David Hafler MD, MSc

William S. and Lois Stiles Edgerly Professor of Neurology and Professor of Immunobiology; Chair, Department of Neurology; Neurologist-in-Chief, Yale New Haven Hospital

Research Interests

Neuroimmunology; Multiple Sclerosis; Autoimmunity; Genetics; Immunobiology

Research Summary

Dr. Hafler’s laboratory has been a major force in defining human autoimmune disease for over a quarter of a century. After demonstrating the presence of an activated peripheral immune system in patients with MS, he was among the first to apply human T cell cloning to human disease, defining the dominant epitopes of myelin antigens in MS (Nature, 1990) and of islet antigens in diabetes (Nature 2005). His lab has deeply examined the mechanism for the loss of suppression, and was among the first to describe regulatory T cells in humans (JI, 2005) and molecular mechanism elucidating defects in regulating tolerance in autoimmune disease (JEM, 2006; Science 2007). Moreover, his lab has recently elucidated the mechanism for induction of Th17 cells in humans (Nature 2008).

He continues to be active as a clinician, and has led a number of clinical trials, including the first therapy of human autoimmune disease with monoclonal antibodies in the 1980s. After a sabbatical with Eric Lander at the Broad Institute, Hafler led the first whole genome scan identifying gene variants associated with MS (NEJM, 2007).

Dr. Hafler is Founder and past president of the Federation of Clinical Immunology Societies and is an NIH Jacob Javits Scholar.

Extensive Research Description

Hafler is a major force in bridging basic immunology, genetics, and neurology deeply probing mechanisms to understand MS. His seminal work in 1985 demonstrating systemic immune involvement in MS (NEJM, 1985) was followed by the first identification of myelin, autoreactive T cells in MS (Nature 1990). In 2004, Hafler was the first to identify human FoxP3 regulatory T cells and then demonstrated that they are defective in MS (JEM, Nature Med, 2011). In 2001, he co-led the international effort that identified the first MS genes outside of MHC (NEJM, 2007) now with over 100 identified genes (Nature 2011). In 2009 Hafler was recruited to become Chairman of Yale Neurology and Professor of Neurology and Immunobiology where he has rapidly built an outstanding clinical program that strongly integrates medical sciences. His scientific leadership has continued where he has deeply examined the function of MS associated risk haplotypes demonstrating their significant biologic effects (JCI 2014), identified NaCl as an environmental cause of of inflammation (Nature 2013), and epigentically fine-mapped MS causal variants discovering the molecular pathways causing MS (Nature 2014). He has received innumerable professional distinctions including being becoming a Jacob Javits Scholar of the NIH, ASCI membership, the ISI most highly cited list, the University of Miami Distinguished Alumni Award and the prestigious John Dystel Prize from the American Academy of Neurology.

Selected Publications

  • 289. Stern JN, Yaari G, Vander Heiden JA Church G, Donahue WF, Hintzen RQ, Huttner AJ, Laman JD, Nagra RM, Nylander A, Pitt D, Ramanan S, Siddiqui BA, Vigneault F, Kleinstein SH, O’Connor KC, Hafler DA*. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014 Aug 6;6(248):248ra107. PMID: 25100741
  • 294. Dominguez-Villar M, Gautron A, de Marcken M, Hafler DA. TLR-7 induced CD4+ T cell Anergy. Nat Immunol. 2014 Nov 17. doi: 10.1038/ni.3036. [Epub ahead of print] PubMed PMID: 25401424
  • Farh K, Marson A, Zhu J, Kleinwietfeld M, Housley WJ, Beik S, Shoresh N, Whitton H, Ryan RJH, Shishkin AA, Hatan M, Carrasco-Alfonso MJ, Mayer D, Luckey CJ, Patsopoulos NA, De Jager PL, Kuchroo VK, Epstein CB, Daly MJ, Bernstein BE, Hafler DA*. Genetic and epigenetic fine-mapping of causal variants in autoimmune disease. Nature. 2014 Oct 29. doi: 10.1038/nature13835. [Epub ahead of print] PMID: 25363779 2014
  • Dominguez-Villar M, Baecher-Allan CM, Hafler DA. Identification of T helper type 1-like, Foxp3(+) regulatory T cells in human autoimmune disease. Nat Med. 2011 Jun;17(6):673-5. Epub 2011 May 3. PMID: 21540856
  • Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic Th17 cells. Nature. 2013 Apr 25;496(7446):518-22. PMID: 23467095
  • Lozano E, Joller N, Cao Y, Kuchroo V, Hafler DA. The CD226/CD155 interaction regulates the proinflammatory (Th1/Th17) anti-inflammatory (Th2) balance in humans. J Immunol. 2013 Oct 1;191(7):3673-3680. Epub 2013 Aug 26. PMID: 23980210
  • Hafler, D.A., Compston, A., Sawcer, S., Lander, S., Daly, M.J., DeJager, P.L., de Bakker, P.I.W., Gabriel, S.B., Mirel, D.B., Ivinson, A.J., Pericak-Vance, M.A., Gregory, S.G., Rioux, J.D., McCauley, J.L., Haines, J.L., Barcellos, L.F., Cree, B., Oksenberg, J.R., Hauser, S.,L. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 30; 357(9):851-62, 2007.
  • Yang L, Anderson DE, Baecher-Allan C, Bettelli E, Oukka M, Kuchroo VK, Hafler DA, IL-21 and TGF-ß are Required for Differentiation of Human Th17 cells Nature 17;454(7202):350-2, 2008.

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