NEUTROPHIL ACTIVATION IN-VITRO AND IN-VIVO IN WEGENERS GRANULOMATOSIS

The mechanisms underlying glomerular capillary wall injury in Wegener' s granulomatosis (WG) are not well understood. Anti-neutrophil cytopla smic antibodies (ANCA), present in sera from patients with WG, are kno wn to stimulate respiratory burst and degranulation of primed polymorp honuclear neutrophils (PMN) in vitro. Experimental studies have shown that oxygen radical production and lysosomal enzymes are important med iators of glomerular capillary wall injury. In the present study we in vestigated the presence of activated PMN and the extracellular localiz ation of lysosomal enzymes in 28 consecutive renal biopsies from patie nts with WG. The presence of activated PMN within the renal biopsies w as compared with the capacity of ANCA, isolated from simultaneously dr awn serum samples, to activate primed PMN obtained from a normal donor . Both parameters were also related to renal function. Renal biopsies were obtained from newly diagnosed WG patients before therapy had star ted. Activation of PMN in the biopsies was assessed by measuring hydro gen peroxide production in situ. The number of activated PMN in the bi opsy correlated with the extent of impairment of renal function, Prote inase 3, myeloperoxidase, and elastase, all targets of ANCA, were loca lized extracellularly in renal tissue and were also found within tubul ar epithelial cells. All ANCA positive samples were capable of activat ing primed PMN. The amount of activation correlated with the ANCA tite r in those samples. No correlation, however, was found between the in vitro capacity of ANCA-positive IgG fractions to activate primed PMN a nd the number of activated PMN present in the renal biopsy. We conclud e that activated PMN producing toxic oxygen metabolites and releasing lysosomal enzymes, are present in renal biopsies from patients with WG . The amount of activated PMN present within the kidney, and not the c apacity of the corresponding ANCA to activate PMN, correlates with ren al tissue damage as assessed by serum creatinine levels.