PATHWAYS TO THE PRODUCTION OF DISEASE-RELATED AUTOANTIBO

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This Program Project will test three proposed mechanisms by which the low level production of natural IgM autoantibodies may be converted into a larger production of disease associated IgG autoantibodies. Project 0001 will test a model in which polyclonal B cell activation by viral infection is followed by specific immunization by both viral and self antigens. Normal humans produce IgM autoantibodies to CD43 (asialoglycophorin). HIV infection leads to polyclonal B cell activation and, in 15-20% of subjects, to formation of selective IgG autoantibodies to CD43. These phenomena appear parallel to the steps proposed for development of autoantibody formation in SLE. Project 0002 will test the proposal that idiotype interactions involving T cells as well as B cells can drive the formation of disease-associated autoantibodies. Certain idiotypes, such as the human idiotype Id 16/6, recur on disease associated immunoglobulins in different patients, and on immunoglobulins deposited in tissue lesions. There is experimental evidence that Id 16/6 has pathogenic potential and that T cells play a role in pathogenesis. This project will define the structural requirements for recognition of Id 16/6 by both antibodies and T cells and test the ability of Id 16/6-responsive T cell clones to drive IgG autoantibody formation. Project 0003 will test the proposal that B cells of autoimmune mice are intrinsically abnormal, in that they develop along a CD5-negative activation pathway in response to stimuli that normally lead to activation through a CD5-positive pathway. The CD5-positive pathway is associated with production of IgM natural autoantibodies, whereas the CD5- negative pathway leads to formation of disease-associated autoantibodies. Elucidation of the mechanisms of autoantibody formation may provide a basis for development of therapeutic measures.