC9964138 DOI: 10.3390/ijms24043750] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/06/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
Inflammation is the first physiological defence mechanism against external and internal stimuli. The prolonged or inappropriate response of the immune system may lead to the persistent inflammatory response that can potentially become a basis for chronic diseases e.g., asthma, type II diabetes or cancer. An important role in the alleviation of inflammatory processes, as an adjunct to traditional pharmacological therapy, is attributed to phytotherapy, especially to raw materials with a long tradition of use, e.g., ash leaves. Despite their long-term use in phytotherapy, the specific mechanisms of action have not been confirmed in a sufficient number of biological or clinical studies. The aim of the study is a detailed phytochemical analysis of infusion and its fractions, isolation of pure compounds from the leaves of Fraxinus excelsior and evaluation of their effect on the secretion of anti-inflammatory cytokines (TNF-α, IL-6) and IL-10 receptor expression in an in vitro model of monocyte/macrophage cells isolated from peripheral blood. Methods: Phytochemical analysis was carried out by the UHPLC-DAD-ESI-MS/MS method. Monocytes/macrophages were isolated from human peripheral blood using density gradient centrifugation on Pancoll. After 24 h incubation with tested fractions/subfractions and pure compounds, cells or their supernatants were studied, respectively, on IL-10 receptor expression by flow cytometry and IL-6, TNF-α, IL-1β secretion by the ELISA test. Results were presented with respect to Lipopolysaccharide (LPS) control and positive control with dexamethasone. Results: The infusion, 20% and 50% methanolic fractions and their subfractions, as well as their dominating compounds, e.g., ligstroside, formoside and oleoacteoside isolated from the leaves, show the ability to increase the IL-10 receptor expression on the surface of monocyte/macrophage cells, stimulated by LPS, and to decrease the secretion of pro-inflammatory cytokines, e.g., TNF-α, IL-6.
Collapse
Affiliation(s)
- Małgorzata Kołtun-Jasion
- Department of Pharmaceutical Biology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
- Correspondence: (M.K.-J.); (A.K.K.); Tel./Fax: +48-22-572-09-85 (M.K.-J.)
| | - Paulina Sawulska
- Department of Pharmaceutical Biology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
| | - Andrzej Patyra
- Department of Pharmaceutical Biology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
- Doctoral School, Medical University of Warsaw, Żwirki i Wigury 81, 02-091 Warsaw, Poland
- Institut des Biomolécules Max Mousseron, Université de Montpellier, CNRS, ENSCM, 34293 Montpellier, France
| | - Marta Woźniak
- Department of Pharmaceutical Biology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
| | - Marta Katarzyna Dudek
- Structural Studies Department, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza H. 112, 90-001 Łódź, Poland
| | - Agnieszka Filipek
- Department of Pharmaceutical Biology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
| | - Anna Karolina Kiss
- Department of Pharmaceutical Biology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
- Correspondence: (M.K.-J.); (A.K.K.); Tel./Fax: +48-22-572-09-85 (M.K.-J.)
| |
Collapse
|
|
25
|
Korol CB, Belkaya S, Alsohime F, Lorenzo L, Boisson-Dupuis S, Brancale J, Neehus AL, Vilarinho S, Zobaida A, Halwani R, Al-Muhsen S, Casanova JL, Jouanguy E. Fulminant Viral Hepatitis in Two Siblings with Inherited IL-10RB Deficiency. J Clin Immunol 2023; 43:406-420. [PMID: 36308662 PMCID: PMC9892130 DOI: 10.1007/s10875-022-01376-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/28/2022] [Indexed: 02/05/2023]
Abstract
Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses.
Collapse
Affiliation(s)
- Cecilia B Korol
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Serkan Belkaya
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Department of Molecular Biology and Genetics, Ihan Dogramaci Bilkent University, Ankara, Turkey
| | - Fahad Alsohime
- Immunology Research Laboratory, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Lazaro Lorenzo
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Stéphanie Boisson-Dupuis
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Joseph Brancale
- Department of Internal Medicine, Section of Digestive Diseases, and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Anna-Lena Neehus
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Silvia Vilarinho
- Department of Internal Medicine, Section of Digestive Diseases, and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Alsum Zobaida
- Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Rabih Halwani
- Department of Clinical Sciences, College of Medicine, Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates
| | - Saleh Al-Muhsen
- Immunology Research Laboratory, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Howard Hughes Medical Institute, New York City, NY, USA
- Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
| | - Emmanuelle Jouanguy
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
- Imagine Institute, Paris Cité University, Paris, France.
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
| |
Collapse
|
|
26
|
Ogishi M, Arias AA, Yang R, Han JE, Zhang P, Rinchai D, Halpern J, Mulwa J, Keating N, Chrabieh M, Lainé C, Seeleuthner Y, Ramírez-Alejo N, Nekooie-Marnany N, Guennoun A, Muller-Fleckenstein I, Fleckenstein B, Kilic SS, Minegishi Y, Ehl S, Kaiser-Labusch P, Kendir-Demirkol Y, Rozenberg F, Errami A, Zhang SY, Zhang Q, Bohlen J, Philippot Q, Puel A, Jouanguy E, Pourmoghaddas Z, Bakhtiar S, Willasch AM, Horneff G, Llanora G, Shek LP, Chai LY, Tay SH, Rahimi HH, Mahdaviani SA, Nepesov S, Bousfiha AA, Erdeniz EH, Karbuz A, Marr N, Navarrete C, Adeli M, Hammarstrom L, Abolhassani H, Parvaneh N, Al Muhsen S, Alosaimi MF, Alsohime F, Nourizadeh M, Moin M, Arnaout R, Alshareef S, El-Baghdadi J, Genel F, Sherkat R, Kiykim A, Yücel E, Keles S, Bustamante J, Abel L, Casanova JL, Boisson-Dupuis S. Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency. J Exp Med 2022; 219:e20220094. [PMID: 36094518 PMCID: PMC9472563 DOI: 10.1084/jem.20220094] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 06/21/2022] [Accepted: 07/14/2022] [Indexed: 12/21/2022] Open
Abstract
Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
Collapse
Affiliation(s)
- Masato Ogishi
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Andrés Augusto Arias
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Primary Immunodeficiencies Group, University of Antioquia, Medellin, Colombia
- School of Microbiology, University of Antioquia, Medellin, Colombia
| | - Rui Yang
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Ji Eun Han
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Peng Zhang
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Darawan Rinchai
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Joshua Halpern
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Jeanette Mulwa
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Narelle Keating
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, Australia
| | - Maya Chrabieh
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Candice Lainé
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Yoann Seeleuthner
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Noé Ramírez-Alejo
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Nioosha Nekooie-Marnany
- Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | | | - Bernhard Fleckenstein
- Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Sara S. Kilic
- Department of Pediatric Immunology and Rheumatology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Yoshiyuki Minegishi
- Division of Molecular Medicine, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Stephan Ehl
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | | | - Yasemin Kendir-Demirkol
- Department of Pediatric Genetics, Umraniye Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Flore Rozenberg
- Laboratory of Virology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France
| | - Abderrahmane Errami
- Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Shen-Ying Zhang
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Qian Zhang
