Systemic lupus erythematosus (SLE) is a chronic multisystem disease that is associated with a deficiency of the C4A but not the C4B isotype of the fourth component of human complement. Pathogenesis is attributed to the inadequate clearance and processing of immune complexes. Normally, processing of immune complexes in vivo requires the activation and covalent binding of C4 (C4b) and C3 (C3b) to the complexes thus preventing aggregation and precipitation of antibody-antigen complexes. The soluble complexes then bind to C4b/C3b receptors (CR1) expressed on erythrocytes and are transported from the circulation to the mononuclear phagocytic system for normal disposal. Studies have shown that immune complexes coated with C4A bind better to CR1 and are less likely to precipitate than C4B-coated complexes. The overall hypothesis to be tested is that structural differences existing between C4 isotypes differentially influence immune binding to CR1 and that during active SLE aberrant forms of C4 are produced mitigating interaction with CR1 thus contributing to pathogenesis. Preliminary data suggest that during active episodes of SLE the folding process of C4 is impaired resulting in a C4 protein that binds poorly to CR1 and C4B seems more affected than C4A. It is hypothesized that this occurs because of a stoichiometric imbalance between certain molecular chaperones, foldases and newly synthesized C4. Therefore, C4 from the sera of SLE patients during remission and during active disease will be compared for structural changes in secondary and tertiary structure using near and far UV circular dichroism and 8-anilino 1-naphalene sulfonate (ANS) fluorescence. The samples will be tested for the ability to inhibit immune precipitation, bind to immune complexes, and to CR1. The results obtained may provide insight into the disease process as well as contribute to better understanding of genetic association between C4A deficiency and SLE.
| Reilly, Brian D (2006) Structural comparison of human C4A3 and C4B1 after proteolytic activation by C1s. Mol Immunol 43:800-11 |
| Lewis, Jennifer D; Reilly, Brian D; Bright, Robert K (2003) Tumor-associated antigens: from discovery to immunity. Int Rev Immunol 22:81-112 |
| Reilly, B D (1999) Analysis of human C4A and C4B binding to an immune complex in serum. Clin Exp Immunol 117:12-8 |
