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Folci M, Ramponi G, Solitano V, Brunetta E. Serum ANCA as Disease Biomarkers: Clinical Implications Beyond Vasculitis. Clin Rev Allergy Immunol 2022; 63:107-123. [PMID: 34460071 DOI: 10.1007/s12016-021-08887-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2021] [Indexed: 01/13/2023]
Abstract
Usually associated with autoimmune diseases, anti-neutrophil cytoplasmic antibodies are also detected in other conditions, such as infections, malignancies, and after intake of certain drugs. Even if the mechanisms of production and their pathogenic role have not been fully elucidated yet, ANCA are widely recognized as a clinically alarming finding due to their association with various disorders. While ANCA target several autoantigens, proteinase-3, and myeloperoxidase are the ones proved to be most frequently related to chronic inflammation and tissue damage in murine models. Albeit these autoantibodies could be present as an isolated observation without any implications, ANCA are frequently used in clinical practice to guide the diagnosis in a suspect of small vessel vasculitis. Conditions that should prompt the clinician to test ANCA status range from various forms of lung disease to renal or peripheral nervous system impairment. ANCA positivity in the presence of an autoimmune disease, especially rheumatoid arthritis, or connective tissue diseases, is frequently correlated with more clinical complications and treatment inefficacy, even in the absence of signs of vasculitis. For this reason, it has been postulated that ANCA could represent the final expression of an immune dysregulation rather than a pathogenic event responsible for organs damage. Recently, it has also been proposed that ANCA specificity (PR3 or MPO) could possibly define ANCA-associated vasculitides better than clinical phenotype. This review aims at summarizing the latest advancements in the field of ANCA study and clinical interpretation.
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Affiliation(s)
- Marco Folci
- Humanitas Clinical and Research Center - IRCCS, Milan, Italy.
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.
| | | | - Virginia Solitano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Enrico Brunetta
- Humanitas Clinical and Research Center - IRCCS, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Rolhion N. A milestone in screening for adherent-invasive E. coli colonization in patients with Crohn's disease? United European Gastroenterol J 2021; 9:995-996. [PMID: 34653319 PMCID: PMC8598956 DOI: 10.1002/ueg2.12162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Affiliation(s)
- Nathalie Rolhion
- Gastroenterology DepartmentINSERMCRSAAP‐HPCentre de Recherche Saint‐AntoineSaint Antoine HospitalSorbonne UniversitéParisFrance
- Paris Center for Microbiome Medicine (PaCeMM) FHUParisFrance
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Vetter M, Neurath MF, Atreya R. [Crohn's disease - use of biomarkers in general practice]. MMW Fortschr Med 2017; 159:63-68. [PMID: 28224516 DOI: 10.1007/s15006-017-9279-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Affiliation(s)
- Marcel Vetter
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Erlangen, Deutschland
| | | | - Raja Atreya
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Ulmenweg 18, D-91054, Erlangen, Deutschland.
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4
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Carbonnel F, Soularue E, Coutzac C, Chaput N, Mateus C, Lepage P, Robert C. Inflammatory bowel disease and cancer response due to anti-CTLA-4: is it in the flora? Semin Immunopathol 2017; 39:327-331. [PMID: 28093620 DOI: 10.1007/s00281-016-0613-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 12/06/2016] [Indexed: 12/13/2022]
Abstract
Checkpoint inhibitors blocking CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have transfigured our cancer treatment paradigm. However, these drugs can induce immune-related adverse events that share clinical and pathological characteristics with immune-mediated diseases. One of the most severe immune-related adverse event observed with anti-CTLA-4 is an enterocolitis that mirrors naturally occurring inflammatory bowel disease. This paper reviews the clinical, immunological, and microbiota data associated with the immune-related enterocolitis induced by the cancer immunotherapy blocking CTLA-4, ipilimumab. A parallel analysis of the mechanisms underlying inflammatory bowel diseases on the one hand, and anti-CTLA-4-induced colitis on the other hand, stresses the crucial role of the gut microbiota and of resident Treg in the genesis of both iatrogenic and spontaneous inflammatory bowel diseases.
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Affiliation(s)
- Franck Carbonnel
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France
- Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, F-94276, France
| | - Emilie Soularue
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France
- Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre, F-94276, France
| | - Clélia Coutzac
- Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, and CNRS-UMS 3655 and INSERM-US23, Villejuif, F-94805, France
| | - Nathalie Chaput
- Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, and CNRS-UMS 3655 and INSERM-US23, Villejuif, F-94805, France
- Université Paris-Sud, Faculté de pharmacie, Chatenay-Malabry, Châtenay-Malabry, F-92296, France
| | - Christine Mateus
- Gustave Roussy, Département de Médecine, Service de Dermatologie, et Université Paris-Sud Villejuif, Villejuif, F-94805, France
| | - Patricia Lepage
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France
| | - Caroline Robert
- Gustave Roussy, Département de Médecine, Service de Dermatologie, et Université Paris-Sud Villejuif, Villejuif, F-94805, France.
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Rizzetto L, De Filippo C, Cavalieri D. Richness and diversity of mammalian fungal communities shape innate and adaptive immunity in health and disease. Eur J Immunol 2014; 44:3166-81. [DOI: 10.1002/eji.201344403] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 09/22/2014] [Accepted: 09/23/2014] [Indexed: 02/06/2023]
Affiliation(s)
- Lisa Rizzetto
- Research and Innovation Centre; Fondazione Edmund Mach; San Michele all'Adige TN Italy
| | - Carlotta De Filippo
- Research and Innovation Centre; Fondazione Edmund Mach; San Michele all'Adige TN Italy
| | - Duccio Cavalieri
- Research and Innovation Centre; Fondazione Edmund Mach; San Michele all'Adige TN Italy
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Cohen-Kedar S, Baram L, Elad H, Brazowski E, Guzner-Gur H, Dotan I. Human intestinal epithelial cells respond to β-glucans via Dectin-1 and Syk. Eur J Immunol 2014; 44:3729-40. [PMID: 25251945 DOI: 10.1002/eji.201444876] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 09/04/2014] [Accepted: 09/22/2014] [Indexed: 12/14/2022]
Abstract
Intestinal epithelial cells (IECs) are the first to encounter luminal antigens and may be involved in intestinal immune responses. Fungi are important components of the intestinal microflora. The potential role of fungi, and in particular their cell wall component β-glucan, in modulating human intestinal epithelial responses is still unclear. Here we examined whether human IECs are capable of recognizing and responding to β-glucans, and the potential mechanisms of their activation. We show that human IECs freshly isolated from surgical specimens, and the human IEC lines HT-29 and SW480, express the β-glucan receptor Dectin-1. The β-glucan-consisting glycans curdlan and zymosan stimulated IL-8 and CCL2 secretion by IEC lines. This was significantly inhibited by a Dectin-1 blockade using its soluble antagonist laminarin. Spleen tyrosine kinase (Syk), a signaling mediator of Dectin-1 activation, is expressed in human IECs. β-glucans and Candida albicans induced Syk phosphorylation, and Syk inhibition significantly decreased β-glucan-induced chemokine secretion from IECs. Thus, IECs may respond to β-glucans by the secretion of pro-inflammatory chemokines in a Dectin-1- and Syk-dependent pathway, via receptors and a signaling pathway described to date only for myeloid cells. These findings highlight the importance of fungi-IEC interactions in intestinal inflammation.
