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Peng B, Liu Z, Huang Z, Lin H, Wang Z, Guo Q. Comparative analysis of enteroscopy, computed tomography enterography, and intestinal ultrasound for the evaluation of small bowel Crohn's disease. Therap Adv Gastroenterol 2025; 18:17562848251318031. [PMID: 39926319 PMCID: PMC11806484 DOI: 10.1177/17562848251318031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 01/17/2025] [Indexed: 02/11/2025] Open
Abstract
Background The comparable evaluation of computed tomography enterography (CTE), enteroscopy, and intestinal ultrasound in small bowel Crohn's disease (CD) is imprecise. Objectives The purpose of this study was to analyze the findings of enteroscopy, CTE, and intestinal ultrasound to determine the advantages and disadvantages of each method for the evaluation of small bowel CD. Design It was a single-center, observational, retrospective study. Methods The differences in localization of disease lesions, mucosal inflammation, and transmural inflammation between enteroscopy, CTE, and intestinal ultrasound for evaluation of small bowel CD were compared. Results A total of 198 patients with small bowel CD were included in the analysis. CTE and intestinal ultrasound had a lower detection rate of upper intestinal lesions compared with enteroscopy (p < 0.05). Enteroscopy was better than CTE and intestinal ultrasound in the detection of stenosis (p < 0.001), and the assessment of fistula by CTE was better than that by enteroscopy and intestinal ultrasound (p < 0.05). Enteroscopy, CTE, and intestinal ultrasound differed in the assessment of inflammatory activity, and the agreement of the three methods was poor (all intra-class correlation coefficient <0.75). Conclusion Enteroscopy is superior to CTE and intestinal ultrasound for the assessment of upper intestinal CD lesions. Enteroscopy, CTE, and intestinal ultrasound were not consistent in evaluating inflammatory activity, and the three methods may need to be combined for an accurate assessment.
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Affiliation(s)
- Bo Peng
- Department of Small Bowel Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Zhongcheng Liu
- Department of Small Bowel Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Zicheng Huang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Huixian Lin
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Zhiyue Wang
- Department of Small Bowel Endoscopy, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Qin Guo
- Departments of Small Bowel Endoscopy and Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, No. 26 Yuancun Road II, Tianhe District, Guangzhou 510000, P.R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
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Cao G, Luo Q, Wu Y, Chen G. Inflammatory bowel disease and rheumatoid arthritis share a common genetic structure. Front Immunol 2024; 15:1359857. [PMID: 38938570 PMCID: PMC11208460 DOI: 10.3389/fimmu.2024.1359857] [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: 12/22/2023] [Accepted: 05/31/2024] [Indexed: 06/29/2024] Open
Abstract
Background The comorbidity rate of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is high; nevertheless, the reasons behind this high rate remain unclear. Their similar genetic makeup probably contributes to this comorbidity. Methods Based on data obtained from the genome-wide association study of IBD and RA, we first assessed an overall genetic association by performing the linkage disequilibrium score regression (LDSC) analysis. Further, a local correlation analysis was performed by estimating the heritability in summary statistics. Next, the causality between the two diseases was analyzed by two-sample Mendelian randomization (MR). A genetic overlap was analyzed by the conditional/conjoint false discovery rate (cond/conjFDR) method.LDSC with specific expression of gene analysis was performed to identify related tissues between the two diseases. Finally, GWAS multi-trait analysis (MTAG) was also carried out. Results IBD and RA are correlated at the genomic level, both overall and locally. The MR results suggested that IBD induced RA. We identified 20 shared loci between IBD and RA on the basis of a conjFDR of <0.01. Additionally, we identified two tissues, namely spleen and small intestine terminal ileum, which were commonly associated with both IBD and RA. Conclusion Herein, we proved the presence of a polygenic overlap between the genetic makeup of IBD and RA and provided new insights into the genetic architecture and mechanisms underlying the high comorbidity between these two diseases.
