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      B-Cell Dysregulation in Crohn's Disease Is Partially Restored with Infliximab Therapy

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          Abstract

          Background

          B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn’s disease.

          Objective

          To elucidate the involvement of B cells in Crohn’s disease, we here performed an ‘in depth’ analysis of intestinal and blood B-cells in this chronic inflammatory disease.

          Methods

          Patients with Crohn’s disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and the phenotype and molecular characteristics of blood B-cell subsets (n = 21). The effects of infliximab treatment were studied in 9 patients.

          Results

          Granulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21 low B cells were elevated. IgM memory B cells were reduced and natural effector cells showed decreased replication histories and somatic hypermutation (SHM) levels. In contrast, IgG and IgA memory B cells were normally present and their Ig gene transcripts carried increased SHM levels. The numbers of transitional and natural effector cells were normal in patients who responded clinically well to infliximab.

          Conclusions

          B cells in patients with Crohn’s disease showed signs of chronic stimulation with localization to granulomatous tissue and increased molecular maturation of IgA and IgG. Therapy with TNFα-blockers restored the defect in IgM memory B-cell generation and normalized transitional B-cell levels, making these subsets candidate markers for treatment monitoring. Together, these results suggest a chronic, aberrant B-cell response in patients with Crohn’s disease, which could be targeted with new therapeutics that specifically regulate B-cell function.

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          Most cited references40

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          Innate and adaptive immunity in inflammatory bowel disease.

          Alessandra Geremia, Paolo Biancheri, Philip Allan … (2014)
          Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). The exact cause of IBD remains unknown. Available evidence suggests that an abnormal immune response against the microorganisms of the intestinal flora is responsible for the disease in genetically susceptible individuals. The adaptive immune response has classically been considered to play a major role in the pathogenesis of IBD. However, recent advances in immunology and genetics have clarified that the innate immune response is equally as important in inducing gut inflammation in these patients. In particular, an altered epithelial barrier function contributes to intestinal inflammation in patients with UC, while aberrant innate immune responses, such as antimicrobial peptide production, innate microbial sensing and autophagy are particularly associated to CD pathogenesis. On the other hand, besides T helper cell type (Th)1 and Th2 immune responses, other subsets of T cells, namely Th17 and regulatory T (Treg) cells, are likely to play a role in IBD. However, given the complexity and probably the redundancy of pathways leading to IBD lesions, and the fact that Th17 cells may also have protective functions, neutralization of IL-17A failed to induce any improvement in CD. Studying the interactions between various constituents of the innate and adaptive immune systems will certainly open new horizons in the knowledge about the immunologic mechanisms implicated in gut inflammation. Copyright © 2013 Elsevier B.V. All rights reserved.
          Article 0 comments Cited 339 times – based on 0 reviews     Review now
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            Mucosal healing in inflammatory bowel diseases: a systematic review.

            Markus F. Neurath, Simon P L Travis (2012)
            Recent studies have identified mucosal healing on endoscopy as a key prognostic parameter in the management of inflammatory bowel diseases (IBD), thus highlighting the role of endoscopy for monitoring of disease activity in IBD. In fact, mucosal healing has emerged as a key treatment goal in IBD that predicts sustained clinical remission and resection-free survival of patients. The structural basis of mucosal healing is an intact barrier function of the gut epithelium that prevents translocation of commensal bacteria into the mucosa and submucosa with subsequent immune cell activation. Thus, mucosal healing should be considered as an initial event in the suppression of inflammation of deeper layers of the bowel wall, rather than as a sign of complete healing of gut inflammation. In this systematic review, the clinical studies on mucosal healing are summarised and the effects of anti-inflammatory or immunosuppressive drugs such as 5-aminosalicylates, corticosteroids, azathioprine, ciclosporin and anti-TNF antibodies (adalimumab, certolizumab pegol, infliximab) on mucosal healing are discussed. Finally, the implications of mucosal healing for subsequent clinical management in patients with IBD are highlighted.
            Article 0 comments Cited 267 times – based on 0 reviews     Review now
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              Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire.

