Chronic signs of memory B cell activation in patients with Behçet's disease are partially restored by anti-tumour necrosis factor treatment

Tim B. Van Der Houwen, P. Martin Van Hagen, Wilhemina M. C. Timmermans, Sophinus J W Bartol, King H. Lam, Jasper H. Kappen, Menno C. van Zelm, Jan A M Van Laar

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4 Citations (Scopus)

Abstract

OBJECTIVES: Behçet's disease (BD), an auto-inflammatory vasculitis with oro-genital ulcerations, skin lesions and uveitis, is regarded as T cell mediated. A successful trial with rituximab suggests an additive role for B cells in the pathogenesis. Therefore, we studied B cell abnormalities in BD patients and the effect of TNF-blocking therapy.

METHODS: B cells in blood (n = 36) and tissue (n = 6) of BD patients were analysed with flow cytometry and/or immunohistochemistry and compared with healthy controls (n = 22). BD current activity form (BDCAF) in relation to B cell somatic hypermutations (SHMs) and immunoglobulin class-switching were studied.

RESULTS: Thirty-six patients (17 males) were included, mean age 44 years, average disease duration 10 years and mean BDCAF 2.7. Blood B cell numbers were significantly lower in patients than in controls (P = 0.0061), mostly due to decreased CD27+ memory B cells expressing IgM (P = 0.0001), IgG (P = 0.0002) and IgA (P = 0.0038) B cell subsets. CD27+ IgA+ B cells showed the highest magnitude of decrease in active disease, measured with BDCAF (P = 0.02). CD27+ IgM+ IgD+ B cells were impaired in replication history (P = 0.0133) and selection of SHM, whereas IgA+ B cells carried elevated SHM levels (P = 0.04) and lower IgA2 subclass usage (P = 0.0004) than controls. Immunohistochemistry revealed B cells in tissue of active mucosal ulcers. In adalimumab-treated patients, blood B cells were similar to controls.

CONCLUSION: We show significant deviations in the memory B cell compartment, related to disease activity and therapeutic efficacy. Pronounced molecular impairments were seen in the fast-responding IgM+-memory and the mucosal IgA+-memory B cells. Because of the demonstrated abundance of B cells in affected tissue, we hypothesize relocation of memory B cells to the site of inflammation could account for the deviations found in blood of BD patients. These peripheral B cells are easily accessible as a marker to monitor therapeutic efficacy.

Original languageEnglish
Pages (from-to)134-144
Number of pages11
JournalRheumatology
Volume56
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Behc¸ et’s disease
  • B cells
  • TNF blockers
  • memory B cell formation

