CD4+ T-cell cooperation promoted pathogenic function of activated naïve B cells of patients with SLE

Abstract

Objective: To explore cooperation between activated naïve (aNAV) B cells and CD4⁺ T cells in the pathogenesis of SLE through autoantibody production, T-cell differentiation and inflammatory cytokine secretion.

Methods: Peripheral blood mononuclear cell samples were obtained from 31 patients with SLE and used to characterise phenotype of aNAV B cells (n=14) and measured the phosphorylation of B-cell receptor (BCR) signalling molecules (n=5). Upregulation of T-cell costimulatory molecules after BCR and toll-like receptor (TLR)-7/TLR-8 stimulation was detected in cells from four subjects. To explore the role of these cells in SLE pathogenesis via T cell-dependent mechanisms, four subjects were analysed to detect the promotion of CD4⁺ T-cell activation and antibody-secreting cell (ASC) differentiation after CD4⁺ T-cell-B-cell cocultures. The aNAV B cells from four patients were used to assess cytokine secretion.

Results: The aNAV B cells of patients with SLE had increased expression of surface CD40, HLA-DR and interleukin-21 receptor (IL-21R) and FCRL5 molecules. With BCR stimulation, these cells greatly increased PLCγ2 phosphorylation. Integrated BCR and TLR-7/TLR-8 signals induced overexpression of CD40, CD86, IL-21R and HLA-DR on lupus aNAV B cells. In T-cell-B-cell cocultures, lupus aNAV B cells (with upregulated costimulatory molecules) promoted CD4⁺ T-cell proliferation and polarisation toward effector Th₂ and Th₁₇ cells. Importantly, in this coculture system, CD4⁺ T-cell signals enhanced aNAV B-cell differentiation into auto-ASCs and produced anti-DNA antibodies. The interaction between CD4⁺ T cell and aNAV B cell increased production of inflammatory cytokines (IL-6, IL-8 and IL-23).

Conclusion: Cooperation between aNAV B cells and CD4⁺ T cells contributed to SLE pathogenesis by promoting both differentiation of pathogenic T cells (Th₂ and Th₁₇) and autoantibody secretion.

Keywords: B-Lymphocytes; autoimmunity; lupus erythematosus, systemic.