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Jonathan Bohlen
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Quentin Philippot
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Anne Puel
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Emmanuelle Jouanguy
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Zahra Pourmoghaddas
- Department of Pediatric Infectious Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahrzad Bakhtiar
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Child and Adolescent Medicine, University Hospital Frankfurt, Frankfurt, Germany
| | - Andre M. Willasch
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Child and Adolescent Medicine, University Hospital Frankfurt, Frankfurt, Germany
| | - Gerd Horneff
- Center for Pediatric Rheumatology, Department of Pediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin, Germany
- Medical Faculty, University of Cologne, Cologne, Germany
| | - Genevieve Llanora
- Division of Allergy and Immunology, Department of Paediatrics, Khoo Teck Puat - National University Children’s Medical Institute, National University Health System, Singapore
| | - Lynette P. Shek
- Division of Allergy and Immunology, Department of Paediatrics, Khoo Teck Puat - National University Children’s Medical Institute, National University Health System, Singapore
- Department of Pediatrics, National University of Singapore, Singapore
| | - Louis Y.A. Chai
- Division of Infectious Diseases, Department of Medicine, National University Health System, Singapore
- Synthetic Biology for Clinical and Technological Innovation, Life Sciences Institute; Synthetic Biology Translational Research Program, National University of Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Sen Hee Tay
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Division of Rheumatology, Department of Medicine, National University Hospital, Singapore
| | - Hamid H. Rahimi
- Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyed Alireza Mahdaviani
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Serdar Nepesov
- Department of Pediatric Allergy and Immunology, Istanbul Medipol University, Istanbul, Turkey
| | - Aziz A. Bousfiha
- Clinical Immunology Unit, Department of Pediatrics, King Hassan II University, Ibn-Rochd Hospital, Casablanca, Morocco
| | - Emine Hafize Erdeniz
- Division of Pediatric Infectious Diseases, Ondokuz Mayıs University, Samsun, Turkey
| | - Adem Karbuz
- Division of Pediatric Infectious Diseases, Okmeydani Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | | | - Carmen Navarrete
- Department of Immunology, Hospital de Niños Roberto del Río, Santiago de Chile, Chile
| | - Mehdi Adeli
- Division of Allergy and Immunology, Sidra Medicine/Hamad Medical Corp., Doha, Qatar
| | - Lennart Hammarstrom
- Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
- Beijing Genomics Institute, Shenzhen, China
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hassan Abolhassani
- Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Parvaneh
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Saleh Al Muhsen
- Immunology Research Laboratory, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed F. Alosaimi
- Immunology Research Laboratory, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Fahad Alsohime
- Pediatric Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Pediatric Intensive Care Unit, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Maryam Nourizadeh
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Moin
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Rand Arnaout
- Section of Allergy & Immunology, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Al Faisal University, Riyadh, Saudi Arabia
| | - Saad Alshareef
- Section of Allergy & Immunology, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - Ferah Genel
- University of Health Sciences, Dr Behçet Uz Children’s Hospital, Division of Pediatric Immunology, Izmir, Turkey
| | - Roya Sherkat
- Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ayça Kiykim
- Pediatric Allergy and Immunology, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Esra Yücel
- Division of Pediatric Allergy and Immunology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Sevgi Keles
- Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
| | - Jacinta Bustamante
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France
| | - Laurent Abel
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| | - Jean-Laurent Casanova
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
- Howard Hughes Medical Institute, New York, NY
- Deparment of Pediatrics, Necker Hospital for Sick Children, Paris, France
| | - Stéphanie Boisson-Dupuis
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
- Paris Cité University, Imagine Institute, Paris, France
| |
Collapse
|
|
27
|
Li C, Wu Y, Xie Y, Zhang Y, Jiang S, Wang J, Luo X, Chen Q. Oral manifestations serve as potential signs of ulcerative colitis: A review. Front Immunol 2022; 13:1013900. [PMID: 36248861 PMCID: PMC9559187 DOI: 10.3389/fimmu.2022.1013900] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/14/2022] [Indexed: 11/23/2022] Open
Abstract
As an immune dysregulation-related disease, although ulcerative colitis (UC) primarily affects the intestinal tract, extraintestinal manifestations of the disease are evident, particularly in the oral cavity. Herein, we have reviewed the various oral presentations, potential pathogenesis, and treatment of oral lesions related to UC. The oral manifestations of UC include specific and nonspecific manifestations, with the former including pyostomatitis vegetans and the latter encompassing recurrent aphthous ulcers, atrophic glossitis, burning mouth syndrome, angular cheilitis, dry mouth, taste change, halitosis, and periodontitis. Although the aetiology of UC has not been fully determined, the factors leading to its development include immune system dysregulation, dysbiosis, and malnutrition. The principle of treating oral lesions in UC is to relieve pain, accelerate the healing of lesions, and prevent secondary infection, and the primary procedure is to control intestinal diseases. Systemic corticosteroids are the preferred treatment options, besides, topical and systemic administration combined with dietary guidance can also be applied. Oral manifestations of UC might accompany or precede the diagnosis of UC, albeit with the absence of intestinal symptoms; therefore, oral lesions, especially pyostomatitis vegetans, recurrent aphthous ulcer and periodontitis, could be used as good mucocutaneous signs to judge the occurrence and severity of UC, thus facilitating the early diagnosis and treatment of UC and avoiding severe consequences, such as colon cancer.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Xiaobo Luo
- *Correspondence: Qianming Chen, ; Xiaobo Luo,
| | | |
Collapse
|
|
28
|
McGregor CGC, Tandon R, Simmons A. Pathogenesis of Fistulating Crohn's Disease: A Review. Cell Mol Gastroenterol Hepatol 2022; 15:1-11. [PMID: 36184031 PMCID: PMC9667304 DOI: 10.1016/j.jcmgh.2022.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 12/10/2022]
Abstract
Sustained, transmural inflammation of the bowel wall may result in the development of a fistula in Crohn's disease (CD). Fistula formation is a recognized complication and cause of morbidity, occurring in 40% of patients with CD. Despite advanced treatment, one-third of patients experience recurrent fistulae. Development of targeting treatment for fistulae will be dependent on a more in depth understanding of its pathogenesis. Presently, pathogenesis of CD-associated fistulae remains poorly defined, in part due to the lack of accepted in vitro tissue models recapitulating the pathogenic cellular lesions linked to fistulae and limited in vivo models. This review provides a synthesis of the existing knowledge of the histopathological, immune, cellular, genetic, and microbial contributions to the pathogenesis of CD-associated fistulae including the widely accredited contribution of epithelial-to-mesenchymal transition, upregulation of matrix metalloproteinases, and overexpression of invasive molecules, resulting in tissue remodeling and subsequent fistula formation. We conclude by exploring how we might utilize advancing technologies to verify and broaden our current understanding while exploring novel causal pathways to provide further inroads to future therapeutic targets.
