The broad, long-term objectives of this proposal are to understand the mechanisms of immune-mediated loss of salivary function, to isolate points at which these mechanisms can be blocked, and to develop therapeutic and preventive interventions targeting these points.
The specific aims are 1) to determine whether autoantibodies and/or autoreactive T cells are necessary and sufficient to induce loss of salivary function in the NOD mouse; 2) to identify the specificities of the T and/or B cells responsible for loss of salivary function; 3) to determine whether humans with SS show evidence of responses to autoantigens similar to those which trigger loss of salivary function in the NOD mouse. The health relatedness of this project is that loss of salivary function is the primary disabling symptom of Sjogren's syndrome, an autoimmune disease that affects approximately one million Americans and is highly detrimental to general oral health, particularly in terms of dental caries. The hypothesis behind this proposal is that loss of salivary function can be induced by lymphocytes, specifically autoantibody-producing B cells, possibly in concert with T cells. The basic experimental design is to use loss of salivary function in the NOD mouse as a model of the salivary hypofunction that results from Sjogren's syndrome. Monoclonal antibodies and T cell clones specific for potential autoantigens in the NOD mouse will be isolated and the genes encoding their antigens will be cloned. Loss of salivary function will be the criterion used to evaluate the immunopathogenic potential of antibodies and T cells with different specificities in adoptive transfer experiments. Antibodies reactive with mouse autoantigens involved in immune-mediated loss of salivary function and DNA probes derived from their genes will be used to identify and clone similar autoantigens found in human tissues. The reactivity of T cells and antibodies from Sjogren's syndrome patients will be evaluated in proliferation and ELISA assays. Autoantigens which may be involved in the pathogenesis of Sjogren's syndrome will be identified by their similarity to mouse autoantigens known to be pathologically relevant and by the presence of T cell and/or antibody reactivity to those antigens in affected individuals.
|Esch, T R; Poveromo, J D; Aikins, M C et al. (2002) A novel lacrimal gland autoantigen in the NOD mouse model of Sjogren's syndrome. Scand J Immunol 55:304-10|
|Esch, T R (2001) Pathogenetic factors in Sjogren's syndrome: recent developments. Crit Rev Oral Biol Med 12:244-51|