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Affiliation(s)
- Sarit Cohen-Kedar
- Inflammatory Bowel Diseases Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Serum anti-glycan antibodies in paediatric-onset Crohn's disease: association with disease phenotype and diagnostic accuracy. GASTROENTEROLOGY REVIEW 2014; 9:232-41. [PMID: 25276255 PMCID: PMC4178050 DOI: 10.5114/pg.2014.45106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 01/05/2014] [Accepted: 01/20/2014] [Indexed: 01/08/2023]
Abstract
Introduction Antibodies reacting with various microbial epitopes have been described in inflammatory bowel disease (IBD) and are associated with a specific diagnosis and clinical presentation. Aim To evaluate the profile of new anti-glycan antibodies, their potential association with disease phenotype and diagnostic accuracy in paediatric Crohn's disease (CD). Material and methods Blood samples from 134 paediatric IBD patients (109 CD, 25 ulcerative colitis (UC)) and 67 controls were blindly analysed for anti-Saccharomyces cerevisiae (ASCA), anti-chitobioside carbohydrate (ACCA), anti-laminaribioside carbohydrate (ALCA), and anti-mannobioside carbohydrate (AMCA) antibodies using commercially available assays. The serological response to glycans was correlated with clinical disease characteristics. Results At least one of the tested anti-glycan antibodies was present in 75% of CD patients. Despite the high frequency of reactivity to glycan epitopes, a limited overlap of serological markers was observed. In total, 49% of ASCA-negative patients presented with one of the following: ACCA, ALCA, or AMCA. The occurrence of one antibody from the anti-glycan panel was independently associated with complicated disease phenotype and ileocolonic disease location. A higher level of immune response as assessed by the quartile sum scores for ACCA, ALCA, and AMCA was linked with older age at diagnosis (10–17 years) and ileocolonic disease location. The ASCA had the greatest accuracy for diagnosis and differentiation of CD. Conclusions Qualitative and quantitative serologicalal response to glycan epitopes was associated with distinct clinical presentation in paediatric CD patients. This raises the possibility for the use of these markers to differentiate subgroups of CD patients with more sever clinical presentation. The ASCA was the most accurate serological marker for CD; however, testing for the new anti-glycan antibodies may constitute an adjunctive tool in a specific group of patients to aid in the differentiation of CD with absent ASCA from ulcerative colitis.
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Saadah OI, Al-Mughales JA. Serological markers of inflammatory bowel disease in children from the Western region of Saudi Arabia. Arab J Gastroenterol 2013; 14:78-82. [PMID: 23820506 DOI: 10.1016/j.ajg.2013.05.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 12/28/2012] [Accepted: 05/10/2013] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND STUDY AIMS Serological markers including peri-nuclear anti-neutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) have been reported in relation to inflammatory bowel disease (IBD). The aim of this study was to ascertain the prevalence and diagnostic accuracy of pANCA and ASCA antibodies in Saudi children with IBD. PATIENTS AND METHODS A retrospective case-control study of children with IBD seen at King Abdulaziz University Hospital, Jeddah, between September 2002 and February 2012. RESULTS The study included 131 patients with IBD (86 Crohn's disease (CD) and 45 ulcerative colitis (UC)) and 67 non-IBD control subjects. Females comprised 51% of CD, 60% of UC and 52% of non-IBD controls. The mean age was 10.7±5.2years for CD, 8.9±5years for UC, and 11.2±6.8years for the non-IBD controls. Positive ASCA-IgA and ASCA-IgG were detected in 35.8% and 35% of CD patients and in 5.8% and 3.7% of the non-IBD controls, respectively. The pANCA was detected in 28.9% of UC patients and in none of the non-IBD controls. The pANCA recognised the myeloperoxidase (MPO) antibody in 36.4% of the patients with UC. No significant difference in the frequency of pANCA between extensive disease and disease limited to the rectosigmoid colon (p=0.48), and no significant difference in the ASCAs antibodies in patients with or without involvement of the terminal ileum (p=0.81). CONCLUSION The prevalence of ASCA and pANCA antibodies was low in Saudi children with IBD. Therefore, it may not be useful as a screening tool for IBD but it may be employed to aid the diagnosis in clinically suspected cases.
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Affiliation(s)
- Omar I Saadah
- Department of Paediatrics, Division of Gastroenterology, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia.
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9
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Huffnagle GB, Noverr MC. The emerging world of the fungal microbiome. Trends Microbiol 2013; 21:334-41. [PMID: 23685069 DOI: 10.1016/j.tim.2013.04.002] [Citation(s) in RCA: 396] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 03/27/2013] [Accepted: 04/15/2013] [Indexed: 02/06/2023]
Abstract
The study of the fungal microbiota ('mycobiome') is a new and rapidly emerging field that lags behind our understanding of the bacterial microbiome. Every human has fungi as part of their microbiota, but the total number of fungal cells is orders of magnitude smaller than that of the bacterial microbiota. However, the impact of the mycobiome on human health is significant, especially as a reservoir for blooms of pathogenic microbes when the host is compromised and as a potential cofactor in inflammatory diseases and metabolic disorders.
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Affiliation(s)
- Gary B Huffnagle
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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10
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Iskandar HN, Ciorba MA. Biomarkers in inflammatory bowel disease: current practices and recent advances. Transl Res 2012; 159:313-25. [PMID: 22424434 PMCID: PMC3308116 DOI: 10.1016/j.trsl.2012.01.001] [Citation(s) in RCA: 146] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Revised: 12/30/2011] [Accepted: 01/03/2012] [Indexed: 02/07/2023]
Abstract
Crohn's disease and ulcerative colitis represent the two main forms of the idiopathic chronic inflammatory bowel diseases (IBD). Currently available blood and stool based biomarkers provide reproducible, quantitative tools that can complement clinical assessment to aid clinicians in IBD diagnosis and management. C-reactive protein and fecal based leukocyte markers can help the clinician distinguish IBD from noninflammatory diarrhea and assess disease activity. The ability to differentiate between forms of IBD and predict risk for disease complications is specific to serologic tests including antibodies against Saccharomyces cerevisiae and perinuclear antineutrophil cytoplasmic proteins. Advances in genomic, proteomic, and metabolomic array based technologies are facilitating the development of new biomarkers for IBD. The discovery of novel biomarkers, which can correlate with mucosal healing or predict long-term disease course has the potential to significantly improve patient care. This article reviews the uses and limitations of currently available biomarkers and highlights recent advances in IBD biomarker discovery.
