Antineutrophil cytoplasmic antibody and vasculitis: much more than a disease marker.

Abstract

Many forms of necrotizing small vessel vasculitis manifest glomerulonephritis, pulmonary hemorrhage and cutaneous purpura. Because the histologic appearance of the vasculitic lesions is similar in these conditions, early pathologists and clinicians resorted to categorizing small vessel vasculitides based on vessel size and systemic distribution. Not surprisingly, due to the tremendous overlap in clinical-pathologic features, these early classifications were woefully inadequate and perpetuated enduring confusion between the different nosologies adopted by internists, rheumatologists, nephrologists, and dermatologists. The introduction of immunofluorescence microscopy in the 1960s provided a major advance by uncovering three major immunopathologic categories of vasculitis. The demonstration of linear staining of alveolar and glomerular basement membranes (GBMs) in Goodpasture Syndrome led to the identification of circulating anti-GBM antibodies that cross-react with alveolar basement membrane, producing a pulmonary-renal syndrome. In the second major category of small vessel vasculitis, granular deposits of immunoglobulin and complement could be demonstrated in vessel walls and glomeruli. IgA-dominant deposits were identified in the cutaneous vessels and glomeruli of patients with Henoch Schonlein purpura, deposits of IgG-IgM in patients with mixed cryoglobulinemia, and IgG-dominant deposits in patients with lupus vasculitis and septic vasculitis. However, there was a third category of vasculitis (including microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, and renal-limited pauci-immune crescentic glomerulonephritis) for which few if any immune deposits could be identified in target tissues. Unraveling the pathogenesis of these pauci-immune vasculitides posed a special challenge, because this group defied existing paradigms of in situ or passive immune complex deposition. In the absence of demonstrable immune deposits, it was naturally assumed that the vascular injury was of a cellular nature, but it would be many years before attention focused on the neutrophil.