Immune-mediated genesis of multiple sclerosis

Abstract

Multiple sclerosis (MS) is widely acknowledged to be an autoimmune disease affecting the neuronal myelin structure of the CNS. Autoantigens recognized as the target of this autoimmune process are: myelin basal protein, anti-proteolipid protein, antimyelin-associated glycoprotein and antimyelin-based oligodendrocytic basic protein. Ample evidence supports the idea of a dysregulation of immunological tolerance towards self-antigens of neuronal myelin structure triggered by one or more viral or bacterial microbial agents in predisposed HLA gene subjects. Genetic predisposition to MS has been highlighted by numerous studies associating the disease to specific HLA haplotypes. Moreover, a wide range of evidence supports the fact that MS may be consequence of one or more viral or bacterial infections such as measles virus, EBV, HHV6, HZV, Chlamydia pneumoniae, Helicobacter Pylori, and other microbial agents. Microbiota elements also seems to have a role on the determinism of the disease as a pathogenic or protective factor. The autoimmune pathogenetic process could arise when a molecular mimicry between a foreign microbial antigen and an auto-antigen occurs in an HLA gene subject competent for that particular antigen. The antigen-presenting cells in this case would induce the activation of a specific Th clone causing a cross-reaction between a foreign antigen and an autoantigen resulting in an autoimmune response.

Fig. 1

Molecular function of class II HLA in antigen presentation.

Fig. 2

Migration and effector function of T cells in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) After immunization with myelin antigens, complete Freund’s adjuvant (CFA) and pertussis toxin, dendritic cells (DC) are activated in the lymph nodes by Toll-like receptor (TLR) agonists within the mycobacterium tuberculosis component of CFA, and present myelin antigen to naive T cells The activated myelin-specific T cells enter the bloodstream and traffic to and enter the CNS Breakdown of the blood-brain barrier (BBB) occurs, allowing recruitment of other inflammatory cells into the CNS. T cells entering the CNS encounter their cognate myelin antigens and become reactivated by local APC. T cells expand and release inflammatory mediators which help recruit other immune cells to the site of inflammation. Activation of local microglial cells and infiltrating cells results in production of proteases, glutamate, reactive oxygen species and other cytotoxic agents which promote myelin breakdown. Damage to the myelin sheath surrounding axons is followed by axonal damage and neurological impairment.

Fig. 3

Molecular mechanisms of pathogen-induced autoimmunity. (A) Pathogen-activated antigen-presenting cells can display self-antigens from dying cells to autoreactive T lymphocytes in a process known as bystander activation. (B) Activation of the immune system resulting from stimulation of pattern recognition receptors by infectious agents can lead to expression of proinflammatory mediators and triggering of autoreactive lymphocytes. (C) Microbial superantigens cross-link MHC class II molecules with TCRs inducing antigen unspecific activation of autoreactive T cells. (D) Certain pathogen-derived antigens share structural similarities with self-peptides causing activation of autoreactive T cells through molecular mimicry. (E) The process of epitope spreading can enhance autoimmune responses by activating autoreactive! T cells to “new” self-antigens during the progression of the disease. (F) Viral agents can enhance the activation state of autoantigen presenting cells and induce the survival of autoreactive lymphocytes. As an example, persistent infection of microglial cells with Theiler’s murine encephalomyelitis virus (TMEV) was shown to upregulate expression of MHC and co-stimulatory molecules and enhance the ability of these cells to function as effective A PCs [34]. Furthermore, EBV infection could assist in the survival of autoreactive B cells [36]. APC antigen-presenting cell: MHC, major histocompatibility complex: PAMP, pathogen-associated molecular pattern: TCR, T-cell receptor, TLR, Toll-like receptor.