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Affiliation(s)
- Guoling Cao
- Department of Anorectal Surgery, The People’s Hospital of Cangnan, Wenzhou, China
| | - Qinghua Luo
- Clinical Medical College, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Yunxiang Wu
- Department of Anorectal Surgery, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Guanghua Chen
- Department of Anorectal Surgery, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
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Sakalyte R, Stropuviene S, Jasionyte G, Bagdonaite L, Venalis A. Association between PYTPN22 rs2476601, VEGF rs833070, TNFAIP3 rs6920220 Polymorphisms and Risk for Rheumatoid Arthritis in Early Undifferentiated Arthritis Patients: A Pilot Study. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1824. [PMID: 37893542 PMCID: PMC10607990 DOI: 10.3390/medicina59101824] [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: 08/26/2023] [Revised: 10/05/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023]
Abstract
Background and Objectives: About 40% of early undifferentiated arthritis (UA) progresses to rheumatoid (RA) or other chronic arthritis. Novel diagnostic tools predicting the risk for this progression are needed to identify the patients who would benefit from early aggressive treatment. Evidence on the role of single-nucleotide polymorphisms (SNPs) in the development of RA has emerged. The aim of our study was to investigate the association between rs2476601, rs833070, and rs6920220 SNPs and UA progression to RA. Materials and Methods: Ninety-two UA patients were observed for 12 months. At study entry, demographic and clinical characteristics were recorded, musculoskeletal ultrasonography was performed, and blood samples were drawn to investigate levels of inflammatory markers, rheumatoid factor (RF), anti-citrullinated protein antibodies (anti-CCP)detect SNPs. After 12 months, UA outcomes were assessed, and patients were divided into two (RA and non-RA) groups. The association between the risk of progression to chronic inflammatory arthritis and analyzed SNPs was measured by computing odds ratios (OR). Results: After a 12-month follow-up, 27 (29.3%) patients developed RA, and 65 (70.7%) patients were assigned to the non-RA group. The arthritis of 21 patients (22.8%) from the non-RA group resolved completely, while the other 44 (47.2%) patients were diagnosed with another rheumatic inflammatory disease. The patients who developed RA had a significantly greater number of tender and swollen joints (p = 0.010 and p = 0.021 respectively) and were more frequently RF or anti-CCP (p < 0.001), and both RF and anti-CCP positive (p < 0.001) at the baseline as compared with the patients in the non-RA group. No significant association between rs2476601 (OR = 0.99, p = 0.98), rs833070 (OR = 1.0, p = 0.97), and rs6920220 (OR = 0.48, p = 0.13) polymorphisms and the risk of developing RA were found. Conclusions: No association between analyzed SNPs and a greater risk to progress from UA to RA was confirmed, although patients with rs6920220 AA + AG genotypes had fewer tender joints at the disease onset.
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Affiliation(s)
- Regina Sakalyte
- The Clinic of Rheumatology, Traumatology Orthopaedics and Reconstructive Surgery, Institute of Clinical Medicine of the Faculty of Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania
- State Research Institute Centre for Innovative Medicine, Santariškių g. 5, 08406 Vilnius, Lithuania
| | - Sigita Stropuviene
- The Clinic of Rheumatology, Traumatology Orthopaedics and Reconstructive Surgery, Institute of Clinical Medicine of the Faculty of Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania
- State Research Institute Centre for Innovative Medicine, Santariškių g. 5, 08406 Vilnius, Lithuania
| | - Gabija Jasionyte
- The Clinic of Rheumatology, Traumatology Orthopaedics and Reconstructive Surgery, Institute of Clinical Medicine of the Faculty of Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania
| | - Loreta Bagdonaite
- Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania
| | - Algirdas Venalis
- The Clinic of Rheumatology, Traumatology Orthopaedics and Reconstructive Surgery, Institute of Clinical Medicine of the Faculty of Vilnius University, M. K. Čiurlionio Str. 21, 03101 Vilnius, Lithuania
- State Research Institute Centre for Innovative Medicine, Santariškių g. 5, 08406 Vilnius, Lithuania
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Goh XT, Fong SK, Chai HC, Kee BP, Chua KH. The first association study of Protein Tyrosine Phosphatase, Non-Receptor Type 2 (PTPN2) gene polymorphisms in Malaysian patients with Crohn's disease. Gene 2022; 836:146661. [PMID: 35680018 DOI: 10.1016/j.gene.2022.146661] [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: 06/21/2021] [Revised: 04/21/2022] [Accepted: 06/03/2022] [Indexed: 11/20/2022]
Abstract
Crohn's disease (CD) is one of the sub-entities of Inflammatory Bowel Disease which causes chronic inflammation in the gastrointestinal tract. The development of CD has shown to have a strong genetic association. Therefore, the present study aimed to investigate the association between genetic polymorphisms in a susceptible locus of CD, the protein tyrosine phosphatase, non-receptor type 2 (PTPN2) gene and the development of CD in Malaysian patients. A total of 137 CD patients and 274 matched healthy controls were recruited in the present study. Genomic DNA was extracted from the venous blood of participants and five targeted single nucleotide polymorphisms (SNPs) in the PTPN2 gene were genotyped using polymerase chain reaction. Associations between the SNPs and CD were determined using Fisher's exact test and odds ratio. Findings showed that all five selected SNPs were not significantly associated with the development of CD in Malaysian patients, which was in contrast to studies among the European populations. Malaysian Chinese with rs487273 heterozygous G/T genotype was found to have a lower occurrence of CD (P-value = 0.0253; OR = 0.4396). Patients with rs2542152 homozygous T genotype were associated with stricturing behaviour (P-value = 0.0302, OR = 2.9944). The rs16939895 A/G genotype was associated with inflammation at the ileum site (P-value = 0.0387, OR = 2.2105)while homozygous G genotype was associated with colonic CD (P-value = 0.0164, OR = 2.3917). Functional studies of these SNPs are needed to evaluate their potential use as a biomarker for disease phenotypes among Asian patients.
