BACKGROUND

Interferon beta (IFN) 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 IFN treatment using an integrated approach.

METHODS

The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFN1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4 T cells and naïve/memory T cell subsets, by measurement of circulating IFN/ proteins with digital ELISA (Simoa) and analysis of ~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 -, and -, using as a control population the cohort of 1,000 French healthy donors.

RESULTS

Clinical responders and non-responders displayed similar plasma levels of IFN and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naïve regulatory T cells, enhanced terminally differentiated effector memory CD4 T cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for 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, and in which CD4 T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.