Many predisposing factors for multiplesclerosis (MS), such as HLA types and geomagnetic fields have been described
but the search for a single essential factor has been like searching for the
rainbow’s end. The most notable feature in the epidemiology of MS in the
Western world has been its rise from unknown to the most prevalent disabling
neurodegenerative disease of young adults. We suggest that this may be largely
or entirely attributable to societal changes that have increasingly isolated
populations from micro-organisms that form part of the human microbiome and
which are essential for an effective maturation of immune defence mechanisms.
This Darwinian explanation suggests a rational approach to both prevention and
treatment of MS, by substituting for the loss or absence of factors that
millions of years of evolution have led the immune system to ‘expect’ to
encounter early in life.
BCG: Bacille Calmette-Guérin; CDMS: Clinically
Definite Multiple Sclerosis; CIS: Clinically Isolated Syndrome; EBV: Epstein-
Barr virus; HERV: Human Endogenous Retrovirus; HLA: Human Leucocyte Antigen;
IL: Interleukin; INF-α: Interferon Alpha; MAIT: Mucosal-associated Invariant T
Cells; MAMP: Microbe-associated Molecular Pattern; MHC: Major
Histocompatibility Complex; MRI: Magnetic Resonance Imaging; MS: Multiple
Sclerosis; TCR: T Cell Antigen Receptor; TNF-α: Tumour Necrosis Factor Alpha;
Treg: Regulatory T Cell; PRR: Pattern Recognition Receptor; TLR: Toll-like
Receptor; RA: Retinoic Acid.
Current treatment strategies for multiple sclerosis (MS) are
essentially empirical because no single clear underlying cause of the disease
has been determined. Numerous genomic and environmental risk factors for MS
have been described, but problems of cause and effect remain unresolved. It has
indeed been stated, with considerable justification, that MS research is “low
on fact, high on fiction”.
Although there is a well-described genetically determined
predisposition to MS, the association is far from complete as, for example, the
risk of an identical twin sibling of an affected person developing MS is only
30%. Thus any genes involved are likely to be of low penetration and influenced
by the expression of some or many other genes. Notwithstanding, a large number
of genetic loci, including many coding for HLA, have been determined and fine-mapped.
These studies have demonstrated a central role for the immune system in the
aetiopathogenesis of MS but the highly complex nature of the data will require
novel tools for their analysis before any unifying factor can be delineated.
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