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Affiliation(s)
- Xiang Ting Goh
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Suh Kuan Fong
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Hwa Chia Chai
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Boon Pin Kee
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Kek Heng Chua
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
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Chatterjee K, Dutta AK, Goel A, Aaron R, Balakrishnan V, Thomas A, John A, Jaleel R, David D, Kurien RT, Chowdhury SD, Simon EG, Joseph AJ, Premkumar P, Pulimood AB. Common polymorphisms of protein tyrosine phosphate non-receptor type 2 gene are not associated with risk of Crohn’s disease in Indian. World J Gastrointest Pathophysiol 2022; 13:114-123. [PMID: 36161231 PMCID: PMC9350595 DOI: 10.4291/wjgp.v13.i4.114] [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: 01/17/2022] [Revised: 03/18/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple genetic risk factors for Crohn’s disease (CD) have been identified. However, these observations are not consistent across different populations. The protein tyrosine phosphate non-receptor type 2 (PTPN2) gene plays a role in various aspects of host defense including epithelial barrier function, autophagy, and innate and adaptive immune response. Two common polymorphisms in the PTPN2 gene (rs2542151 and rs7234029) have been associated with risk of CD in Western countries.
AIM To evaluate the association of PTPN2 gene polymorphisms with risk of CD in Indian population.
METHODS We conducted a prospective case-control study. Patients with CD were recruited, and their clinical and investigation details were noted. Controls were patients without organic gastrointestinal disease or other comorbid illnesses. Two common polymorphisms in the PTPN2 gene (rs2542151 and rs7234029) were assessed. DNA was extracted from peripheral blood samples of cases and controls and target DNA was amplified using specific sets of primers. The amplified fragments were digested with restriction enzymes and the presence of polymorphism was detected by restriction fragment length polymorphism. The frequency of alleles was determined. The frequencies of genotypes and alleles were compared between cases and controls to look for significant differences.
RESULTS A total of 108 patients with CD (mean age 37.5 ± 12.7 years, females 42.6%) and 100 controls (mean age 39.9 ± 13.5 years, females 37%) were recruited. For the single nucleotide polymorphism (SNP) rs7234029, the overall frequency of G variant genotype (AG or GG) was noted to be significantly lower in the cases compared to controls (35.2% vs 50%, P = 0.05). For the SNP rs2542151, the overall frequency of G variant genotype (GT or GG) was noted to be similar in cases compared to controls (43.6% vs 47%, P = 0.73). There were no significant differences in minor allele (G) frequency for both polymorphisms between the cases and controls. Both the SNPs had no significant association with age of onset of illness, gender, disease location, disease behaviour, perianal disease, or extraintestinal manifestations of CD.
CONCLUSION Unlike observation form the West, polymorphisms in the PTPN2 gene (rs7234029 and rs2542151) are not associated with an increased risk of developing CD in Indian patients.
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Affiliation(s)
- Kaushik Chatterjee
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Amit Kumar Dutta
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Ashish Goel
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Rekha Aaron
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Vijayalekshmi Balakrishnan
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Ajith Thomas
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Anoop John
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Rajeeb Jaleel
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Deepu David
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - Reuben Thomas Kurien
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - SD Chowdhury
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Ebby George Simon
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - AJ Joseph
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - Prasanna Premkumar
- Departments of Biostatistics, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - Anna B Pulimood
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
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Dow CT, Alvarez BL. Mycobacterium paratuberculosis zoonosis is a One Health emergency. ECOHEALTH 2022; 19:164-174. [PMID: 35655048 PMCID: PMC9162107 DOI: 10.1007/s10393-022-01602-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 04/29/2022] [Indexed: 05/05/2023]
Abstract
A singular pathogen has been killing animals, contaminating food and causing an array of human diseases. Mycobacterium avium subspecies paratuberculosis (MAP) is the cause of a fatal enteric infectious disease called Johne's (Yo'-nees), a disorder mostly studied in ruminant animals. MAP is globally impacting animal health and imparting significant economic burden to animal agriculture. Confounding the management of Johne's disease is that animals are typically infected as calves and while commonly not manifesting clinical disease for years, they shed MAP in their milk and feces in the interval. This has resulted in a "don't test, don't tell" scenario for the industry resulting in greater prevalence of Johne's disease; furthermore, because MAP survives pasteurization, the contaminated food supply provides a source of exposure to humans. Indeed, greater than 90% of dairy herds in the US have MAP-infected animals within the herd. The same bacterium, MAP, is the putative cause of Crohn's disease in humans. Countries historically isolated from importing/exporting ruminant animals and free of Johne's disease subsequently acquired the disease as a consequence of opening trade with what proved to be infected animals. Crohn's disease in those populations became a lagging indicator of MAP infection. Moreover, MAP is associated with an increasingly long list of human diseases. Despite MAP scientists entreating regulatory agencies to designate MAP a "zoonotic agent," it has not been forthcoming. One Health is a global endeavor applying an integrative health initiative that includes the environment, animals and humans; One Health asserts that stressors affecting one affects all three. Recognizing the impact MAP has on animal and human health as well as on the environment, it is time for One Health, as well as other global regulatory agencies, to recognize that MAP is causing an insidious slow-motion tsunami of zoonosis and implement public health mitigation.
