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Functional Role of the HLA-DR15 Haplotype in Multiple Sclerosis

Periodic Report Summary 2 - HLA-DR15 IN MS (Functional Role of the HLA-DR15 Haplotype in Multiple Sclerosis)

Autoimmune diseases (AID) such as rheumatoid arthritis, type I diabetes, and multiple sclerosis (MS) affect >4% of Europeans and increase in prevalence. MS leads to central nervous system (CNS) damage in young adults and preferentially in women.
A complex genetic trait and environmental factors contribute to MS etiology. In many AID HLA-class II genes confer most of the genetic risk, and in MS up to 60% stem from the HLA-DR15 haplotype, which consists of two tigthly linked genes DRB1*15:01 (also referred to as DR2b) and DRB5*01:01 (or DR2a). Recent data indicate that DR15 alleles act in concert with environmental risk factors such as Epstein Barr virus infection, Vit D3 and smoking. However, how the HLA molecules contribute to MS risk and probably also its disease course is only partially understood. Hence, understanding how HLA-DR contributes to AID- and MS pathogenesis remains a challenge.
The association of MS with HLA-DR15 and animal model data support a major role of CD4+ autoimmune T cells in MS. It is assumed that DR15 alleles present self peptides that select an „autoimmune-prone“ T cell repertoire. This hypothesis is supported by human data, transgenic mouse models, and a clinical trial with a modified myelin peptide. The ERC project investigates these mechanisms in detail and aims at clarifying open questions regarding the roles of DR15 in central versus peripheral T cell selection, which foreign triggers activate CNS-autoreactive T cells and cause their proinflammatory phenotype, and whether both DR15 alleles are relevant.
During the last two years a series of experiments have been started. A first important observation indicates that the activation and propagation of pathogenic CD4+ T cells is driven by activated proinflammatory B cells, which present self peptides from various sources. We have developed an assay system that allows for the first time to detect and isolate brain-homing autoreactive CD4+ T cells from the peripheral blood of patients. Their increased proliferation and phenotypic characteristics correlate well with clinical observations including relapse activity and response to treatments. The fraction of spontaneously proliferating CD4+ T cells is enriched for brain-homing T cells, and hence we can examine cells that are likely involved in the pathogenesis of MS. T cell clones (TCC) from this cell population have already been instrumental in identifying novel target autoantigens, which are currently being evaluated in detail. The functional characteristics of the responding CD4+ T cells and stimulating B cells are dissected by genotyping, transcriptomics, proteomics (with R. Aebersold et al., ETH Zurich), epigenetic studies and a wide range of focused methods (with T Olsson et al., Karolinska Institute, Stockholm). Furthermore, we assess if the experimental system is suited as a platform to identify novel treatments. Another major focus of the project is the detailed analysis of the peptides presented by DR2a and DR2b in the key immune compartments, the thymus (collaboration with M Hauri, Zurich), the peripheral immune system, and the brain of MS patients (collaboration with R Reynolds, London). We pursue the peptidome analyses with HG Rammensee and S Stevanovic (Tübingen). Molecular dynamics simulations of T cell receptor - HLA/peptide interactions in collaboration with A Caflisch (Zurich) aim at developing a better understanding, how modifications of antigenic peptides influence T cell recognition. These data shall advance our knowledge on the molecular pathogenesis of MS and AID in general and will be incorporated in antigen-specific tolerization therapies, which are currently being started at our group.
The ERC project involves investigators across a broad range of disciplines from clinical neurology, neuropathology over immunology, peptide chemistry and mass spectrometry, bioinformatics to molecular dynamics studies and reaches from basic mechanisms of the immune system to clinical application.