The long term objective of the proposed research is to better understand the individual contributions of B cell subsets to the overall humoral response, and to determine whether a distinct B cell subset is associated with autoimmune disease. At present, our understanding of the basic characteristics and functions of the various B cell subsets is limited. Moreover, studies suggesting that damaging autoantibodies are primarily derived from a particular B cell subset remain controversial. Part of the difficulty in approaching these problems has been the lack of definitive markers to delineate different B cell populations. Our laboratory has found that the low affinity FceR may be quite useful in this regard, as it distinguishes conventional B cells from Ly 1 lineage and marginal zone B cells. Accordingly, the specific aims of the proposal are to: 1) Determine whether a particular B cell population, as defined by the FceR, is associated with the production of autoantibodies. This will be done by carefully analyzing the B cell subset composition of 15 lines of recombinant inbred mice derived from NZB and SM/J parents, and the progeny of these RI lines when crossed with NZW mice. The genetic predisposition for severe autoimmune disease has been segregated among the RI lines, and becomes manifest when the mice are mated to the NZW. 2) Determine whether FceR+ and FceR- B cells differentially respond to polyclonal stimuli. 3) Determine whether the FceR+ and FceR- B cells differentially respond to T helper cell stimuli. 4) Ascertain whether TI-1 and TI-2 antigen-specific responses are primarily derived from FceR-B cells. 5) Better understand the differing roles of FceR+ and FceR- B cells by attempting to gain new information as to the function of the FceR. This will be done by testing whether the FceR, when crosslinked to surface IgM or IgD, can modulated the activity of FceR+ B cells. The methods to be employed include extensive use of flow cytometry for analysis and cell sorting, polyclonal activation of B cells with anti-Ig, LPS and lymphokines, T cell dependent stimulation of B cells with activated TH1 and TH2 membranes plus lymphokines, and antigen-specific stimulation B cells with haptenated TI-1 and TI- 2 antigens. The health relatedness of this proposal is derived from the fact that all individuals depend upon a healthy and coordinated humoral response to produce protective antibodies. Failure of the B cell compartment to function properly not only compromises our ability to respond to pathogens, but can also lead to destructive autoimmune diseases such as rheumatoid arthritis, Sjorgren's syndrome and systemic lupus. Accordingly, it is essential to understand the complexity of the B cell population, and the conditions which lead to the production of autoantibodies.
