Our proposal is designed to test the hypothesis that there are normal restraints preventing the producers of natural autoantibody - CD5+ B cells - from progressing via somatic mutation and isotype switching to the production of pathogenic autoantibody. The likely restraints include: a specific prohibition against cognate interaction with T helper cells; prohibition of somatic mutation or switching, and a resistance to the induction of tolerance. We go on to suggest that in autoimmune prone individuals (strains), cognate interaction does take place, resulting in switching, mutation, and clonal expansion of cells producing high-affinity autoantibodies, and, ultimately, significant pathology. We will test the proposition that natural autoantibody producing B cells from autoimmune prone mouse strains (individuals) can respond to cognate interactions with helper T cells, generating isotype switching and somatic mutation. We will test the idea that stimuli which ordinarily induce programmed cell death or anergy have no such affect on B cells from the autoimmune prone. These experiments are based on our recent work showing that the B cell CD5 phenotype arises from thymus independent type 2 (sIg cross-linking) activation, while cognate interaction with T cells generates CD5 j11dlow cells. We have also found that once generated normal CD5+ B cells die in response to sIg cross-linking. the basic hypothesis to be tested is that CD5+ cells from disease prone individuals are resistant to these restraints. If validated, this would explain the many hitherto puzzling observations which link polysystem autoimmune disease, natural autoantibodies, CD5+ B cells and chronic lymphatic leukemia.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Stollar, B D; Lecerf, J M; Hirabayashi, Y (1997) The role of autoreactivity in B cell selection. Ann N Y Acad Sci 815:30-9
Stollar, B D (1997) Bacterial expression of anti-DNA antibody domains. Methods 11:12-9
Anderson, J S; Teutsch, M; Dong, Z et al. (1996) An essential role for Bruton's [corrected] tyrosine kinase in the regulation of B-cell apoptosis. Proc Natl Acad Sci U S A 93:10966-71
Kalsi, J K; Martin, A C; Hirabayashi, Y et al. (1996) Functional and modelling studies of the binding of human monoclonal anti-DNA antibodies to DNA. Mol Immunol 33:471-83
Wortis, H H; Teutsch, M; Higer, M et al. (1995) B-cell activation by crosslinking of surface IgM or ligation of CD40 involves alternative signal pathways and results in different B-cell phenotypes. Proc Natl Acad Sci U S A 92:3348-52
Teutsch, M; Higer, M; Wang, D et al. (1995) Induction of CD5 on B and T cells is suppressed by cyclosporin A, FK-520 and rapamycin. Int Immunol 7:381-92
Stollar, B D (1995) The expressed heavy chain V gene repertoire of circulating B cells in normal adults. Ann N Y Acad Sci 764:265-74
McFarland, T A; Ardman, B; Manjunath, N et al. (1995) CD43 diminishes susceptibility to T lymphocyte-mediated cytolysis. J Immunol 154:1097-104
Manjunath, N; Ardman, B (1995) CD43 regulates tyrosine phosphorylation of a 93-kD protein in T lymphocytes. Blood 86:4194-8
Hirabayashi, Y; Lecerf, J M; Dong, Z et al. (1995) Kinetic analysis of the interactions of recombinant human VpreB and Ig V domains. J Immunol 155:1218-28

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