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Affiliation(s)
- Coad Thomas Dow
- Department of Ophthalmology and Visual Sciences, 9431 Wisconsin Institutes for Medical Research (WIMR), McPherson Eye Research Institute, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI, 53705, USA.
| | - Briana Lizet Alvarez
- Biology and Global Health, University of Wisconsin-Madison, 120 N Orchard St #1, Madison, WI, 53705, USA
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Ozana V, Hruska K, Sechi LA. Neglected Facts on Mycobacterium Avium Subspecies Paratuberculosis and Type 1 Diabetes. Int J Mol Sci 2022; 23:3657. [PMID: 35409018 PMCID: PMC8998319 DOI: 10.3390/ijms23073657] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 12/18/2022] Open
Abstract
Civilization factors are responsible for the increasing of human exposure to mycobacteria from environment, water, and food during the last few decades. Urbanization, lifestyle changes and new technologies in the animal and plant industry are involved in frequent contact of people with mycobacteria. Type 1 diabetes is a multifactorial polygenic disease; its origin is conditioned by the mutual interaction of genetic and other factors. The environmental factors and certain pathogenetic pathways are shared by some immune mediated chronic inflammatory and autoimmune diseases, which are associated with triggers originating mainly from Mycobacterium avium subspecies paratuberculosis, an intestinal pathogen which persists in the environment. Type 1 diabetes and some other chronic inflammatory diseases thus pose the global health problem which could be mitigated by measures aimed to decrease the human exposure to this neglected zoonotic mycobacterium.
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Affiliation(s)
- Veronika Ozana
- Faculty of Pharmacy, Masaryk University, 612 00 Brno, Czech Republic;
- Orlova Department, Karvina-Raj Hospital, 734 01 Karvina, Czech Republic
| | - Karel Hruska
- Veterinary Research Institute, 612 00 Brno, Czech Republic
- Institute for Research and Education, 621 00 Brno, Czech Republic
| | - Leonardo A. Sechi
- Dipartimento di Scienze Biomediche, Sezione di Microbiologia Sperimentale e Clinica, Università degli Studi di Sassari, 07100 Sassari, Italy
- AOU Sassari, UC Microbiologia e Virologia, 07100 Sassari, Italy
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Donda KT, Torres BA, Khashu M, Maheshwari A. Single Nucleotide Polymorphisms in Neonatal Necrotizing Enterocolitis. Curr Pediatr Rev 2022; 18:197-209. [PMID: 35040407 DOI: 10.2174/1573396318666220117091621] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/10/2021] [Accepted: 11/16/2021] [Indexed: 11/22/2022]
Abstract
The etiopathogenesis of necrotizing enterocolitis (NEC) remains unclear, but increasing information suggests that the risk and severity of NEC may be influenced by single nucleotide polymorphisms in many genes. In this article, we have reviewed gene variations that have either been specifically identified in NEC or have been noted in other inflammatory bowel disorders with similar histopathological abnormalities. We present evidence from our own peer-reviewed laboratory studies and data from an extensive literature search in the databases PubMed, EMBASE, and Scopus. To avoid bias in the identification of existing studies, search keywords were short-listed both from our own studies and from PubMed's Medical Subject Heading (MeSH) thesaurus.
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Affiliation(s)
- Keyur T Donda
- Department of Pediatrics, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA
| | - Benjamin A Torres
- Department of Pediatrics, University of South Florida Health Morsani College of Medicine, Tampa, FL, USA
| | - Minesh Khashu
- Poole Hospital NHS Foundation Trust and Bournemouth University, Poole, United Kingdom
| | - Akhil Maheshwari
- Department of Pediatrics, Johns Hopkins University, Baltimore, ML, USA
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Vilas Boas L, Bezerra Sobrinho C, Rahal D, Augusto Capellari C, Skare T, Nisihara R. Antinuclear antibodies in patients with endometriosis: A cross-sectional study in 94 patients. Hum Immunol 2021; 83:70-73. [PMID: 34686383 DOI: 10.1016/j.humimm.2021.10.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/07/2021] [Accepted: 10/07/2021] [Indexed: 01/12/2023]
Abstract
Markers of autoimmunity, such as autoantibodies, have been found in patients with endometriosis. These include the antinuclear antibodies (ANA). We aimed to evaluate the prevalence of ANA in a sample of patients with endometriosis and its possible clinical associations. Ninety-four patients with endometriosis and 91 controls were studied for ANA and extractable nuclear antigen (ENA; anti-Ro, anti-La, anti-Sm, and anti-RNP) profiles and anti-dsDNA. Epidemiological, clinical, and staging data in endometriosis were obtained. Patients with autoimmune disorders were excluded. Patients with endometriosis had a 21.2% prevalence of positive ANA vs. 5.4% in controls (P = 0.001). The ENA profile and anti-dsDNA were negative. Patients with positive ANA were more asymptomatic (P = 0.03) and had less dysmenorrhea. No associations with disease duration, patient age, or endometriosis stage were found. We found a high prevalence of positive ANA in patients with endometriosis. The presence of this autoantibody may be linked to a milder clinical expression of the disease.
