Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disorder that affects mostly young females. It causes significant morbidity and mortality. Effective therapies without significant side effects for induction of remission and prevention of relapses are wanting. Our novel hypothesis that links the HLA-D region to the pathogenesis of SLE is that autoantibodies (auto-Ab) and auto-reactive T cells are generated by the activation of T cells cross-reactive with autoantigens (auto-Ag) and enviromental (such as bacterial) Ag in the HLA-DR restricted manner. Over a period of time accumulation of auto-reactive T cells leads to the production of complex auto-Ab, resulting in clinical disease in suitable hosts. Remission occurs with reduction of auto- reactive T cells and of auto-Ab specificities. Relapses occur with repeated stimulation by molecular mimics in the host. The initial clinical presentation and the relapses depend on the nature of the stimulation by the molecular mimics. We have extensively mapped the T cell epitopes in a lupus-related Ag, SmD. This auto-Ag has cross reactive intra- and inter-molecular T cell epitopes. The presence of intra-molecular cross-reactive T cell epitopes is the reason why they are targeted in SLE. The presence of multiple cross-reactive T cell epitopes among polypeptides of snRNP provides us the understanding of the mechanism of B cell epitope spreading in SLE. Multiple T cell antigenic regions have been identified in SmD. Each region appears to induce unique patterns of auto-Ab specificity. Multiple T cell receptors (TCR) are utilized in responses to immunization with SmD. Several microbial mimics from commansal flora were identified with the capability of inducing diverse auto-Ab in a similar manner as the parental peptide. There are cross reactive B cell epitopes between the mimics and the parental SmD peptides. Cross reactivity between tetenus toxoid (TT) T cell epitopes and those of SmD have been documented. These results and other preliminary data provide the basis for the current proposal for us to understand better the role of environmental Ag in the induction of SLE-related auto-Ab.
Three specific aims are proposed:
Specific Aim 1 : To translate our observations in our DR3 transgenic model to normal individuals and SLE patients and to relate SLE-related Ab induction to microbiota and tetanus toxoid;
Specific Aim 2 : To demonstrate that antibiotic treatments that deplete or modulate the gut microbiota will modulate autoantibody production and/or disease course with prolonged survival in (NZM2328xNOD)F1, NZM2328 and NZM2328.DR3;
and Specific Aim 3 : To derive germ-free mice from NZM2328 and NZM2328.DR3 to show that lupus nephritis and lupus related auto-Ab will not develop in a germ-free or gnotobiotic environment, supporting the thesis that microbiota play a crucial role in the development of SLE-related auto-Abs. On the basic level, the expected results will provide insight to the origin of auto-Ab in SLE and will provide evidence that both T and B cells play important roles in SLE. They will also support targeting microbiota as a novel approach to treating and preventing the development of SLE.
This is a new application to study causes of systemic lupus erythematosus (SLE). SLE causes significant economic loss and suffering. We have evidence to support the thesis that lupus autoantibody production is the result of immune responses to bacterial or viral molecules that can stimulate some T cells, which are also reactive with self antigen. In this application we plan to show that these T cells exist in our bodies and that they can respond to multiple antigens. These cells accumulate in our body over a period of time, resulting in the production of autoantibodies to multiple autoantigens and autoreactive T cells. These antibodies and T cells cause damage to various organs, resulting in various clinical presentations during the initial diagnosis of the disease and during flares. Clinical diseases occur in genetically susceptible individuals whose white cells are more reactive and/or their organs are more susceptible to damage. The results of the proposed studies may allow us to link microbiome to the generation of lupus related autoantibodies and to devise strategies to change microbiome as an adjunct therapeutic approach for the treatment of SLE. The new knowledge obtained from the proposed experiments challenges the current dogma and will have an impact on our ability to treat patients with active disease and to maintain the patients' quality of life.
