Is PR3-ANCA formation initiated in Wegener's granulomatosis lesions? Granulomas as potential lymphoid tissue maintaining autoantibody production.
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.
Voswinkel
J
J
Department of Rheumatology, University of Lübeck, Lübeck, Germany. voswinkel@rheuma-zentrum.de
Müller
A
A
Lamprecht
P
P
D019268:Antibodies, Antineutrophil Cytoplasmic / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology; D018106:CD28 Antigens / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D006099:Granuloma / Q000276:immunology*; D014890:Granulomatosis with Polyangiitis / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008221:Lymphoid Tissue / Q000276:immunology*; D053146:Myeloblastin; D012697:Serine Endopeptidases / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D019268:Antibodies, Antineutrophil Cytoplasmic; D018106:CD28 Antigens; D016207:Cytokines; D012697:Serine Endopeptidases; D053146:Myeloblastin