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PMID: 11067882 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2.

The Journal of experimental medicine ·Vol. 192 ·No. 9 ·2000-11-06 ·Pages 1339-52

Chen Z, Koralov SB, Kelsoe G

Abstract

The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans. In mice, disruption of the C1qa gene also results in spontaneous autoimmunity. Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses. These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity. Here we report high titers of spontaneous antinuclear antibody (ANA) in C4(-/)- mice. This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA. In contrast, titers and frequencies of ANA in Cr2(-)(/)- mice, which are deficient in CR1 and CR2, never rose significantly above those in normal controls. Glomerular deposition of immune complexes (ICs), glomerulonephritis, and splenomegaly were observed in C4(-)(/)- but not Cr2(-)(/)- mice. C4(-)(/)-, but not Cr2(-)(/)-, mice accumulate activated T and B cells. Clearance of circulating ICs is impaired in preautoimmune C4(-)(/)-, but not Cr2(-)(/)-, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2.

MeSH Terms
Animals Antibodies, Antinuclear/biosynthesis,blood,immunology Antigen-Antibody Complex/immunology Autoimmunity/immunology Cells, Cultured Complement C4/deficiency,genetics,immunology,metabolism Disease Models, Animal Enzyme-Linked Immunosorbent Assay Female Gene Deletion Histocytochemistry Kidney/immunology,pathology Lupus Erythematosus, Systemic/complications,immunology,pathology Lymphocyte Activation/immunology Male Mice Mice, Inbred Strains Mice, Knockout Receptors, Complement 3b/immunology,metabolism Receptors, Complement 3d/deficiency,genetics,immunology,metabolism Spleen/immunology,pathology Splenomegaly/complications,immunology,pathology
Chemicals
Antibodies, Antinuclear Antigen-Antibody Complex Complement C4 Receptors, Complement 3b Receptors, Complement 3d
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Chen Z
Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Koralov S B
Kelsoe G
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.192.9.1339
Published
2000-11-06
Pages
1339-52
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193358
Subset
IM
Grants
NIA NIH HHS · AG10207 · United States
NIA NIH HHS · AG13789 · United States
NIAID NIH HHS · AI24335 · United States
External Links
PubMed source DOI: 10.1084/jem.192.9.1339 PMC Full Text View journal details
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