T cell alterations and lymphoid neogenesis favoring autoimmunity in Wegener's granulomatosis

Abstract

Wegener’s granulomatosis (WG) is a chronic inflammatory autoimmune disease of as-yet-unknown etiology characterized by necrotizing granulomatous lesions, glomerulonephritis, and an autoimmune vasculitis that predominantly affects small vessels (i.e., arterioles, capillaries, and venules). WG usually starts as a granulomatous disease of the respiratory tract (so-called localized WG, according to the European Vasculitis Study Group [EUVAS] definition [1]) and then, in most patients, it converts to a systemic disease (generalized WG, according to the EUVAS definition), with the emergence of antineutrophil cytoplasmic autoantibodies (ANCAs) specific for “Wegener’s autoantigen” proteinase 3 (PR3) and PR3 ANCA–associated vasculitis. PR3 ANCAs are highly specific for WG (2). In vitro studies support the concept that PR3 ANCAs interact with neutrophil granulocytes to cause premature intravascular neutrophil activation and degranulation, with subsequent endothelial damage and further leukocyte recruitment to the site of vasculitis (3). Multiple organs can be affected by granulomatous and/or vasculitic lesions. Deterioration of organ function as a consequence of pulmonary hemorrhage and rapidly progressive glomerulonephritis is seen in patients with severe, full-blown WG. Although WG is controlled by immunosuppressive treatment with cytotoxic agents, relapses are common and appear to be related to persistent granulomatous inflammation of the respiratory tract (“grumbling disease”) (2). While a great deal of attention has been paid to the mechanism of induction of the vasculitis, many other questions remain unanswered: How are PR3 ANCAs induced? Why and where does PR3 become the target of autoimmunity in WG (and why not one of the many other neutrophil constituents)? What is the relationship between granulomatous inflammation and autoimmunity in WG?