Anti-neutrophil cytoplasmic autoantibodies (ANCA) are found in patients with Wegener's granulomatosis, polyarteritis nodosa and idiopathic crescentic glomerulonephritis. All three diseases are characterized by pathologically identical necrotizing and crescentic glomerulonephritis, with the first two also having necrotizing arteritis. ANCA are not found in a wide spectrum of other renal diseases. Preliminary data suggest that ANCA are specific for constituents of the primary granule, one of which is myeloperoxidase, and that ANCA may induce granulocyte degranulation and a respiratory burst.
The aims of the proposed research are: 1) to determine ANCA specificity, sensitivity and utility as a diagnostic and prognostic marker in a wide spectrum of human diseases, especially those characterized by necrotizing and crescentic glomerulonephritis and vasculitis! 2) to discover all of the antigens for which ANCA have specificity; and 3) to determine the in vitro effects of ANCA on granulocyte function.
The first aim will be accomplished by using indirect immunofluorescence microscopy and enzyme immunoassays to analyze sera from a large population of patients with well characterized renal, vascular, inflammatory or infectious diseases. We will correlate the presence and titer of ANCA with clinical and pathologic data.
The second aim will be met by determining the reactivity of ANCA with subcellular fractions and isolated molecular constituents of granulocytes using several analytical and purification techniques.
The third aim will probe in vitro the ability of ANCA to induce granulocyte degranulation and a respiratory burst, as well as the consequence of ANCA granulocyte activation on endothelial cell monolayers. The long term objectives of the proposed research are to elucidate the pathogenic mechanism underlying necrotizing and crescentic glomerulonephritis and necrotizing arteritis. The discovery of a common serological marker in patients with different clinical manifestations of disease will improve the diagnosis and management of necrotizing and crescentic glomerulonephritis and necrotizing arteritis. The discovery that ANCA cause granulocytes to release reactive oxygen species and proteolytic enzymes will provide novel insights into the pathogenesis of arteritis.
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