Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies

Abstract

The complement system plays a paradoxical role in the development and expression of autoimmunity in humans. The activation of complement in systemic lupus erythematosus (SLE) contributes to tissue injury. In contrast, inherited deficiency of classical pathway components, particularly C1q (ref. 1), is powerfully associated with the development of SLE. This leads to the hypothesis that a physiological action of the early part of the classical pathway protects against the development of SLE (ref. 2) and implies that C1q may play a key role in this respect. C1q-deficient (C1qa-/-) mice were generated by gene targeting and monitored for eight months. C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.

Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

“…Mapping of loci predisposing to lupus in the (129 Â B6).C1qa À/À mice The observation that 129.C1qa À/À and B6.C1qa À/À mice did not develop any autoimmune traits 16 while the (129 Â B6).C1qa À/À mice developed a lupus-like disease 3 suggest that the disease-modifying loci may arise as a result of interaction between specific combinations of alleles inherited from both the 129 and B6 parental strains. In order to investigate the genetic contribution of 129 and B6 genes to the lupus-like disease observed in the (129 Â B6).C1qa À/À mice, we generated a new cohort of (129 Â B6)F2.C1qa À/À animals and monitored these for a year.…”

“…The C1q-deficient mice, C1qa À/À were generated as previously reported 3 and the (129 Â B6)F1.C1qa À/À mice were generated by crossing 129.C1qa À/À mice with B6.C1qa À/À mice that had been backcrossed onto B6 for 10 generations. (129 Â B6)F2.C1qa À/À were obtained by intercrossing the (129 Â B6)F1.C1qa À/À mice.…”

“…In this regard, it is of note that the majority of the gene-targeted strains are initially developed on a hybrid genetic background between 129 and C57BL/6 (B6) mice, which has been shown to be spontaneously predisposed to development of humoral autoimmunity with low levels of glomerulonephritis. [2][3][4][5] The initial knockout strain is then usually backcrossed onto B6 in order to remove as much 129 genome as possible. However, despite 10 or more generations of backcrossing, a considerable 129-derived genome interval, flanking the targeted gene, will remain.…”

“…5,15,16 For example, C1q deficiency, a condition that in humans is strongly associated with the development of a lupus-like disease, 17 in mice appears to have a disease-accelerating effect only in lupus-prone strains, including the (129 Â B6) genetic background. 3,16 Likewise, inactivation of the FcgRIIB gene results in the development of a lupus-like phenotype in the context of the B6 genomic background, but not the BALB/c genomic background. 15 In this example, it is of note that two recessive B6-derived loci outside the targeted region were linked to the development of the disease phenotype.…”

Disposal of dying cells: A balancing act between infection and autoimmunity

“…Defects in the scavenging process of apoptotic cells have been postulated to play a crucial role in the development and expression of autoimmunity in humans (32)(33)(34)(35). SLE is a prototypic systemic autoimmune disease.…”