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Affiliation(s)
- Laura Vilas Boas
- Mackenzie Evangelical School of Medicine Paraná, Curitiba, Brazil
| | | | - Danilo Rahal
- Post Graduate Program in Gynecology and Obstetrics, Federal University of Paraná, Curitiba, Brazil
| | - Cesar Augusto Capellari
- Post Graduate Program in Gynecology and Obstetrics, Federal University of Paraná, Curitiba, Brazil
| | - Thelma Skare
- Mackenzie Evangelical School of Medicine Paraná, Curitiba, Brazil
| | - Renato Nisihara
- Mackenzie Evangelical School of Medicine Paraná, Curitiba, Brazil; Post Graduate Program in Gynecology and Obstetrics, Federal University of Paraná, Curitiba, Brazil.
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Epidemiology and genetics of granulomatosis with polyangiitis. Rheumatol Int 2021; 41:2069-2089. [PMID: 34635927 DOI: 10.1007/s00296-021-05011-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 09/20/2021] [Indexed: 01/09/2023]
Abstract
Granulomatosis with polyangiitis (GPA) previously known as Wegener's granulomatosis (WG) is a rare rheumatic disease affecting subjects of all ages. Prevalence and incidence of this systemic disease greatly varies across different ethnic groups. GPA is the commonest form of ANCA-associated vasculitis (AAV) with PR3 positivity among 85-95% of the cases. Scientific investigations of GPA is warranted because its severity, clinical heterogeneity, fast disease manifestation and end-organ damage. The etiology of GPA is still unknown. Major role of HLA and non-HLA genes with immune functions were identified, however, very limited replication was observed in different ethnic populations. In the present review, we have discussed the updates on the global epidemiology and contribution of HLA and major non-HLA genes/loci in GPA. We have also highlighted the cross disease association of GPA associated genes that may help in better disease management and predictive medicine. We proposed that high-resolution HLA typing and development of genetic risk model would help in early disease diagnosis and understanding the prognosis.
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Shaw AM, Qasem A, Naser SA. Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn's Disease and Rheumatoid Arthritis. Int J Mol Sci 2021; 22:8883. [PMID: 34445589 PMCID: PMC8396355 DOI: 10.3390/ijms22168883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 12/02/2022] Open
Abstract
Crohn's Disease (CD) and Rheumatoid Arthritis (RA) share some single nucleotide polymorphisms (SNPs) in protein tyrosine phosphatase non-receptor types 2 and 22 (PTPN2/22). Recently, we reported that clinical samples from CD and RA patients associated with PTPN2:rs478582 or PTPN22:rs2476601 genotypes were linked to overactive immune response and exacerbation of inflammation. Here, we investigated in vitro the effects of these SNPs in Jurkat T-cells using CRISPR-Cas9. All cells were evaluated for PTPN22/22 loss of function and effects on cell response. We measured gene expression via RT-qPCR and cytokines by ELISA. We also measured cell proliferation using a BrdU labeling proliferation ELISA, and T-cell activation using CD-25 fluorescent immunostaining. In PTPN2 SNP-edited cells, PTPN2 expression decreased by 3.2-fold, and proliferation increased by 10.2-fold compared to control. Likewise, expression of PTPN22 decreased by 2.4-fold and proliferation increased by 8.4-fold in PTPN22 SNP-edited cells. IFN-γ and TNF-α secretions increased in both edited cell lines. CD25 expression (cell activation) was 80.32% in PTPN2 SNP-edited cells and 85.82% in PTPN22 SNP-edited cells compared to 70.48% in unedited Jurkat T-cells. Treatment of PTPN2 and PTPN22-edited cells with a maximum 20 μM spermidine restored PTPN2/22 expression and cell response including cell proliferation, activation, and cytokines secretion. Most importantly, the effect of spermidine on edited cells restored normal expression and secretion of IFN-γ and TNF-α. The data clearly demonstrated that edited SNPs in PTPN2 or PTPN22 were associated with reduced gene expression, which resulted in an increase in cell proliferation and activation and overactive immune response. The data validated our earlier observations in CD and RA clinical samples. Surprisingly, spermidine restored PTPN2/22 expression in edited Jurkat T-cells and the consequent beneficial effect on cell response and inflammation. The study supports the use of polyamines dietary supplements for management of CD and in RA patients.
