Abstract PL1.1
 
Approaching the cause of multiple sclerosis Print
 
DA Hafler1,2
1Yale School of Medicine, New Haven, CT, United States, 2Broad Institute of MIT and Harvard University, Cambridge, MA, United States
 
Since the clinical description of MS by Charcot over 160 years ago, there has been a gradual understanding of the underlying etiology of the disease based first on microscopy revealing inflammatory cells accompanying losses of myelin. As new technologies have been applied an emerging disease model has evolved driven by modern genetics, epigenetics, and observations in the EAE model. First, MS is inheritable, strongly clustering with other autoimmune diseases; genome wide association studies have identified variation in predominantly immune genetic loci. Recent techniques have allowed a more precise identification of nucleotide changes and the mechanisms that cause heritable differences among individuals. MS is dictated by genetic variants that are predominantly in the open chromatid of T cells and B cells associated in particular with the NFkB, EBF1, and MEF2A transcription factor binding sites. Environmental stimuli interacting with these genetic factors appear to trigger the activation of myelin reactive T cells. CD4 cell libraries generated from patients and control subjects from naïve, CCR6 neg memory, or CCR6+ memory populations isolated ex vivo from blood and interrogated for reactivity to myelin self-antigens revealed that autoreactive T cells in patients with MS predominantly resided in CCR6 positive memory T cell compartment, secreting the pro-inflammatory cytokines IL-17, GM-CSF, and IFNγ, but less IL-10 as compared to controls. Moreover, myelin-reactive T cells from MS patients exhibited a pathogenic gene expression signature similar to the encephalitogenic T cells in EAE. However, MS is not simple due to “bad genes”, but instead is the bad outcome of too many variants in non-coding regions leading to a lower threshold of T cell activation in response to multiple environmental factors, including lower vitamin D, smoking, higher body mass index, exposure to EBV, and perhaps higher salt intake. In this regard, increased salt in the diet dramatically boost the induction of Th17 cells mediated by SGK1. Th17 cells generated under high-salt display a pathogenic phenotype characterized by the up-regulation of the pro-inflammatory cytokines IL-17, GM-CSF, TNFα and IL-2. In summary, myelin-reactive T cells have a lower threshold of activation in MS that is genetically determined. Environmental stimuli interacting with these genetic factors appear to trigger the activation of myelin reactive T cells secreting inflammatory cytokines mediating the disease.


Assigned speakers:
M.D. David Hafler , Yale School of Medicine , New Haven , US

Assigned in sessions:
11.09.2014, 09:00-10:00, Plenaries, PL1, Plenary Session 1 (PL1.1), Auditorium