[The Svedberg seminar] – The Underlying Cause of Human Autoimmune Disease
March 27, 2023 @ 15:15 – 16:15 CEST
DAVID A. HAFLER, MD, FANA
William S. and Lois Styles Professor of Neurology and Immunobiology
Chair, Department of Neurology, Yale School of Medicine
Neurologist-in-Chief, Yale New Haven Hospital
Founding Associate Member, Broad Institute of MIT and Harvard
David A. Hafler, M.D. is the William S. and Lois Stiles Edgerly Professor and Chairman Department of
Neurology and Professor of Immunobiology, Yale School of Medicine, and is the Neurologist-in-Chief
of the Yale-New Haven Hospital. He has made seminal discoveries in the pathogenesis of multiple
sclerosis and autoimmune diseases including identification of human autoreactive T cells and
the mechanisms that underlie their dysregulation with the discovery of human regulatory T cells.
He led the discovery of genetic variants causing. He was awarded the Dystel Prize for MS research
and the 2023 AAI Steinman Award for Human Immunology Research. He is an Honorary Member of
the Scandinavian Society for Immunology and has been elected to membership in the American
Society of Clinical Investigation, The Association of American Physicians, and the National Academy of Medicine.
The Underlying Cause of Human Autoimmune Disease
Multiple sclerosis (MS) is a prototypic, genetically mediated autoimmune disease induced by environmental factors where genetic perturbation of cis-regulatory elements leads to immune dysregulation and generation of myelin reactive T cells secreting inflammatory cytokines. We have identified 233 common allelic variants associated with MS risk where approximately 60% of candidate causal variants map to enhancers and super-enhancers marked by chromatin features in T and B cells. We found that CD4+Foxp3+ Tregs are defective in MS and by performing transcriptomic and epigenomic profiling discovered that upregulation of a primate-specific short PRDM1 isoform (PRDM1-S) induces SGK1 independent from evolutionally conserved long PRDM1, leading to destabilization of Foxp3 and Treg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases and it is of interest that SGK-1 is induced by high salt, an environmental risk factor in MS. Finally, as suggested by genetic mapping, B cells play a critical role in the disease and B cell depletion is highly effective in treating early disease.
Host: Katarina Lundblad firstname.lastname@example.org, UU