Elevation of serum interleukin‐21 in patients with epidermolysis bullosa acquisita

Abstract

Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune bullous disease (AIBD) caused by autoantibodies targeting type VII collagen. Although the exact pathomechanism involved in EBA is unclear, a considerable amount of evidence shows that autoantibodies against type VII collagen play a major role in subepidermal blister formation. In fact, it has been reported that the titers of these autoantibodies positively correlate with disease severity in EBA. Rituximab, a monoclonal anti-CD20 antibody, is known to be effective for long-term remission in patients with EBA because of its ability to target B cells producing autoantibodies. T-follicular helper (Tfh) cells are a subset of CD4 T cells that induce the activation and differentiation of B cells into the antibody-producing plasma cells and the long-lived memory B cells. Tfh cells secrete interleukin (IL)-21, which promotes the growth, differentiation and class switching of B cells. Serum cytokine analyses in AIBD have been conducted to understand disease pathogenesis. However, cytokines in the sera of patients with EBA have not previously been analyzed. This study aimed to investigate the level of Tfh cytokines in patients with AIBD. Each case of AIBD was diagnosed by clinical, histological, and direct and indirect immunofluorescent studies. Diagnosis of EBA was confirmed through enzymelinked immunoassay (MBL Diagnostics, Nagoya, Japan) for type VII collagen. We used a cytometric bead array (Biolegend, San Diego, CA, USA) to evaluate serum levels of the cytokines IL-6, IL-10, IL-21 and tumor necrosis factor-a (TNF-a) in 14 patients with EBA, 10 with bullous pemphigoid (BP), 10 with pemphigus vulgaris (PV), 10 with pemphigus foliaceus (PF), six with paraneoplastic pemphigus (PNP) and in 18 healthy controls. Mann–Whitney U-tests were performed between each result and differences were defined as statistically significant at P < 0.05. The results revealed that serum IL-6 and IL-10 levels were significantly elevated in all patients with AIBD in comparison with healthy controls (Fig. 1a,b). Patients with PF showed elevated TNF-a and IL-21 levels and those with EBA showed elevated IL-21 levels in comparison with healthy controls (Fig. 1c,d). In patients with EBA, TNF-a and IL-21 levels showed positive correlation (Fig. 1e). However, the level of antibodies against type VII collagen and IL-21 were not significantly correlated in these patients (Fig. 1f). We did not find any difference in the IL-21 level between cases of mechanobullous (n = 5) and inflammatory types (n = 8) of EBA (data not shown).