Cite this

Van Der Houwen, T. B., Van Hagen, P. M., Timmermans, W. M. C., Bartol, S. J. W., Lam, K. H., Kappen, J. H., ... Van Laar, J. A. M. (2017). Chronic signs of memory B cell activation in patients with Behçet's disease are partially restored by anti-tumour necrosis factor treatment. Rheumatology, 56(1), 134-144. https://doi.org/10.1093/rheumatology/kew366
Van Der Houwen, Tim B. ; Van Hagen, P. Martin ; Timmermans, Wilhemina M. C. ; Bartol, Sophinus J W ; Lam, King H. ; Kappen, Jasper H. ; van Zelm, Menno C. ; Van Laar, Jan A M. / Chronic signs of memory B cell activation in patients with Behçet's disease are partially restored by anti-tumour necrosis factor treatment. In: Rheumatology. 2017 ; Vol. 56, No. 1. pp. 134-144.
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title = "Chronic signs of memory B cell activation in patients with Beh{\cc}et's disease are partially restored by anti-tumour necrosis factor treatment",
abstract = "OBJECTIVES: Beh{\cc}et's disease (BD), an auto-inflammatory vasculitis with oro-genital ulcerations, skin lesions and uveitis, is regarded as T cell mediated. A successful trial with rituximab suggests an additive role for B cells in the pathogenesis. Therefore, we studied B cell abnormalities in BD patients and the effect of TNF-blocking therapy.METHODS: B cells in blood (n = 36) and tissue (n = 6) of BD patients were analysed with flow cytometry and/or immunohistochemistry and compared with healthy controls (n = 22). BD current activity form (BDCAF) in relation to B cell somatic hypermutations (SHMs) and immunoglobulin class-switching were studied.RESULTS: Thirty-six patients (17 males) were included, mean age 44 years, average disease duration 10 years and mean BDCAF 2.7. Blood B cell numbers were significantly lower in patients than in controls (P = 0.0061), mostly due to decreased CD27+ memory B cells expressing IgM (P = 0.0001), IgG (P = 0.0002) and IgA (P = 0.0038) B cell subsets. CD27+ IgA+ B cells showed the highest magnitude of decrease in active disease, measured with BDCAF (P = 0.02). CD27+ IgM+ IgD+ B cells were impaired in replication history (P = 0.0133) and selection of SHM, whereas IgA+ B cells carried elevated SHM levels (P = 0.04) and lower IgA2 subclass usage (P = 0.0004) than controls. Immunohistochemistry revealed B cells in tissue of active mucosal ulcers. In adalimumab-treated patients, blood B cells were similar to controls.CONCLUSION: We show significant deviations in the memory B cell compartment, related to disease activity and therapeutic efficacy. Pronounced molecular impairments were seen in the fast-responding IgM+-memory and the mucosal IgA+-memory B cells. Because of the demonstrated abundance of B cells in affected tissue, we hypothesize relocation of memory B cells to the site of inflammation could account for the deviations found in blood of BD patients. These peripheral B cells are easily accessible as a marker to monitor therapeutic efficacy.",
keywords = "Behc¸ et’s disease, B cells, TNF blockers, memory B cell formation",
author = "{Van Der Houwen}, {Tim B.} and {Van Hagen}, {P. Martin} and Timmermans, {Wilhemina M. C.} and Bartol, {Sophinus J W} and Lam, {King H.} and Kappen, {Jasper H.} and {van Zelm}, {Menno C.} and {Van Laar}, {Jan A M}",
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Van Der Houwen, TB, Van Hagen, PM, Timmermans, WMC, Bartol, SJW, Lam, KH, Kappen, JH, van Zelm, MC & Van Laar, JAM 2017, 'Chronic signs of memory B cell activation in patients with Behçet's disease are partially restored by anti-tumour necrosis factor treatment', Rheumatology, vol. 56, no. 1, pp. 134-144. https://doi.org/10.1093/rheumatology/kew366

Chronic signs of memory B cell activation in patients with Behçet's disease are partially restored by anti-tumour necrosis factor treatment. / Van Der Houwen, Tim B.; Van Hagen, P. Martin; Timmermans, Wilhemina M. C.; Bartol, Sophinus J W; Lam, King H.; Kappen, Jasper H.; van Zelm, Menno C.; Van Laar, Jan A M.

In: Rheumatology, Vol. 56, No. 1, 01.01.2017, p. 134-144.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Chronic signs of memory B cell activation in patients with Behçet's disease are partially restored by anti-tumour necrosis factor treatment

AU - Van Der Houwen, Tim B.

AU - Van Hagen, P. Martin

AU - Timmermans, Wilhemina M. C.

AU - Bartol, Sophinus J W

AU - Lam, King H.

AU - Kappen, Jasper H.

AU - van Zelm, Menno C.

