Multiple sclerosis

Etiology
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By Anthony T Reder MD

Although there appears to be an "autoimmune" attack against myelin and myelin-forming cells in the brain and spinal cord, multiple sclerosis cannot be called a true autoimmune disease. No target antigen has been demonstrated reproducibly. The antigen-induced animal model, experimental allergic encephalomyelitis (EAE), does not appear spontaneously in wild mice. HLA types are associated with multiple sclerosis, but the mechanism is unclear. There are surprisingly few links to autoimmune disease, except Crohn disease and possibly thyroid disease. Systemic lupus erythematosus is underrepresented in multiple sclerosis and is linked to opposite responses to type I interferons (Javed and Reder 2006).

Specific antigenic targets for inflammation in multiple sclerosis. Candidate central nervous system antigens and targets include:

  • Proteins from infectious agents (viruses, chlamydia) that match brain antigens.
  • Proteins from neurons (synapsin).
  • Myelin (eg, myelin oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein, and myelin-associated glycoprotein) and glycolipids (ganglioside GD1a). Antibodies to MOG may cross react with Epstein-Barr virus nuclear antigen. Heat shock protein-65 is highly conserved between bacteria and man, and it is cross-reactive with the myelin antigen cyclic nucleotide phosphohydrolase (Birnbaum et al 1996).
  • Proteins from glia (astrocyte alpha-B crystallin, S100-beta, and arrestin; plus oligodendroglial 2’,3’ cyclic nucleotide 3’ phosphodiesterase, alpha-B crystallin, and transaldolase) (Schmidt 1998) and oligodendrocyte-specific protein (Cross et al 2001). Alpha-B crystallin may bind immunoglobulin and not vice versa, but these proteins could trigger antigen-specific responses or be involved in a gradual evolution in immune reactivity over time, ie, "epitope spreading" to related antigens.

Antibody response to central nervous system antigens varies between patients. Anti-myelin basic protein responses are weak in multiple sclerosis, differing from the strong responses in animal models. However, pro-inflammatory cells recognizing myelin basic protein are increased when low concentrations of myelin basic protein are used to detect high avidity human T cell clones (Bielekova et al 2004). Anti-proteolipid antibodies in CSF are more common in women than men, in patients with later onset of multiple sclerosis, in patients without a family history of multiple sclerosis, and in those who have low levels of CSF immunoglobulin and oligoclonal bands (Warren et al 1994). Antibodies to myelin oligodendrocyte protein are debatably elevated in all forms of multiple sclerosis (and other inflammatory brain diseases). However, normal subjects have anti-MBP T cells and also activated anti-MOG memory T cells that produce IFN-gamma and nerve growth factor. Antibodies to myelin basic protein are low in early multiple sclerosis and increase over time (Reindl et al 1999), but detection is erratic between laboratories. Even if antibodies to brain antigens do not cause multiple sclerosis, they could modify disease course.

Arguments are made against the presence of a “multiple sclerosis antigen.” For instance, 1 in 220 people vaccinated with the Semple rabies vaccine—which contains central nervous system tissue—develop autoimmune encephalitis (similar to EAE). Patients susceptible to this encephalitis, however, have a human leukocyte antigen (HLA) makeup that is distinct from multiple sclerosis patients (Piyasirisilp et al 1999).

The lack of a causative antigen suggests that fundamental control of immune responses may be abnormal and that oligodendroglia are innocent bystanders damaged by unregulated inflammation. Activated lymphocytes and monocytes might enter the central nervous system because of nonspecific adhesion to endothelial cells, become activated within the central nervous system, stay longer during trafficking through the central nervous system, and escape from the normal CNS suppression of the immune response. Putative antigen-specific responses are described below.

Non-antigen-specific immunity in multiple sclerosis inflammation. Etiologies that do not invoke specific target antigens are possible.

Viruses. Viruses could cause direct damage to oligodendroglia; retrovirus could incorporate into oligodendroglia and T cells and could trigger immune reactivity to determinants shared with oligodendroglia. The role of human herpes virus-6 (HHV-6) and human endogenous retroviruses (HERV) awaits confirmation in multiple sclerosis. HERV make up 10% to 30% of the human genome correlate with a more progressive course. However, detection of these viruses or their proteins is possibly a byproduct of immune activation and not the cause of the disease. Activated astrocytes produce retrovirus-encoded syncytin, which is toxic to oligodendrocytes.

Antibodies to Epstein-Barr virus correlate with brain atrophy and are elevated early in the course of multiple sclerosis. This may simply reflect multiple sclerosis-characteristic high titers to many antigens and many viruses, possible because HLA-DR2 is over-represented in multiple sclerosis and because DR2-positive people have higher antibody titers to Epstein-Barr virus, measles, and rubella (Compston et al 1986). Anti-Epstein-Barr virus antibodies could arise from persistent infection of astrocytes or B cells, causing costimulatory molecule expression, IL-6 secretion, and immune activation. Epstein-Barr virus infects B cells and could generate an autoreactive B cell population resistant to apoptosis and immune control. Epstein-Barr virus-encoded RNA in white matter lesions of multiple sclerosis is associated with interferon-alpha production by macrophages and microglia (Tzartos et al 2012). Lesions of CNS lymphoma and stokes are similar, arguing against a unique link between Epstein-Barr virus and multiple sclerosis. Epstein-Barr virus nuclear antigen blocks the vitamin D receptor, linking two environmental factors.

Antibodies to cytomegalovirus, in contrast, correlate with better outcome (Zivadinov et al 2006). Varicella-zoster virus DNA increases briefly in mononuclear cells during relapses, but varicella-zoster virus does not increase the risk of multiple sclerosis. Report of varicella-zoster virus particles in multiple sclerosis brains has not been confirmed (Burgoon et al 2009).

In children, seropositivity to Epstein-Barr virus NA-1 protein increases the risk of multiple sclerosis 3.8-fold. Cytomegalovirus positive serum confers a lower risk of multiple sclerosis in children 0.27-fold (Waubant et al 2011).

Bacteria and chlamydia. Could trigger attacks through cross-reactive antigens, superantigen activation of pathogenic T cells, responses to induced heat shock proteins (all trigger cytokine release), and release of bacterial toxins, possibly from posterior sinuses and submucosa (Gay 2007). Conversely, parasite infestation could be protective.

Oligodendroglia. Defective function or repair.

Diet. Affects immunity through oral tolerance and shapes the microbiome. Diet can modify macrophage function, membrane composition of immune cells, and prostaglandin synthesis.

Genetic. Predisposition is likely in responses to brain antigens, altered control of the immune response to brain antigens, lack of neurotrophic proteins, or poor ability to repair CNS damage.

Other mechanisms. Toxins, microchimerism of circulating blood cells, and endocrine, catecholamine, and stress interrelations with immunity have been proposed.

In the 1950s, it was theorized that CNS microvessels had poor blood flow in multiple sclerosis. Anticoagulants, however, did not impact the course of multiple sclerosis. Recent use of venous stenting to reverse putative cerebral venous outflow problems (CCSVI) has not been beneficial in controlled studies, despite anecdotes of benefit. Although the early studies that generated the hypothesis appear to have been carefully performed, they have been difficult to replicate. Tens of millions of dollars in research money and medical costs, huge amounts of investigators’ intellectual energy, and misplaced hope by patients are being directed at this questionable therapy.

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
Anesthesia
References cited
Contributors