BAFF modulates T follicular helper cell differentiation through the BAFFR-PI3K/AKT-mTOR signaling pathway in bullous pemphigoid.

Abstract

Background: Bullous pemphigoid (BP) is an autoimmune blistering disease primarily affecting older individuals. B-cell activating factor (BAFF), a member of the tumor necrosis factor superfamily, is crucial for B cell survival and T cell function. However, its role in the development of BP remains unclear.

Objective: To explore the BAFF expression and its specific role in the pathogenesis of BP.

Methods: BAFF levels in the serum, skin lesions, and blister fluid (BF) were measured using enzyme-linked immunosorbent assay, immunofluorescence, and flow cytometry. Naïve CD4⁺ T cells derived from healthy volunteers were cultured with BAFF to evaluate T cell activation, proliferation, and differentiation in vitro. A BP-like mouse model was constructed using BP180 immunization to analyze the therapeutic effects of anti-BAFF monoclonal antibody (mAb).

Results: BAFF levels were elevated in the serum, BF, and skin lesions of patients with BP, and the BAFF levels in the serum and BF were correlated with disease severity. Additionally, monocytes, neutrophils, and eosinophils were the likely sources of BAFF in the circulation and skin lesions of BP patients. In vitro, BAFF facilitated the activation and differentiation of naïve CD4⁺ T cells into T follicular helper cells (Tfh). Moreover, BAFF mediated Tfh differentiation via the BAFF receptor (BAFFR)-PI3K/AKT-mTOR pathway. Anti-BAFF mAb treatment reduced both the proportions of Tfh cells and autoantibody production in vivo.

Conclusion: These findings suggested that BAFF mediated Tfh differentiation via the BAFFR-PI3K/AKT-mTOR pathway, highlighting its promise as a therapeutic target for the management of BP.