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Affiliation(s)
- Heba N Iskandar
- Division of Gastroenterology, Washington University in Saint Louis School of Medicine, Saint Louis, MO, USA
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11
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Hisamatsu T, Okamoto S, Hashimoto M, Muramatsu T, Andou A, Uo M, Kitazume MT, Matsuoka K, Yajima T, Inoue N, Kanai T, Ogata H, Iwao Y, Yamakado M, Sakai R, Ono N, Ando T, Suzuki M, Hibi T. Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease. PLoS One 2012; 7:e31131. [PMID: 22303484 PMCID: PMC3269436 DOI: 10.1371/journal.pone.0031131] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 01/03/2012] [Indexed: 12/16/2022] Open
Abstract
Background Inflammatory bowel disease (IBD) is a chronic intestinal disorder that is associated with a limited number of clinical biomarkers. In order to facilitate the diagnosis of IBD and assess its disease activity, we investigated the potential of novel multivariate indexes using statistical modeling of plasma amino acid concentrations (aminogram). Methodology and Principal Findings We measured fasting plasma aminograms in 387 IBD patients (Crohn's disease (CD), n = 165; ulcerative colitis (UC), n = 222) and 210 healthy controls. Based on Fisher linear classifiers, multivariate indexes were developed from the aminogram in discovery samples (CD, n = 102; UC, n = 102; age and sex-matched healthy controls, n = 102) and internally validated. The indexes were used to discriminate between CD or UC patients and healthy controls, as well as between patients with active disease and those in remission. We assessed index performances using the area under the curve of the receiver operating characteristic (ROC AUC). We observed significant alterations to the plasma aminogram, including histidine and tryptophan. The multivariate indexes established from plasma aminograms were able to distinguish CD or UC patients from healthy controls with ROC AUCs of 0.940 (95% confidence interval (CI): 0.898–0.983) and 0.894 (95%CI: 0.853–0.935), respectively in validation samples (CD, n = 63; UC, n = 120; healthy controls, n = 108). In addition, other indexes appeared to be a measure of disease activity. These indexes distinguished active CD or UC patients from each remission patients with ROC AUCs of 0.894 (95%CI: 0.853–0.935) and 0.849 (95%CI: 0.770–0.928), and correlated with clinical disease activity indexes for CD (rs = 0.592, 95%CI: 0.385–0.742, p<0.001) or UC (rs = 0.598, 95%CI: 0.452–0.713, p<0.001), respectively. Conclusions and Significance In this study, we demonstrated that established multivariate indexes composed of plasma amino acid profiles can serve as novel, non-invasive, objective biomarkers for the diagnosis and monitoring of IBD, providing us with new insights into the pathophysiology of the disease.
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Affiliation(s)
- Tadakazu Hisamatsu
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
- * E-mail: (T.Hisamatsu); (T.Hibi)
| | - Susumu Okamoto
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Masaki Hashimoto
- Institute of Life Sciences and Pharmaceutical Research Laboratories, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Takahiko Muramatsu
- Institute of Life Sciences and Pharmaceutical Research Laboratories, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Ayatoshi Andou
- Institute of Life Sciences and Pharmaceutical Research Laboratories, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Michihide Uo
- Institute of Life Sciences and Pharmaceutical Research Laboratories, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Mina T. Kitazume
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Katsuyoshi Matsuoka
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Tomoharu Yajima
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Nagamu Inoue
- Center for Diagnostic and Therapeutic Endoscopy, Keio University, Tokyo, Japan
| | - Takanori Kanai
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
| | - Haruhiko Ogata
- Center for Diagnostic and Therapeutic Endoscopy, Keio University, Tokyo, Japan
| | - Yasushi Iwao
- Center for Diagnostic and Therapeutic Endoscopy, Keio University, Tokyo, Japan
| | - Minoru Yamakado
- Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital, Tokyo, Japan
| | - Ryosei Sakai
- Institute of Life Sciences and Pharmaceutical Research Laboratories, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Nobukazu Ono
- Institute of Life Sciences and Pharmaceutical Research Laboratories, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Toshihiko Ando
- Institute of Life Sciences and Pharmaceutical Research Laboratories, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Manabu Suzuki
- Institute of Life Sciences and Pharmaceutical Research Laboratories, Ajinomoto Co. Inc., Kawasaki, Japan
| | - Toshifumi Hibi
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
- * E-mail: (T.Hisamatsu); (T.Hibi)
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Zhou LF, Miao YL. Progress in research of biological activity markers for inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2011; 19:3229-3236. [DOI: 10.11569/wcjd.v19.i31.3229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The incidence of inflammatory bowel disease (IBD) has been increasing in recent years. The clinical manifestations of IBD are complicated, and both intestinal and extraintestinal symptoms may develop. Due to the lack of specific index, IBD is easy to be misdiagnosed, and evaluating disease activity is more difficult. Radiology, endoscopic and histological biopsy for diagnosis are expensive. Currently, there is an urgent need of a simple, noninvasive, sensitive, economic, and highly specific method for diagnosis of IBD. Biological activity markers may meet this demand. In this paper, the clinical applicability of biological activity markers, which come from both ulcerative colitis (UC) and Crohn's disease (CD), in identifying the presence or extent of inflammatory response, is reviewed.
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Stanghellini V, Barbara G, Cremon C, Cogliandro R, Antonucci A, Gabusi V, Frisoni C, De Giorgio R, Grasso V, Serra M, Corinaldesi R. Gut microbiota and related diseases: clinical features. Intern Emerg Med 2010; 5 Suppl 1:S57-63. [PMID: 20865476 DOI: 10.1007/s11739-010-0451-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Intestinal microbiota is essential for gut homeostasis. Specifically, the microorganisms inhabiting the gut lumen interact with the intestinal immune system, supply key nutrients for the major components of the gut wall, and modulate energy metabolism. Host-microbiome interactions can be either beneficial or deleterious, driving gastrointestinal lymphoid tissue activities and shaping gut wall structures. This overview briefly focuses on the potential role played by abnormalities in gut microbiota and relative responses of the gastrointestinal tract in the determination of important pathological conditions such as the irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer.
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Affiliation(s)
- Vincenzo Stanghellini
- Department of Clinical Medicine, St. Orsola-Malpighi Hospital, University of Bologna, Building No. 5, Via Massarenti, 9, 40138, Bologna, Italy.
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Sarra M, Monteleone I, Stolfi C, Fantini MC, Sileri P, Sica G, Tersigni R, Macdonald TT, Pallone F, Monteleone G. Interferon-gamma-expressing cells are a major source of interleukin-21 in inflammatory bowel diseases. Inflamm Bowel Dis 2010; 16:1332-1339. [PMID: 20186935 DOI: 10.1002/ibd.21238] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND We previously demonstrated that in inflammatory bowel disease (IBD) there is enhanced production of interleukin (IL)-21, a cytokine that activates multiple pathways that sustain mucosal inflammation. However, the phenotype of IL-21-producing cells in IBD, and the cytokine(s) they coproduce, is not known. We here characterized the cell source of IL-21 and determined which factors regulate IL-21 in the human gut. METHODS Cytokines were analyzed in CD4+ T intestinal lamina propria lymphocytes (T-LPL) isolated from IBD patients and controls by flow cytometry. Moreover, IL-21 was evaluated in mucosal T follicular cells (TFH). To assess the involvement of IL-12 and IL-23 in the production of IL-21, T-LPL were activated in the presence or absence of IL-12 or IL-23. RESULTS The proportion of IL-21-producing CD4+ T-LPL was increased in IBD compared to controls. The majority of IL-21-producing T-LPL coexpressed interferon (IFN)-gamma, and to a lesser extent IL-4 or IL-17A. Activation of CD4+ T-LPL with IL-12 but not IL-23 enhanced the fraction of cells coexpressing IL-21 and IFN-gamma. TFH cells in LPL were identified by CXCR5 expression and expressed IL-21 both in IBD and controls; however, the fraction of IL-21-positive TFH cells was higher in Crohn's disease than in ulcerative colitis and controls. Treatment of CD4+ T-LPL with IL-12 enhanced the frequency of CXCR5+ IL-21-producing TFH cells. CONCLUSIONS These findings indicate that in IBD IL-21 is mostly produced by CD4+ T-LPL coexpressing IFN-gamma, reinforcing the concept that distinct subsets of T cells can produce IL-21.
