Identification of cellular factors associated with inflammation and neurodegeneration in multiple sclerosis

Abstract

Cellular phenotype and function; Demyelinating disease of central nervous system; Glial fibrillary acidic protein

Fenotip i funció cel·lular; Malaltia desmielinitzant del sistema nerviós central; Proteïna àcida fibril·lar glial

Fenotipo y función celular; Enfermedad desmielinizante del sistema nervioso central; Proteína ácida fibrilar glial

Background: Serum biomarkers as neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) enabled early identification of multiple sclerosis (MS) patients at risk of relapse-associated worsening (RAW) or progression independent of relapses (PIRA). However, the immunological mechanisms underlying these clinical phenotypes remain unclear. Methods: We conducted a cross-sectional study including 117 MS patients and 84 healthy controls (HC). Patients were stratified as NLGL (low sNfL and sGFAP), NH (high sNfL at different levels of sGFAP), and NLGH (low sNfL and high sGFAP). Percentages of blood and cerebrospinal fluid (CSF) mononuclear cells, and intracellular production of cytokines by T and B cells after “in vitro” stimulation were analyzed by flow cytometry. Results: We identified a common inflammatory profile present in the blood of all MS groups comprising significant increases of effector CD4+ and CD8+ T cells, of memory and antigen-presenting B cells, of CD4+ and CD8+ T cells producing interferon-gamma, interleukin-17 and tumor necrosis factor-alpha (TNF-α) and of B cells producing TNF-α. Additionally, the highly inflammatory NH group showed lower frequencies of different regulatory subsets (transitional B cells, PDL1+ monocytes and Treg cells) compared to HC and increased percentages of CD4+ and CD8+ T cells producing granulocyte-macrophage colony-stimulating factor and of effector CD56dim NK cells. They also showed lower percentages of Treg in blood and CSF compared to the low inflammatory NLGL group, which also displayed higher frequencies of regulatory CD56dim, NKG2A+ cells. Conclusion: All MS patients share increased inflammatory B and T cells, but differ in regulatory or NK subsets, which identify highly inflammatory or benign disease courses.

The authors declare financial support was received for the research, authorship, and/or publication of this article. This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project “PI21/00828” and by grant RD21/0002/0053 from La Red Española de Enfermedades Inflamatorias and cofunded by the European Union.