Targeted Disruption of the Murine Gene Coding for the Third Complement Component (C3)

Pekna, Marcela; Hietala, Max Albert; Rosklint, T.; Betsholtz, Christer; Pekny, Milos

doi:10.1046/j.1365-3083.1998.00274.x

Cited by 23 publications

(20 citation statements)

References 40 publications

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“…Serum creatinine, urea nitrogen, cholesterol, and triglycerides were determined by standard methods in the department of clinical chemistry at the university hospital. Complement dependency was tested in one experimental series with C3-deficient C57BL/6N mice (24) and control C57BL/6N mice. Five C3-deficient and control mice were injected with 300 ml anti-podocyte serum, and four C3-deficient and control mice were injected with preimmune serum.…”

Section: Murine Model Of Sheep Anti-podocyte Nephritismentioning

confidence: 99%

Nephrotic Syndrome and Subepithelial Deposits in a Mouse Model of Immune-Mediated Anti-Podocyte Glomerulonephritis

Meyer-Schwesinger

Dehde

Klug

et al. 2011

The Journal of Immunology

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Subepithelial immune complex deposition in glomerular disease causes local inflammation and proteinuria by podocyte disruption. A rat model of membranous nephropathy, the passive Heymann nephritis, suggests that Abs against specific podocyte Ags cause subepithelial deposit formation and podocyte foot process disruption. In this study, we present a mouse model in which a polyclonal sheep anti-mouse podocyte Ab caused subepithelial immune complex formation. Mice developed a nephrotic syndrome with severe edema, proteinuria, hypoalbuminemia, and elevated cholesterol and triglycerides. Development of proteinuria was biphasic: an initial protein loss was followed by a second massive increase of protein loss beginning at approximately day 10. By histology, podocytes were swollen. Electron microscopy revealed 60–80% podocyte foot process effacement and subepithelial deposits, but no disruption of the glomerular basement membrane. Nephrin and synaptopodin staining was severely disrupted, and podocyte number was reduced in anti-podocyte serum-treated mice, indicating severe podocyte damage. Immunohistochemistry detected the injected anti-podocyte Ab exclusively along the glomerular filtration barrier. Immunoelectron microscopy localized the Ab to podocyte foot processes and the glomerular basement membrane. Similarly, immunohistochemistry localized mouse IgG to the subepithelial space. The third complement component (C3) was detected in a linear staining pattern along the glomerular basement membrane and in the mesangial hinge region. However, C3-deficient mice were not protected from podocyte damage, indicating a complement-independent mechanism. Twenty proteins were identified as possible Ags to the sheep anti-podocyte serum by mass spectrometry. Together, these data establish a reproducible model of immune-mediated podocyte injury in mice with subepithelial immune complex formation.

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Section: Murine Model Of Sheep Anti-podocyte Nephritismentioning

confidence: 99%

Nephrotic Syndrome and Subepithelial Deposits in a Mouse Model of Immune-Mediated Anti-Podocyte Glomerulonephritis

Meyer-Schwesinger

Dehde

Klug

et al. 2011

The Journal of Immunology

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“…Mice carrying the C3 [42] or FB null allele [43] were backcrossed to the DBA/1J genetic background (Bomholtgaard Ltd. Ry, Denmark) for six generations. Animals heterozygous for the respective null mutation were intercrossed to generate homozygous C3-deficient (C3 -/-), FB-deficient (FB -/-) and control lines.…”

Section: Micementioning

confidence: 99%

Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis

et al. 2004

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To analyze the role of the classical and alternative pathways of complement activation in the effector phase of arthritis, we have induced arthritis in C3-and factor B (FB)-deficient (C3 -/-and FB -/-) DBA/1J mice using well-defined monoclonal IgG2b and IgG2a antibodies to type II collagen. In control DBA/1J mice, severe swelling of the joints, destruction of cartilage and erosion of bone developed very rapidly with a 100% incidence and a peak on days 7-10. Although 75% of C3 -/-mice developed arthritis, the clinical severity was very mild and the onset was delayed. Severity of arthritis in FB -/-mice ranked intermediate in comparison with C3 -/-and control mice with an incidence of 100%. Immunohistochemical analysis of the inflamed joints demonstrated substantial reduction in macrophage and neutrophilic leukocyte infiltration in both C3 -/-and FB -/-mice, thereby confirming the clinical findings. We conclude that both the classical and the alternative pathways of complement activation are involved in the effector phase of arthritis.