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Affiliation(s)
- Massimiliano Sarra
- Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy
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15
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New pathophysiological insights and modern treatment of IBD. J Gastroenterol 2010; 45:571-83. [PMID: 20213337 DOI: 10.1007/s00535-010-0219-3] [Citation(s) in RCA: 142] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2010] [Accepted: 02/03/2010] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD), which comprises two main types, namely, Crohn's disease and ulcerative colitis, affects approximately 3.6 million people in the USA and Europe, and an alarming rise in low-incidence areas, such as Asia, is currently being observed. In the last decade, spontaneous mutations in a diversity of genes have been identified, and these have helped to elucidate pathways that can lead to IBD. Animal studies have also increased our knowledge of the pathological dialogue between the intestinal microbiota and components of the innate and adaptive immune systems misdirecting the immune system to attack the colon. Present-day medical therapy of IBD consists of salicylates, corticosteroids, immunosuppressants and immunomodulators. However, their use may result in severe side effects and complications, such as an increased rate of malignancies or infectious diseases. In clinical practice, there is still a high frequency of incomplete or absent response to medical therapy, indicating a compelling need for new therapeutic strategies. This review summarizes current epidemiology, pathogenesis and diagnostic strategies in IBD. It also provides insight in today's differentiated clinical therapy and describes mechanisms of promising future medicinal approaches.
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Chosa M, Soeta S, Ichihara N, Nishita T, Asari M, Matsumoto S, Amasaki H. Pathomechanism of cellular infiltration in the perivascular region of several organs in SAMP1/Yit mouse. J Vet Med Sci 2010; 71:1553-60. [PMID: 20046021 DOI: 10.1292/jvms.001553] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We investigated the histological changes of extra-intestinal organs, such as the liver, kidney, lung and pancreas in SAMP1/Yit mice, a human Crohn's disease model, using immunohistochemical techniques. The perivascular cellular infiltration was detected around the small vessels after 30 weeks. These infiltrating cells consisted of many CD4-positive T-lymphocytes, and small numbers of CD8- positive T-lymphocytes and IgG-positive B-lymphocytes. MAdCAM-1 and VCAM-1 were detected in vascular endothelial cells in non-affected regions of 13 and 20 week-old, as well as in the affected regions showing perivascular cellular infiltration after 30 weeks. In addition, integrin alpha4beta7 was detected on these infiltrating cells in the perivascular regions after 30 week-old. LT-beta and IL-12, cytokines of the Th-1-type immune response, were not observed in these affected regions. However, IL-4, one of the cytokines of the Th-2-type immune response, was detected on the perivascular infiltrating cells after 30 week-old. These results revealed that the changes in extra-intestinal organs were mainly caused by infiltration of CD4-positive T-lymphocytes into the perivascular regions in SAMP1/Yit mice. These cellular infiltrations were thought to be initiated by adhesion of CD4-positive T-lymphocytes to the endothelial cells mediated by MAdCAM-1 and integrin beta7. Immunohistochemistry for Th related cytokines indicated that the perivascular cellular infiltration was developed by the Th-2-type immune response in the extra-intestinal organs of SAMP1/Yit mouse.
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Affiliation(s)
- Mizuki Chosa
- Department of Anatomy 1, School of Veterinary Medicine, Azabu University, Kanagawa Pref 229-8501, Japan
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Hisamatsu T, Hibi T. Pathogen-specific antibody: cause or effect? Gastroenterology 2009; 137:1570-3. [PMID: 19789083 DOI: 10.1053/j.gastro.2009.09.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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Low Mannan-binding lectin serum levels are associated with complicated Crohn's disease and reactivity to oligomannan (ASCA). Am J Gastroenterol 2009; 104:2508-16. [PMID: 19532127 DOI: 10.1038/ajg.2009.315] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Mannan-binding lectin (MBL) acts as a pattern-recognition molecule directed against oligomannan, which is part of the cell wall of yeasts and various bacteria. We have previously shown an association between MBL deficiency and anti-Saccharomyces cerevisiae mannan antibody (ASCA) positivity. This study aims at evaluating whether MBL deficiency is associated with distinct Crohn's disease (CD) phenotypes. METHODS Serum concentrations of MBL and ASCA were measured using ELISA (enzyme-linked immunosorbent assay) in 427 patients with CD, 70 with ulcerative colitis, and 76 healthy controls. CD phenotypes were grouped according to the Montreal Classification as follows: non-stricturing, non-penetrating (B1, n=182), stricturing (B2, n=113), penetrating (B3, n=67), and perianal disease (p, n=65). MBL was classified as deficient (<100 ng/ml), low (100-500 ng/ml), and normal (500 ng/ml). RESULTS Mean MBL was lower in B2 and B3 CD patients (1,503+/-1,358 ng/ml) compared with that in B1 phenotypes (1,909+/-1,392 ng/ml, P=0.013). B2 and B3 patients more frequently had low or deficient MBL and ASCA positivity compared with B1 patients (P=0.004 and P<0.001). Mean MBL was lower in ASCA-positive CD patients (1,562+/-1,319 ng/ml) compared with that in ASCA-negative CD patients (1,871+/-1,320 ng/ml, P=0.038). In multivariate logistic regression modeling, low or deficient MBL was associated significantly with B1 (negative association), complicated disease (B2+B3), and ASCA. MBL levels did not correlate with disease duration. CONCLUSIONS Low or deficient MBL serum levels are significantly associated with complicated (stricturing and penetrating) CD phenotypes but are negatively associated with the non-stricturing, non-penetrating group. Furthermore, CD patients with low or deficient MBL are significantly more often ASCA positive, possibly reflecting delayed clearance of oligomannan-containing microorganisms by the innate immune system in the absence of MBL.
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Schoepfer AM, Schaffer T, Mueller S, Flogerzi B, Vassella E, Seibold-Schmid B, Seibold F. Phenotypic associations of Crohn's disease with antibodies to flagellins A4-Fla2 and Fla-X, ASCA, p-ANCA, PAB, and NOD2 mutations in a Swiss Cohort. Inflamm Bowel Dis 2009; 15:1358-67. [PMID: 19253375 PMCID: PMC2732763 DOI: 10.1002/ibd.20892] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Distinct Crohn's disease (CD) phenotypes correlate with antibody reactivity to microbial antigens. We examined the association between antibody response to 2 new flagellins called A4-Fla2 and Fla-X, anti-Saccharomyces cerevisiae antibodies (ASCA), anti-neutrophil cytoplasmic antibodies (p-ANCA), anti-pancreas antibodies (PAB), NOD2 mutations (R702W, G908R, and L1007fsinsC), and clinical CD phenotypes (according to Vienna criteria). METHODS All the above-mentioned antibodies as well as NOD2 mutations were determined in 252 CD patients, 53 with ulcerative colitis (UC), and 43 healthy controls (HC) and correlated with clinical data. RESULTS A seroreactivity for A4-Fla2/Fla-X/ASCA/p-ANCA/PAB (in percent) was found in 59/57/62/12/22 of CD patients, 6/6/4/51/0 of UC patients, and 0/2/5/0/0 of healthy controls. CD behavior: 37% B1, 36% B2, and 27% B3. In multivariate logistic regression, antibodies to A4-Fla2, Fla-X, and ASCA were significantly associated with stricturing phenotype (P = 0.027, P = 0.041, P < 0.001), negative associations were found with inflammatory phenotype (P = 0.001, P = 0.005, P < 0.001). Antibodies to A4-Fla2, Fla-X, ASCA, and NOD2 mutations were significantly associated with small bowel disease (P = 0.013, P = 0.01, P < 0.001, P = 0.04), whereas ASCA was correlated with fistulizing disease (P = 0.007), and small bowel surgery (P = 0.009). Multiple antibody responses against microbial antigens were associated with stricturing (P < 0.001), fistulizing disease (P = 0.002), and small bowel surgery (P = 0.002). CONCLUSIONS Anti-flagellin antibodies and ASCA are strongly associated with complicated CD phenotypes. CD patients with serum reactivity against multiple microbes have the greatest frequency of strictures, perforations, and small bowel surgery. Further prospective longitudinal studies are needed to show that antibody-based risk stratification improves the clinical outcome of CD patients.