Collapse
Affiliation(s)
- Colleen Georgette Chantelle McGregor
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Headington, Oxford, United Kingdom
| | - Ruchi Tandon
- Pathology, Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Alison Simmons
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
| |
Collapse
|
|
29
|
Wang D, Jin H, Sheng J, Cheng L, Lin Q, Lazerev M, Jin P, Li X. A high salt diet protects interleukin 10-deficient mice against chronic colitis by improving the mucosal barrier function. Mol Immunol 2022; 150:39-46. [PMID: 35944464 DOI: 10.1016/j.molimm.2022.07.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 07/04/2022] [Accepted: 07/31/2022] [Indexed: 11/24/2022]
Abstract
A high salt diet (HSD) is often associated with a high risk for a variety of diseases, such as obesity and cardiovascular disease. Previous studies have demonstrated that an HSD enhances Th17 responses and increases the severity of autoimmune diseases. In this study, we investigated the effects of HSD (4% NaCl w/w) on colitis in IL-10-/- mice by comparing it with IL-10-/- mice on a normal salt diet (NSD, 1% NaCl w/w). The colonic epithelial barrier integrity in IL-10-/- mice, as well as differentiated Caco-2 cells exposed to high NaCl and proinflammatory cytokines, was also evaluated. Surprisingly, an HSD significantly ameliorated macroscopic colitis, improved the intestinal permeability of FITC-dextran, and decreased multiple proinflammatory cytokines in the colonic mucosa of IL-10-/- mice. While occludin and claudin-1, two major tight-junction proteins, were markedly down-regulated in IL-10-/- mice, HSD effectively restored their expressions. In Caco-2 cells, proinflammatory cytokines (TNF-α and IL-1β) potently decreased the expression of occludin and claudin-1 regardless of salt conditions [0.9% (standard), 1.2%, or 1.5% NaCl]. Under high salt conditions (1.5% NaCl), transepithelial electrical resistance (TEER) was elevated, while the addition of IL-10 further downregulated occludin and claudin-1 expressions by ~50% and lowered TEER. These findings suggest that, in the absence of IL-10, HSD promotes intestinal epithelial integrity and exerts an anti-inflammatory role as demonstrated by alleviated colitis in IL-10-/- mice. Moreover, Caco-2 data indicate that, in an inflammatory environment and under high NaCl conditions, IL-10 may play a proinflammatory role by disrupting colonic epithelial integrity and thus further promoting inflammation.
Collapse
Affiliation(s)
- Dezhi Wang
- Department of Gastroenterology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China; Department of Medicine/GI Division, School of Medicine, Johns Hopkins University, Baltimore 21205, United States
| | - Hua Jin
- Department of Pathology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China
| | - Jianqiu Sheng
- Department of Gastroenterology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China
| | - Leon Cheng
- Division of Pediatric Allergy and Immunology, Johns Hopkins University, Baltimore 21205, United States
| | - Qing Lin
- Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore 21205, United States
| | - Mark Lazerev
- Department of Medicine/GI Division, School of Medicine, Johns Hopkins University, Baltimore 21205, United States
| | - Peng Jin
- Department of Gastroenterology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China; Senior Department of Gastroenterology, the First Medical Center of PLA General Hospital, Beijing 100853, China.
| | - Xuhang Li
- Department of Medicine/GI Division, School of Medicine, Johns Hopkins University, Baltimore 21205, United States.
| |
Collapse
|
|
30
|
Sharifinejad N, Zaki-Dizaji M, Sepahvandi R, Fayyaz F, Dos Santos Vilela MM, ElGhazali G, Abolhassani H, Ochs HD, Azizi G. The clinical, molecular, and therapeutic features of patients with IL10/IL10R deficiency: a systematic review. Clin Exp Immunol 2022; 208:281-291. [PMID: 35481870 PMCID: PMC9226142 DOI: 10.1093/cei/uxac040] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/19/2022] [Accepted: 04/25/2022] [Indexed: 01/19/2023] Open
Abstract
Interleukin10 (IL10) and IL10 receptor (IL10R) deficiencies are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). In this report, we systematically reviewed articles that included related keywords using PubMed, Web of Science, and Scopus databases. The articles were screened for eligibility criteria before data extraction. We assessed 286 patients (44.5% female) with IL10 and/or IL10R deficiencies who were predominantly from China (40.7%), Italy (13.9%), and South Korea (8.5%). The median age of onset was 1.0 (0.3-4.0) months with a median age of genetic diagnosis at 16.0 (7.4-81.0) months. Consanguinity was reported in all evaluable patients with IL10 deficiency and in 38.2% of patients with IL10R deficiency (22.9% of patients with IL10RA, and 79.4% of patients with IL10RB deficiency). The most prevalent mutations in IL10RA were c.301C>T (p.R101W) and c.537G>A (p.T179T), those in IL10RB were c.139A>G (p.K47E) and c.611G>A (p.W204X). Auto-inflammation and enteropathy were present in all cases. The first presentation of both groups was protracted diarrhea (45.7%), bloody diarrhea (17.8%), and colitis (15.5%). Patients with IL10R deficiency had a high frequency of dermatologic manifestations (50.5%) and failure to thrive (60.5%), while IL10-deficient patients lacked those complications. In the majority of patients, the basic immunologic parameters were in normal ranges. Of the entire publications, 30.7% underwent hemopoietic stem cell transplantation, 57.5% surgery, and 86.6% immunosuppressive treatment. The 10-year survival rate was higher in patients with IL10 deficiency than in patients with IL10R deficiency. In conclusion, IL10/IL10R deficiency predominantly presents with treatment-resistant, early-onset IBD within the first months of life. We detected no clear correlation between the phenotype of patients carrying the same variant. The high prevalence of distinct clinical manifestations reported in IL10RA- and IL10RB-deficient patients might be attributable to the interactions between the target tissue and cytokines other than IL10 capable of binding to IL10RB. These results gain translational significance by contributing to earlier diagnosis, adequate therapy, and avoiding delay in the diagnosis and unfavorable outcomes.
Collapse
Affiliation(s)
- Niusha Sharifinejad
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Majid Zaki-Dizaji
- Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
| | - Roya Sepahvandi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Farimah Fayyaz
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran.,Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maria Marluce Dos Santos Vilela
- Center for Investigation in Pediatrics, Pediatrics Department, Faculty of Medical Sciences, State University of Campinas (UNICAMP). Campinas, SP, Brazil
| | - Gehad ElGhazali
- Department of Clinical Microbiology and Immunology, Sheikh Khalifa Medical City, Abu Dhabi, UAE
| | - Hassan Abolhassani
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hans D Ochs
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.,Seattle Children's Research Institute, Seattle, WA, USA
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
31
|
Ye H, Pan J, Cai X, Yin Z, Li L, Gong E, Xu C, Zheng H, Cao Z, Chen E, Qian J. IL‑10/IL‑10 receptor 1 pathway promotes the viability and collagen synthesis of pulmonary fibroblasts originated from interstitial pneumonia tissues. Exp Ther Med 2022; 24:518. [PMID: 35837039 PMCID: PMC9257754 DOI: 10.3892/etm.2022.11445] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 03/04/2021] [Indexed: 11/07/2022] Open
Abstract
Interstitial pneumonia is a pulmonary interstitial inflammatory and fibrosis disease with a variety of causes that causes respiratory disorders and threatens the lives of patients. The present study aimed to investigate the expression of interleukin (IL)-10 in peripheral blood of patients with interstitial pneumonia and its biological functions in pulmonary fibroblasts. A total of 42 patients with idiopathic pulmonary fibrosis (IPF) and 20 healthy subjects were included. ELISA was used to determine IL-10 concentration in serum from the patients and healthy subjects. Primary fibroblasts were isolated from lung tissue successfully and determined by morphology. The CCK-8 assay was performed to determine the effect of IL-10 expression on cell viability. Western blotting was used to determine COL1a1, COL1a2 and IL-10R1 protein expression. Flow cytometry was used for cell cycle analysis and to determine the number of IL-10+ cells. Expression of IL-10 in serum from IPF patients was higher compared to that from healthy subjects. IL-10 promoted the viability and collagen synthesis and secretion of MRC-5 cells and primary pulmonary fibroblasts. IL-10 and IL-10 receptor (R) 1 served regulatory roles in the viability and collagen synthesis of MRC-5 cells. The ratio of peripheral mononuclear lymphocytes with positive expression of IL-10 was elevated in peripheral blood from patients with IPF. The present study demonstrated that IL-10 expression in peripheral blood of patients with IPF is increased significantly compared with healthy subjects. Activation of the IL-10/IL-10R1 signaling pathway promoted the viability and collagen synthesis and secretion of pulmonary fibroblasts, leading to pulmonary fibrosis. The present study provided experimental basis for further understanding the development mechanism of pulmonary fibrosis.
