Systemic lupus erythematosus (SLE) is an autoimmune disorder which affects over 200,000 women in the USA and it is characterized by anti-nuclear antibodies and a high incidence of glomerulonephritis. A major risk factor for SLE is deficiency in early classical pathway complement components C1, C2 or C4. This association presents a paradox because it is not expected that an immune deficiency would result in an autoimmune disease. One explanation is that early complement is involved in maintenance of B cell tolerance and in its absence, self-reactive B cells accumulate in the periphery where they potentially may be activated. The goal of this proposal is to test this hypothesis and it is divided into 3 specific aims: (i) Test the hypothesis that early classical pathway complement components C1, C4 and C3 are directly involved in negative selection of self-reactive B lymphocytes. The approach used in this aim is to breed mice deficient in C1, C4, or C3 with two well established immunoglobulin transgenic models (anti-HEL and anti-dsDNA) and determine if complement is essential in B cell anergy. (ii) The second aim will test the hypothesis that deficiency in classical pathway complement results in increased severity of disease in a well defined mouse model of lupus, i.e. lpr strain. The advantage of this aim is that it will examine the importance of early complement in the autoimmune response to natural lupus antigens such as dsDNA and nuclear proteins. (iii) The third aim will test the hypothesis that impaired self-tolerance in C4null mice can be rescued by protein replacement or gene therapy and if so compare C4A and C4B isotypes. It will also examine the mechanism of C4 in B cell tolerance using a fusion protein of C4d linked to sHEL antigen to uncouple solubilization of immune complexes from targeting of antigen to the lymphoid compartment via C4d.
This aim i s important as it will establish the feasibility of protein or gene therapy in lupus and clarify our understanding of B cell tolerance.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038749-03
Application #
6387704
Study Section
Special Emphasis Panel (ZHD1-SRC (99))
Program Officer
Lock, Allan
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$279,307
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115
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Paul, Elahna; Lutz, Johannes; Erikson, Jan et al. (2004) Germinal center checkpoints in B cell tolerance in 3H9 transgenic mice. Int Immunol 16:377-84
Paul, Elahna; Pozdnyakova, Olga O; Mitchell, Elizabeth et al. (2002) Anti-DNA autoreactivity in C4-deficient mice. Eur J Immunol 32:2672-9
Einav, Shirit; Pozdnyakova, Olga O; Ma, Minghe et al. (2002) Complement C4 is protective for lupus disease independent of C3. J Immunol 168:1036-41
Gadjeva, Mihaela; Verschoor, Admar; Brockman, Mark A et al. (2002) Macrophage-derived complement component C4 can restore humoral immunity in C4-deficient mice. J Immunol 169:5489-95