David Hafler

Yale School of Medicine, USA

Title: The genetic basis of human autoimmune disease

Abstract:

Autoimmune diseases exhibit significant heritability. The sequencing of the human genome has allowed large scale, replicated whole genome association scan aimed at identifying risk alleles associated with risk to developing autoimmune disease.  We have employed a staged performing a series of whole genome association scans followed by replication to interrogate the allelic variation associated with disease susceptibility in patients with MS and compare these data to other human autoimmune diseases. As expected, the HLA-DR locus was unequivocally associated with disease susceptibility (P = 8.94 x 10-81). We identified SNPs within genes encoding the IL-2Rα (p=9.6 x10-27), IL-7Rα (p=5.4x10-20) chain gene, KIA0350 (p=6.8x10-15) and CD58 (p=2.3x10-7), and other non-immune related genes. Correlation of genotype/phenotype function has begun to provide insight into disease pathogenesis. For CD58 (LFA-3), the allelic variant was in a haplotype block and in 88 unrelated lymphoblastic cell lines, the level of expression of CD58 RNA is increased in a dose-dependent manner in the presence of an allelic variant that is a surrogate marker for the protective haplotype (P=1.5x10-14). The IL2RA gene has previously been associated to Type 1 Diabetes (T1D) and Graves Disease, making it a shared autoimmune susceptibility locus. With careful examination of this region, we observed ‘allelic heterogeneity’ at the IL2RA region between MS and T1D, where we observe an allele associated with susceptibility to one disease and risk to the other. At least three pathways contribute to risk at IL2RA, one of which may involve the production of soluble IL-2 receptor. Finally, we have extended our initial genome scan that discovered non-MHC susceptibility loci by performing a meta-analysis of the original and two novel, independent whole genome association scans of subjects with MS. This meta-analysis considers 2624 subjects with MS and 7220 control subjects, and we have replicated a selection of its results in an additional 2600 subjects with MS and 2400 control subjects identifying nearly 20 fully replicated allelic variants associated with risk to developing MS.

Biography:

Dr. Hafler is the Gilbert H. Glaser Professor and Chairman Department of Neurology, Yale School of Medicine and is the Neurologist-in-Chief of the Yale-New Haven Hospital. He graduated magna cum laude in 1974 from Emory University with combined B.S. and M.Sc. degrees in biochemistry, and the University of Miami School of Medicine in 1978. He then completed his internship in internal medicine at Johns Hopkins followed by a neurology residency at Cornell Medical Center-New York Hospital in New York. Dr. Hafler received training in immunology at the Rockefeller University then at Harvard where he joined the faculty in 1984. He is one of the Executive Directors of the Program in Immunology at Harvard Medical School and is on the faculty of the Harvard-MIT Health Science and Technology program where he has been actively involved in the training of graduate students and post-doctoral fellows.  Dr. Hafler has been elected to membership in the American Society of Clinical Investigation, The American Neurological Association, the Alpha Omega Society, and was a Harvey Weaver Scholar of the National Multiple Sclerosis Society. He is currently a member of the editorial boards for Journal of Clinical Investigation and the Journal of Experimental Medicine, and is co-founder of the Federation of Clinical Immunology Societies.

Dr. Hafler is a clinical scientist with a research interest in understanding the mechanism of autoimmunity with a particular interest in inflammatory central nervous system diseases, with over 300 publications in the field of autoimmunity and immunology. He received the 1st National Multiple Sclerosis five year Collaborative Center Award for tackling the MS genetic effort. Hafler leads the NIH Autoimmunity Prevention Center Grant at Harvard, and is a Jacob Javits Merit Award Recipient from the NIH.

His laboratory focuses on the understanding of human autoimmune diseases with the theme that investigation of naturally occurring human diseases give insight into the basic processes of T cell regulation, in addition to providing fundamental understanding and development of new therapies for human diseases. The laboratory has defined immunodominant epitopes of autoantigens, and has developed new technologies to measure both functionality and frequency of autoreactive T cells. More recently, Dr. Hafler has focused on broadly characterizing the molecular pathogenesis of the disease, both at the DNA, mRNA, and proteomic level. Dr. Hafler is a founding member of the International MS Genetic Consortium, a group recently formed to define the genetic causes of MS including scientists from University of Cambridge and University of California, San Francisco.