Abstract

Break of tolerance driving autoimmune disease is initiated by a combination of predisposing genetic and environmental factors resulting in self-perpetuating chronic inflammation and tissue damage. Effector molecules and cells targeting tissues housing the inciting autoantigen(s) maintain tissue damage and the autoimmune response. Granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) is a prototypical autoimmune disease characterized by extravascular necrotizing granulomatous inflammation and a systemic autoimmune vasculitis associated with anti-neutrophil cytoplasmic autoantibodies specific for the neutrophil- and monocyte-derived serine-protease proteinase 3 (PR3-ANCA). GPA is strongly associated with HLA-DPB1*0401 polymorphisms. Its association with the R620W variant of the PTPN22 gene has been linked to reduced immune-regulatory interleukin (IL)-10 transcription. Epidemiological studies and molecular analysis of immune cells suggests a multifactorial pathogenesis of GPA, in which a potentially metachronous and individually varying sequence of infectious agents contributes to the break of tolerance and chronic inflammation sustaining autoimmunity in GPA.