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Multiple Sclerosis Progression, Disease Response Informed by Blood-Based Immune Signatures

Antibody Protein Cell-Free Blood

NEW YORK – New research suggests that early multiple sclerosis (MS) cases cluster into a handful of immunological subtypes with distinct immune features, disease trajectories, and treatment outcomes that can be identified with peripheral blood-based proteomic profiling.

"One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories," co-first and co-corresponding author Catharina Gross, a researcher at the University of Münster's Institute of Translational Neurology, and her colleagues wrote in Science Translational Medicine on Wednesday.

Starting from data on more than 1,200 participants with early-stage MS from the prospective, longitudinal German National MS Cohort (NationMS cohort) study, the researchers used flow cytometry in combination with Olink targeted proximity extension assays to assess some 1,500 proteins in blood serum and peripheral blood mononuclear cells from a subset of 309 individuals with early-stage, treatment-naïve MS enrolled at several centers in Germany.

The team saw three clusters with distinct peripheral blood immune signatures that were subsequently confirmed with proteomic data for another 232 individuals with MS who were not part of the NationMS cohort, prompting the group to propose a set of three "immunological endophenotypes" involving different immune cell compartments.

While a structural brain damage-related cluster dubbed endophenotype 1 (E1) was marked by CD4 T-cell changes, among other immune alterations, the endophenotype 2 (E2) cluster had enhanced natural killer cell activity, the researchers explained. On the other hand, an inflammatory endophenotype 3 (E3) cluster included CD8 T-cell immune changes.

With the help of longitudinal clinical and laboratory data, they found further ties between the immunological endophenotypes, disease trajectory, and responses to first-line MS treatments.

"We uncovered endophenotypes exhibiting patterns shifted toward inflammatory or degenerative disease features and revealed discrete endophenotype-specific treatment responses to commonly applied [disease-modifying treatments (DMTs)]," the authors reported.

In MS cases classified into the endophenotype 3 (E3) group based on blood proteomic data, for example, the team detected relatively poor response to interferon-beta-based immunotherapy. Likewise, the E3 group had higher rates of disease progression during four years of follow-up when treated with interferon-beta compared to other treatments such as glatiramer acetate (GA) or dimethyl fumarate (DMF).

"Whereas immune signatures associated with E1 and E2 were normalized to a comparable extent by all three DMTs investigated," the authors reported, the interferon-beta treatment "exhibited only limited effects on signature alterations associated with the inflammatory E3 as compared with GA and DMF."

Together, they suggested, findings from the study point to the possibility of using blood-based endophenotype testing to offer tailored treatment options to individuals with MS.

"The concept of personalized treatment selection, as it has already been implemented in oncology, still needs to be successfully translated into the field of autoimmunity," the authors explained, noting that "[t]reatments tailored to patients' subgroups instead of the one drug fits all [approach] will pave the way to precision medicine in MS."