Is PR3‐ANCA Formation Initiated in Wegener's Granulomatosis Lesions? Granulomas as Potential Lymphoid Tissue Maintaining Autoantibody Production

A bstract : In Wegener's granulomatosis (WG), antiproteinase 3 (PR3) autoantibodies (PR3‐ANCA) are crucial in the development of generalized vasculitis. Wegener's pathognomonic lesion, a granulomatous inflammation of the upper and lower respiratory tract, contains abundant lymphocytes and macrophages. Lymphocyte clusters in germinal center‐like formation within the granulomatous lesion are frequently observed, which suggests antigen‐driven B cell maturation. Wegener's autoantigen PR3, the target for autoreactive B and T cells, is expressed in granulomatous lesions. Disease progression in WG is accompanied by a profound generalized alteration of T cell differentiation with an increase of effector memory T cells (CD4 + CD28 − ). The cytokine profile suggests an aberrant Th1‐type response either to an environmental trigger and/or the autoantigen PR3 itself. Staphylococcus aureus , a risk factor for disease exacerbation, is widely present in the upper airways in WG. The Ig gene repertoire from WG lesions indicates a predominance of VH3+ B cells with affinity to PR3 as well as to the S. aureus B cell superantigen SPA. Hence, within the WG lesion, S. aureus might support the maturation of PR3‐affinity B cells that enter a germinal center reaction in contact with PR3 and T cells and expand, leading to PR3‐ANCA production. Thus, granulomatous lesions could represent a potential lymphoid tissue‐maintaining autoantibody production rather than a simple, random leukocyte accumulation in WG.