Multiple sclerosis (MS), a central nervous system (CNS) inflammatory demyelinating disease, is a leading cause of disability in the young adult population. While dramatic progress has been made in our understanding of the disease pathogenesis, the initial disease-triggering events remain poorly understood. Since immunomodulatory therapies are most effective when administered early in the course of the disease, we are seeking biomarkers of the clinically isolated syndrome (CIS) suggestive of MS, the earliest phase of the disease. Our preliminary studies have identified IL-11, a new Th17 cell-polarizing cytokine, as the most significantly increased cytokine in the serum and cerebrospinal fluid (CSF) of CIS patients, whose serum levels are increased during clinical exacerbations of the disease. CD4+ cells are the main source of IL-11 in the peripheral circulation. The percentage of IL- 11+CD4+ cells is increased in the peripheral circulation of CIS patients in comparison to matched healthy controls (HCs), and they significantly accumulate in the CSF and the active brain MS lesions in comparison to matched blood samples. Animal studies have confirmed the causal role of IL-11 in the exacerbation of relapsing remitting (RR) experimental autoimmune encephalomyelitis (EAE), since IL- 11 administration worsened clinical course and induced increased numbers of IL-17A+CD4+ cells in the central nervous system (CNS) inflammatory infiltrates. Our central hypothesis is that IL-11 induces CD4+ cell migratory capacity and encephalitogenicity, mediated via up-regulation of CCR6, ICAM-1 and VLA-4, which mediate CD4+ cells trans-endothelial migration. We propose that IL-11+CD4+ cells, which are also expanded in the presence of IL-11, may represent a pathogenic cell subset, whose transcriptional profiling and T cell receptor (TCR)Vb repertoire will elucidate their function and antigen specificity. aIL-11R mAb treatment of RRAEA will provide pre-clinical data and identify markers of therapeutic effect for this new therapeutic approach. The objective of this study is (1) to identify the molecular mechanisms involved in IL-11-induced migration of CD4+ cell subsets to the CNS in CIS patients, (2) to characterize the phenotype, transcriptional profile and TCRVb repertoire of CSF- enriched IL-11+CD4+ cells in CIS patients, and (3) to examine the potential of IL-11 to induce encephalitogenic CD4+ cells capable of passively transferring disease, and to determine the therapeutic effect of aIL-11R mAb in RREAE, an animal model of the disease. The results are expected to provide biomarkers of early autoimmune response in CIS patients and to identify selective therapeutic targets for this disabling disease.