Contributions
Abstract: P1880
Type: Poster
Abstract Category: Late breaking news
More than one hundred genetic and environmental risk factors have been implicated in the autoimmune disease multiple sclerosis (MS). The presence of the HLA-DR15 MHC Class II haplotype confers the strongest genetic risk, however its contribution to disease remains poorly understood. Of the environmental risk factors, infection with Epstein-Barr virus (EBV) is strongly correlated with increased MS risk, especially in patients who have experienced infectious mononucleosis (IM), the severe acute form of EBV infection. IM synergizes with the HLA locus for a seven-fold increased risk for developing MS. The mechanisms behind this interplay are not known. Our study aims to use humanized mice as an in vivo EBV infection model to investigate T cell responses in animals reconstituted with donors positive for genetic MS risk factors.
Using our model of NOD-scid gamma chain-deficient (NSG) mice reconstituted with human immune system components (huNSG), animals reconstituted with HLA-DR15+ donors possess hyperactivated CD4+ T cells in the steady state. Furthermore, following EBV infection, these huNSG mice developed elevated blood viral titres, as well as higher frequencies of CD3+ and CD8+ T cells and higher activation of CD3+ and CD4+ T cells. Recently, genome-wide association studies have identified multiple single nucleotide polymorphisms (SNPs) that seem to increase the risk of MS. We find that a higher immune activation in HLA-DR15+ donor-reconstituted animals is associated with certain SNPs in immune related genes, including endocytosis receptors, signaling molecules and transcription factors involved in antigen processing and differentiation of cytotoxic effector CD8+ T cells. Thus, MS-associated genetic risk factors could predispose individuals to elevated, poorly protective T cell responses after EBV infection, possibly priming autoreactive T cell specificities in the process.
Disclosure: H.Z., B.C., L.D.V., M.R., C.M. have no conflicts of interest to disclose. C.M. is supported by Cancer Research Switzerland (KFS-3234-08-2013), Worldwide Cancer Research (14-1033), SPARKS (15UOZ01), KFSPMS and KFSPHHLD of the University of Zurich, the Sobek Foundation, the Swiss Vaccine Research Institute, and the Swiss National Science Foundation (310030_162560 and CRSII3_160708). B.C. is supported by a Marie-Heim Vögtlin fellowship from the Swiss National Science Foundation.
Abstract: P1880
Type: Poster
Abstract Category: Late breaking news
More than one hundred genetic and environmental risk factors have been implicated in the autoimmune disease multiple sclerosis (MS). The presence of the HLA-DR15 MHC Class II haplotype confers the strongest genetic risk, however its contribution to disease remains poorly understood. Of the environmental risk factors, infection with Epstein-Barr virus (EBV) is strongly correlated with increased MS risk, especially in patients who have experienced infectious mononucleosis (IM), the severe acute form of EBV infection. IM synergizes with the HLA locus for a seven-fold increased risk for developing MS. The mechanisms behind this interplay are not known. Our study aims to use humanized mice as an in vivo EBV infection model to investigate T cell responses in animals reconstituted with donors positive for genetic MS risk factors.
Using our model of NOD-scid gamma chain-deficient (NSG) mice reconstituted with human immune system components (huNSG), animals reconstituted with HLA-DR15+ donors possess hyperactivated CD4+ T cells in the steady state. Furthermore, following EBV infection, these huNSG mice developed elevated blood viral titres, as well as higher frequencies of CD3+ and CD8+ T cells and higher activation of CD3+ and CD4+ T cells. Recently, genome-wide association studies have identified multiple single nucleotide polymorphisms (SNPs) that seem to increase the risk of MS. We find that a higher immune activation in HLA-DR15+ donor-reconstituted animals is associated with certain SNPs in immune related genes, including endocytosis receptors, signaling molecules and transcription factors involved in antigen processing and differentiation of cytotoxic effector CD8+ T cells. Thus, MS-associated genetic risk factors could predispose individuals to elevated, poorly protective T cell responses after EBV infection, possibly priming autoreactive T cell specificities in the process.
Disclosure: H.Z., B.C., L.D.V., M.R., C.M. have no conflicts of interest to disclose. C.M. is supported by Cancer Research Switzerland (KFS-3234-08-2013), Worldwide Cancer Research (14-1033), SPARKS (15UOZ01), KFSPMS and KFSPHHLD of the University of Zurich, the Sobek Foundation, the Swiss Vaccine Research Institute, and the Swiss National Science Foundation (310030_162560 and CRSII3_160708). B.C. is supported by a Marie-Heim Vögtlin fellowship from the Swiss National Science Foundation.