Collapse
Affiliation(s)
- Hong Ye
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| | - Jiongwei Pan
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| | - Xiaoping Cai
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| | - Zhangyong Yin
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| | - Lu Li
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| | - Enhui Gong
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| | - Cunlai Xu
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| | - Hao Zheng
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| | - Zhuo Cao
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| | - Enguo Chen
- Department of Respiratory and Critical Care Medicine, Sir Run Run Shaw Hospital, Affiliated to Zhejiang University School of Medicine, Hangzhou, Zheijang 310016, P.R. China
| | - Junfeng Qian
- Respiratory Department, The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospital, Lishui, Zheijang 323000, P.R. China
| |
Collapse
|
|
32
|
Ye Z, Qian L, Hu W, Miao S, Wang Y, Lu J, Zhou Y, Lu X, Zhang Y, Zheng C, Sun H, Tang W, Tang Z, Sun S, Dong K, Qian X, Zhai X, Huang Y. Clinical outcome of infantile-onset inflammatory bowel disease in 102 patients with interleukin-10 signalling deficiency. Aliment Pharmacol Ther 2022; 55:1414-1422. [PMID: 35187668 DOI: 10.1111/apt.16837] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/07/2021] [Accepted: 02/04/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Infantile-onset inflammatory bowel disease can be caused by defects in interleukin-10 signalling. The natural history and clinical outcomes of allogeneic haematopoietic stem cell transplantation, medical treatment and surgery have not been thoroughly described. AIMS This study evaluates disease progression and clinical outcome in patients with interleukin-10 signalling deficiency. METHODS One hundred and nine patients with interleukin-10 signalling deficiency were retrospectively reviewed from a single tertiary centre. The Kaplan-Meier method was applied to calculate probabilities of survival and interval between transplant and stoma closure. RESULTS One hundred and nine patients were reviewed, and 102 patients were included in the survival analysis. One hundred and eight patients were identified with IL10RA mutations, and one patient harboured IL10RB mutation. Seventy-three patients received haematopoietic stem cell transplantation. The overall survival after transplantation was 64.2% (95% confidence interval, 52.8 to 75.6), and without transplantation, it was 47.5% (95% confidence interval, 14.8 to 80.2, P = 0.47). The median timeframe between transplant and stoma closure was 19.6 months. The probability of survival was significantly lower in patients with perforation (P < 0.001), ileus (P = 0.038) and without thalidomide treatment (P < 0.001) among patients who did not receive haematopoietic stem cell transplantation. The survival probability was not associated with timeframe between transplant and onset, graft source and genotypes. CONCLUSIONS The survival probability was not significantly different between patients with transplantation and the non-transplanted patients.
Collapse
Affiliation(s)
- Ziqing Ye
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Lai Qian
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Wenhui Hu
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Shijian Miao
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Yuhuan Wang
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Junping Lu
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Ying Zhou
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Xiaolan Lu
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Ye Zhang
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Cuifang Zheng
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Hua Sun
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Wenjuan Tang
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Zifei Tang
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| | - Song Sun
- Department of Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Kuiran Dong
- Department of Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Xiaowen Qian
- Department of Hematology and Oncology, Children's Hospital of Fudan University, Shanghai, China
| | - Xiaowen Zhai
- Department of Hematology and Oncology, Children's Hospital of Fudan University, Shanghai, China
| | - Ying Huang
- Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China
| |
Collapse
|
|
33
|
Weber K, Zeißig Y, Haag C, Schmelz R, Pazmandi J, Kalinichenko A, Boztug K, Zeißig S, Aust D, Laass MW, Schuetz C. [Chronic or severe enteropathy and immunodeficiency: be prepared for a rara avis]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:1668-1677. [PMID: 35297030 DOI: 10.1055/a-1709-5024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
In the work-up of chronic enteropathies an underlying inborn error of immunity (IEI) should be considered in certain cases. IEI are rare, but approximately 10% of patients may present with symptoms of inflammatory bowel disease (IBD), which is a much more common entity. Patients with IEI associated IBD may show extraintestinal symptoms or signs, and are often refractory to conventional anti-inflammatory treatment. In case of early-onset bowel inflammation and other intestinal or extraintestinal manifestations, an IEI should be excluded. A small fraction of monogenic IEI can be amenable to targeted therapies, or even corrected by allogeneic stem cell transplantation. Therefore, early diagnosis is crucial. This paper shows examples of clinical - gastrointestinal as well as extraintestinal - signs and findings which require immunological and possibly genetic workup.
Collapse
Affiliation(s)
- Katrin Weber
- Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
| | - Yvonne Zeißig
- Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
| | - Cornelie Haag
- Universitätsklinikum Carl Gustav Carus Medizinische Klinik und Poliklinik I, Dresden, Germany
| | - Renate Schmelz
- Universitätsklinikum Carl Gustav Carus Medizinische Klinik und Poliklinik I, Dresden, Germany
| | - Julia Pazmandi
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
| | - Artem Kalinichenko
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
| | - Kaan Boztug
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.,St. Anna Kinderspital und Universitätsklinik für Kinder und Jugendliche, Medizinische Universitat Wien, Wien, Austria.,St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
| | - Sebastian Zeißig
- Center for Regenerative Therapies Dresden, Dresden, Germany.,Klinik und Poliklinik für Innere Medizin I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
| | - Daniela Aust
- Institut für Pathologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
| | - Martin W Laass
- Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
| | - Catharina Schuetz
- Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
| |
Collapse
|
|
34
|
Flinn AM, Gennery AR. Primary immune regulatory disorders: Undiagnosed needles in the haystack? Orphanet J Rare Dis 2022; 17:99. [PMID: 35241125 PMCID: PMC8895571 DOI: 10.1186/s13023-022-02249-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 02/13/2022] [Indexed: 12/16/2022] Open
Abstract
Primary Immune Regulatory Disorders (PIRD) describe a group of conditions characterized by loss of normal inflammatory control and immune tolerance mechanisms, with autoimmunity as a predominant clinical feature. PIRD can arise due to defects in the number or function of regulatory T-lymphocytes, defects in the immune mechanisms required to ‘turn off’ inflammation such as in perforin-dependent cytotoxicity or alterations in cytokine signalling pathways. Diagnosis of PIRD is a significant challenge to physicians due to their rarity, complexity, and diversity in clinical manifestations. Many of these individual conditions lack a genotype–phenotype correlation and display incomplete penetrance. However, establishing a diagnosis is integral in optimizing patient management, including the use of individualized treatment approaches. Increasing awareness among physicians is necessary as patients are likely to present to different subspecialties. Due to the rarity of these conditions, worldwide collaboration and data-sharing is essential to improve our knowledge of the clinical spectrum and disease course in PIRD, and to optimize therapeutic strategies including identification of which patients can benefit from hematopoietic stem cell transplant.
