The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis

Abstract

Multiple sclerosis is one of the most common causes of chronic neurological disability beginning in early to middle adult life. Multiple sclerosis is idiopathic in nature, yet increasing correlative evidence supports a strong association between one's genetic predisposition, the environment and the immune system. Symptoms of multiple sclerosis have primarily been shown to result from a disruption in the integrity of myelinated tracts within the white matter of the central nervous system. However, recent research has also highlighted the hitherto underappreciated involvement of gray matter in multiple sclerosis disease pathophysiology, which may be especially relevant when considering the accumulation of irreversible damage and progressive disability. This review aims at providing a comprehensive overview of the interplay between inflammation, glial/neuronal damage and regeneration throughout the course of multiple sclerosis via the analysis of both white and gray matter lesional pathology. Further, we describe the common pathological mechanisms underlying both relapsing and progressive forms of multiple sclerosis, and analyze how current (as well as future) treatments may interact and/or interfere with its pathology. Understanding the putative mechanisms that drive disease pathogenesis will be key in helping to develop effective therapeutic strategies to prevent, mitigate, and treat the diverse morbidities associated with multiple sclerosis.

Keywords: Demyelination; Immune modulation; Inflammation; Multiple sclerosis; Neuroimmunology; Regeneration.

Fig. 1

Active white matter lesions in multiple sclerosis can be grouped in pattern I (A), II (B), III (C) and IV (D). Abbreviations: Igs: immunoglobulins; MAG: myelin-associated glycoprotein; CNPase: 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase.

Fig. 2

Gray matter lesions in multiple sclerosis. Meningeal infiltrates are characterized by the presence of lymphocytes intermingled with stromal cells and macrophages. The core of these lymphoid organs consists of B cells whose maturation process is supported by FDCs, while the cortex of the tertiary lymphoid organ consists of T cells and macrophages. Meningeal infiltrates (especially in deep cortical sulci) are associated with extensive microglia activation in the underlying cortex and gray matter damage. The most likely justification for the association of microglial activation in the cortex and meningeal inflammation is a soluble factor produced within the meningeal inflammatory infiltrate and accumulated in the cerebrospinal fluid. Abbreviations: FDCs: follicular dendritic cells.