Projects of the nims laboratory
Memory B Cells Activate Brain Homing, Autoreactive CD4+ T Cells In Multiple Sclerosis
Jelcic, I., and Al Nimer, F. et al. Cell (2018)
Based on an experimental human in vitro system, an increased activation and cell division of autoreactive T cells from the peripheral blood of MS patients could be identified. Interestingly, the research team showed that this increased activation is mainly dependent on the interaction of autoreactive T cells with B cells.
The elimination of B cells, e.g. with therapy-used antibodies that deplete B cells, effectively inhibits T cell activation. So far, this mechanism was unknown. Another novelty of the work is the finding that dividing, autoreactive T cells in the blood are especially those that are also found in the brain lesions of MS patients. This indicates that activation of the autoreactive T cells by B cells in the peripheral blood leads to the activation of T cells in the brain and inflammatory lesions.
The research team has thus decoded a decisive step in the development of MS with these new research results on the interaction between B and T cells. The latter not only explains the previously unclear mechanism of action of therapeutically efficient B-cell depletion in MS, but also paves the way for new therapeutic approaches and research on the foundations of MS.
Role of Human Leukocyte Antigens (HLA) molecules in MS pathogenesis
Ivan Jelcic, Jian Wang, Reza Naghavian 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
Carolina Cruciani, Marco Puthenparampil and 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.
GDP-L-Fucose Synthase As A Novel CD4+ T Cell-Specific Autoantigen in DRB3*02:02 Multiple Sclerosis Patients.
Planas et al., Science Transl. Med. (2018)
New findings made by the research group of Mireia Sospedra and Roland Martin from the University of Zurich’s Clinical Research Priority Program Multiple Sclerosis now suggest that it is worth broadening the research perspective to gain a better understanding of the pathological processes.In the journal Science Translational Medicine, the scientists report that T cells – i.e. the immune cells responsible for pathological processes – react to a protein called GDP-L-fucose synthase. This enzyme is formed in human cells as well as in bacteria frequently found in the gastrointestinal flora of patients suffering from multiple sclerosis. “We believe that the immune cells are activated in the intestine and then migrate to the brain, where they cause an inflammatory cascade when they come across the human variant of their target antigen,” says Mireia Sospedra.For the genetically defined subgroup of MS patients examined by the researchers, results show that gut microbiota could play a far greater role in the pathogenesis of the disease than previously assumed. Mireia Sospedra hopes that these findings can soon also be translated into therapy; she plans to test the immunoactive components of GDP-L-fucose synthase using an approach that the researchers have been pursuing for several years already.
MS Brain Tissue Project
In collaboration with the UK MS Tissue Bank, Imperial College London (head: Prof. Richard Reynolds) and Dr. Katrin Frauenknecht, Pathology, USZ
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.