Molecular Mechanisms and Treatment Of Autoimmunity In Humans And Animal Models

National Institute Of Allergy And Infectious Diseases

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Abstract

The purpose of this project was to develop new diagnostic and therapeutic approaches to immune dysregulatory diseases. First, we pursued novel therapeutic approaches focusing on multiple sclerosis (MS) as well as new immunological diseases for which we had determined the genetic basis. Our principle approach was to use antigen itself to program the specific cognate T cells to die through apoptosis via a process termed restimulation-induced cell death (RICD). The death is clonally specific and represents a way to eliminate disease-causing T cells by using antigen. Additionally, depending on the molecular and genetic mechanism of disease, we also planned to investigate using other small molecules or protein-based therapeutics. The key was to precisely tailor the therapy to the pathophysiological mechanism of the disease so that it will be highly effective. This is the overarching goal of "precision" medicine. This past year, we chose to focus on developing new, highly effective therapeutics against MS using immunological and genetic approaches. Evidence suggests that myelin proteins antigens are targets of the autoimmune attack, but how the specificities determine disease outcome in progressive and relapsing-remitting MS is unclear. By programming the T cells that recognize such antigens to die, the effect of eliminating these cells on the disease can be demonstrated. Although twin studies show that there is a significant genetic component to MS susceptibility, there is little concrete knowledge about the genes or pathways involved. Genome-wide association studies (GWAS) have unearthed a variety of single nucleotide polymorphisms (SNPs) that are statistically associated with disease. The International MS Genetics Consortium has performed numerous GWAS but the number of identified SNPs with strong association with MS has been much lower than anticipated. However, these studies showed that the correlated SNPs are in or around mainly immune genes rather than central nervous system genes. Nonetheless, the implication of specific pathways in various subtypes of MS has not been achieved. Therefore, we have concluded that approaching the problem by searching for Mendelian or de novo genetic variants may provide more definitive information about pathogenesis. Using next generation sequencing (NGS) techniques such as whole exome sequencing (WES) and whole genomic sequencing (WGS) we are now capable of identifying causal genes in rare and severe disorders that do not have enough fitness to be inherited broadly in the population and detected by GWAS. Moreover, these highly penetrant and deleterious variants likely contribute strongly to de novo and Mendelian forms of autoimmune disease as well as susceptibility to common autoimmune diseases. Identification of rare genetic variants generally provides key information about disease mechanisms, biological pathways, and novel avenues for clinical treatments. We have established a collaboration with investigators at the University of British Columbia, Canada who have assembled a DNA biobank of nearly 14,000 samples, including over 450 Multiplex MS families: 1. Families with 3 or more affected members with MS (400 families); 2. Families with index cases with age of onset < 12 years old (extremely rare and available under this study). Approximately 35% of the samples are from affected patients, and most were diagnosed with MS between the ages of 21 and 40 years old, with the average age of onset being 31.4 years old. These patients, family members, and relatives have been subjected to WES through a collaboration with the Regeneron Sequencing Center. We expect that gene variants found by NGS in these patients, particular in the first two categories, will unveil major pathogenic pathways for MS. Candidate gene variants contributing to disease are being evaluated with collaborators in NINDS.