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Affiliation(s)
- Alain M. Schoepfer
- Department of Gastroenterology, Inselspital/Bern University Hospital, Switzerland
| | - Thomas Schaffer
- Department of Clinical Research, University of Bern, Switzerland
| | - Stefan Mueller
- Department of Clinical Research, University of Bern, Switzerland
| | | | - Erik Vassella
- Institute of Pathology, University of Bern, Switzerland
| | | | - Frank Seibold
- Department of Gastroenterology, Inselspital/Bern University Hospital, Switzerland
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Biological markers in inflammatory bowel disease: Practical consideration for clinicians. ACTA ACUST UNITED AC 2009; 33 Suppl 3:S158-73. [DOI: 10.1016/s0399-8320(09)73151-3] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Cremon C, Pallotti F, Bacchilega M, Stanghellini V, Corinaldesi R, Barbara G. Antiflagellin antibodies suggest infective participation in irritable bowel syndrome pathogenesis. Expert Rev Gastroenterol Hepatol 2008; 2:735-40. [PMID: 19090734 DOI: 10.1586/17474124.2.6.735] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Irritable bowel syndrome (IBS) is a functional disorder of multifactorial origin. Recent attention has been paid to the potential role of immune activation in intestinal sensorimotor dysfunction and symptom generation in patients with IBS. The link between immune activation and IBS is further supported by the evidence that IBS may develop after an acute episode of infectious gastroenteritis, IBS-like symptoms may precede the diagnosis or accompany a period of remission of inflammatory bowel disease (IBD), and quantitative histopathologic data demonstrate the presence of low-grade mucosal immune infiltration in a large subset of patients with IBS. These data also suggest some areas of potential overlap between IBS and IBD. The present study explored the possibility that, similarly to IBD patients, IBS patients have antibodies directed against certain components of indigenous flora, such as flagellin (the primary structural component of bacterial flagella). The authors demonstrated that, compared with healthy controls, antibodies against flagellin were recognized more frequently in patients with IBS. Furthermore, these antibodies were found more frequently in postinfectious compared with unspecific IBS. In patients with Crohn's disease, antiflagellin antibodies were detected with an increased frequency and at higher concentrations than in patients with IBS. All together, these results indicated the presence of a systemic immune activation in IBS patients, characterized by specific antibodies directed against luminal bacterial antigens. Furthermore, these results support the hypothesis that a subset of IBS presents an immune activation with pathogenic features common with IBD.
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Affiliation(s)
- Cesare Cremon
- Department of Internal Medicine and Gastroenterology, St Orsola Hospital, Via Massarenti, 9, Building 5, I-40138 Bologna, Italy.
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Chen X, Feng BS, Zheng PY, Liao XQ, Chong J, Tang SG, Yang PC. Fc gamma receptor signaling in mast cells links microbial stimulation to mucosal immune inflammation in the intestine. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 173:1647-56. [PMID: 18974296 DOI: 10.2353/ajpath.2008.080487] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Microbes and microbial products are closely associated with the pathogenesis of inflammatory bowel disease (IBD); however, the mechanisms behind this connection remain unclear. It has been previously reported that flagellin-specific antibodies are increased in IBD patient sera. As mastocytosis is one of the pathological features of IBD, we hypothesized that flagellin-specific immune responses might activate mast cells that then contribute to the initiation and maintenance of intestinal inflammation. Thirty-two colonic biopsy samples were collected from IBD patients. A flagellin/flagellin-specific IgG/Fc gamma receptor I complex was identified on biopsied mast cells using both immunohistochemistry and co-immunoprecipitation experiments; this complex was shown to co-localize on the surfaces of mast cells in the colonic mucosa of patients with IBD. In addition, an ex vivo study showed flagellin-IgG was able to bind to human mast cells. These cells were found to be sensitized to flagellin-specific IgG; re-exposure to flagellin induced the mast cells to release inflammatory mediators. An animal model of IBD was then used to examine flagellin-specific immune responses in the intestine. Mice could be sensitized to flagellin, and repeated challenges with flagellin induced an IBD-like T helper 1 pattern of intestinal inflammation that could be inhibited by pretreatment with anti-Fc gamma receptor I antibodies. Therefore, flagellin-specific immune responses activate mast cells in the intestine and play important roles in the pathogenesis of intestinal immune inflammation.
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Affiliation(s)
- Xiao Chen
- Brain Body Institute, McMaster University, Ontario, Canada
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Antibodies against glucan, chitin, and Saccharomyces cerevisiae mannan as new biomarkers of Candida albicans infection that complement tests based on C. albicans mannan. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2008; 15:1868-77. [PMID: 18971303 DOI: 10.1128/cvi.00200-08] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Antibodies against Saccharomyces cerevisiae mannan (ASCA) and antibodies against synthetic disaccharide fragments of glucans (ALCA) and chitin (ACCA) are biomarkers of Crohn's disease (CD). We previously showed that Candida albicans infection generates ASCA. Here, we explored ALCA and ACCA as possible biomarkers of invasive C. albicans infection (ICI). ASCA, ALCA, ACCA, and Candida mannan antigen and antibody detection tests were performed on 69 sera obtained sequentially from 18 patients with ICIs proven by blood culture, 59 sera from CD patients, 47 sera from hospitalized subjects colonized by Candida species (CZ), and 131 sera from healthy controls (HC). ASCA, ALCA, and ACCA levels in CD and ICI patients were significantly different from those in CZ and HC subjects (P<0.0001). In ICI patients, these levels increased as infection developed. Using ASCA, ALCA, ACCA, and Platelia Candida tests, 100% of ICIs were detected, with the kinetics of the antibody response depending on the patient during the time course of infection. A large number of sera presented with more than three positive tests. This is the first evidence that the detection of antibodies against chitin and glucans has diagnostic value in fungal infections and that these tests can complement more specific tests. Future trials are necessary to assess the value of these tests in multiparametric analysis, as well as their pathophysiological relevance.
