B-cell dysregulation in Crohn's disease is partially restored with infliximab therapy

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

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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 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. 

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.

Original languageEnglish
Article numbere0160103
Number of pages15
JournalPLoS ONE
Volume11
Issue number7
DOIs
Publication statusPublished - 1 Jul 2016

Cite this

Timmermans, W. M. C., van Laar, J. A. M., van der Houwen, T. B., Kamphuis, L. S. J., Bartol, S. J. W., Lam, K. H., Ouwendijk, R. J., Sparrow, M. P., Gibson, P. R., van Hagen, P. M., & van Zelm, M. C. (2016). B-cell dysregulation in Crohn's disease is partially restored with infliximab therapy. PLoS ONE, 11(7), [e0160103]. https://doi.org/10.1371/journal.pone.0160103