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The immune system in MS


Multiple sclerosis (MS) is a highly complex chronic immune mediated disease of the central nervous system (CNS). Although the underlying pathophysiology of MS is not fully understood,1 it is known to encompass multifactorial dysregulation of the immune system involving genetic susceptibility, epigenetic and post-genomic events, and environmental factors such as viral pathogens (e.g. Epstein Barr virus), chemicals, smoking, diet, obesity and vitamin D levels.2

MS phenotypes expressed by relapses (relapsing–remitting MS, secondary progressive MS with relapses) are characterised by a predominance of multifocal inflammation.

The principal event leading to a relapse in MS is the influx of immune cells, including monocytes and T-helper type 1 (Th1) and Th17 cells, from the circulation into the CNS through a breached blood-brain barrier.2–4 

Important factors that trigger the influx of immune cells into the CNS include systemic infections, increased osteopontin levels, lower serum vitamin D levels, reduced interleukin (IL)-10-producing Bcells (Bregs) and decreased levels of terminally differentiated autoregulatory CD8+ T-cells (CD8+ Tregs).4 


Once within the CNS, T-cells activate microglia (a type of neuroglia [glial cell] located throughout the brain and spinal cord) and macrophages causing them to gain a proinflammatory phenotype4 and trigger the release of proinflammatory cytokines. This leads to oxidative injury and mitochondrial dysfunction that promotes demyelination, neuronal and glial cell damage.2 Antibody producing Bcells also appear to play a role in MS pathophysiology following the introduction of B-cell targeted therapies.

What is the role of T-cells in MS?

Both the innate and adaptive arms of the immune system are dysregulated in MS, and it is believed that myelin-reactive CD4+ T-cells play a central role in driving the pathogenesis of MS.

The peripheral activation and subsequent migration of autoreactive Th1 and Th17 cells into the CNS is widely thought to be an essential step in the pathogenesis of MS.4

Studies in experimental autoimmune encephalomyelitis (EAE) models have helped to identify the key immune cells involved in the inflammatory pathology of MS. As shown in Figure 1, the key steps in the process are as follows:

  • T-cell intrinsic factors (for example, costimulatory molecules, cytokine receptors, and microRNA [miR]) and extrinsic factors (mainly Treg dysfunction) dysregulate CD4+ T-cell responses.4
  • Breakdown of the blood-brain barrier.5
  • Peripheral activation and subsequent migration of autoreactive Th1 and Th17 cells into the CNS.5
  • Innate IL-17 and IL-21 secretion from a subset of T-cells, which amplifies Th17 cell responses.5
  • Activation of inflammatory myeloid cells by release of granulocyte-macrophage colonystimulating factor (GM-CSF) from Th17 cells, which activates inflammatory myeloid cells and in turn amplifies T-cell activation.5
  • Activation of resident microglia.5
  • Clonal expansion of Th1 and Th17 cells.5
  • Release of inflammatory mediators by Th1 and Th17 cells (e.g. IL-17, GM-CSF, interferon gamma [IFN-γ] and tumour necrosis factor [TNF]) and production of reactive oxygen and nitrogen species, cytotoxic products and proteases that promote the destruction of myelin and oligodendrocytes, which are responsible for remyelination of axons.5

 

Figure 1: Key pathological processes within the CNS during EAE and MS5 

Key pathological processes within the CNS during EAE and MS5

 

Adapted from McGinley AM, J Aut Immun 2018; 87: 97–108. 

 

What is the role of B-cells in MS?

B-cells, which develop from haematopoietic stem cells in the bone marrow, mature into naive B-cells upon entering the circulation.6 Following exposure to antigens, B-cells undergo a proliferative phase where they develop into antibody-producing plasma blasts/plasma cells, or memory B-cells.6

Plasma B-cells produce antibodies and auto-antibodies which have been used for decades to diagnose MS when visualised as intrathecal oligoclonal bands.6 Non-plasma B-cells also exert other effector functions, including cytokine production, antigen presentation and complement-mediated damage to myelin. This process could provide an explanation for the pathogenic contribution of these cells in MS.6

Several studies suggest that MS could be associated with abnormal B-cell cytokine responses, including the production of abnormally high levels of TNF-α and lymphotoxin-α, and an increase in the frequency of GM-CSF-producing B-cells6



B-cells could also play a role in the presentation of auto-antigens to CD4+ T-cells, thereby promoting Th1 and Th17 responses. Furthermore, B-cells recognise myelin and promote T-cell recruitment, thus promoting the release of proinflammatory cytokines.6

 

Figure 2: B-cell involvement in MS6 

B-cell involvement in MS

 

B-cells contribute to MS pathogenesis by (i) secreting pro- and anti-inflammatory cytokines; (ii) releasing antibodies including various auto-antibodies; and (iii) acting as antigen-presenting cells that present auto-antigens to CD4+ T-cells, which together with cytokines promote Th1 and Th17 responses Adapted from Nguyen AL, et al. Br J Pharm 2017; 174: 1895–1907. 

Interestingly, the presence of lymphoid follicle-like structures in the meninges surrounding the CNS of secondary progressive MS cases suggest that B-cells could also play a role in progressive disease.6 

 

Future perspectives and therapeutic implications

Inflammation is present at all stages of MS, but with variable predominance of the cell types involved.2 The inflammation present is dynamic, as demonstrated by increasing compartmentalisation in meningeal B-cell follicles and diffuse microglial activation over time.2 Furthermore, the inflammatory process involves many cellular players which interact in a collaborative fashion, providing possible targets for therapeutic intervention.2 The inflammation is likely to be heterogeneous among disease subtypes.2

A number of key challenges can be identified which should be considered in future MS research. Among these challenges is the need to define correlations between genotypes and phenotypes2 and the importance of identifying the key triggers for immunological processes.2 In addition, developing an understanding of the relationship between inflammation and neurodegeneration or failure of repair will be critical for the development of new approaches to managing MS.2

At the clinical level, it will also be highly beneficial to define biomarkers that will assist in the diagnosis, prognosis and response or non-response of MS patients to disease-modifying therapy.2

Such an approach will become increasingly important as new, targeted therapies are developed.

 

References

  1. Lassmann H, van Horssen J. The molecular basis of neurodegeneration in multiple sclerosis. FEBS Letters 2011; 585: 3715–3723.

  2. Grigoriadis NC, van Pesch V, ParadigMS Group. A basic overview of multiple sclerosis immunopathology. Eur J Neurol 2015; 22(Suppl. 2): 3–13.

  3. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 2014; 89: 225–240.

  4. Yadav SK, Mindur JE, Ito K, et al. Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol 2015; 28: 1350–7540.

  5. McGinley AM, Edwards SC, Raverdeau M, Mills KHG. Th17 cells, γδ T-cells and their interplay in EAE and multiple sclerosis. J Aut Immun 2018; 87: 97–108.

  6. Nguyen AL, Gresle M, Marshall T, Butzkueven H, Field J. Monoclonal antibodies in the treatment of multiple sclerosis: emergence of B-cell-targeted therapies. Br J Pharm 2017; 174: 1895–1907.