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MESH Headings
- Arthritis, Rheumatoid/genetics
- CRISPR-Cas Systems
- Crohn Disease/genetics
- Gene Expression Regulation, Leukemic/drug effects
- Genetic Predisposition to Disease
- Humans
- Jurkat Cells
- Leukemia, T-Cell/drug therapy
- Leukemia, T-Cell/genetics
- Leukemia, T-Cell/pathology
- Lymphocyte Activation
- Polymorphism, Single Nucleotide
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/antagonists & inhibitors
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/antagonists & inhibitors
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism
- Spermidine/pharmacology
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Affiliation(s)
| | | | - Saleh A. Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4110 Libra Drive, Orlando, FL 32816, USA; (A.M.S.); (A.Q.)
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12
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Tizaoui K, Terrazzino S, Cargnin S, Lee KH, Gauckler P, Li H, Shin JI, Kronbichler A. The role of PTPN22 in the pathogenesis of autoimmune diseases: A comprehensive review. Semin Arthritis Rheum 2021; 51:513-522. [PMID: 33866147 DOI: 10.1016/j.semarthrit.2021.03.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 01/16/2021] [Accepted: 03/03/2021] [Indexed: 02/07/2023]
Abstract
The incidence of autoimmune diseases is increasing worldwide, thus stimulating studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors. Genetic association studies have shown the PTPN22 gene as a shared genetic risk factor with implications in multiple autoimmune disorders. By encoding a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems, the PTPN22 gene may have a fundamental role in the development of immune dysfunction. PTPN22 polymorphisms are associated with rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and many other autoimmune conditions. In this review, we discuss the progress in our understanding of how PTPN22 impacts autoimmunity in both humans and animal models. In addition, we highlight the pathogenic significance of the PTPN22 gene, with particular emphasis on its role in T and B cells, and its function in innate immune cells, such as monocytes, dendritic and natural killer cells. We focus particularly on the complexity of PTPN22 interplay with biological processes of the immune system. Findings highlight the importance of studying the function of disease-associated PTPN22 variants in different cell types and open new avenues of investigation with the potential to drive further insights into mechanisms of PTPN22. These new insights will reveal important clues to the molecular mechanisms of prevalent autoimmune diseases and propose new potential therapeutic targets.
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Affiliation(s)
- Kalthoum Tizaoui
- Department of Basic Sciences, Division of Histology and Immunology, Faculty of Medicine Tunis, Tunis El Manar University, Tunis 1068, Tunisia
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Philipp Gauckler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
| | - Han Li
- University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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13
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Keewan E, Naser SA. MiR-146a rs2910164 G > C polymorphism modulates Notch-1/IL-6 signaling during infection: a possible risk factor for Crohn's disease. Gut Pathog 2020; 12:48. [PMID: 33072191 PMCID: PMC7557229 DOI: 10.1186/s13099-020-00387-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/03/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND MiR-146a, an effector mediator, targets Notch-1 and regulates the innate and adaptive immune systems response. Recently, we reported that Notch-1 signaling plays a key role in macrophage polarization and response during infection. We employed Mycobacterium avium paratuberculosis (MAP) infection in Crohn's disease (CD) as a model to demonstrate the role of Notch-1/IL-6 signaling on MCL-1 based apoptosis and intracellular MAP infection and persistence. This study was designed to investigate the impact of polymorphisms in miR146a on the immune response and infection in our MAP-CD model. METHODS We determined the incidence of miR-146a rs2910164 G > C in 42 blood samples from clinical CD patients and controls. We also measured the effect of rs2910164 on expression of Notch-1 and IL-6, and plasma IL-6 protein levels in our study group. Finally, we analyzed the blood samples for MAP DNA and studied any correlation with miR-146a polymorphism. Samples were analyzed for statistical significance using unpaired tow-tailed t-test, unpaired two-tailed z-score and odds ratio. P < 0.05 considered significant. RESULTS MiR-146a rs2910164 GC was detected at a higher incidence in CD (52.6%) compared to healthy controls (21.7%) rs2910164 GC Heterozygous polymorphism upregulated Notch-1 and IL-6, by 0.9 and 1.7-fold, respectively. As expected, MAP infection was detected more in CD samples (63%) compared to healthy controls (9%). Surprisingly, MAP infection was detected at a higher rate in samples with rs2910164 GC (67%) compared to samples with normal genotype (33%). CONCLUSIONS The data clearly associates miR-146a rs2910164 GC with an overactive immune response and increases the risk to acquire infection. The study is even more relevant now in our efforts to understand susceptibility to SARS-CoV-2 infection and the development of COVID-19. This study suggests that genetic variations among COVID-19 patients may predict who is at a higher risk of acquiring infection, developing exacerbating symptoms, and possibly death. A high scale study with more clinical samples from different disease groups is planned.
