Systemic autoimmune diseases such as systemic lupus erythematosus (SLE) are characterized by polyclonal activation of B cells and the production of a variety of autoantibodies. Despite extensive investigation, the mechanism underlying polyclonal B cell activation and the production of specific autoantibodies has not been delineated. Recently, the potential role of microbially encoded superantigens in autoimmune conditions has been suggested. Of note, a number of superantigens have been shown to stimulate T cell-dependent polyclonal activation of B cells. Moreover, one of these superantigens, staphylococcal enterotoxin D (SED) has been shown to induce preferential production of the autoantibody, rheumatoid factor. One potential explanation for this finding is that SED may have the capacity to bind specific immunoglobulin Vh gene products, as well as T cell receptor molecules, and thereby function to stimulate B cells expressing these gene products preferentially. Thus, SED may function as a 'B cell superantigen' as well as a classic T cell superantigen. The proposed research will explore this possibility. The studies will delineate the production of immunoglobulin and autoantibodies by B cells from normals and persons with SLE to a battery of superantigens including SEA, SEB, SEC1, SEC2, SEC3, SED, SEE, and toxic shock syndrome toxin. The proposed work will examine the nature of the Vh (or Vl) gene segments expressed by B cells stimulated with the various superantigens, and will examine the binding of superantigens of interest to monoclonal immunoglobulin molecules containing specific Vh (Vl) segments. The proposed studies will also examine B cells from normals and patients with SLE for the signaling potential of superantigens and abnormalities characteristics of autoimmune diseases. Finally, the proposed studies will examine B cells from patients with SLE for biased expression of Vh (or Vl) gene segments that could be accounted for by in vivo superantigen stimulation. The proposed studies should provide insight into the possibility that 'B cell superantigens' may play a role in biasing the repertoire toward the production of autoantibodies in patients with autoimmune diseases such as SLE.
Showing the most recent 10 out of 53 publications
