Altered Immune Phenotypes And Hla-Dqb1 Gene Variation In Multiple Sclerosis Patients Failing Interferon Beta Treatment

Background: Interferon beta (IFN beta) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients.Aim: To determine a combination of cellular and molecular blood signatures associated with the efficacy of IFNO treatment using an integrated approach.Methods: The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFN beta 1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4(+) T cells and naive/memory T cell subsets, by measurement of circulating IFN alpha/beta proteins with digital ELJSA (Simoa) and analysis of similar to 600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping HLA-DRB1, -DRB3,4,5, -DOA1, and -DQB1 , using as a control population the Milieu Interieur cohort of 1,000 French healthy donors.Results: Clinical responders and non-responders displayed similar plasma levels of IFN beta and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naive regulatory T cells, enhanced terminally differentiated effector memory CD4(+) T-EMRA cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for HLA-DQB1 genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFN beta, and in which CD4(+) T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.