Autoimmune diseases in aggregate represent a leading cause of morbidity and mortality. Despite apparent clinical heterogeneity among human autoimmune diseases, the potential for shared pathogenetic mechanisms involving inflammatory cascades, is increasingly appreciated. Dysregulation of biochemical pathways leading to production of type 1 interferon (T1 IFN) represents a candidate shared mechanism of enhanced susceptibility to diverse syndromes including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Type I diabetes (T1D). Genome-wide association studies have identified a number of genetic polymorphisms that convey an increased risk for autoimmune diseases through largely unknown mechanisms. One such genetic variant is the PTPN22 C1858T, which leads to an Arginine to Tryptophan (R->W) change in the Lymphoid tryrosine phosphatase (Lyp). This variant is associated with increased risk for SLE, RA, T1D, and autoimmune thyroiditis. Expression surveys reveal that PTPN22 is highly expressed in the myeloid cells implicated in host defense responses involving T1 IFN. Other phosphatases, such as PTPN11 and SHIP-1 have been shown to regulate innate immune responses in myeloid cells through Toll-like receptor (TLR) signaling pathways. TLRs recognize components derived from microbial pathogens and play a central role in innate immunity. However, abnormal TLR activation can modulate human immunodeficiency or autoimmunity. My overall hypothesis is that abnormal innate and adaptive immune responses resulting from the disease-associate Lyp (LypW) variant contribute to pathogenesis of autoimmune diseases. I plan to address this hypothesis through completion of specific Aims designed to not only contribute significantly to the biology of PTPN22, but also provide me with training essential for successful transition to independence.
In Aim 1, I will determine the role of PTPN22 in TLR signaling by using bone-marrow derived macrophages (BMMs) and dendritic cells (BMDCs) from PTPN22 deficient mice. I will compare gene expression and transcription factor activation as well as IFN-dependent phosphorylation of STAT1 and upregulation of costimulatory molecules in wild-type and PTPN22 deficient cells after TLR activation. I will also determine the role of PTPN22 in controlling antigen-specific T cell proliferation and activation. I will identify PTPN22 containing protein complexes involved in TLR signaling by Mass Spectrometry.
In Aim 2, I will address the impact of LypW on TLR signaling by using BMMs and BMDCs from LypW transgenic mice. I will also investigate the role of LypW in pathogenesis of rheumatoid arthritis using the K/BxN TCR transgenic mouse model.
In Aim 3, I will compare gene expression and surface phenotype after TLR activation in human peripheral mononuclear cells from LypW carriers and non-carriers. I will determine the role of LypW in host immune responses to viruses.
Autoimmune diseases are complex polygenic diseases. Identifying the functional significance of the genetic variants associated with these diseases will provide insight into novel therapeutic targets and treatment for these diseases. In this grant I wil study the function of a genetic variant associated with multiple autoimmune diseases, the PTPN22 1858T variant, to examine its role in immune responses and disease pathogenesis. Autoimmune diseases are complex polygenic diseases. Identifying the functional significance of the genetic variants associated with these diseases will provide insight into novel therapeutic targets and treatment for these diseases. In this grant I wil study the function of a genetic variant associated with multiple autoimmune diseases, the PTPN22 1858T variant, to examine its role in immune responses and disease pathogenesis.