Requirements for anti‐aquaporin 5 autoantibody production in a mouse model

Abstract

AbstractSeveral oral bacteria, including Prevotella melaninogenica (Pm), have aquaporin (AQP) proteins homologous to human AQP5, a major water channel protein targeted in Sjogren's syndrome. This study aimed to understand the antigenic characteristics that induce autoantibodies against an AQP5 “E” epitope (AQP5E) in a mouse model using C57BL/6 mice. Immunization with a PmE‐L peptide derived from Pm AQP, which contains amino acid mismatches both at the B‐ and T‐cell epitopes, efficiently induced anti‐AQP5E autoantibodies accompanied by increased germinal center (GC) B and follicular helper T cells in the draining lymph nodes. However, PmE, a peptide lacking a T‐cell epitope, and AQP5E‐L, an AQP5‐derived self‐peptide, hardly induced either anti‐AQP5E autoantibodies or GC responses. Surprisingly, OTII‐AQP5E, a peptide that replaced the self T‐cell epitope of AQP5E‐L with an ovalbumin‐derived foreign T‐cell epitope, was not any better than AQP5E‐L in the induction of anti‐AQP5E autoantibodies and GC response, despite the substantial expansion of CD4+ T cells and production of anti‐OTII‐AQP5E antibodies. The complex of biotinylated PmE‐L peptide and highly immunogenic streptavidin (SA) induced a strong extrafollicular B‐cell response skewed toward the expansion of SA‐specific B cells. However, the expansion of AQP5E‐specific GC B cells was limited, resulting in the inefficient induction of anti‐AQP5E autoantibodies. Collectively, our results have demonstrated that anti‐AQP5E autoantibody production is only allowed when foreign B‐ and T‐cell epitopes drive a strong GC response of AQP5E‐specific B cells for affinity maturation. This study helps explain why cross‐reactive anti‐AQP5 autoantibodies are not produced during the immune response to Pm in most healthy people.