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

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.

Keywords: B cells; Behçet’s disease; TNF blockers; memory B cell formation.