              Sandra Weller, Moritz C. Braun, Bruce K Tan … (2004)
              The human peripheral B-cell compartment displays a large population of immunoglobulin M-positive, immunoglobulin D-positive CD27(+) (IgM(+)IgD(+)CD27(+)) "memory" B cells carrying a mutated immunoglobulin receptor. By means of phenotypic analysis, complementarity-determining region 3 (CDR3) spectratyping during a T-independent response, and gene-expression profiling of the different blood and splenic B-cell subsets, we show here that blood IgM(+)IgD(+)CD27(+) cells correspond to circulating splenic marginal zone B cells. Furthermore, analysis of this peripheral subset in healthy children younger than 2 years shows that these B cells develop and mutate their immunoglobulin receptor during ontogeny, prior to their differentiation into T-independent antigen-responsive cells. It is therefore proposed that these IgM(+)IgD(+)CD27(+) B cells provide the splenic marginal zone with a diversified and protective preimmune repertoire in charge of the responses against encapsulated bacteria.
              Article 0 comments Cited 208 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yolande Richard: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 28 July 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 7
                Electronic Location Identifier: e0160103
                Affiliations
                [1 ]Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
                [2 ]Department of Immunology, Erasmus MC, Rotterdam, The Netherlands
                [3 ]Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
                [4 ]Department of Gastroenterology, Ikazia Hospital, Rotterdam, The Netherlands
                [5 ]Department of Gastroenterology, Alfred Hospital, Monash University and Alfred Health, Melbourne, VIC, Australia
                [6 ]Department of Immunology and Pathology, Monash University, Melbourne, VIC, Australia
                COCHIN INSTITUTE, Institut National de la Santé et de la Recherche Médicale, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: WMCT JAMvL PMvH MCvZ. Performed the experiments: WMCT TBvdH LSJK SJWB KHL RJO MPS PRG. Analyzed the data: WMCT SJWB KHL. Contributed reagents/materials/analysis tools: KHL RJO MPS PRG MCvZ. Wrote the paper: WMCT JAMvL PMvH MCvZ. Interpretation of data: WMCT JAMvL PMvH MCvZ. Revising manuscript: TBvdH LSJK SJWB KHL RJO MPS PRG. Approval final manuscript: WMCT JAMvL TBvdH LSJK SJWB KHL RJO MPS PRG PMvH MCvZ.

                Author information
                http://orcid.org/0000-0003-4161-1919
                Article
                Publisher ID: PONE-D-16-00597
                DOI: 10.1371/journal.pone.0160103
                PMC ID: 4965034
                PubMed ID: 27468085
                SO-VID: 610b4f3b-2856-4cc2-9d36-390815bad432
                Copyright © © 2016 Timmermans et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 7 January 2016
                Date accepted : 11 July 2016
                Page count
                Figures: 5, Tables: 1, Pages: 15
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: Antibody-Producing Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Antibody-Producing Cells
                Subject: B Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Antibody-Producing Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Blood Cells
                Subject: White Blood Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
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                Subject: Immunology
                Subject: Immune Cells
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                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: B Cells
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Clinical Immunology
                Subject: Autoimmune Diseases
                Subject: Crohn's Disease
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Clinical Immunology
                Subject: Autoimmune Diseases
                Subject: Crohn's Disease
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Clinical Immunology
                Subject: Autoimmune Diseases
                Subject: Crohn's Disease
                Subject: Medicine and Health Sciences
                Subject: Gastroenterology and Hepatology
                Subject: Inflammatory Bowel Disease
                Subject: Crohn's Disease
                Subject: Biology and life sciences
                Subject: Cell biology
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                Subject: Memory B cells
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                Subject: Memory B cells
                Subject: Medicine and health sciences
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                Subject: B cells
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                Subject: Biology and life sciences
                Subject: Cell biology
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                Subject: B cells
                Subject: Memory B cells
                Subject: Biology and life sciences
                Subject: Cell biology
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                Subject: Granulomas
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                Subject: Granulomas
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                Subject: Granulomas
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                Subject: Anatomy
                Subject: Body Fluids
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                Subject: Anatomy
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                Subject: Physiology
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                Subject: Hematology
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                Subject: Gastroenterology and Hepatology
                Subject: Inflammatory Bowel Disease
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                Subject: T Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
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                Subject: Immune Cells
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                Subject: T Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
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