Graduate Student Oklahoma Medical Research Foundation, Oklahoma, United States
Disclosure(s):
Melissa Testut: No financial relationships to disclose
Introduction/Rationale: Multiple sclerosis (MS) is a demyelinating autoimmune disease that is heterogeneous in prognosis. This variability is evident with interferon-β (IFN-β) therapy, where certain patients are non-responders. Elevated type I IFN signatures have been associated with IFN-β non-response. Obesity, an increasingly prevalent environmental factor, can elevate innate immune responses. We hypothesized there is an amplification of type I IFN signaling in obese females that impairs IFN-β efficacy. Here, we examine the relationship between obesity, interferon signaling, and IFN-β treatment response in female patients and in the EAE models.
Methods: Chart reviews were performed for 86 patients treated with IFN-β and 113 treated with glatiramer acetate (GA) to determine relapse status on therapy. Multivariable logistic regression assessed demographic factors associated with relapses during treatment. Serum proteins were quantified using Olink Explore 1536 and stratified by sex and obesity status. Complementary studies were conducted in high-fat diet fed mice with EAE treated with IFN-β or vehicle.
Results: In IFN-β treated patients, obesity was associated with increased relapse risk, whereas this was not observed in GA treated patients. This reduction in IFN-β efficacy was observed in women but not men. Proteomic profiling of serum from untreated obese women revealed increased type I IFN pathways, along with increased Th1 and Th17 signatures. In obese female mice, high-fat diet was associated with elevated IFN-α in gonadal adipose tissue, increased interferon-stimulated gene expression in the spleen, and more severe EAE that was not ameliorated by IFN-β treatment.
Conclusion: Elevated type I interferon signaling was associated with reduced IFN-β treatment efficacy in obese females across human and mouse studies, suggesting obesity-associated dysregulation of innate immune signaling as a contributor to reduced therapeutic responsiveness in MS.
