Most primary salivary gland lymphomas are B cell malignancies of mucosa associated lymphoid tissue (MALT) type that develop out of an organized reactive lymphoid infiltrate termed lymphoepithelial sialadenitis (LESA) which represents the salivary gland lesion seen in all patients with Sjogren's syndrome. The cause of LESA is unknown, although it is thought to represent an immune response to some as yet unidentified autoantigen or exogenous (infectious) antigen. The transition from reactive infiltrate to monoclonal lymphoma that sometimes occurs is poorly understood. We have shown that salivary gland MALT lymphomas from different patients often express remarkably similar immunoglobulin heavy chain variable (VH) genes suggesting they recognize the same antigen. Based on these data, we hypothesize that chronic stimulation by a single or limited number of antigens is responsible for the selection of B cells that express the frequently used VH genes, and that continued stimulation by this antigen promotes the development of neoplasia. The goal of the proposed research is to identify specific antigens that may be playing a role in the development of salivary gland MALT lymphomas and the mechanism whereby B cells with particular VH genes are preferentially targeted for malignant transformation. We have already made several different antibodies from 5 representative salivary gland MALT lymphoma cases by expressing the cloned lymphoma VH and VL genes in mammalian tissue culture adapted cells. To identify the antigen(s) hypothesized to be promoting salivary gland lymphomagenesis, we will use these recombinant lymphoma antibodies in western blot and immunoprecipitation studies of salivary gland and other tissues, and also to screen random peptide and cDNA expression libraries. Molecules of interest will be further characterized by tandem mass spectroscopy, or cloning. Particular features of lymphoma antibody binding molecules such as their anatomic locations or homology to pathogens may help explain a possible role in lymphoma development. Since salivary gland MALT lymphomas may be responding to the antigenic trigger of LESA, these studies could also provide insight into the etiology of Sjogren's syndrome and lead to new types of effective treatments or prevention strategies. In addition, this system may further aid in understanding how antigen receptor mediated selection contributes to the development of other B-cell malignancies. PROJECT NARRATIVE: The incidence of lymphoma, a type of immune system cancer, is increasing. The research in these studies should help explain how lymphomas arise out of organ specific chronic autoimmune diseases such as Sjogrens syndrome. Our findings may also lead to a better understanding of other types of immune system cancers and result in new or better treatments for both lymphomas and autoimmune diseases.