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Schoepfer AM, Schaffer T, Seibold-Schmid B, Müller S, Seibold F. Antibodies to flagellin indicate reactivity to bacterial antigens in IBS patients. Neurogastroenterol Motil 2008; 20:1110-8. [PMID: 18694443 DOI: 10.1111/j.1365-2982.2008.01166.x] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
One of the several possible causes of irritable bowel syndrome (IBS) is thought to be low-grade mucosal inflammation. Flagellin, the primary structural component of bacterial flagellae, was shown in inflammatory bowel disease patients to activate the innate and adaptive immunity. It has not yet been conclusively established if IBS patients show reactivity to luminal antigens. In 266 patients [112 IBS, 61 Crohn's disease (CD), 50 ulcerative colitis (UC) and 43 healthy controls (HC)], we measured antibodies to flagellin (FAB, types A4-Fla2 and Fla-X), anti-Saccharomyces cerevisiae antibodies (ASCA) (both ELISA), antipancreas antibodies (PAB) and perinuclear antineutrophil cytoplasmatic antibodies (p-ANCA) (both IF). All IBS patients had normal fecal calprotectin (mean 21 microg mL(-1), SD 6.6) and fulfilled the ROME II criteria. Frequencies of antibodies in patients with IBS, CD, UC and HC, respectively, are as follows (in per cent): antibodies against A4-Fla2: 29/48/8/7; antibodies against Fla-X: 26/52/10/7; ASCA: 6/59/0/2; p-ANCA: 0/10/52/0; and PAB: 0/28/0/0. Antibodies against A4-Fla2 and Fla-X were significantly more frequent in IBS patients than in HC (P = 0.004 and P = 0.009). Antibodies to A4-Fla2 and Fla-X were significantly more frequent in IBS patients with antecedent gastroenteritis compared to non-postinfectious IBS patients (P = 0.002 and P = 0.012). In contrast to ASCA, PAB and p-ANCA, antibodies against A4-Fla2 and Fla-X were found significantly more often in IBS patients, particularly in those with postinfectious IBS, compared to HC. This observation supports the concept that immune reactivity to luminal antigens has a putative role in the development of IBS, at least in a subset of patients.
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Affiliation(s)
- A M Schoepfer
- Department of Gastroenterology, Inselspital, Bern University Hospital, Bern, Switzerland.
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25
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Simondi D, Mengozzi G, Betteto S, Bonardi R, Ghignone RP, Fagoonee S, Pellicano R, Sguazzini C, Pagni R, Rizzetto M, Astegiano M. Antiglycan antibodies as serological markers in the differential diagnosis of inflammatory bowel disease. Inflamm Bowel Dis 2008. [PMID: 18240283 DOI: 10.1007/978-1-60327-433-3_15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The objective of the study was to evaluate the diagnostic accuracy of recently developed antiglycan serological tests in clinical practice for the diagnosis of Crohn's disease. METHODS This study was a cohort analysis of both clinical and biochemical parameters of patients with diagnosed inflammatory bowel disease compared with those in a control population. Antiglycan antibodies were determined using commercially available enzyme immunoassays. The setting was the outpatient unit of the gastroenterology department of a large, tertiary-care referral academic hospital. Participants were 214 consecutive patients, enrolled over a 5-month period, including 116 with Crohn's disease and 53 with ulcerative colitis, as well as 45 with other gastrointestinal diseases and 51 healthy controls. RESULTS Anti-Saccharomyces cerevisiae antibodies showed the best performance (54% sensitivity and 88%-95% specificity for Crohn's disease). Among patients with negative anti-Saccharomyces antibodies, 19 (34%) had high titers of at least another tested antiglycan antibody. Anti-Saccharomyces and anti-laminaribioside antibodies were associated with disease involving the small bowel and with penetrating or stricturing phenotype. Anti-laminaribioside was significantly higher in patients with a familial history of inflammatory bowel disease. CONCLUSIONS The new proposed serological markers are significantly associated with Crohn's disease, with low sensitivity but good specificity. About one third of anti-Saccharomyces-negative patients may be positive for at least 1 of those markers. Antiglycan antibodies appear to be associated with characteristic localization and phenotype of the disease.
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Affiliation(s)
- Daniele Simondi
- Department of Gastrohepatology, San Giovanni Battista Hospital of Turin, Turin, Italy
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26
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Vandewalle-El Khoury P, Colombel JF, Joossens S, Standaert-Vitse A, Collot M, Halfvarson J, Ayadi A, Landers CJ, Vermeire S, Rutgeerts P, Targan SR, Chamaillard M, Mallet JM, Sendid B, Poulain D. Detection of antisynthetic mannoside antibodies (ASigmaMA) reveals heterogeneity in the ASCA response of Crohn's disease patients and contributes to differential diagnosis, stratification, and prediction. Am J Gastroenterol 2008; 103:949-57. [PMID: 18047546 DOI: 10.1111/j.1572-0241.2007.01648.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Anti-S. cerevisiae mannan antibodies (ASCA) are human antibodies associated with Crohn's disease (CD) reacting with Saccharomyces cerevisiae (S. cerevisiae) mannan polymer. As mannan is a complex and variable repertoire of oligomannoses acting as epitopes, we chemically synthesized (Sigma) two major oligomannose epitopes, Man alpha-1,3 Man alpha-1,2 Man (SigmaMan3) and Man alpha-1,3 Man alpha-1,2 Man alpha-1,2 Man (SigmaMan4), and then explored how antisynthetic mannoside antibodies (ASigmaMA) compare with ASCA as markers of CD. METHODS The study involved different cohorts of CD and ulcerative colitis (UC) patients and healthy controls who had been studied previously in several medical centers in Europe, the United States, and North Africa to determine the clinical value of ASCA in terms of differential diagnosis, evolution of indeterminate colitis (IC), and serotype-phenotype correlations. The comparison of ASigmaMA and ASCA included a total of 1,365 subjects: 772 CD, 261 UC, 43 IC, and 289 controls. RESULTS The specificity of ASigmaMA was similar to that of ASCA (89% vs 93%), although the sensitivity was lower (38% vs 55%). Unexpectedly, 24% of the CD patients who were negative for ASCA and/or other CD-associated serologic markers were positive for ASigmaMA. ASigmaMA were associated with colonic involvement in CD (odds ratio [OR] 1.609, 95% confidence interval [CI] 1.033-2.506, P = 0.03) and were 100% predictive of CD in patients with IC. CONCLUSIONS ASigmaMA reveal the heterogeneity of the antioligomannose antibody response in CD patients and increase the sensitivity of CD diagnosis when combined with ASCA. The subset of ASCA-negative CD patients diagnosed by ASigmaMA had preferentially a colonic involvement, which confirms the high predictive value of ASigmaMA for determining IC evolution toward CD.
