The immunogenetics of MS has been a difficult and disappointing field, since very few genes could reliably be identified, and the longstanding association with the Major Histocompatibility Complex may still prove to be based on a non-HLA gene in the region. Hence, limited genetic evidence for a role of adaptive immunity and inflammation was available. This field has very recently been re-energized by genomewide association (GWA) studies identifying the IL-7 receptor (R) gene polymorphism as an MS susceptibility risk factor. IL-7 is an important growth and survival factor for adaptive immune cells (T and B lymphocytes) and controls cell homeostasis and memory. However, the exact mechanism underlying the role of this IL-7R polymorphism in MS pathogenesis remains poorly understood. We have confirmed IL-7R as a risk gene in our unique Dutch genetic isolate. In collaboration with the Oxford group (prof. G. Ebers and Dr. S. Ramagopalan) we also found a weak but significant association with the EVI5, a gene that has been implicated in retroviral insertion and lymphomagenesis (submitted). Most significant however in our GWA studies is that other loci show even higher associations with MS, with the highest score for an area at chromosome X. This region has been relatively neglected in previous genetic studies, partly because of technical reasons. The X chromosome is of additional interest, in view of a female skew in both susceptibility and transmission of MS. Importantly, the X chromosomal region of interest encodes an important structural and functional relative of the IL-7R, the receptor for the cytokine growth factor thymic stromal lymphopoietin (TSLPR). The current proposal capitalizes on these recent insights on IL-7R by optimally employing the ongoing cohorts and genetic isolates of MS patients at ErasMS. The project will 1. validate newly identified risk loci in MS (including the X-linked region), 2. investigate the role of the TSLPR gene as well as its expression in MS, 3. interrelate clinical correlates of well-characterized patient groups with IL-7R polymorphism, expression and function. 4. link our cellular immunological studies to novel MS related SNPs of interest, including the now identified EVI5 gene. We anticipate that many novel risk genes for MS will all exert a weak effect, but may link to a final common influence on T-lymphocyte differentiation and survival. Special attention will be paid to EBV history, as mononucleosis is one of the few clinical risk factors for MS and this virus can strikingly influence survival function in the immune system (for example IL7-R expression). The combination of selected biological parameters with the unique patient cohorts will ensure that this project will significantly contribute in the international arena where this new topic is heavily investigated.