Stage-Specific Immune Dysregulation in Multiple Sclerosis

Abstract

A large body of data indicates that multiple sclerosis (MS) is an autoimmune disease which is initiated by CD4 + T-helper 1 (Th1) and Th17 cells that are reactive against proteins in the myelin sheath. MS typically begins with a relapsing-remitting course, punctuated by clinical exacerbations associated with the development of focal inflammatory lesions in central nervous system white matter, followed by a secondary progressive (SP) phase, characterized by a gradual accumulation of neurological disability associated with widespread microglial activation and axonal loss. The molecular and cellular basis for this transition is unclear, and the role of inflammation during the SP stage is a subject of active debate. As of now, no immunological biomarkers have been identified in MS that are predictive of the clinical course or therapeutic responsiveness to diseasemodifying agents, or that correlate with new lesion development, cumulative lesion load, or degree of disability. The discovery of such biomarkers would greatly facilitate clinical management and provide power for smaller and shorter clinical trials. In this article, we discuss the literature on immunological biomarkers in MS with a focus on stage-specific differences and similarities.

Phenotypic and functional alterations of myeloid‐derived suppressor cells during the disease course of multiple sclerosis

“…Another more recent report presented a reduction in number of miR‐223 producing Mo‐MDSCs in RRMS during remission (RRMS‐rem) compared to HC . The role of MDSCs in MS pathogenic mechanisms is poorly investigated but since previous research has demonstrated innate immune cell changes during progression of disease, we hypothesize that MDSC populations may also exert phenotopic and functional alterations between the different stages of MS …”

Opportunities for Translation from the Bench: Therapeutic Intervention of the JAK/STAT Pathway in Neuroinflammatory Diseases

“…92–97 Enhanced STAT1 and STAT3 activation in T cells has been identified in MS patients during relapse compared with cells from patients in remission, and elevated levels of activated STAT1 and STAT3 strongly correlate with enhanced disease activity in the brain and spinal cord, suggesting an association of increased STAT1 and STAT3 activation and MS relapse. 98 In addition, persistent high levels of activated STAT3 in circulating CD4 + T cells from patients with clinically isolated syndrome predicts conversion to clinically defined MS. 99 …”

The contribution of neutrophils to CNS autoimmunity

“…RRMS can persist for many years; however, approximately 80% of RRMS patients eventually convert to the secondary progressive stage of disease (SPMS) in which the extent of recovery after each episode of neurological deficit diminishes [1]. In contrast to RRMS, gadolinium-enhancing MRI lesions are less common during SPMS, despite the steady increase in brain atrophy and disability that occurs during this stage of disease [6, 7]. …”