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Schoepfer AM, Trummler M, Seeholzer P, Seibold-Schmid B, Seibold F. Discriminating IBD from IBS: comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis 2008; 14:32-9. [PMID: 17924558 DOI: 10.1002/ibd.20275] [Citation(s) in RCA: 193] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Symptoms of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) can overlap. We aimed to determine the accuracy of fecal markers, C-reactive protein (CRP), blood leukocytes, and antibody panels for discriminating IBD from IBS and to define a "best test." METHODS We prospectively included 64 patients with IBD (36 Crohn's disease [CD], 28 ulcerative colitis [UC]), 30 with IBS, and 42 healthy controls. Besides CRP and blood leukocytes, blinded fecal samples were measured for calprotectin (PhiCal Test, enzyme-linked immunosorbent assay [ELISA]), lactoferrin (IBD-SCAN, ELISA), Hexagon-OBTI (immunochromatographic test for detection of human hemoglobin), and LEUKO-TEST (lactoferrin latex-agglutination test). Blinded serum samples were measured for the antibodies ASCA (ELISA) and pANCA (immunofluorescence). RESULTS Overall accuracy of tests for discriminating IBD from IBS: IBD-SCAN 90%, PhiCal Test 89%, LEUKO-TEST 78%, Hexagon-OBTI 74%, CRP 73%, blood leukocytes 63%, CD antibodies (ASCA+/pANCA- or ASCA+/pANCA+) 55%, UC antibodies (pANCA+/ASCA-) 49%. ASCA and pANCA had an accuracy of 78% for detecting CD and 75% for detecting UC, respectively. The overall accuracy of IBD-SCAN and PhiCal Test combined with ASCA/pANCA for discriminating IBD from IBS was 92% and 91%, respectively. CONCLUSIONS The PhiCal Test and IBD-SCAN are highly accurate for discriminating IBD from IBS. There is only marginal additional diagnostic accuracy when the PhiCal Test and IBD-SCAN are combined with ASCA and pANCA. ASCA and pANCA have a high specificity for IBD.
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Affiliation(s)
- Alain M Schoepfer
- Department of Gastroenterology, Inselspital/University of Bern, Switzerland.
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Peyrin-Biroulet L, Standaert-Vitse A, Branche J, Chamaillard M. IBD serological panels: facts and perspectives. Inflamm Bowel Dis 2007; 13:1561-6. [PMID: 17636565 DOI: 10.1002/ibd.20226] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Beyond a defective innate immune response in inflammatory bowel disease (IBD), an increased immunological response toward microbial and self antigens has been intrinsically linked to the pathogenesis of such common immunopathologies of the gut. Mounting evidence indicates that increased seroreactivity toward certain antigens are a predictive and quantitative heritable trait, including the anti-Saccharomyces cerevisiae antibody (ASCA). Consistently, Candida albicans and Crohn's disease-associated NOD2 mutations have been recently identified as immunogen and genetic determinants for ASCA, respectively. In clinical practice, current panels of serological markers are not recommended for diagnosis, stratifying, and monitoring IBD. Therefore, prospective studies and highly sensitive serological panels of markers are eagerly awaited before guiding clinical decisions. Better understanding of the serological response in IBD might also provide new insights into their epidemiology and pathophysiology.
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Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology 2007; 133:1670-89. [PMID: 17983810 DOI: 10.1053/j.gastro.2007.09.001] [Citation(s) in RCA: 290] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2007] [Accepted: 08/30/2007] [Indexed: 02/06/2023]
Abstract
The diagnosis of inflammatory bowel disease (IBD) with its 2 main subforms, Crohn's disease and ulcerative colitis, is based on clinical, endoscopic, radiologic, and histologic criteria. This paradigm remains unchanged despite the advent of new molecular technologies for the examination of serum proteins and genetic sequences, respectively. The main innovations in diagnostic technologies include the development of more sophisticated endoscopic and noninvasive imaging techniques with the aim of improving the identification of complications, in particular malignant diseases associated with IBD. The future will see further progress in the identification of genetic susceptibility factors and of protein biomarkers and their use to describe the molecular epidemiology of IBD. It can be expected that future diagnostic algorithms will include molecular parameters to detect early disease or guide therapies by predicting the individual course of disease.
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Affiliation(s)
- Susanna Nikolaus
- Department of General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
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Papp M, Altorjay I, Lakatos PL. [Relevance of serologic studies in inflammatory bowel diseases]. Orv Hetil 2007; 148:887-896. [PMID: 17478404 DOI: 10.1556/oh.2007.28064] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The panel of serologic markers for inflammatory bowel diseases (IBDs) is rapidly expanding. Although anti- Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmic antibodies (atypical P-ANCA) remain the most widely investigated, an increasing amount of experimental data is available on newly discovered antibodies directed against various microbial antigens. Such antibodies include anti-OmpC (outer membrane porin C), anti- Pseudomonas fluorescens (anti-I2) and antiglycan antibodies (anti-laminaribioside carbohydrate antibody [ALCA]), anti-chitobioside carbohydrate antibody [ACCA]), anti-mannobioside carbohydrate antibody [AMCA]) and anti-CBir1; this latter is the first bacterial antigen to induce colitis in animal models of IBD and also leads to a pathological immune response in IBD patients (anti-flagellin antibody). The role of assessment of various antibodies in the current diagnostic algorithm of IBD is rather questionable due to their limited sensitivity. In contrast, the association of serologic markers with disease behavior and phenotype is getting more into the focus of interest. An increasing number of observations confirm that patients with Crohn's disease expressing multiple serologic markers at high titers are more likely to have complicated small bowel disease (e.g. stricture and/or perforation) and are at higher risk for surgery than those without, or with low titer of antibodies. Creating homogenous disease sub-groups based on serologic response may help develop more standardized therapeutic approaches and may help in a better understanding of the pathomechanism of IBD. Further prospective clinical studies are needed to establish the clinical role of serologic tests in IBD.
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Affiliation(s)
- Mária Papp
- Debreceni Egyetem, Orvos- és Egészségtudományi Centrum Belgyógyászati Intézet, Gasztroenterológiai Tanszék, Debrecen.
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Papp M, Norman GL, Altorjay I, Lakatos PL. Utility of serological markers in inflammatory bowel diseases: gadget or magic? World J Gastroenterol 2007; 13:2028-2036. [PMID: 17465443 PMCID: PMC4319120 DOI: 10.3748/wjg.v13.i14.2028] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2007] [Revised: 03/02/2007] [Accepted: 03/12/2007] [Indexed: 02/06/2023] Open
Abstract
The panel of serologic markers for inflammatory bowel diseases (IBD) is rapidly expanding. Although anti-Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) remain the most widely investigated, an increasing amount of experimental data is available on newly discovered antibodies directed against various microbial antigens. The role of the assessment of various antibodies in the current IBD diagnostic algorithm is often questionable due to their limited sensitivity. In contrast, the association of serologic markers with disease behavior and phenotype is becoming increasingly well-established. An increasing number of observations confirms that patients with Crohn's disease expressing multiple serologic markers at high titers are more likely to have complicated small bowel disease (e.g. stricture and/or perforation) and are at higher risk for surgery than those without, or with low titers of antibodies. Creating homogenous disease sub-groups based on serologic response may help develop more standardized therapeutic approaches and may help in a better understanding of the pathomechanism of IBD. Further prospective clinical studies are needed to establish the clinical role of serologic tests in IBD.
