Pathomechanisms Inducing and Perpetuating an Autoimmune Response in Psoriasis vulgaris

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Psoriasis is a complex T-cell mediated autoimmune disease involving genetic predisposition and environmental risk factors. The HLA-class I-allele HLA-C*06:02 is the main psoriasis risk gene. Psoriasis risk is modulated by epistasis between HLA-C*06:02 and certain variants of endoplasmic reticulum aminopeptidase I (ERAP1) which trims precursor peptides to the appropriate length for binding to the peptide-binding groove of HLA class I molecules. Because HLA-class I-molecules present peptide antigens from intracellular proteins to CD8+ T cells, an HLA-class I restricted immune response must be directed against a particular target cell. Psoriasis lesions develop upon epidermal infiltration and activation of CD8+ T cells. Using a pathogenic T-cell receptor (TCR) from a lesional epidermal CD8+ T cell clone of an HLA-C*06:02-positive psoriasis patient we had shown that HLA-C*06:02 mediates an autoimmune response against melanocytes, and we had identified a peptide autoantigen from ADAMTS-like protein 5 (ADAMTSL5) as melanocytic autoantigen. These data established direct experimental evidence for the autoimmune nature of psoriatic inflammation and they provide the basis for the ongoing and the projected research project. For this, the pathogenic psoriatic V Alpha 3S1 / V Beta 13S1-TCR represents a unique opportunity for elucidating the immunopathogenesis of psoriasis. In no other human autoimmune disease a similar approach has been successfully conducted yet. In the ongoing project we could demonstrate that proinflammatory signals cooperate with predisposing HLA-class alleles in promoting the T-cell mediated psoriatic autoimmune response, and we provided data showing that systemic inflammation in psoriasis at least partially results from skin inflammation. We characterized particular structural features of the autoantigenic psoriatic ADAMTLS5 peptide. We showed that protective and risk variants of ERAP1 affect the HLA-C*06:02-restricted autoimmune response against ADAMTSL5 through differential supply of antigenic peptides from NH2-terminal elongated peptide precursors for HLA binding. We identified several environmental antigens from pathogens, microbiota and food that might induce an ADAMTSL5-specific autoimmune response through cross-reactivity of the Vα3S1/Vβ13S1-TCR.In the renewal proposal we plan to finalize the analysis of the specific role of ERAP1 in the HLA-C*06:02-restricted autoimmune response against ADAMTSL5 and melanocytes; we intend to analyze the potential relevance of environmental trigger antigens for inducing a cross-reactive autoimmune response against ADAMTSL5; and we plan to identify B-cell autoantigen(s) which may activate the ADAMTSL5-specific Vα3S1/Vβ13S1-TCR and maintain a continuous supply of autoreactive melanocyte-specific psoriatic T cells. Overall, the insights obtained from these approaches may complete understanding of psoriatic autoimmune pathogenesis and provide a general concept for T-cell mediated autoimmunity.