Extrarenal cytokines modulate the glomerular response to IgA immune complexes.
Clinical episodes of IgA nephropathy coincide recurrently with microbial infections. Cytokines produced during such infections may play a role in the pathogenesis of IgA-associated glomerulonephritis. To test this hypothesis, we examined the influence of passively administered proinflammatory cytokines (IL-1, IFN-gamma and IL-6) on the development of glomerulonephritis in an experimental model of IgA nephropathy. Glomerular IgA immune deposits were induced in mice by administration of IgA anti-phosphorylcholine (PC) with either a PC-containing carbohydrate antigen of Pneumococcal C polysaccharide (PnC) or a protein antigen of PC-conjugated bovine serum albumin (PC-BSA). The effect of IL-1 on the IgA-PC-BSA induced glomerular changes resulted in an increase of mesangial hypercellularity that was associated with mild proteinuria and hematuria. Mice treated with IL-1 and IgA-PnC developed diffuse proliferative glomerulonephritis with proteinuria and hematuria. In contrast, IL-6 treatment with IgA-PC-BSA of IgA-PnC failed to exert any significant renal effect. The combination of IL-6 and IL-1, however, intensified the mesangial hypercellularity of the IgA-PC-BSA, and induced severe proliferative glomerulonephritis with inflammatory monocytes and neutrophils infiltrates in the IgA-PnC treated mice. These glomerular changes were also accompanied by increased proteinuria and hematuria. Similarly, the combination of IFN with IL-1 produced histologic changes and compromised renal function more than IFN or IL-1 exerted independently. These results suggest that extrarenal cytokines influence the renal response to IgA immune deposits. We also conclude that a synergy of multiple cytokines and nephritogenic antigens immobilized in glomerular IgA immune deposits may lead to rapid progression of IgA-associated glomerulonephritis.
Montinaro
V
V
Department of Pathology, Rhode Island Hospital, Providence.
Hevey
K
K
Aventaggiato
L
L
Fadden
K
K
Esparza
A
A
Chen
A
A
Finbloom
D S
DS
Rifai
A
A
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005922:Glomerulonephritis, IGA / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D007070:Immunoglobulin A / Q000378:metabolism; D007239:Infections / Q000150:complications; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL
D000936:Antigen-Antibody Complex; D016207:Cytokines; D007070:Immunoglobulin A