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Affiliation(s)
- Xavier Treton
- Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie et Assistance Nutritive, Université Paris VII, and Service de Radiologie, Hôpital Beaujon, Clichy, France
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Martland GT, Shepherd NA. Indeterminate colitis: definition, diagnosis, implications and a plea for nosological sanity. Histopathology 2007; 50:83-96. [PMID: 17204023 DOI: 10.1111/j.1365-2559.2006.02545.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
In 1978, Price introduced the concept of indeterminate colitis to describe cases in which colonic resections had been undertaken for chronic inflammatory bowel disease (CIBD), but a definitive diagnosis of either of the classical types of CIBD, ulcerative colitis and Crohn's disease, was not possible. This was especially apposite in cases of acute fulminant disease of the colorectum. More recently, the term indeterminate colitis has been applied to biopsy material, when it has not been possible to differentiate between ulcerative colitis and Crohn's disease. In our opinion, and in those of other workers in this field, the term should be restricted to that originally suggested by Price. This then provides a relatively well-defined group of patients in whom the implications and management of the disease are becoming much clearer. Cases where there are only biopsies with CIBD, but equivocal features for ulcerative colitis and Crohn's disease, should be termed 'CIBD, unclassified', 'equivocal/non-specific CIBD' or IBD unclassified (IBDU), in line with recent recommendations. When the diagnosis is correctly restricted to colectomy specimens, there is now good evidence that the majority of cases will behave like ulcerative colitis. Furthermore, the diagnosis should not be a contraindication to subsequent pouch surgery. When the latter is undertaken, surgeons and patients can expect an increased complication rate, compared with classical ulcerative colitis, especially of pelvic sepsis, but most patients fare well. Only very occasional patients, around 10%, will eventually be shown to have Crohn's disease. This review describes the pathology of cases appropriately classified as indeterminate colitis and the implications of that diagnosis. It also highlights recent advances in its pathological features, clinical management and its immunological and genetic associations.
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Affiliation(s)
- G T Martland
- Departments of Histopathology, Gloucestershire Royal Hospital, Gloucester and Cheltenham General Hospital, Cheltenham, UK
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Sabery N, Bass D. Use of serologic markers as a screening tool in inflammatory bowel disease compared with elevated erythrocyte sedimentation rate and anemia. Pediatrics 2007; 119:e193-9. [PMID: 17158948 DOI: 10.1542/peds.2006-1361] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVES The purpose of this work was to evaluate the use of serologic testing as a screening test for inflammatory bowel disease compared with erythrocyte sedimentation rate and hemoglobin in a referred patient population with suspected inflammatory bowel disease. PATIENTS AND METHODS A retrospective study was performed, reviewing medical charts of patients who had inflammatory bowel disease serology performed at Prometheus Laboratories from September 2002 to September 2004. Patients were divided into 4 categories: ulcerative colitis, Crohn disease, indeterminate colitis, and noninflammatory bowel disease groups. Patients were categorized based on clinical evaluation by board-certified pediatric gastroenterologists. RESULTS A total of 227 patients seen at the Lucile Packard Children's Hospital Gastroenterology Clinic had inflammatory bowel disease serology performed at or before the time of diagnosis. Seventeen charts were excluded secondary to inadequate information. Forty children were found to have inflammatory bowel disease, a prevalence of 19%. Overall, serologic testing for inflammatory bowel disease had 60% sensitivity and 92% specificity. A positive laboratory test for anemia or an elevated erythrocyte sedimentation rate had 83% sensitivity, whereas the combination of anemia and elevated erythrocyte sedimentation rate had 96% specificity. The positive predictive value of serologic testing was 60% compared with 79% in patients with anemia and elevated erythrocyte sedimentation rate. The positive predictive value of serologic testing in the subgroup of subjects without rectal bleeding (139 subjects) was only 35% compared with 60% using routine tests. Almost one third of all positive serologic tests were in patients with no demonstrable inflammatory bowel disease. CONCLUSIONS As a pediatric inflammatory bowel disease screening strategy for the general pediatrician or gastroenterologist, the measurement of the combination of erythrocyte sedimentation rate and hemoglobin has a higher positive predictive value and is more sensitive, more specific, and less costly than commercial serologic testing.
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Affiliation(s)
- Nasim Sabery
- Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA
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Stucchi AF, Aarons CB, Becker JM. Surgical approaches to cancer in patients who have inflammatory bowel disease. Gastroenterol Clin North Am 2006; 35:641-73. [PMID: 16952745 DOI: 10.1016/j.gtc.2006.07.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IBD clearly increases the risk for GI malignancies, especially CRC. The absolute number of patients that develops such malignancies is low compared with the overall cancer rate; however, younger age of onset, higher relative risk, unique clinical presentations, and problems with early diagnosis make this a serious complication of IBD. With the exception of patients with comorbid complications, such as primary sclerosing cholangitis, the prognosis is no worse for CRCs that arise as the result of IBD compared with those that arise sporadically. The prognosis remains poor for small bowel adenocarcinomas in patients who have CD, primarily because of their advanced stage at detection. Diligent surveillance is essential for early detection and treatment of IBD-related CRCs in patients with unresected colons, long-standing or extensive disease, and in those who have early-onset CD, although pundits still question whether it significantly affects prognosis and survival. Better surveillance techniques for small bowel dysplasia or malignancy in patients who have CD is needed, especially given the poor prognosis of these patients when advanced cancers are detected. Depending on the presentation and disease diagnosis, patients have several surgical treatment options and can expect good outcomes for all. When the appropriate surgical technique is used in patients who have colon or rectal cancer, along with adjuvant chemotherapy when appropriate, prognosis and function is good; however, the experience of the surgeon can affect the prognosis for IBD-related GI cancers. Surgical therapy is based not only on general oncologic principles, but also on the surgery that is appropriate for the IBD diagnosis. Resection of the mesentery and lymphadenectomy should be performed according to oncologic principles. Postoperative survival for IBD-related CRC is good, and diligent surveillance and follow-up are critical to the patient's overall prognosis.
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Affiliation(s)
- Arthur F Stucchi
- Department of Surgery, Boston University School of Medicine, Boston, MA 02118, USA
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Koutroubakis IE, Drygiannakis D, Karmiris K, Drygiannakis I, Makreas S, Kouroumalis EA. Pancreatic autoantibodies in Greek patients with inflammatory bowel disease. Dig Dis Sci 2005; 50:2330-4. [PMID: 16416183 DOI: 10.1007/s10620-005-3056-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2005] [Accepted: 03/15/2005] [Indexed: 12/20/2022]
Abstract
Pancreatic autoantibodies (PAbs) have been suggested as a specific but not sensitive marker for Crohn's disease (CD). The aim of this study was to assess the value of detecting PAbs in Greek patients with ulcerative colitis (UC) and CD. Sera were collected from 150 patients with IBD (73 with UC and 77 with CD), 31 cases with non-IBD intestinal inflammation, 16 cases with other autoimmune diseases, and 104 healthy controls. Determination of PAbs was performed by a standard indirect immunofluorescence technique. PAbs were detected in 18 of 73 (24.7%) samples from UC patients and in 32 of 77 (41.6%) samples from CD patients. The prevalence of positive PAbs was significantly higher in CD than in UC (P = 0.04). None of the 104 samples from healthy controls and the 31 cases with non-IBD intestinal inflammation had detectable PAbs. One patient with Sjogren's syndrome was PAbs positive. No association of PAbs with IBD activity, IBD localization, or medical treatment was found. Patients with stenotic CD had a significantly higher prevalence of PAbs positivity (60%) compared with patients with inflammatory (28.6%) and fistulizing (41.2%) disease (P = 0.02). The prevalence of PAbs in Greek CD patients was found to be similar to that in previous reports. In contrast to these studies we found also increased prevalence of PAbs in UC patients. These findings suggest that PAbs should be considered as a specific marker for IBD rather than for CD.
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