Alteration of B-Cell Responses and Tolerance by Mer Deficiency at the Germinal Center Tolerance Checkpoint

The current proposal focuses on identifying the mechanisms by which failure to clear dead cells from our body leads to autoantibody production, resulting in the autoimmune disease called systemic lupus erythematosus (SLE). Autoantibodies are proteins produced by immune cells called 'B cells' and are directed against one's healthy tissue (autoimmunity). SLE/lupus is one of the Topic Areas listed in the Fiscal Year 2013 Peer Reviewed Medical Research Program.

SLE is an autoimmune disease -- that is, the immune system, which is designed to protect us from infection and cancer, mistakenly sees our own healthy tissue as foreign. This results in long-term or 'chronic' inflammation. For SLE, this inflammation affects many organs, including the skin, heart, kidneys, lungs, joints and brain, resulting in a loss in quality of life and a shortened lifespan. The exact cause of SLE is not known. As a result, treatment of SLE, as well as other autoimmune diseases, is limited to alleviating disease symptoms, or drugs that globally suppress the immune system and increase susceptibility to infection. If we understood the cause(s) for this loss of 'tolerance' of our immune system ('immunological tolerance'), we could develop effective treatment regimens tailored for SLE. Immunological tolerance, where the immune system does not attack healthy tissue, is maintained through elimination of mature immune cells that undergo cell death. Rapid clearance of these dead cells is crucial to maintaining immunological tolerance, as delayed clearance of such cells can trigger inflammation. A group of immune cells called phagocytes clear dead cells from our body by ingesting them and thus help maintain immunological tolerance. A particular protein called 'Mer,' expressed on the surface of phagocytes, helps the ingestion and clearance of dead cells, thus playing an important role in the maintenance of immunological tolerance. Animals (mice) deficient in the Mer protein develop SLE-like disease, which is attributed to impaired clearance of dead cells in the absence of Mer protein. These findings are consistent with human SLE patients, showing a defect in clearance of dead cells. Genetic variation in the Mer gene has recently been associated with SLE and multiple sclerosis (MS) susceptibility. Using mice deficient in Mer protein, we will be able to study the mechanisms by which impaired clearance of dead cells alters immune cell tolerance at the level of B cells and causes SLE in our mouse model. Understanding such mechanisms will lead to identifying therapeutic or specific clinical intervention in SLE and possibly other autoimmune diseases. SLE patients including all military service members, veterans, and beneficiaries will benefit from the findings of this project.