Evolution of the pathogenic autoimmun response in bullous pemphigoid

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Autoimmune diseases, similarly to cancer, generally show an increased frequency at higher age. While mechanisms of autoaggressive tissue damage have been increasingly investigated, the progression from autoimmunity to a pathogenic autoantibody response resulting in clinically overt disease is largely unexplored. The pemphigoids comprise a group of immunobullous skin disorders which affect the elderly and are typically preceded by a prodromal non-bullous stage. Therefore, the pemphigoids represent an exquisite model to study the initiation and regulation of a pathogenic autoimmune response in ageing individuals. By connecting basic to clinical research, the present project will allow to characterize the pathogenic mechanisms of the initiation of autoimmunity and its coupling to tissue damage in pemphigoids. Specifically, the autoantigenic epitopes that are recognized by autoreactive T cells as well as different possible determinants of the autoantibody pathogenicity, including their molecular specificity, isotype and glycosylation will be characterized in patients with “pre-pemphigoid” and full-blown pemphigoid as well as in a recently established mouse model of pemphigoid. In addition, to new mechanistic insights, the results of the present study will greatly facilitate the identification of subjects at risk to develop pemphigoid, the development of new diagnostic and prognostic tools, and of more effective therapeutic strategies. Importantly, new insights into the pathogenesis of the pemphigoids and newly developed diagnostic tools may be translated to more comprehensive research and, eventually, the management of other age-related inflammatory and autoimmune disorders.