Collapse
Affiliation(s)
- Aisling M Flinn
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Andrew R Gennery
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
| |
Collapse
|
|
35
|
Sasahara Y, Uchida T, Suzuki T, Abukawa D. Primary Immunodeficiencies Associated With Early-Onset Inflammatory Bowel Disease in Southeast and East Asia. Front Immunol 2022; 12:786538. [PMID: 35095863 PMCID: PMC8792847 DOI: 10.3389/fimmu.2021.786538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/21/2021] [Indexed: 12/02/2022] Open
Abstract
Background Causes of early-onset inflammatory bowel disease (IBD) vary, and primary immunodeficiency diseases (PIDs) are associated with early-onset IBD as monogenic disorders. Aim This review investigates the prevalence, clinical manifestation, genetic profile, and treatment of patients with early-onset IBD in Southeast and East Asia. Methods A systemic review of articles reporting PID patients associated with early-onset IBD in Southeast and East Asia was conducted. Results The prevalence of PID associated with IBD was higher than that reported in western nations, and the frequency of patients with bloody stools as an early symptom was relatively higher in monogenic diseases. A total 13 (12.0%) of 108 patients with early-onset IBD were diagnosed as PID by exome sequencing and targeted gene panel analysis in Japan, including four patients with XIAP, three with IL10RA, and two or one patient with other gene mutations. In addition, ten patients were reported as having IL-10 receptor alpha (IL-10RA) deficiency in China and Hong Kong. Allogeneic hematopoietic stem cell transplantation was performed in patients with X-linked inhibitor of apoptosis deficiency, IL-10RA deficiency, or other PID as a curative treatment, and the preferable outcome of reduced-intensity conditioning and complete resolution of IBD symptoms and dysbiosis were achieved. Conclusion Comprehensive molecular diagnosis has been widely applied to screen for patients with PID-associated IBD in Southeast and East Asia. These results contributed to the awareness of monogenic PID in early-onset IBD patients and their differences in clinical manifestations and genetic profiles compared to the patients in western counties.
Collapse
Affiliation(s)
- Yoji Sasahara
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Uchida
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tasuku Suzuki
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Daiki Abukawa
- Department of General Pediatrics, Gastroenterology and Hepatology, Miyagi Children's Hospital, Sendai, Japan
| |
Collapse
|
|
36
|
Morita M, Takeuchi I, Kato M, Migita O, Jimbo K, Shimizu H, Yoshimura S, Tomizawa D, Shimizu T, Hata K, Ishiguro A, Arai K. Intestinal outcome of bone marrow transplantation for monogenic inflammatory bowel disease. Pediatr Int 2022; 64:e14750. [PMID: 33884705 DOI: 10.1111/ped.14750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/09/2021] [Accepted: 04/16/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Some monogenic inflammatory bowel diseases (IBDs) are known to be refractory to conventional treatments. Although allogeneic hematopoietic stem-cell transplantation (allo-HSCT) has become a curative therapeutic option for certain monogenic IBDs, its effectiveness regarding endoscopic improvements has not been clarified. METHODS The clinical course and endoscopic findings of patients with monogenic IBDs who were treated with allo-HSCT between December 2017 and November 2018 at the National Center for Child Health and Development, were retrospectively reviewed. The clinical disease activity was assessed using the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) and the endoscopic finding was evaluated using the Simple Endoscopic Score for Crohn's Disease (SES-CD). Clinical remission was defined as a wPCDAI <10 and endoscopic remission was defined as an SES-CD of 2 or less. RESULTS Four patients with severe monogenic IBDs, including three with X-linked inhibitors of apoptosis protein (XIAP) deficiency and one with interleukin-10 signaling defect, were treated with allo-HSCT with reduced-intensity conditioning. In four patients, the maximum scores of wPCDAI and SES-CD before allo-HSCT ranged from 67.5 to 120 and 20 to 34, respectively. After allo-HSCT, all four patients showed a significant improvement in intestinal inflammation and achieved both clinical and endoscopic remission. Although patients with XIAP deficiency presented with post-transplant hemophagocytic lymphohistiocytosis and a relatively late engraftment, all patients achieved prolonged clinical remission, and IBD medications were successfully discontinued in all patients. CONCLUSION Allo-HSCT for monogenic IBD resulted in complete clinical resolution with endoscopically confirmed mucosal healing.
Collapse
Affiliation(s)
- Mari Morita
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan.,Center for Postgraduate Education and Training, National Center for Child Health and Development, Tokyo, Japan
| | - Ichiro Takeuchi
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan.,Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Motohiro Kato
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Ohsuke Migita
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Keisuke Jimbo
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Shimizu
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan.,Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Yoshimura
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Daisuke Tomizawa
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Toshiaki Shimizu
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kenichiro Hata
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Akira Ishiguro
- Center for Postgraduate Education and Training, National Center for Child Health and Development, Tokyo, Japan
| | - Katsuhiro Arai
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| |
Collapse
|
|
37
|
Li QQ, Zhang HH, Dai SX. New Insights and Advances in Pathogenesis and Treatment of Very Early Onset Inflammatory Bowel Disease. Front Pediatr 2022; 10:714054. [PMID: 35299671 PMCID: PMC8921506 DOI: 10.3389/fped.2022.714054] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 01/25/2022] [Indexed: 12/26/2022] Open
Abstract
Very early onset inflammatory bowel disease (VEO-IBD) is characterized by multifactorial chronic recurrent intestinal inflammation. Compared with elderly patients, those with VEO-IBD have a more serious condition, not responsive to conventional treatments, with a poor prognosis. Recent studies found that genetic and immunologic abnormalities are closely related to VEO-IBD. Intestinal immune homeostasis monogenic defects (IIHMDs) are changed through various mechanisms. Recent studies have also revealed that abnormalities in genes and immune molecular mechanisms are closely related to VEO-IBD. IIHMDs change through various mechanisms. Epigenetic factors can mediate the interaction between the environment and genome, and genetic factors and immune molecules may be involved in the pathogenesis of the environment and gut microbiota. These discoveries will provide new directions and ideas for the treatment of VEO-IBD.
Collapse
Affiliation(s)
- Qi-Qi Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hui-Hong Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Shi-Xue Dai
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Gastroenterology, Guangdong Provincial Geriatrics Institute, National Key Clinical Specialty, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, South China University of Technology, Guangzhou, China
| |
Collapse
|
|
38
|
Swaminathan A, Sathiyasekaran M, Padankatti S, Padankatti RB, Arulprakash S, Raj R. A Rare Cause of Rectovaginal Fistula in Early Infancy: It is in the Genes! J Indian Assoc Pediatr Surg 2021; 26:442-444. [PMID: 34912145 PMCID: PMC8637981 DOI: 10.4103/jiaps.jiaps_217_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/18/2020] [Accepted: 09/05/2020] [Indexed: 11/24/2022] Open
Abstract
Acquired Rectovaginal Fistula (RVF) is rare in infants. Interleukin10/ Interleukin 10 receptor deficiencies are monogenic disorders presenting as aggressive forms of infantile onset inflammatory bowel disease with perianal abscess and fistula. Genetic studies assist in confirming the diagnosis. We present a two month old infant with rectovaginal fistula, severe colitis, failure to thrive and recurrent infections in whom colonoscopy revealed irregular colonic ulcers, and genetic studies confirmed an IL10RB mutation. Hematopoietic Stem cell transplantation is the definitive therapy for this disorder which the child underwent. We report this infant with an acquired RVF with extraintestinal features due to IL10RB mutation to highlight the importance of thinking beyond the local anatomy and looking into the genetic domain.
