Pso p27, a SERPINB3/B4-derived protein, is most likely a common autoantigen in chronic inflammatory diseases

Autoimmune diseases are characterized by chronic inflammatory reactions localized to an organ or organ-system. They are caused by loss of immunologic tolerance toward self-antigens, causing formation of autoantibodies that mistakenly attack their own body. Psoriasis is a chronic inflammatory autoimmune skin disease in which the underlying molecular mechanisms remain elusive. In this review, we present evidence accumulated through more than three decades that the serpin-derived protein Pso p27 is an autoantigen in psoriasis and probably also in other chronic inflammatory diseases. Pso p27 is derived from the serpin molecules SERPINB3 and SERPINB4 through non-canonical cleavage by mast cell chymase. In psoriasis, it is exclusively found in skin lesions and not in uninvolved skin. The serpins are cleaved into three fragments that remain associated as a Pso p27 complex with novel immunogenic properties and increased tendency to form large aggregates compared to native SERPINB3/B4. The amount of Pso p27 is directly correlated to disease activity, and through formation of complement activating immune-complexes, Pso p27 contribute to the inflammation in the skin lesions. SERPINB3/B4 are expressed in skin fibroblasts and keratinocytes, but normally absent in mast cells. Overexpression of the serpins may be induced by inflammation and hypoxia, resulting in mast cell uptake via yet unknown mechanisms. Here the generation and subsequent release of Pso p27 aggregates may promote an inflammatory loop that contributes to the chronicity of psoriasis and other autoimmune diseases.