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Advanced Neurology Multiple sclerosis: Immunopathogenesis

Ongoing research on MHC maps identified the HLA- estimated by large-scale genome-wide association studies
DRB1 gene, specifically the DRB1*15:01 allele, with six data . Therefore, there is no single predominant factor
[20]
statistically independent effects. The function of the non- causing MS; instead, a multitude of various genetic and
classical HLA and non-HLA genomes in the MHC is also environmental components, as well as their complex
highlighted. This allele remains the most potent genetic interaction, that lead to increased risk and development of
risk factor with an average odds ratio (OR) of 3.08 [13,19,20] . this disease should be taken into consideration.
The majority of risk alleles associated with MS outside the
HLA region have been detected in intronic and intragenic 4. Pathogenesis
[20]
regions . HLA-DRB1*15:01 correlates with higher rates In progressive MS, neuron degeneration is a predominant
of IgG abnormalities in CSF. Optic nerve involvement, hallmark, whereas in RRMS, inflammation, which
that is, optic neuritis (ON), was observed at increased tends to lessen over the course of MS, is the main factor
rates in individuals with DRB1*15:01 and also DRB1*04:05 causing RRMS. Neuroaxonal damage is more prevalent
compared to individuals without these alleles. Individuals in individuals with progressive MS (PMS) than in
with DRB1*15:01-positive MS had statistically significant those with other phenotypes of MS . Despite the fact
[5]
(P = 0.036) IgG abnormalities in the CSF and were more that the coexistence of inflammatory responses and
likely (P = 0.044) to have optic nerve damage than those neurodegeneration is common in the patients and they are
with DRB1*15:01-negative MS. In addition, they tended usually manifested in all lesions at all stages of the disease,
to have higher foveal sensitivity visual function scores innate cells and B cells are often cited as the culprits of
compared to allele-negative patients (P = 0.060) . neurodegeneration, while a complex interplay between
[19]
Genome-wide association studies (GWAS) have identified oxidative stress, activation of microglia, remyelination
at least 200 single nucleotide polymorphisms outside the deficiency and its failure, iron toxicity, mitochondrial
MHC region, which are associated with the risk for MS dysfunction, and many other processes is also suspected
development [21,22] . An extensive genetic association study to support the process of neuronal injury and progression
on MS found 233 significant independent MS susceptibility of MS [5,10,23-25] .
genomic factors, 200 of which were in the autosomal non-
MHC genome. In the same study, microglia and various By releasing perforin or granzymes, T cells induce a
immune system cells (B, T, natural killer, and myeloid cytotoxic effect on structures, interact with microglia, and
[26]
cells) were also associated with an excess of MS-linked increase inflammation and neurotoxicity . B cells are
genes. The mentioned genome-wide significant SNPs had usually located in the meninges and perivascular spaces of
postcapillary venules and secrete antibodies that damage
odd ratios from 1.06 to 2.06 and the allele frequencies of the cortex. In addition, B cells also secrete cytotoxic factors
the respective risk allele also varied from 2.1% to 98.4% . that can lead to direct destruction of oligodendrocytes
[20]
It has been found that these types of mutations were quite and neurons . Lymphoid follicles, consisting of T and B
[27]
common (>2.1% risk allele frequency) and were also lymphocytes, plasma cells, and macrophages, are formed
observed in healthy individuals .
[22]
in the CNS of patients with PMS . Microglia and
[28]
No variants were found on the male sex chromosome Y macrophages are thought to be strongly involved in the
whose P-value was lower than 0.05. In contrast, analyses on process of neurodegeneration. Increased numbers of these
the X chromosome identified rs2807267 as genome-wide cells are associated with the occurrence of demyelination
-9 [20]
significant with OR = 1.0 (P = 6.86 × 10 ) . These results and axonal damage. A positron emission tomography
justify the higher rates of MS in females, although the X (PET)-based study found that the activation of microglia/
chromosome cannot be the sole explanation for why MS macrophages could predict disability of MS . Through
[29]
occurs predominantly in females. Remarkable enrichment the release of myeloperoxidase, proteases, and matrix
of MS susceptibility loci was found in various immune metalloproteinases, microglia/macrophages can exert a
cell types and tissues, whereas CNS profiles showed no direct cytotoxic effect . It is worth noting that microglia
[30]
enrichment at the tissue level. In addition to the intensively and macrophages play an important role in remyelination:
studied T and B cells, cell types belonging to the innate These cells phagocytose myelin remnants and synthesize
immune system, namely, natural killer cells and dendritic growth factors needed for successful repair of damaged
cells, were highly enriched in MS. It is worth noting that neuronal sheaths, although long-term activation of these
microglia, rather than neurons and astrocytes, showed cells stimulates pro-inflammatory responses, resembling
enrichment of MS-linked genes. This draws attention to the activation of microglia in slowly expanding lesions
the fact that local immune cells of the CNS may play a role (SELs) [31,32] . Astrocytes also play a role in the progression
in MS susceptibility. The study concluded that heritability of MS, exemplified by reactive astrogliosis that is common
of MS accounts for up to 48% of all cases, which can be in MS plaques and causes continuous secretion of tumor

Volume 2 Issue 3 (2023) 3 https://doi.org/10.36922/an.1319