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Key Regulator of Inflammation Disrupted by Gene Variants Linked to Multiple Sclerosis

With genetic roots of many autoimmune diseases pinpointed, scientists are zeroing in on the variety of molecular mechanisms triggered by these harmful variants. A team led by Yale School of Medicine researchers has implicated a central regulator of inflammation as a cause of many cases of multiple sclerosis (MS) — and intriguingly, the researchers note — ulcerative colitis as well.

The study was published in the June 10 issue of the journal Science Translational Medicine.

“After identifying the genes that cause MS, we are starting to generate a comprehensive roadmap of the how these genes operate together in allowing immune cells to become activated and attack the myelin,” says David A. Hafler, the William S. and Lois Stiles Professor of Neurology and Immunobiology at Yale and chair of Yale’s Department of Neurology.

Last fall, a consortium of researchers identified genetic variants that play a role in onset of 21 different autoimmune diseases. Ninety-seven variants were associated with multiple sclerosis. The new Yale research led by Hafler and first author William J. Housley shows that 17 of these MS variants affect the NFkB pathway, which controls a host of immune system responses to environmental threats, and that one variant associated with MS near the NFkB gene profoundly increased gene activity.

The findings illustrate the complexity of individual diseases like MS, in which variants can contribute to small increases in risk of disease through different molecular mechanisms. They also illustrate how same molecular pathways, such as NFkB, can trigger a variety of autoimmune diseases with fundamentally different symptoms — such as MS and ulcerative colitis.

This image shows colored squares in a magnifying glass.

Armed with knowledge of the genetic roots of autoimmune diseases like MS, scientists are zeroing in on their molecular causes. Image credit: Michael S. Helfenbein.

“Identifying these like-minded genes that by themselves contribute only a small risk to disease but together lead to major alterations in immune function may allow a more precise approach in deciding which drug should be used to treat patients,” Hafler said.

About this genetics research

Funding: Primary funding for the research came from grants from the National Institute of Health and the National Multiple Sclerosis Society.

Source: Bill Hathaway – Yale
Image Credit: The image is credited to Michael S. Helfenbein
Original Research: Abstract for “Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli” by William J. Housley, Salvador D. Fernandez, Kenneth Vera, Sasidhar R. Murikinati, Jaime Grutzendler, Nicole Cuerdon, Laura Glick, Phillip L. De Jager, Mitja Mitrovic, Chris Cotsapas and David A. Hafler in Science Translational Medicine. Published online June 10 2015 doi:10.1126/scitranslmed.aaa9223


Abstract

Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli

The transcription factor nuclear factor κB (NFκB) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFκB. We report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after tumor necrosis factor–α (TNFα) stimulation. Both variants result in increased degradation of inhibitor of NFκB α (IκBα), a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering the expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway: TNFα-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1). Finally, naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.

“Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli” by William J. Housley, Salvador D. Fernandez, Kenneth Vera, Sasidhar R. Murikinati, Jaime Grutzendler, Nicole Cuerdon, Laura Glick, Phillip L. De Jager, Mitja Mitrovic, Chris Cotsapas and David A. Hafler in Science Translational Medicine. Published online June 10 2015 doi:10.1126/scitranslmed.aaa9223

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