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

David A. Hafler, MD, MA

 We've known for a long time that MS is a genetically mediated autoimmune disease. We've identified over 230 genetic variants which are associated with a risk of developing the disease. But it's not just the genes, it’s the bad interaction between genes the environment. In terms of the actual cause of the disease, the working model is that autoreactive T cells—T cells reactive to myelin antigens—become activated, go into the nervous system, and cause tissue destruction. That's based on animal models and a fair amount of experimental work.

The question is, why did these T cells get activated? A major finding the field of immunology is a new population of T cells, called regulatory T cells, expressing the transcription factor Foxp3. They were discovered in mice and shown to be very important in an animal model for autoimmunity. Our lab identified these cells in humans back in the early 2000s, and then showed they're defective in patients with MS. We went on to show that rather than being suppressive cells, they are more effective T regs. We wanted to know what was the mechanism—that is, what is the molecular mechanism—that led to this defect in regulatory T cells, which then allow autoreactive T cells to become unbridled attack the brain?

We did a very simple experiment we took over 50 patients with MS—these are new-onset patients coming into Yale-New Haven Hospital, who had not had previous disease, and had not ever received any therapy, and compared to the age match controls. We extracted the RNA from these regulatory T cells, called T regs, and asked what was different. We, in fact, found one transcription factor that was different between the T regs in patients with MS compared to controls. This is unpublished work, but the name of the transcription factor is PRDM1—that’s the RNA—and the protein is called BLIMP-1. BLIMP-1 has been previously associated, in mice, with regulatory T cell function.

We then looked at other autoimmune diseases, where there were also defects in T regs, and found this was also altered on T reg populations, so it appears to be common among different autoimmune diseases. The question is, why is it dysregulated? We then took this protein and transfected it into a T reg and then asked what the protein network is and identified a particular kinase, SGK1, that was induced. Why is that of interest? But we previously had shown that salt, which we believe is a risk factor for MS, was increased in the tissue of patients with MS. This is driven by SGK1. So this PRDM1-SGK1 access is fundamental in the loss of regulation of T cells in patients with MS, and suggests a link between the environment and immune dysfunction in patients with the disease.

Videos

The William S. and Lois Stiles Edgerly Professor of Neurology and Professor of Immunobiology, and Neurologist-in-Chief at Yale-New Haven Hospital spoke to the findings of a recent assessment of T cells in multiple sclerosis. [WATCH TIME: 4 minutes]

David A. Hafler, MD, MA

Articles

Role of Antigen Reactive T Cells in Multiple Sclerosis

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