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Affiliation(s)
- Esra’a Keewan
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4110 Libra drive, Orlando, FL 32816 USA
| | - Saleh A. Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4110 Libra drive, Orlando, FL 32816 USA
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14
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Niechcial A, Butter M, Manz S, Obialo N, Bäbler K, van der Lely L, Lang S, Gottier C, McCole DF, Scharl M, Spalinger MR. Presence of PTPN2 SNP rs1893217 Enhances the Anti-inflammatory Effect of Spermidine. Inflamm Bowel Dis 2020; 26:1038-1049. [PMID: 32031616 PMCID: PMC7931847 DOI: 10.1093/ibd/izaa013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND The single nucleotide polymorphism (SNP) rs1893217 within the gene locus encoding PTPN2 represents a risk factor for inflammatory bowel disease (IBD). Our previous work demonstrated reduced PTPN2 activity and subsequently increased inflammatory signaling upon presence of SNP rs1893217. The naturally occurring polyamine spermidine reduces pro-inflammatory signaling via induction of PTPN2 activity; however, the effect of SNP rs1893217 on the anti-inflammatory potential of spermidine is still unknown. Here, we investigated how presence of SNP rs1893217 affects treatment efficacy of spermidine and whether it might serve as a potential biomarker for spermidine treatment. METHODS Human T84 (wild-type [WT] for PTPN2 SNP rs1893217) and HT29 (heterozygous for PTPN2 SNP rs1893217) intestinal epithelial cells (IECs) were treated with several polyamines from the putrescine-spermidine pathway. T84 and HT29 IECs, THP-1 monocytes (WT and transfected with a lentiviral vector expressing PTPN2 SNP rs1893217) and genotyped, patient-derived peripheral blood mononuclear cells were challenged with IFN-γ and/or spermidine. RESULTS Among the analyzed polyamines, spermidine was the most efficient activator of PTPN2 phosphatase activity, regardless of the PTPN2 genotype. Spermidine suppressed IFN-γ-induced STAT1 and STAT3 phosphorylation, along with decreased mRNA expression of ICAM-1, NOD2, and IFNG in IECs and monocytes. Of note, these effects were clearly more pronounced when the disease-associated PTPN2 C-variant in SNP rs1893217 was present. CONCLUSIONS Our data demonstrate that spermidine is the most potent polyamine in the putrescine-spermine axis for inducing PTPN2 enzymatic activity. The anti-inflammatory effect of spermidine is potentiated in the presence of SNP rs1893217, and this SNP might thus be a useful biomarker for possible spermidine-treatment in IBD patients.
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Affiliation(s)
- Anna Niechcial
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Matthias Butter
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Salomon Manz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Nicole Obialo
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Katharina Bäbler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Lisa van der Lely
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Claudia Gottier
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Declan F McCole
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland,Division of Biomedical Sciences, School of Medicine, University of Riverside, Riverside, California, USA,Address correspondence to: Dr. Michael Scharl, Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland., E-mail:
| | - Marianne R Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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15
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Sharp RC, Naser ES, Alcedo KP, Qasem A, Abdelli LS, Naser SA. Development of multiplex PCR and multi-color fluorescent in situ hybridization ( m-FISH) coupled protocol for detection and imaging of multi-pathogens involved in inflammatory bowel disease. Gut Pathog 2018; 10:51. [PMID: 30534203 PMCID: PMC6280354 DOI: 10.1186/s13099-018-0278-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 11/29/2018] [Indexed: 12/28/2022] Open
Abstract
Background Several pathogens have been debated to play a role in inflammatory bowel disease (IBD) including Crohn's disease (CD). None of these pathogens have been investigated together in same clinical samples. We developed a multiplex PCR and multi-color fluorescent in situ hybridization (m-FISH) protocols for simultaneous detection of CD-associated pathogens including Mycobacterium avium subspecies paratuberculosis (MAP), Klebsiella pneumoniae, and adherent-invasive Escherichia coli strain LF82. Methods The multiplex PCR is based on 1-h DNAzol® extraction protocol modified for rapid extraction of bacterial DNA from culture, blood, and intestinal biopsies. Oligonucleotide primers sequences unique to these pathogens were evaluated individually and in combinations using bioinformatics and experimental approaches. m-FISH was based on fluorescent-tagged oligonucleotides and confocal scanning laser microscopy (CSLM). Results Following several attempts, the concentration of the oligonucleotide primers and DNA templates and the PCR annealing temperatures were optimized. Multiplex PCR analyses revealed excellent amplification signal in trials where a single primer set and combinations of two and three primers sets were tested against a mixture of DNA from three different bacteria or a mixture of three bacterial cultures mixed in one tube before DNA extraction. Slides with individual and mixtures of bacterial cultures and intestinal tissue sections from IBD patients were tested by m-FISH and the CSLM images verified multiplex PCR results detected on 3% agarose gel. Conclusion We developed a 4-h multiplex PCR protocol, which was validated by m-FISH images, capable of detecting up to four genes from major pathogens associated with CD. The new protocol should serve as an excellent tool to support efforts to study multi-pathogens involved in CD and other autoimmune disease.
