Complement Factor H Deficiency Accelerates Development of Lupus Nephritis

• Published in: Journal of the American Society of Nephrology Vol. 22; no. 2; pp. 285 - 295
• Main Authors: LIHUA BAO, HAAS, Mark, QUIGG, Richard J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01-02-2011
• Subjects: Animals; Antibodies, Antinuclear - blood; Basic Research; Biological and medical sciences; Blood Urea Nitrogen; CD11b Antigen - analysis; Complement Factor H - deficiency; Complement Factor H - physiology; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Kidney Glomerulus - ultrastructure; Kidneys; Lupus Nephritis - etiology; Lupus Nephritis - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Nephrology. Urinary tract diseases; Renal Insufficiency - etiology; Urinary system involvement in other diseases. Miscellaneous; Kidney disease; Immunopathology; Connective tissue disease; Skin disease; Nephrology; Factor H; Urinary system disease; Autoimmune disease; Lupus nephritis; Immune deficiency; Urology; Systemic lupus erythematosus; Systemic disease; Complement deficiency; Development
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2010060647

Complement factor H (CfH) is a key regulator of the alternative pathway, and its presence on mouse platelets and podocytes allows the processing of immune complexes. Because of the role of immune complexes in the pathophysiology of lupus nephritis, we studied the role of CfH in the development of nephritis in MRL-lpr mice, an animal model of lupus. At 12 weeks, CfH-deficient MRL-lpr mice had significantly more albuminuria and higher BUN levels than MRL-lpr controls. Cfh-deficient MRL-lpr mice also experienced earlier mortality: at 14 weeks, 6 of 9 CfH-deficient MRL-lpr mice had died of renal failure, whereas all 11 littermate CfH-sufficient MRL-lpr mice were alive (P ≤ 0.001). Histologically, CfH-deficient MRL-lpr mice developed severe diffuse lupus nephritis by 12 weeks (glomerulonephritis scores of 2.6 ± 0.4 versus 0.4 ± 0.2 in littermate controls, P = 0.001). Similar to other CfH-deficient mouse models on nonautoimmune backgrounds, immunofluorescence staining showed extensive linear C3 staining along glomerular capillary walls. IgG was present in the mesangium and peripheral capillary walls along with excessive infiltration of macrophages and neutrophils. Ultrastructurally, there were subendothelial and subepithelial immune deposits and extensive podocyte foot process effacement. In summary, the loss of CfH accelerates the development of lupus nephritis and recapitulates the functional and structural features of the human disease. This illustrates the critical role of complement regulation and metabolism of immune complexes in the pathogenesis of lupus nephritis.