Genome wide association (GWA) scans have allowed an assessment of disease pathways in patients with MS and Tl D based on the unbiased identification of gene variants. We will investigate these allelic variants and their pathways that are both common (CD226/TIGIT) and unique (CTLA4-T1D and CD6-MS) to these diseases. The central role of Thi7 and regulatory T cells in MS has recently been elucidated, and as part of this PPG we demonstrated a loss of regulatory T cell function in MS. We also discovered that increasing the strength of signal through the TCR influences the plasticity of CD4+CD25high Tregs to become Thi7 cells. These data have led to the underlying hypothesis that allelic variants in multiple costimulatory pathways lead to a shift from regulatory to inflammatory T cell function. We will explore the costimulatory pathways identified from GWA scans in relationship to Treg and Thi7 function, investigating the CTLA-4/CD28, CD226/TIGIT, and CD6 pathways. Specifically, we will determine: 1) the role of sCTLA4 in the function and plasticity of human Treg populations in close collaboration with Wicker/Todd;2) how CD6 MS-risk alleles that induce splice variants alter the CD6 costimulatory pathway, investigating the hypothesis that alterations in the CD6 isoforms affect binding to its ligand results in changes influencing the function of Tri and Tregs in patients with MS;and 3) how the CD226/TIGIT costimulatory pathway modulate Treg and Thi 7 function in human autoimmune disease. Our preliminary data demonstrate a lack of TIGIT expression on Thi7 cells while blocking CD226 corrects defects in Treg function in MS leading us to hypothesize that allelic variants in the CD226/TIGIT pathways influence Th17 and Treg function. We will directly examine whether defects in Treg suppression in MS and hyperactivation of monocytes in patients with T1D are corrected by promoting TIGIT signaling. In summary, it is clear that genetic risk to develop autoimmune disease is due to many common and rare allelic variants each with a small effect that together lead to organ specific inflammation in response to undefined environmental challenges. We will apply new tools to examine how genetic variants lead to the heightened immune responses observed in patients with autoimmune diseases.
Understanding the underlying disease pathophysiology is key to developing new therapies before signficant tissue damage occurs. We have recently elucidated key co-stimulatory pathways by performing whole genome association scans in patients with MS and T1D. This grant is translating those genotypic findings to a fundamental understanding of immune phenotypes to identify pathways for future drug targeting.
|Nylander, Alyssa N; Ponath, Gerald D; Axisa, Pierre-Paul et al. (2017) Podoplanin is a negative regulator of Th17 inflammation. JCI Insight 2:|
|Lucca, Liliana E; Hafler, David A (2017) Co-inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma. Immunol Rev 276:9-25|
|Wallrapp, Antonia; Riesenfeld, Samantha J; Burkett, Patrick R et al. (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351-356|
|Wu, Chuan; Chen, Zuojia; Dardalhon, Valerie et al. (2017) The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program. Nat Immunol 18:344-353|
|Lucca, Liliana E; Hafler, David A (2017) Resisting fatal attraction: a glioma oncometabolite prevents CD8+ T cell recruitment. J Clin Invest 127:1218-1220|
|Anderson, Ana C; Joller, Nicole; Kuchroo, Vijay K (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 44:989-1004|
|Chastre, Anne; Hafler, David A; O'Connor, Kevin C (2016) Evaluation of KIR4.1 as an Immune Target in Multiple Sclerosis. N Engl J Med 374:1495-6|
|Cao, Yonghao; Nylander, Alyssa; Ramanan, Sriram et al. (2016) CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. Neurology 86:1553-6|
|Axisa, Pierre-Paul; Hafler, David A (2016) Multiple sclerosis: genetics, biomarkers, treatments. Curr Opin Neurol 29:345-53|
|Longbrake, Erin E; Hafler, David A (2016) Linking Genotype to Clinical Phenotype in Multiple Sclerosis: In Search of the Holy Grail. JAMA Neurol 73:777-8|
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