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(The FASEB Journal. 2008;22:lb478)
© 2008 FASEB
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lb478

Role of Complement C4 in the Regulation of Self-Reactive B Cells

AMMA AGYEMANG1, MARAT B ALIMZHANOV2,3, THEREZA IMANISHI-KARI4 and MICHAEL C CARROLL5

1 IMMUNE DISEASE INSTITUTE, HARVARD MEDICAL SCHOOL, DIVISION OF MEDICAL SCIENCES, BOSTON, MA,
2 IMMUNE DISEASE INSTITUTE, HARVARD MEDICAL SCHOOL, BOSTON, MA,
3 AstraZeneca R&D Boston, Waltham, MA,
4 DEPARTMENT OF PATHOLOGY AND PROGRAM IN IMMUNOLOGY, TUFTS UNIVERSITY SCHOOL OF MEDICINE & SACKLER SCHOOL OF GRADUATE BIOMEDICAL SCIENCES, BOSTON, MA,
5 DEPARTMENT OF PATHOLOGY AND PEDIATRICS, HARVARD MEDICAL SCHOOL, IMMUNE DISEASE INSTITUTE, BOSTON, MA

ABSTRACT

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by nephritis, arthritis, dermatitis and antibody production against nuclear antigens. In humans and mice, deficiency in the classical complement components C1, C2 and C4 is strongly associated with SLE. Studies suggest that complement proteins ameliorate SLE by enhancing the 1) efficient removal of immune complexes and apoptotic debris and/or 2) negative selection of developing B cells. In this study, we used the 564 immunoglobulin (Ig) heavy and light chain knock-in mouse model on a C4-deficient or complement receptor 1/2 (CR1/2) deficient background to examine the effects of complement C4 on the regulation of nuclear antigen specific (NAS) B cells. In control mice, NAS B cells were negatively selected. Those that escaped had an immature, anergic phenotype and were excluded from B cell follicles. C4–/–564Ig and CR1/2–/–564Ig NAS B cells differentiated into non-anergic, mature B cells without follicular exclusion. Production of anti-nuclear antibodies was detected in both C4–/–564Ig mice and controls. However, specific antibody deposition in kidneys was only observed in C4–/–564Ig mice. These data suggest that complement C4 is involved in negative selection of NAS B cells and clearance of potentially pathogenic antibodies. This role of complement C4 may be partially dependent on complement receptors CR1 and CR2.





This Article
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