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Affiliation(s)
- Robert C Sharp
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Ebraheem S Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Karel P Alcedo
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Ahmad Qasem
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Latifa S Abdelli
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
| | - Saleh A Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 4110 Libra Drive, Orlando, FL USA
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16
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Sanchez-Blanco C, Clarke F, Cornish GH, Depoil D, Thompson SJ, Dai X, Rawlings DJ, Dustin ML, Zamoyska R, Cope AP, Purvis HA. Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses. J Autoimmun 2018; 94:45-55. [PMID: 30054208 PMCID: PMC6198113 DOI: 10.1016/j.jaut.2018.07.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/13/2018] [Accepted: 07/13/2018] [Indexed: 02/07/2023]
Abstract
A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22−/− T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22−/− T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22−/− T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22−/− bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.
PTPN22R620W is one of the strongest risk factors for multiple autoimmune diseases. In Ptpn22−/− and Ptpn22R619W mice IFNy+ Th1 cells preferentially and significantly expand with age or following immune challenge. PTPN22 negatively regulates IFNγ+ Th1 cells by T-cell and dendritic cell LFA-1-ICAM-1 dependent mechanisms. PTPN22 negatively regulates LFA-1 induced Th1 cells enhancing T-cell LFA-1 clustering and immune synapse formation. Repeated stimulation of T-cells with Ptpn22−/− BMDC enhances Th1 responses.
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Affiliation(s)
- Cristina Sanchez-Blanco
- Centre for Inflammation Biology and Cancer Immunology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Fiona Clarke
- Centre for Inflammation Biology and Cancer Immunology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Georgina H Cornish
- Centre for Inflammation Biology and Cancer Immunology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - David Depoil
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Stephen J Thompson
- Centre for Inflammation Biology and Cancer Immunology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Xuezhi Dai
- Seattle Children's Research Institute, Departments of Pediatrics and Immunology, University of Washington School of Medicine, Seattle, WA, USA
| | - David J Rawlings
- Seattle Children's Research Institute, Departments of Pediatrics and Immunology, University of Washington School of Medicine, Seattle, WA, USA
| | - Michael L Dustin
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Rose Zamoyska
- Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
| | - Andrew P Cope
- Centre for Inflammation Biology and Cancer Immunology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Harriet A Purvis
- Centre for Inflammation Biology and Cancer Immunology, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
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Cao BL, Qasem A, Sharp RC, Abdelli LS, Naser SA. Systematic review and meta-analysis on the association of tuberculosis in Crohn’s disease patients treated with tumor necrosis factor-α inhibitors (Anti-TNFα). World J Gastroenterol 2018; 24:2764-2775. [PMID: 29991880 PMCID: PMC6034143 DOI: 10.3748/wjg.v24.i25.2764] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 04/30/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To perform a meta-analysis on the risk of developing Mycobacterium tuberculosis (TB) infection in Crohn’s disease (CD) patients treated with tumor necrosis factor-alpha (TNFα) inhibitors.
METHODS A meta-analysis of randomized, double-blind, placebo-controlled trials of TNFα inhibitors for treatment of CD in adults was conducted. Arcsine transformation of TB incidence was performed to estimate risk difference. A novel epidemiologically-based correction (EBC) enabling inclusions of studies reporting no TB infection cases in placebo and treatment groups was developed to estimate relative odds.
RESULTS Twenty-three clinical trial studies were identified, including 5669 patients. Six TB infection cases were reported across 5 studies, all from patients receiving TNFα inhibitors. Eighteen studies reported no TB infection cases in placebo and TNFα inhibitor treatment arms. TB infection risk was significantly increased among patients receiving TNFα inhibitors, with a risk difference of 0.028 (95%CI: 0.0011-0.055). The odds ratio was 4.85 (95%CI: 1.02-22.99) with EBC and 5.85 (95%CI: 1.13-30.38) without EBC.
CONCLUSION The risk of TB infection is higher among CD patients receiving TNFα inhibitors. Understanding the immunopathogenesis of CD is crucial, since using TNFα inhibitors in these patients could favor mycobacterial infections, particularly Mycobacterium avium subspecies paratuberculosis, which ultimately could worsen their clinical condition.
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Affiliation(s)
- Brent L Cao
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
| | - Ahmad Qasem
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
| | - Robert C Sharp
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
| | - Latifa S Abdelli
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
| | - Saleh A Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
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