Collapse
Affiliation(s)
| | | | - Swathi Padankatti
- Department of Pediatrics, Sundaram Medical Foundation, Chennai, Tamil Nadu, India
| | - Rajiv B Padankatti
- Department of Pediatric Surgery, Sundaram Medical Foundation, Chennai, Tamil Nadu, India
| | - S Arulprakash
- Department of Gastroenterlogy, MGM Healthcare, Chennai, Tamil Nadu, India
| | - Revathi Raj
- Department of Pediatric Hemato-oncology, Apollo Children's Hospital Chennai, Tamil Nadu, India
| |
Collapse
|
|
39
|
Sandy NS, Marega LF, Bechara GD, Riccetto AGL, Bonfim C, Vilela MMDS, Ribeiro AF, Servidoni MDF, Lomazi EA. Elevated IgA and IL-10 levels in very-early-onset inflammatory bowel disease secondary to IL-10 receptor deficiency. REVISTA PAULISTA DE PEDIATRIA 2021; 40:e2020434. [PMID: 34730757 PMCID: PMC8565602 DOI: 10.1590/1984-0462/2022/40/2020434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/21/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To report two patients with very-early-onset inflammatory bowel disease (VEOIBD) secondary to interleukin-10 receptor (IL-10R) mutations, explore immunophenotyping data and plasma cytokine profile on these cases compared to healthy controls, and describe the phenotype of IL-10/IL-10R mutations based on a literature review. CASE DESCRIPTION We report on two female infants referred to our tertiary center at the age of ten months, with severe colonic and perianal disease, as well as significant malnutrition, who had shown limited response to usual inflammatory bowel disease (IBD) therapy agents. In the first case, whole-exome sequencing (WES) revealed a homozygous (c.537G>A/p.T179T) mutation in exon 4 of the IL-10RA gene, while in the second patient, compound heterozygosity was identified, also in the IL-10RA gene (chr11:117.859.199 variant A>G/p.Tyr57Cys and chr11: 117.860.335 variant G>T/p.Val123Leu). Both patients underwent hematopoietic cell transplantation (HCT). Immunological work-up of these patients revealed increased IL-10 plasma levels and increased IgA. COMMENTS Our case reports disclose novel findings on plasma cytokine profile in IL-10R deficiency, and we describe the severe phenotype of IL-10/IL-10R deficiency that should be recognized by physicians.
Collapse
|
|
40
|
Intestinal immunoregulation: lessons from human mendelian diseases. Mucosal Immunol 2021; 14:1017-1037. [PMID: 33859369 DOI: 10.1038/s41385-021-00398-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 02/04/2023]
Abstract
The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.
Collapse
|
|
41
|
Ruiz NC, Kamel AY, Liu X, Pham A, Forsmark C, Glover S. Failure to thrive: A severe manifestation of interleukin 10 receptor A mutation in adult inflammatory bowel disease. JPEN J Parenter Enteral Nutr 2021; 46:238-242. [PMID: 34423458 DOI: 10.1002/jpen.2254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/30/2021] [Accepted: 08/17/2021] [Indexed: 11/12/2022]
Abstract
BACKGROUND Very early-onset inflammatory bowel disease (VEO-IBD) secondary to interleukin 10 receptor A (IL-10RA) mutations has aggressive disease courses with increased nutrition needs compared with those in other monogenic forms of IBD. PRESENTATION A male patient was hospitalized when he was 18 days old for bloody diarrhea, which was diagnosed as Crohn's disease at 6 months old. He showed failure to thrive (FTT) and worsening inflammation while receiving enteral nutrition (EN) and standard IBD treatment. He was hospitalized in 2016, at 28 years old, for a Crohn's flare when sequencing confirmed a heterozygous mutation in IL10-RA. His weight and plasma micronutrient levels improved when he transitioned to parenteral nutrition (PN). He was initiated on anakinra while awaiting hematopoietic stem cell transplant, with substantial decrease in inflammation. He was able to gain weight, initiate an oral diet, and decrease his PN requirement. CONCLUSION Our patient experienced progressive FTT while receiving EN. VEO-IBD incidence is rising, and its diagnosis is often delayed. Therefore, prompt recognition with treatment initiation is essential to improving nutrition outcomes in this patient population. Further investigation is warranted to determine whether these patients would benefit from early initiation of PN.
Collapse
Affiliation(s)
- Nicole C Ruiz
- Department of Internal Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Amir Y Kamel
- Department of Pharmacy, UF Health Shands Hospital, Gainesville, Florida, USA
| | - Xiuli Liu
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
| | - Angela Pham
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, Gainesville, Florida, USA
| | - Christopher Forsmark
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, Gainesville, Florida, USA
| | - Sarah Glover
- Department of Digestive Diseases, University of Mississippi Medical Center, Jackson, Mississippi, USA
| |
Collapse
|
|
42
|
Nguyen HD, Aljamaei HM, Stadnyk AW. The Production and Function of Endogenous Interleukin-10 in Intestinal Epithelial Cells and Gut Homeostasis. Cell Mol Gastroenterol Hepatol 2021; 12:1343-1352. [PMID: 34271223 PMCID: PMC8463866 DOI: 10.1016/j.jcmgh.2021.07.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 07/08/2021] [Accepted: 07/08/2021] [Indexed: 02/06/2023]
Abstract
The healthy gut is achieved and maintained through a balanced relationship between the mucosal immune system, microbial communities resident in the lumen, and the intestinal epithelium. The intestinal epithelium plays an exceptionally important role in harmonizing the interaction between the host immunity and the luminal residents, as this selectively permeable barrier separates but also allows interchange between the 2 environments. Interleukin (IL)-10 has been well established to play an important role in maintaining gut homeostasis by imparting diverse effects on a variety of cell types in this relationship. In the intestine, the source and the target of IL-10 include leukocytes and epithelial cells. Given that both the epithelium and IL-10 are essential players in supporting homeostasis, we discuss the relationship between these 2 factors, focusing on epithelial sources of IL-10 and the effects of IL-10 on the intestinal epithelium. Insight into this relationship reveals an important aspect of the innate immune function of intestinal epithelial cells.
Collapse
Affiliation(s)
- Huong D. Nguyen
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Hanan M. Aljamaei
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Andrew W. Stadnyk
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada,Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada,Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada,Division of Gastroenterology & Nutrition, IWK Health Centre, Halifax, Nova Scotia, Canada,Correspondence Address correspondence to: Andrew W. Stadnyk, PhD, MIRA-lab, IWK Health Centre, 5850/5980 University Avenue, Halifax, Nova Scotia, Canada B3K 6R8. fax: (902) 470-7812.
| |
Collapse
|
|
43
|
Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:3767-3780. [PMID: 34246792 DOI: 10.1016/j.jaip.2021.05.045] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. OBJECTIVE To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. METHODS A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. RESULTS Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT. CONCLUSIONS This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.
