This proposal focuses on the pathogenesis of Sjogren's Syndrome (SS), a systematic autoimmune disease largely affecting the exocrine glands. The disease has been defined as the combination of dry eyes and dry mouth due to lymphocytic infiltration of these glands (sialoadenitis). The syndrome is often, if not always, associated with autoantibodies to SSA/Ro and SSB/La. It is a prevalent disorder with considerable ocular and oral morbidity. long term goal of the research program is to elucidate the immunological and genetic factors which are important in the development of sialoadenitis. In this application a murine model of sialoadenitis will be defined.
Four specific aims are included.
Four specific aims are included.
In Specific Aim 1, different strains of mice will be identified which are susceptible to the induction of sialoadenitis by immunization with recombinant Ro60, Ro522 or La. Functional, histochemical and immunocytochemical studies will be done to monitor the development of sialoadenitis. In animals with salivary infiltrates, the involvement of other exocrine glands and tissues will be determined. Further studies will identify Ro60 peptides capable of inducing sialoadenitis. Considerable efforts will be devoted to determining whether salivary gland dysfunction is present in mice which have developed antigen induced sialoadenitis in order to validate this model to studying SS.
In Specific Aim 2, T cell lines and clones from infiltrating T cells of disease salivary glands and the draining lymph nodes will be generated after stimulation with mouse salivary gland cellular extract. The responsible antigens will be identified and pathogenic potential of the T cell lines determine by cell transfer experiments. Additionally, the T cell specificities of cell lines derived from these mice will be compared with those derived from NOD mice, a model for spontaneous autoimmunity.
In Specific Aim 3, the feasibility of developing an autoantigen-induced sialoadenitis in mice expressing certain HLA-DR and/or HLA-DQ transgenes will be explored. By a rapid breeding scheme, these transgenes will be bred into appropriate background for the development of sialoadenitis as determined in Specific Aim 1. In the fourth specific aim, B-less mice which are congenic with the sialoadenitis susceptible strains will be generated to explore the role of B cells in both the spontaneous and antigen-induced autoimmune model.
| Deshmukh, Umesh S; Ohyama, Yukiko; Bagavant, Harini et al. (2008) Inflammatory stimuli accelerate Sjogren's syndrome-like disease in (NZB x NZW)F1 mice. Arthritis Rheum 58:1318-23 |
| Deshmukh, Umesh S; Gaskin, Felicia; Lewis, Janet E et al. (2003) Mechanisms of autoantibody diversification to SLE-related autoantigens. Ann N Y Acad Sci 987:91-8 |
| Deshmukh, U S; Lewis, J E; Gaskin, F et al. (1999) Immune responses to Ro60 and its peptides in mice. I. The nature of the immunogen and endogenous autoantigen determine the specificities of the induced autoantibodies. J Exp Med 189:531-40 |
