The long term goal of this proposal is to gain insight into the mechanisms underlying the generation of autoantibodies in systemic lupus erythematosis (SLE), a major human autoimmune disease. The predominant and pathogenic anti-self response in these autoimmune patients consists of autoantibodies to nuclear components, including DNA. The origin of these autoantibodies remains enigmatic, but antibodies with similar binding activity are expressed by the normal B cell repertoire (natural autoantibodies). Compared to naturally occurring anti-DNA autoantibodies, lupus autoantibodies of similar specificity are """"""""affinity mature"""""""", i.e., they are somatically mutated and antigen-selected. In addition, while the former are IgM, the latter are in general IgG, suggesting that class switching, a crucial mechanism in the maturation of any antibody response, is also important in the generation of autoantibodies in SLE. In class switching to IgG, the constant (C) region of the mu H chain is replaced by Cgamma region, resulting in the acquisition of novel biological activities, including the ability to pass into the extravascular space, and, therefore, in the case of autoantibodies to produce tissue damage. IgG-switched B cells are numerous in the circulation of SLE patients, and IgG accounts for the majority of the pathogenic autoantibodies in these patients. We formally argue here that class switching to IgG occurs more frequently and more effectively in lupus mu+ B cells than in normal mu"""""""" B cells. We further argue that this enhanced IgM->IgG switching results from a higher expression of CD40L by lupus T and B cells, as well as from a higher switching propensity of the B cells of these patients, due to a polymorphism of the Cgamma gene promoter or switch regions, and/or to dysregulation of the CD30-dependent mechanism that, as we have recently shown, physiologically dampens IgG-inducing stimuli. To test our hypothesis, we propose: (i) to study CD40L expression in SLE B cells, and their capacity to promote switching to IgG hypothesis, we propose: (i) to study CD40L expression in SLE B cells, and their capacity to promote switching to IgG using our unique in vitro human monoclonal (CL-01) IgM+ IgD+ B cell system; (ii) to analyze the in vitro spontaneous and CD40:CD40-induced IgG class switching in SLE IgM+ IgD+ B cells; (iii) to analyze the regulatory regions upstream of the Cgamma1, Cgamma2, Cgamma3, and Cgamma4 genes in SLE patients, their family members, and for comparison healthy subjects; and finally, (iv) to analyze the down-regulation of the CD40-mediated Ig class switching by CD30, another cell surface molecule of the TNFR family, and the interference with this mechanism by soluble CD30. The proposed experiments should further our understanding of the means that lead to Ig class switching and generation of IgG autoantibodies in lupus, and may help design specific means of therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI045011-01A1
Application #
6044320
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Kirshner, Susan
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$296,045
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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Pone, Egest J; Lam, Tonika; Lou, Zheng et al. (2015) B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses. J Immunol 194:3065-78
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Zan, Hong; Casali, Paolo (2013) Regulation of Aicda expression and AID activity. Autoimmunity 46:83-101
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Pone, Egest J; Zhang, Jinsong; Mai, Thach et al. (2012) BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-?B pathway. Nat Commun 3:767
Li, Guideng; Pone, Egest J; Tran, Daniel C et al. (2012) Iron inhibits activation-induced cytidine deaminase enzymatic activity and modulates immunoglobulin class switch DNA recombination. J Biol Chem 287:21520-9
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Xu, Zhenming; Zan, Hong; Pone, Egest J et al. (2012) Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat Rev Immunol 12:517-31
Zan, Hong; White, Clayton A; Thomas, Lisa M et al. (2012) Rev1 recruits ung to switch regions and enhances du glycosylation for immunoglobulin class switch DNA recombination. Cell Rep 2:1220-32

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