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

Wilhelmina M C Timmermans,Sophinus J W Bartol,Rob J Ouwendijk,Tim B Van Der Houwen,Menno C Van Zelm,Jan A M Van Laar,Lieke S J Kamphuis,Miles P Sparrow,Peter R Gibson,P Martin Van Hagen,King H Lam

doi:10.1371/journal.pone.0160103

Abstract

BackgroundB-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn’s disease.ObjectiveTo 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.MethodsPatients 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.ResultsGranulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21low 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.ConclusionsB 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.

Highlights

The human intestinal tract contains a complex interplay between commensal bacteria, food antigens and the host immune system to limit inflammation, while preventing the translocation of intestinal microbiota
B-Cell Abnormalities in Crohn's Disease levels, making these subsets candidate markers for treatment monitoring. These results suggest a chronic, aberrant B-cell response in patients with Crohn’s disease, which could be targeted with new therapeutics that regulate B-cell function
An abnormal Th1 response is induced by dendritic cells that present commensal bacteria [3], which leads to overproduction of pro-inflammatory cytokines, including interferon-γ (IFN-γ) and tumor necrosis factor-alpha (TNF-α)

Summary

Introduction

The human intestinal tract contains a complex interplay between commensal bacteria, food antigens and the host immune system to limit inflammation, while preventing the translocation of intestinal microbiota. This delicate balance is disrupted in Crohn’s disease, a chronic inflammatory disease characterized by transmural inflammation of the gastrointestinal tract [1]. B-cells were found to affect regulatory T cell through production of IL-10 [15] It is not been clarified how B cells influence disease activity, because studies in murine models have reported ambiguous results, supporting either a suppressive or exacerbating role in gut inflammation [16,17,18]. B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn’s disease

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Conclusion