Collapse
|
|
44
|
Nedelkopoulou N, Taparkou A, Agakidis C, Mavroudi A, Xinias I, Farmaki E. IL-10 receptor expression on lymphocytes and monocytes in children with food allergy. Pediatr Allergy Immunol 2021; 32:1108-1111. [PMID: 33595140 DOI: 10.1111/pai.13475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/09/2021] [Accepted: 01/28/2021] [Indexed: 11/26/2022]
Affiliation(s)
- Natalia Nedelkopoulou
- 1st Department of Paediatrics, Paediatric Immunology and Rheumatology Referral Centre, Hippokration General Hospital, Aristotle University, Thessaloniki, Greece.,Pediatric Gastroenterology Department, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
| | - Anna Taparkou
- 1st Department of Paediatrics, Paediatric Immunology and Rheumatology Referral Centre, Hippokration General Hospital, Aristotle University, Thessaloniki, Greece
| | - Charalampos Agakidis
- 1st Department of Paediatrics, Hippokration General Hospital, Aristotle University, Thessaloniki, Greece
| | - Antigoni Mavroudi
- 3rd Department of Paediatrics, Hippokration General Hospital, Aristotle University, Thessaloniki, Greece
| | - Ioannis Xinias
- 3rd Department of Paediatrics, Hippokration General Hospital, Aristotle University, Thessaloniki, Greece
| | - Evangelia Farmaki
- 1st Department of Paediatrics, Paediatric Immunology and Rheumatology Referral Centre, Hippokration General Hospital, Aristotle University, Thessaloniki, Greece
| |
Collapse
|
|
45
|
Hung HH, Lee HC, Yeung CY, Wang NL, Tang TY, Winter HS, Kelsen JR, Jiang CB. Importance of early detection of infantile inflammatory bowel disease with defective IL-10 pathway: A case report. Medicine (Baltimore) 2021; 100:e25868. [PMID: 34032699 PMCID: PMC8154448 DOI: 10.1097/md.0000000000025868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/14/2021] [Accepted: 04/21/2021] [Indexed: 01/04/2023] Open
Abstract
RATIONALE Infantile inflammatory bowel disease (IBD) is an extremely rare subgroup of IBD that includes patients whose age of onset is younger than 2 years old. These patients can have more surgical interventions, and a severe and refractory disease course with higher rates of conventional treatment failure. Monogenic defects play an important role in this subgroup of IBD, and identification of the underlying defect can guide the therapeutic approach. PATIENT CONCERNS In 2007, a 4-month-old girl from a nonconsanguineous family presenting with anal fistula, chronic diarrhea, and failure to thrive. She underwent multiple surgical repairs but continued to have persistent colitis and perianal fistulas. DIAGNOSIS Crohn's disease was confirmed by endoscopic and histologic finding. INTERVENTION Conventional pediatric IBD therapy including multiple surgical interventions and antitumor necrosis factor alpha agents were applied. OUTCOMES The patient did not respond to conventional pediatric IBD therapy. Interleukin-10 (IL-10) receptor mutation was discovered by whole-exome sequencing and defective IL-10 signaling was proved by functional test of IL-10 signaling pathway by the age of 12. The patient is currently awaiting hematopoietic stem cell transplantation. LESSONS Early detection of underlying genetic causes of patients with infantile-IBD is crucial, since it may prevent patients from undergoing unnecessary surgeries and adverse effects from ineffective medical therapies. Moreover, infantile-IBD patients with complex perianal disease, intractable early onset enterocolitis and extraintestinal manifestations including oral ulcers and skin folliculitis, should undergo genetic and functional testing for IL-10 pathway defect.
Collapse
Affiliation(s)
- Hua-Hsi Hung
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei
| | - Hung-Chang Lee
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei
| | - Chun-Yan Yeung
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei
- Department of Medicine, MacKay Medical College, New Taipei City
| | - Nien-Lu Wang
- Department of Pediatric Surgery, MacKay Children's Hospital
| | - Tzu-Yin Tang
- Department of Pathology, MacKay Memorial Hospital, Taipei, Taiwan
| | - Harland S. Winter
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, MassGeneral Hospital for Children, Boston, MA
| | - Judith R. Kelsen
- Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA
| | - Chuen-Bin Jiang
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children's Hospital, Taipei
- Department of Medicine, MacKay Medical College, New Taipei City
| |
Collapse
|
|
46
|
Cooper MA, Zimmerman O, Nataraj R, Wynn RF. Lifelong Immune Modulation Versus Hematopoietic Cell Therapy for Inborn Errors of Immunity. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:628-639. [PMID: 33551038 DOI: 10.1016/j.jaip.2020.11.055] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/23/2020] [Accepted: 11/25/2020] [Indexed: 02/06/2023]
Abstract
Advances in diagnosis of inborn errors of immunity (IEI) and an understanding of the molecular and immunologic mechanisms of these disorders have led to both the development of new therapies and improved approaches to hematopoietic cell transplantation (HCT). For example, monoclonal antibodies (mAbs) and small molecules, such as Janus tyrosine kinase inhibitors, that can modulate immunologic pathways have been designed for or repurposed for management of IEI. A better understanding of molecular mechanisms of IEI has led to use of drugs typically considered "immunosuppressive" to modulate the immune response, such as mammalian target of rapamycin inhibitors in disorders of phosphoinositide 3-kinase gain of function. Since the first HCT in a patient with severe combined immunodeficiency (SCID) in 1968, transplantation strategies have improved, with more than 90% probability of survival after allogeneic HCT in SCID and hence HCT is now the therapeutic standard for SCID and many other IEI. When tailoring treatment for IEI, multiple disease-specific and individual factors should be considered. In diseases such as SCID or agammaglobulinemia, the choice between HCT or medical management is straightforward. However, in many IEI, the choice between the options is challenging. This review focuses on the factors that should be taken into account in the quest for the optimal treatment for patients with IEI.
Collapse
Affiliation(s)
- Megan A Cooper
- Department of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo.
| | - Ofer Zimmerman
- Department of Medicine, Division of Allergy/Immunology, Washington University in St Louis, St Louis, Mo
| | - Ramya Nataraj
- Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Robert F Wynn
- Department of Blood and Marrow Transplant, Royal Manchester Children's Hospital, Manchester, United Kingdom.
| |
Collapse
|
|
47
|
Bosman-Schluep D, de Pril R, Verbaken B, Legent A, Stallen J, de Jong EC, Janssen RAJ. siRNA-based identification of IBD-related targets in human monocyte-derived dendritic cells. J Immunol Methods 2021; 494:113058. [PMID: 33891922 DOI: 10.1016/j.jim.2021.113058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/31/2021] [Accepted: 04/16/2021] [Indexed: 01/09/2023]
Abstract
Inflammatory bowel disease (IBD) is thought to be caused by an aberrant host response to the commensal enteric flora in genetically susceptible individuals. Dendritic cells (DCs) play a key role in the regulation of this response as they sample gut commensals. In healthy individuals DCs actively contribute to tolerance upon recognition of these resident bacteria, whereas in individuals with IBD, DCs will initiate an inflammatory response. To mimic the disease response in vitro, human monocyte-derived DCs were matured with E. coli causing the cells to produce high levels of the pro-inflammatory cytokine IL-12/IL-23p40 (p40) and low levels of the anti-inflammatory cytokine IL-10. A siRNA-based screening assay was developed and screened to identify potential therapeutic targets that shift this balance towards an immunosuppressive state with lower levels of p40 and higher levels of IL-10. The screening assay was optimized and quality controlled using non-targeting controls and positive control siRNAs targeting IL12B and TLR4 transcripts. In the primary screen, smartpool siRNAs were screened for reduction in p40 expression, induction of IL-10 levels, or increase in IL-10:p40 ratios without affecting cell viability. All potential targets were taken forward into a confirmation screen in a different DC donor in which four individual siRNAs per target were screened. At least two siRNAs per target should have an effect to be considered a valid target. This screen resulted in a concise list of ten genes, of which their role in DC maturation is currently being investigated.