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“…36) mice on a C57BL/6 background, IgAdeficient (IgA Ϫ/Ϫ ; Ref. 37) mice on a mixed (C57BL/6 ϫ 129Sv) background, and C3-deficient mice on a 129Ola/C57BL/6 background (38) were bred in ventilated cages under pathogen-free conditions at the Laboratory for Experimental Biomedicine, University of Göteborg, (Göteborg, Sweden). To obtain single and double gene knockout mice we crossed IL-10 Ϫ/Ϫ (C57BL/6) mice with IgA Ϫ/Ϫ (C57BL/6 ϫ 129Sv) mice and the F 1 offspring was subsequently crossed to obtain F 2 mice that were typed for IL-10 and IgA.…”

Section: Il-10-deficient (Il-10mentioning

confidence: 99%

IgA Antibodies Impair Resistance againstHelicobacter pyloriInfection: Studies on Immune Evasion in IL-10-Deficient Mice

Akhiani

Stensson

Schön

et al. 2005

The Journal of Immunology

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We recently reported that Helicobacter pylori-specific Abs impair the development of gastritis and down-regulate resistance against H. pylori infection. In this study, we asked whether IgA Abs specifically can have an impact on H. pylori colonization and gastric inflammation. To obtain a sensitive model for the study of inflammation we crossed IgA- and IL-10-deficient mice. We found that IL-10−/−/IgA−/− mice were significantly less colonized than IL-10−/−/IgA+/+ mice, which in turn were less colonized than wild-type (WT) mice. The IL-10−/−/IgA−/− mice exhibited a 1.2-log reduction in bacterial counts compared with that in IL-10−/−/IgA+/+ mice, suggesting that IgA Abs rather promoted than prevented infection. The reduced colonization in IL-10−/−/IgA−/− mice was associated with the most severe gastritis observed, albeit all IL-10−/− mice demonstrated more severe gastric inflammation than wild-type mice. The gastritis score and the infiltration of CD4+ T cells into the gastric mucosa were significantly higher in IL-10−/−/IgA−/− mice than in IL-10−/−/IgA+/+ mice, arguing that IgA Abs counteracted inflammation. Moreover, following oral immunization, IL-10−/−/IgA−/− mice were significantly better protected against colonization than IL-10−/−/IgA+/+ mice. However, the stronger protection was associated with more severe postimmunization gastritis and gastric infiltration of CD4+ T cells. There was also a clear increase in complement receptor-expressing cells in IL-10−/−/IgA−/− mice, though C3b-fragment deposition in the gastric mucosa was comparable between the two. Finally, specific T cell responses to recall Ag demonstrated higher levels of IFN-γ production in IL-10−/−/IgA−/− as compared with IL-10−/−/IgA+/+ mice. Thus, it appears that IgA and IL-10 help H. pylori bacteria evade host resistance against infection.

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Targeted Disruption of the Murine Gene Coding for the Third Complement Component (C3)

Cited by 23 publications

References 40 publications

Nephrotic Syndrome and Subepithelial Deposits in a Mouse Model of Immune-Mediated Anti-Podocyte Glomerulonephritis

Nephrotic Syndrome and Subepithelial Deposits in a Mouse Model of Immune-Mediated Anti-Podocyte Glomerulonephritis

Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis

IgA Antibodies Impair Resistance againstHelicobacter pyloriInfection: Studies on Immune Evasion in IL-10-Deficient Mice

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