Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronic inflammatory disease that affects the brain and the spinal cord.1,2 Environmental factors such as vitamin D levels, viral infections, obesity, and smoking can contribute to MS development.3 Genetic factors also have a significant role in MS formation as several genes can increase susceptibility to the disease.1,2,4

MS is typically characterized by inflammation, demyelination, and axonal loss.1 Axonal loss may not appear in the acute phase of the disease but may be the eventual cause of irreversible neurological deficits.1,5 As demyelination occurs, the conduction of electrical signals by neurons is compromised and patients show significant neurological disabilities as a result. The motor, sensory, visual, and autonomic systems are compromised.1 Months or years may elapse between MS symptomatic episodes.

This disease is viewed in 2 distinct stages, allowing the identification of 3 clinical forms.2,6 One phase corresponds with an early inflammation leading to a form of relapsing-remitting disease (RRMS). In this phenotype, periods of neurological dysfunction alternate with periods of remission. A different phase, where delayed neurodegeneration with nonrelapsing progression occurs, corresponds with primary progressive MS (PPMS).6 In PPMS, neurological degeneration occurs beginning with the onset of the disease. In the secondary phenotype, neurological damage settles in gradually and a reduced number of relapses is reported.

Breaking the Blood-Brain Barrier (BBB)

MS begins with an increased migration of autoreactive lymphocytes through the blood-brain barrier (BBB).1 Crossing the BBB requires an active expression of adhesion molecules by lymphocytes and macrophages that become able to breach the BBB. The breakdown of the protective barrier of the brain is an early event in MS that leads to the stimulation of destructive cytokines and to additional symptoms such as swelling. BBB breakdown can be recognized during MRI.

Regulatory T cell function is altered in MS with the absence of suppression of effector cells promoting the settling of an immune response in the brain. These defects in the regulatory T cell function potentiate inflammation within the brain.1,7

Demyelination and the Formation of MS Lesions

After crossing the BBB, cells infiltrate the white matter of the central nervous system (CNS).1 This damaged matter is designated as “normal-appearing white matter” (NAWM).8 Lymphocytes attack myelin as they recognize it as a foreign substance. Oligodendrocytes are consequently lost, with dramatic effects on myelin production and axonal damage.5 Remyelination can occur in early stages of the disease, however, as MS progresses and oligodendrocytes are unable to keep up with myelin replacement, remyelination becomes a difficult process, and scar-like plaques form.9

Examination of MS plaques reveals oligodendrocyte reduction, inflammatory T-cell infiltrates, essentially MHC class I restricted CD8+ T-cells, and myelin destruction10. B-cells and plasma cells are also present.10 Even though RRMS and progressive MS are both characterized by inflammatory changes, this event is more pronounced in RRMS. B-cell level and plasma cells in RRMS are lower when compared to progressive MS.11 Classical plaques are predominant in RRMS and characterized by activated microglia and macrophages in the progressive form of the disease.

ms demyelination
Coloured FLAIR magnetic resonance imaging (MRI) scan of a section through the brain of a 60 year old patient with progressive multifocal leukoencephalopathy (PML). This disease leads to the destruction of myelin around nerves in the brains white matter. In this scan areas of demyelination are bright. It is caused by the JC virus, but only occurs in immunocompromised individuals.

Within MS subtypes, there are differences among CNS areas in the proportion of lesions. Studies report the existence of 4 different histopathological patterns of lesions in the brain of patients with early stages of the disease that correlate with cerebrospinal fluid (CSF) analysis.13 In pattern I, lesions are characterized by infiltration of lymphocytes and macrophages. In pattern II they present the same features of pattern I with additional involvement of the complement system which is activated. Oligodendrogliopathy characterizes pattern III, with simultaneous dysregulation of myelin expression. In pattern IV, lesions show oligodendrocyte degeneration in the center of the lesion while a border of normal white matter can be seen.13

Inflammation in MS

As T-lymphocytes enter the CNS and react against myelin, an inflammatory process begins. This inflammation also stimulates the release of cytokines and other soluble factors that can interfere with the neurotransmission processes and potentially influence the loss of myelin.1 Few clinical trials and studies have shown that inflammation leads to relapses and potentiates neurological damage.14

Inflammation varies according to the stage of MS. Early stages of the disease are linked to significant BBB breakdown, while progressive stages of the disease show inflammation around blood vessels, but no BBB disruption.15

T-cell mediated immunity was regarded for a long time as a key and solitary player in MS. Tregs (T-lymphocytes with regulatory roles) that show a decreased function have been pointed out as influencers in MS development. Research has shown B-cell therapy effects on MS and that the disease can no longer be understood as only a T-cell disease.16 B cells have indeed an important role in MS pathology, from antigen presentation to autoantibody production. This B-cell active participation in MS pathogenesis is supported by high levels of immunoglobulin G (IgG) that can be found in the CSF of patients.17


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11. Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(5):1175-1189. doi:10.1093/brain/awp070

12. Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47(6):707-717 doi:10.1002/1531-8249(200006)47:6<707::aid-ana3>;2-q

13. Jarius S, König FB, Metz I, et al. Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis. J Neuroinflammation. 2017;14(1):171. doi:10.1186/s12974-017-0929-z

14. Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol. 1999;46(3):296-304. doi:10.1002/1531-8249(199909)46:3<296::AID-ANA4>3.0.CO;2-%23

15. Hochmeister S, Grundtner R, Bauer J, et al. Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J Neuropathol Exp Neurol. 2006;65(9):855-65. doi:10.1097/01.jnen.0000235119.52311.16

16. Greenfield AL, Hauser SL. B-cell therapy for multiple sclerosis: entering an era. Ann Neurol. 2018;83(1):13-26. doi:10.1002/ana.2511917. Burgoon MP, Gilden DH, Owens GP. B cells in multiple sclerosis. Front Biosci. 2004;9:786-796. doi:10.2741/1278

Reviewed by Michael Sapko, MD on 7/1/2021

Reviewed by Michael Sapko, MD, on 7/1/2021.