Author/Editor		Kärner, J.; Trebušak Podkrajšek, Katarina; Bratanič, Nevenka; Battelino, Tadej
Title		Anti-cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice
Type		članek
Vol. and No.		Letnik 171, št. 3
Publication year		2013
Volume		str. 263-272
ISSN		0009-9104 - Clinical and experimental immunology
Language		eng
Abstract		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 (Th17) cell-associated cytokines, whose biological actions theyneutralize 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 Th17 cell-associated cytokines correlate withchronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin (Ig)Gs but not the IgAs in APECED sera are responsiblefor neutralizing IFN-Ž, IFN-Ž2a, interleukin (IL)-17A and IL-22. Their dominant subclasses proved to be IgG1 and, surprisingly, IgG4 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-Ž2a appeared mainly conformational. We also found mainly IgG1 neutralizingautoantibodies to IL-17A 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 deficiencyis not simply a mere side effect of chronic mucosal Candida infection, but appears to be related more closely to disease initiation.
Keywords		AIRE APECED IgG4 IL-22 thymoma type I interferons