AU - Van Laar, Jan A M

PY - 2017/1/1

Y1 - 2017/1/1

N2 - OBJECTIVES: Behçet's disease (BD), an auto-inflammatory vasculitis with oro-genital ulcerations, skin lesions and uveitis, is regarded as T cell mediated. A successful trial with rituximab suggests an additive role for B cells in the pathogenesis. Therefore, we studied B cell abnormalities in BD patients and the effect of TNF-blocking therapy.METHODS: B cells in blood (n = 36) and tissue (n = 6) of BD patients were analysed with flow cytometry and/or immunohistochemistry and compared with healthy controls (n = 22). BD current activity form (BDCAF) in relation to B cell somatic hypermutations (SHMs) and immunoglobulin class-switching were studied.RESULTS: Thirty-six patients (17 males) were included, mean age 44 years, average disease duration 10 years and mean BDCAF 2.7. Blood B cell numbers were significantly lower in patients than in controls (P = 0.0061), mostly due to decreased CD27+ memory B cells expressing IgM (P = 0.0001), IgG (P = 0.0002) and IgA (P = 0.0038) B cell subsets. CD27+ IgA+ B cells showed the highest magnitude of decrease in active disease, measured with BDCAF (P = 0.02). CD27+ IgM+ IgD+ B cells were impaired in replication history (P = 0.0133) and selection of SHM, whereas IgA+ B cells carried elevated SHM levels (P = 0.04) and lower IgA2 subclass usage (P = 0.0004) than controls. Immunohistochemistry revealed B cells in tissue of active mucosal ulcers. In adalimumab-treated patients, blood B cells were similar to controls.CONCLUSION: We show significant deviations in the memory B cell compartment, related to disease activity and therapeutic efficacy. Pronounced molecular impairments were seen in the fast-responding IgM+-memory and the mucosal IgA+-memory B cells. Because of the demonstrated abundance of B cells in affected tissue, we hypothesize relocation of memory B cells to the site of inflammation could account for the deviations found in blood of BD patients. These peripheral B cells are easily accessible as a marker to monitor therapeutic efficacy.

AB - OBJECTIVES: Behçet's disease (BD), an auto-inflammatory vasculitis with oro-genital ulcerations, skin lesions and uveitis, is regarded as T cell mediated. A successful trial with rituximab suggests an additive role for B cells in the pathogenesis. Therefore, we studied B cell abnormalities in BD patients and the effect of TNF-blocking therapy.METHODS: B cells in blood (n = 36) and tissue (n = 6) of BD patients were analysed with flow cytometry and/or immunohistochemistry and compared with healthy controls (n = 22). BD current activity form (BDCAF) in relation to B cell somatic hypermutations (SHMs) and immunoglobulin class-switching were studied.RESULTS: Thirty-six patients (17 males) were included, mean age 44 years, average disease duration 10 years and mean BDCAF 2.7. Blood B cell numbers were significantly lower in patients than in controls (P = 0.0061), mostly due to decreased CD27+ memory B cells expressing IgM (P = 0.0001), IgG (P = 0.0002) and IgA (P = 0.0038) B cell subsets. CD27+ IgA+ B cells showed the highest magnitude of decrease in active disease, measured with BDCAF (P = 0.02). CD27+ IgM+ IgD+ B cells were impaired in replication history (P = 0.0133) and selection of SHM, whereas IgA+ B cells carried elevated SHM levels (P = 0.04) and lower IgA2 subclass usage (P = 0.0004) than controls. Immunohistochemistry revealed B cells in tissue of active mucosal ulcers. In adalimumab-treated patients, blood B cells were similar to controls.CONCLUSION: We show significant deviations in the memory B cell compartment, related to disease activity and therapeutic efficacy. Pronounced molecular impairments were seen in the fast-responding IgM+-memory and the mucosal IgA+-memory B cells. Because of the demonstrated abundance of B cells in affected tissue, we hypothesize relocation of memory B cells to the site of inflammation could account for the deviations found in blood of BD patients. These peripheral B cells are easily accessible as a marker to monitor therapeutic efficacy.

KW - Behc¸ et’s disease

KW - B cells

KW - TNF blockers

KW - memory B cell formation

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U2 - 10.1093/rheumatology/kew366

DO - 10.1093/rheumatology/kew366

M3 - Article

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JO - Rheumatology

JF - Rheumatology

SN - 1462-0324

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