Glomerular inflammation: Use of genetically deficient mice to elucidate the roles of leukocyte adhesion molecules and Fc-gamma receptors in vivo

Current Opinion in Nephrology and Hypertension

Volumn 8, Issue 3, 1999, Pages 293-298

  Mayadas, Tanya N ^a   Rosenkranz, Alexander ^a,b   Cotran, Ramzi S ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

[No Author keywords available]

Indexed keywords

CD11B ANTIGEN; CD18 ANTIGEN; CELL ADHESION MOLECULE; COMPLEMENT; COMPLEMENT COMPONENT C3; ENDOTHELIAL LEUKOCYTE ADHESION MOLECULE 1; FC RECEPTOR; INTERCELLULAR ADHESION MOLECULE 1; L SELECTIN; PADGEM PROTEIN; SELECTIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; GENETIC ENGINEERING; IMMUNE COMPLEX NEPHRITIS; IMMUNE MEDIATED INJURY; IMMUNOPATHOGENESIS; KNOCKOUT MOUSE; LEUKOCYTE ACTIVATION; LEUKOCYTE ADHERENCE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; REVIEW;

ANIMALS; CELL ADHESION MOLECULES; COMPLEMENT SYSTEM PROTEINS; DISEASE MODELS, ANIMAL; GLOMERULONEPHRITIS; IMMUNE COMPLEX DISEASES; LEUKOCYTES; MICE; MICE, KNOCKOUT; RECEPTORS, IGG; SELECTINS;

EID: 0032796115     PISSN: 10624821     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041552-199905000-00004     Document Type: Review

References (26)

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21. Clynes R, Dumitru C, Ravetch JV. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 1998; 279:1052-1054. This was the first study to demonstrate a primary role for FcγR in mediating the glomerular inflammatory response to immune complex deposition. Mice deficient in the signalling γ-chain of FcγR were crossed with NZB/NZW mice, which develop spontaneous lupus nephritis with mesangial thickening and hypercellularity evolving into end-stage sclerotic and crescentic changes. Despite significant immune complex and complement deposition, γ-chain-deficient mice did not develop severe nephritis with little hypercellularity and no evidence of end-stage glomerular changes, although the development of mesangial thickening was observed. γ-Chain NZB/NZW mice also had enhanced survival compared with wild-type NZB/NZW animals.
22. Park SY, Ueda S, Ohno H, Hamano Y, Tanaka M, Shiratori T, et al. Resistance of Fc receptor-deficient mice to fatal glomerulonephritis. J Clin Invest 1998; 102:1229-1238. The autologous phase of experimental anti-GBM nephritis was examined in γ-chain knock-outs generated by this group. Heterologous and autologous antibody deposition in the glomeruli of both wild-type and γ-chain-deficient mice was the same, as was the complement deposition. Whereas wild-type mice had a marked increase in serum levels of blood urea nitrogen and creatinine, indicating the development of renal failure, γ-chain-deficient mice stayed within the normal range. Proteinuria was delayed in the γ-chain-deficient mice and all γ-chain-deficient mice survived, whereas all wild-type mice died with azotemia by days 10-14 after the induction of glomerulonephritis. Wild-type mice developed severe glomerulonephritis with tubular changes, hypercellularity and thrombosis, whereas the renal morphology in γ-chain-deficient mice was almost normal with no indication of an inflammatory response. These results suggested that FcγRs played a primary pathogenic role in the development of glomerulonephritis.
23. Suzuki Y, Shirato I, Okumura K, Ravetoh JV, Takai T. Tornino Y, Ra C. Distinct contribution ot Fc receptors and angiotensin II-dependent pathways in anti-GBM glomerulonephritis. Kidney Int 1998; 54:1166-1174. The role of FcγR in the autologous phase of anti-GBM nephritis was examined using FcR γ-chain or FcγRHB-deficient mice, Proteinuria in γ-chain-deficient mice was substantially attenuated compared with wild-type mice, whereas it was accelerated in FcγRIIB-deficient mice, γ-Chain-deficient mice had less PMN influx, whereas FcγRIIB mice suffered accelerated glomerular injury, including thrombosis and fibrin deposition and cellular necrosis in spite of normal levels of PMNs. The levels of serum creatinine and blood urea nitrogen reflected the severity of proteinuria and histological changes in these animals. These studies suggest opposing roles for FcγRs in glomerulonephritis. The FcγR independent pathway of glomerular injury, including macrophage accumulation and mesangial cell expansion, were related to the angiotensin-renin system and not complement because an antagonist to angiotensin II type I receptor antagonist but not decomplementation with cobra venom factor ameliorated these injuries in γ-chain- deficient mice.
24. Ouigg RJ, Lim A, Haas M, Alexander JJ, He C, Carroll MC. Immune complex glomerulonephritis in C4- and C3-deficient mice. Kidney Int 1998; 53:320- 330.
25. Hebert MJ, Takano T, Papayianni A, Rennke HG, Minto A, Salant DJ, et al. Acute nephrotoxic serum nephritis in complement knockout mice: relative roles of the classical and alternate pathways in neutrophil recruitment and proteinuria, Nephrol Dial Transplant 1998; 13:2799-2803. C3- and C4-deficient mice were used to study the heterologous phase of nephritis after the injection of sheep anti-rat nephrotoxic serum that cross-reacts with murine glomerular antigens. In this model, PMN accumulation was complement dependent whereas proteinuria was largely complement independent.
26. Sheerin NS, Springall T, Carroll MC, Hartley B, Sacks SH. Protection against anti-glomerular basement membrane (GBM)-mediated nephritis in C3- and C4-deficient mice. Clin Exp Irnmunol 1997; 110:403-409. Anti-GBM antibody and C3- and C4-deficient mice, used in reference [18*], were also used in this study to investigate the role ot complement in the heterologous phase of anti-GBM nephritis. Neutrophil accumulation was complement independent or dependent depending on the dose of nephritogenic antibody injected. It is possible that at higher doses the neutrophil accumulation is more Fc and FcγR dependent as reported in reference [18*], whereas at lower doses complement plays a greater role. Proteinuria was complement dependent at low and high doses of antibody.