Collapse
Affiliation(s)
| | | | | | | | | | - Esther C de Jong
- Department of Experimental Immunology, Amsterdam UMC, the Netherlands
| | | |
Collapse
|
|
48
|
Tang Z, Zhang P, Ji M, Yin C, Zhao R, Huang Z, Huang Y. Characterization of novel and large fragment deletions in exon 1 of the IL10RA gene in Chinese children with very early onset inflammatory bowel diseases. BMC Gastroenterol 2021; 21:167. [PMID: 33849446 PMCID: PMC8045347 DOI: 10.1186/s12876-021-01756-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 04/08/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Defects in interleukin 10 (IL10) and its receptors are particularly involved in very early onset inflammatory bowel disease (VEOIBD). However, large fragment deletions of IL10 receptor A (IL10RA) are rare. METHODS VEOIBD patients with confirmed mutations in the IL10RA gene were enrolled from January 1, 2019 to June 30, 2020. The clinical features and endoscopic-radiological findings of the patients with large fragment deletions of the IL10RA gene were determined and followed up. RESULTS Thirty-five patients with IL10RA gene mutations, namely, 28 compound heterozygous mutations and 7 homozygote mutations, were enrolled in this study. Six patients carried the reported point mutation c.301C > T (p. R101RW) or c.537 G > A (p. T179T) in one locus and a large fragment deletion in exon 1 in another locus, which were novel mutations in this gene. A 333-bp deletion of exon 1 (117857034-11857366 del) was the main mutation in this locus in 85.7% of the patients with large fragment deletions. The time of disease onset ranged from birth to 4 years, and diarrhea was the main initial symptom. In total, 6/7 patients had perianal complications, including perianal abscess, fistula and skin tags. Six patients accepted thalidomide treatment, 5/7 accepted mesalamine, 3/7 accepted hematopoietic stem cell transplantation (HSCT), and 3/7 were waiting for HSCT. CONCLUSIONS We identified a novel large deletion of exon 1 involving the IL10RA gene for the first time and showed the characteristics of VEOIBD patients. This study expands the spectrum of Chinese VEOIBD patients with IL0RA gene mutations.
Collapse
Affiliation(s)
- Zifei Tang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 China
| | - Ping Zhang
- Center for Molecular Medicine, Pediatrics Research Institute, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Min Ji
- Department of Radiology, Children’s Hospital of Fudan University, Shanghai, 201102 China
| | - Chunlan Yin
- Department of Gastroenterology, Children’s Hospital of Hebei Province, Shijiazhuang, 050030 China
| | - Ruiqin Zhao
- Department of Gastroenterology, Children’s Hospital of Hebei Province, Shijiazhuang, 050030 China
| | - Zhiheng Huang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 China
| | - Ying Huang
- Department of Gastroenterology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai, 201102 China
| |
Collapse
|
|
49
|
Genetic Correction of IL-10RB Deficiency Reconstitutes Anti-Inflammatory Regulation in iPSC-Derived Macrophages. J Pers Med 2021; 11:jpm11030221. [PMID: 33804706 PMCID: PMC8003874 DOI: 10.3390/jpm11030221] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/14/2021] [Accepted: 03/16/2021] [Indexed: 12/17/2022] Open
Abstract
Patient material from rare diseases such as very early-onset inflammatory bowel disease (VEO-IBD) is often limited. The use of patient-derived induced pluripotent stem cells (iPSCs) for disease modeling is a promising approach to investigate disease pathomechanisms and therapeutic strategies. We successfully developed VEO-IBD patient-derived iPSC lines harboring a mutation in the IL-10 receptor β-chain (IL-10RB) associated with defective IL-10 signaling. To characterize the disease phenotype, healthy control and VEO-IBD iPSCs were differentiated into macrophages. IL-10 stimulation induced characteristic signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) downstream signaling and anti-inflammatory regulation of lipopolysaccharide (LPS)-mediated cytokine secretion in healthy control iPSC-derived macrophages. In contrast, IL-10 stimulation of macrophages derived from patient iPSCs did not result in STAT3 phosphorylation and subsequent SOCS3 expression, recapitulating the phenotype of cells from patients with IL-10RB deficiency. In line with this, LPS-induced cytokine secretion (e.g., IL-6 and tumor necrosis factor-α (TNF-α)) could not be downregulated by exogenous IL-10 stimulation in VEO-IBD iPSC-derived macrophages. Correction of the IL-10RB defect via lentiviral gene therapy or genome editing in the adeno-associated virus integration site 1 (AAVS1) safe harbor locus led to reconstitution of the anti-inflammatory response. Corrected cells showed IL-10RB expression, IL-10-inducible phosphorylation of STAT3, and subsequent SOCS3 expression. Furthermore, LPS-mediated TNF-α secretion could be modulated by IL-10 stimulation in gene-edited VEO-IBD iPSC-derived macrophages. Our established disease models provide the opportunity to identify and validate new curative molecular therapies and to investigate phenotypes and consequences of additional individual IL-10 signaling pathway-dependent VEO-IBD mutations.
Collapse
|
|
50
|
Krawiec P, Pawłowska-Kamieniak A, Pac-Kożuchowska E. Interleukin 10 and interleukin 10 receptor in paediatric inflammatory bowel disease: from bench to bedside lesson. J Inflamm (Lond) 2021; 18:13. [PMID: 33691712 PMCID: PMC7948370 DOI: 10.1186/s12950-021-00279-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 03/04/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND The differences between adults and children in inflammatory bowel disease (IBD) phenotype, severity, complications, co-morbidities, and response to the therapy resulted in the extraction of paediatric IBD. It has been revealed that the substantial role in the development of IBD in children under 6 years of age plays a single genetic mutation (monogenic IBD). On the other hand, in older children and adolescents IBD is usually associated with number of interactions between susceptibility loci (polygenic IBD). MAIN BODY Until now there have been described about 60 monogenic defects which affect the variety of immune mechanisms in IBD pathogenesis including epithelial barrier, function of neutrophil granulocytes and phagocytes, T- and B-cell selection and activation, immune inhibitory mechanisms, or apoptosis. Il-10 is an anti-inflammatory cytokine which modulates innate and adaptive immunity affecting expression of pro-inflammatory molecules and function of the variety of immune cells. Patients with identified defects in Il-10 pathway manifest with life-threating colitis with perianal lesions which occurs within first months of life. Allogenic hematopoietic stem cell transplantation is curative therapy in children with Il-10 signalling defects. CONCLUSION Clinical awareness of Il-10 signalling defects enables early recognition and prompt management of the disease.
Collapse
Affiliation(s)
- Paulina Krawiec
- Department of Paediatrics and Gastroenterology, Medical University of Lublin, Racławickie 1, 20-059 Lublin, Poland
| | | | - Elżbieta Pac-Kożuchowska
- Department of Paediatrics and Gastroenterology, Medical University of Lublin, Racławickie 1, 20-059 Lublin, Poland
| |
Collapse
|