Abstract
Monogenic autoimmune syndromes provide a rare yet powerful glimpse into the fundamental mechanisms of immunologic tolerance. Such syndromes reveal not only the contribution of an individual breakpoint in tolerance but also patterns in the pathogenesis of autoimmunity. Disturbances in innate immunity, a system built for ubiquitous sensing of danger signals, tend to generate systemic autoimmunity. For example, defects in the clearance of self-antigens and chronic stimulation of type 1 interferons lead to the systemic autoimmunity seen in C1q deficiency, SPENCDI, and AGS. In contrast, disturbances of adaptive immunity, which is built for antigen specificity, tend to produce organ-specific autoimmunity. Thus, the loss of lymphocyte homeostasis, whether through defects in apoptosis, suppression, or negative selection, leads to organ-specific autoimmunity in ALPS, IPEX, and APS1. We discuss the unique mechanisms of disease in these prominent syndromes as well as how they contribute to the spectrum of organ-specific or systemic autoimmunity. The continued study of rare variants in autoimmune disease will inform future investigations and treatments directed at rare and common autoimmune diseases alike.