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Rheumatic Diseases Research Core
Research SummaryHafler, in many respects, is credited with identifying the central mechanisms underlying the likely cause of MS. His early seminal work demonstrated that the disease began in the blood, not the brain, which eventually led to the development of Tysabri to treat the disease by blocking the movement of immune cells from the blood to the brain. He was the first to identify myelin-reactive T cells in the disease, published in Nature, showing that indeed, MS was an autoimmune disorder. He then went on to show why autoreactive T cells were dysregulated by the first identification of regulatory T cells in humans followed by demonstration of their dysfunctional state in MS. As a founding, Broad Institute member, Hafler identified the genes that cause MS, published in the New England Journal of Medicine and Nature. More recently, he identified the key transcription factors and signaling pathways associated with MS genes as potential treatment targets. Finally, he recently discovered that salt drives induction of these pathogenic myelin reactive T cells, both works published in Nature. Hafler was the Breakstone Professor of Neuroscience at Harvard, and became Chairman of Neurology at Yale in 2009, where he has built an outstanding clinical and research program that strongly integrates medical sciences. He has received numerous honors including the Dystel Prize from the AAN for his MS research and is among the most highly cited living neurologists.
Specialized Terms: Neuroimmunology; Multiple Sclerosis; Autoimmunity; Genetics; Immunobiology
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.
|Genetics - Adult, Immune System||The PhenoGenetic Project|
|Diseases of the Nervous System||Study to Explore the Mechanism of Action of Ocrelizumab and B-Cell Biology in Participants With Relapsing Multiple Sclerosis (RMS)|
|Diseases of the Nervous System||The Effect of Dietary Salt Intake on Immune Function in Patients With Multiple Sclerosis|
|Diseases of the Nervous System||Phase II Trial of Rituximab In Myasthenia Gravis|
AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease.
Kitz A, de Marcken M, Gautron AS, Mitrovic M, Hafler DA, Dominguez-Villar M. AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease. EMBO Reports 2016, 17:1169-83. 2016
PD-1 marks dysfunctional regulatory T cells in malignant gliomas.
Lowther DE, Goods BA, Lucca LE, Lerner BA, Raddassi K, van Dijk D, Hernandez AL, Duan X, Gunel M, Coric V, Krishnaswamy S, Love JC, Hafler DA. PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 2016, 1. 2016
Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells.
Hernandez AL, Kitz A, Wu C, Lowther DE, Rodriguez DM, Vudattu N, Deng S, Herold KC, Kuchroo VK, Kleinewietfeld M, Hafler DA. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. The Journal Of Clinical Investigation 2015, 125:4212-22. 2015
Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli.
Housley WJ, Fernandez SD, Vera K, Murikinati SR, Grutzendler J, Cuerdon N, Glick L, De Jager PL, Mitrovic M, Cotsapas C, Hafler DA. Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli. Science Translational Medicine 2015, 7:291ra93. 2015
Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis.
Cao Y, Goods BA, Raddassi K, Nepom GT, Kwok WW, Love JC, Hafler DA. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Science Translational Medicine 2015, 7:287ra74. 2015
Integrative Analysis of 111 Reference Genomes.
Roadmap Epigenomics Consortium. Integrative Analysis of 111 Reference Genomes. Nature. 2015 Feb 19;518(7539):317-30. doi: 10.1038/nature14248. PMID: 25693563
Cost effectiveness of thrombolytic therapy with streptokinase in elderly patients with suspected acute myocardial infarction.
Krumholz HM, Pasternak RC, Weinstein MC, Friesinger GC, Ridker PM, Tosteson AN, Goldman L. Cost effectiveness of thrombolytic therapy with streptokinase in elderly patients with suspected acute myocardial infarction. The New England Journal Of Medicine 1992, 327:7-13. 1992
B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes.
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, Hafler DA, O'Connor KC. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Science Translational Medicine 2014, 6:248ra107. 2014
TLR-7 induced CD4+ T cell Anergy.
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 2014
The CD226/CD155 interaction regulates the proinflammatory (Th1/Th17)/anti-inflammatory (Th2) balance in humans.
Lozano E, Joller N, Cao Y, Kuchroo VK, Hafler DA. The CD226/CD155 interaction regulates the proinflammatory (Th1/Th17)/anti-inflammatory (Th2) balance in humans. Journal Of Immunology (Baltimore, Md. : 1950) 2013, 191:3673-80. 2013
Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.
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, 496:518-22. 2013
Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease.
Dominguez-Villar M, Baecher-Allan CM, Hafler DA. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nature Medicine 2011, 17:673-5. 2011
IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.
Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 2008, 454:350-2. 2008
Risk alleles for multiple sclerosis identified by a genomewide study.
Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL. Risk alleles for multiple sclerosis identified by a genomewide study. The New England Journal Of Medicine 2007, 357:851-62. 2007