Autoreactive lymphocytes in multiple sclerosis: Pathogenesis and treatment target

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by destruction of the myelin sheath structure. The loss of myelin leads to damage of a neuron's axon and cell body, which is identified as brain lesions on magnetic resonance image (MRI). The pathogenesis of MS remains largely unknown. However, immune mechanisms, especially those linked to the aberrant lymphocyte activity, are mainly responsible for neuronal damage. Th1 and Th17 populations of lymphocytes were primarily associated with MS pathogenesis. These lymphocytes are essential for differentiation of encephalitogenic CD8⁺ T cell and Th17 lymphocyte crossing the blood brain barrier and targeting myelin sheath in the CNS. B-lymphocytes could also contribute to MS pathogenesis by producing anti-myelin basic protein antibodies. In later studies, aberrant function of Treg and Th9 cells was identified as contributing to MS. This review summarizes the aberrant function and count of lymphocyte, and the contributions of these cell to the mechanisms of MS. Additionally, we have outlined the novel MS therapeutics aimed to amend the aberrant function or counts of these lymphocytes.

Keywords: B lymphocytes; CNS; T lymphocytes; biomarkers; immune pathogenesis; multiple sclerosis; therapy.

Figure 1

Autoreactive T cells in pathogenesis of MS. In the lymph node, T cells are primed to CNS autoantigens presented by APC, then cross the Blood brain barrier (BBB) and enter the brain. In CNS, they activate macrophages and microglia, which release cytokines promoting local inflammation and tissue injury.

Figure 2

CD4+T cells cross react with Epstein Barr Virus (EBV) and DR2 derived peptides in the periphery and myelin in the brain. Myelin mimotopes could induce autoreactive CD4+ T cells by presenting EBV and DR2a/DR2b derived peptides sharing similarities with CNS self-antigens (i.e. myelin). These T cells could recognize the target antigen on microglia, leading to activation of CD4+ T cells. Activated T cells release cytokines which could trigger demyelination and axon loss, CNS inflammation and tissue injury.

Figure 3

Role of Tregs in pathogenesis of MS. Tregs control of the immune homeostasis focused on preventing differentiation, proliferation and survival of autoreactive myelin targeting CD8+, Th17 and B cells. This control depends on the direct contact as well as the release of IL-10 and TGF-β by Tregs. It is believed that in MS, decreased activity and lower counts could reduce the regulatory capacity of Tregs. This could promote survival, proliferation and differentiation of myelin reactive CD8, Th17 and B cells.

Figure 4

Role of cytokines in activation of T and B lymphocytes in MS. Activation of Th1 and Th2 lymphocytes was demonstrated in MS. Th1 lymphocyte differentiation is regulated by IFN-γ. Once Th1 cells are activated they produce more IFN-γ stimulating differentiation and proliferation of CD8 cells. CD8 cells also release IFN-γ, which together with Il-12 supports CD8 and Th1 proliferation. Activated myelin primed activated CD8 lymphocytes could damage myelin sheets. Activated by IL-18 and IL-33, Th2 lymphocytes secrete IL-4 and IL-10 which support proliferation and differentiation of B cells. Myelin antigen primed B cells could terminally differentiate to plasma cells producing anti-BMP antibodies targeting myelin sheets. Th17 lymphocytes proliferation and differentiation is supported by IL-6, IL-21, IL-23 and TGF-β. These activated Th17 lymphocytes could also target axon myelin sheets and contribute to the local inflammation.

Figure 5

A timeline of FDA approval for MS therapeutics. The increasing color gradient in the circles indicates potential for higher toxicity, while the increasing size of the circles indicates higher efficacy.