Pathogenic T Cells in Guillain Barré Syndrome

Guillain Barré Syndrome (GBS) results from immune-mediated destruction of the peripheral nervous system (PNS) and occurs at increased incidence among military personnel. Mortality associated with GBS is 2%-3%, and many patients experience long-term disability, fatigue, and pain, even after receiving current treatments. These currently consist of administration of intravenous immunoglobulin (IVIG) or plasmapheresis, both with nonspecific mechanisms of action. Given the continued morbidity and mortality associated with GBS, there is a need for more effective treatments that target the pathogenic mechanisms underlying GBS. A major obstacle in the development of improved therapies has been the lack of understanding of the cellular and molecular processes causing GBS immune pathology. Using a mouse model of autoimmune peripheral neuropathy that recapitulates clinical features of GBS, we show that T cell expression of UTX, an epigenetic regulator of gene expression, is critical for the development of PNS autoimmunity. As an epigenetic regulator, UTX functions to promote gene expression through pleiotropic mechanisms, including the removal of suppressive H3K27me3 marks on histones. Lower H3K27me3 levels are noted in nerve-infiltrating T cells, suggesting increased UTX activity in pathogenic T cells. Moreover, UTX has been implicated in the differentiation of two T cell subtypes [T follicular helper (Tfh) and T helper 17 (Th17)] that are increased in patients with GBS. Based on these findings, we hypothesize that UTX's H3K27me3 demethylase activity promotes autoimmune peripheral neuropathy through its role in promoting Tfh and Th17 differentiation.

In Aim 1, we will define the molecular mechanism by which UTX functions in T cells to promote PNS autoimmunity. UTX has pleiotropic functions, and whether blocking UTX's demethylase function is sufficient to prevent PNS autoimmunity will be tested in a GBS mouse model. In Aim 2, we will determine whether Tfh and/or Th17 subsets are required for PNS autoimmunity by inhibiting their development and/or function of their effector molecules in a GBS mouse model. In Aim 3, we will use human samples from GBS and non-GBS subjects to define the role of blocking UTX function in T cell differentiation. A strength of this proposal is the combined expertise of the partnering PIs – Dr. Su in mouse models of autoimmune peripheral neuropathy and Dr. Whitmire in T cell regulation and responses. Additionally, our collaborator Kazim Sheikh, MD, PhD, will provide expertise on clinical neurology and provide GBS patient samples to our study.

Findings from these aims will pave the path to the development of new classes of therapies for GBS. These studies will inform whether small molecule inhibition of H3K27me3 demethylases may be an effective therapy for GBS. Epigenetic-based therapies have proven to be highly effective in the treatment of cancer, but are not currently in use for autoimmune diseases such as GBS. Additionally, these studies will provide evidence to support the development of inhibitors of Tfh and Th17 development for GBS. Finally, anti-IL-21/IL-21r antibodies are currently under active investigation for a number of inflammatory conditions, but not yet for GBS. Given the increased incidence of GBS among military personnel, we anticipate that this work will have substantial benefits for military Service Members.