Anti‐cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice

Summary Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy ( APECED ) is a recessive disorder resulting from mutations in the autoimmune regulator ( AIRE ). The patients' autoantibodies recognize not only multiple organ‐specific targets, but also many type I interferons ( IFNs) and most T helper type 17 ( T h17) cell‐associated cytokines, whose biological actions they neutralize in vitro . These anti‐cytokine autoantibodies are highly disease‐specific: otherwise, they have been found only in patients with thymomas, tumours of thymic epithelial cells that fail to express AIRE . Moreover, autoantibodies against T h17 cell‐associated cytokines correlate with chronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin ( Ig)Gs but not the IgAs in APECED sera are responsible for neutralizing IFN ‐ω, IFN ‐α2a, interleukin ( IL) ‐17 A and IL ‐22. Their dominant subclasses proved to be IgG 1 and, surprisingly, IgG 4 without IgE , possibly implicating regulatory T cell responses and/or epithelia in their initiation in these AIRE ‐deficiency states. The epitopes on IL ‐22 and IFN ‐α2a appeared mainly conformational. We also found mainly IgG 1 neutralizing autoantibodies to IL ‐17 A in aged AIRE ‐deficient BALB /c mice – the first report of any target shared by these human and murine AIRE ‐deficiency states. We conclude that autoimmunization against cytokines in AIRE deficiency is not simply a mere side effect of chronic mucosal C andida infection, but appears to be related more closely to disease initiation.