Projects of the nims laboratory
Role of Human Leukocyte Antigens (HLA) molecules in MS pathogenesis
Ivan Jelcic, Jian Wang, Verena Lentsch and Roland Martin
In each of the genetic studies on MS patients performed until now, HLA molecules emerge as the strongest genetic susceptibility factors. In particular, the HLA-DR15 haplotype in Caucasians (DRB1*15:01, DRB5*01:01) is associated in different populations with higher incidence of MS, but it is still not clear how these molecules confer susceptibility to MS. HLA class II molecules present antigens to T cells in order to signal proliferation or activation. T cell receptors (TCRs) recognize these presented antigens, and previous small-scale studies have found that a subset of TCRs is expanded in MS patients. This subset may represent cells expanded by activation from contact with self-antigens, or it may represent cells which have increased homeostatically to maintain T cell numbers in MS patients, whose thymuses release fewer cells. In either case, these expanded cells are suspects for causing the myelin/neuronal damage of MS. We are currently studying the T cell repertoire in MS patients to determine the nature of the bias, if it is dependent upon HLA-DR15, if it appears in a population that has never been stimulated by foreign antigens, and if the T cells which invade the CNS of MS patients are members of a biased subset. These studies shall lead to a better understanding how the HLA-DR15 haplotype as major genetic risk factor for MS influences, which T cells are positively selected in the thymus and which are preferentially expanded in the peripheral immune system by antigen stimulation or homeostasis.
Search for candidate autoantigens and foreign (viral/bacterial) triggers in MS
Paula Tomas, Carolina Cruciani, Mireia Sospedra
In many T cell-mediated autoimmune diseases including MS there is currently only an incomplete understanding, which is/are the most important autoantigen/s in the context of the disease-associated HLA-class II alleles. Furthermore and directly related, the knowledge about environmental triggers, e.g. viruses, of autoimmune diseases and MS is only limited. While myelin antigens are considered relevant autoantigens in MS, and Epstein Barr virus (EBV) is a known environmental risk factor of MS, we believe that the search for autoantigens and foreign triggers in MS has been too hypothesis-driven in the past, i.e. the focus was almost entirely put on myelin proteins. This narrow focus probably in part explains why antigen-specific tolerization has not been successful so far in MS. In order to identify candidate autoantigens and/or molecular mimics in MS, we are examining the antigen specificity of T cells that are clonally expanded within the brains of MS patients by testing them with two broad-based and largely hypothesis-free approaches: a) combinatorial peptide libraries in the positional scanning format (ps-SCL), and b) lentiviral expression libraries using large numbers of DNAs from MS brain tissue, which is used to transfect antigen-presenting cells. These studies will likely lead to important insights about the target antigens in MS, possibly to new biomarkers and hopefully also provide a basis for future treatments by antigen-specific tolerization.
MS Brain Tissue Project
In collaboration with the UK MS Tissue Bank, Imperial College London (head: Prof. Richard Reynolds).
Wolfgang Faigle, Carolina Cruciani, Roland Martin
Research on pathogenetic mechanisms in MS has major drawbacks due to the limitation of available biopsies and has relied on primarily on animal models. Advances in MS genetics and generally in methodologies that allow studying the physiology and disease mechanisms at a systematic level have opened new opportunities to approach the complexity of diseases like MS to understand the interactions of risk factors from gene to protein, disturbed pathways and eventually clinical presentation.
Here we want to elucidate in depth pathogenetic mechanisms of MS by using postmortem brain tissue samples. We have obtained histopathologically well-characterized brain tissues from the UK MS Tissue Bank with defined types, stage and location of lesions. With this information on hand, we apply genotyping analysis and proteomics, T cell receptor and immunoglobulin deep sequencing. In parallel proteomics analysis of cerebrospinal fluid (CSF) is performed, as well as autoradiographic studies with PET ligands, which will ideally translate findings to clinical observations in MS.
After merging the wealth of information from the different analyses, we expect to contribute substantially to MS biomarker research and want to identify new clinical opportunities.