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Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
The influence of HLA-DRB1*15 on motor cortical pathology in multiple sclerosis
Richard L Yates1, Margaret M Esiri, Jacqueline Palace
1Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Aim:
Multiple sclerosis (MS) is a common and heterogeneous CNS inflammatory demyelinating disease. The HLA-DRB1 locus may influence clinical outcome. MS cortical pathology is frequent and correlates with measures of clinical disability, including motoric dysfunction that is a predominant feature of disease progression. The influence of HLA-DRB1*15 on motor cortical pathology is unknown.
Methods:
A pathologically confirmed age- and sex-matched HLA-DRB1*15+ (n = 21) and HLA-DRB1*15- (n = 26) MS post-mortem cohort was used for detailed pathologic analyses. For each case, adjacent sections of motor cortex were stained for myelin and inflammation, to evaluate the extent and distribution of motor cortical pathology. A subset of MS cases (n = 42) had spinal cord (SC) pathologic outcome data available for comparison.
Results:
Motor cortical demyelination was more pronounced in younger cases (r = -0.337, P < 0.05), with MS cases carrying the HLA-DRB1*15 allele driving this effect (r = -0.612, P < 0.01). HLA-DRB1*15+ MS cases had more severe motor cortical parenchymal (P < 0.05), perivascular (P < 0.05) and meningeal (P < 0.05) T-cell inflammation compared to HLA-DRB1*15- cases. HLA-DRB1*15 status significantly influenced the extent of motor cortical microglial burden in both NAGM (P < 0.0001) and lesions (P < 0.01) in MS cases. Relationships between the extent of motor cortical and SC pathology were limited, but when present were primarily driven by HLA-DRB1*15+ cases.
Conclusion:
HLA-DRB1*15 status has a significant association with the extent of inflammation in the MS motor cortex, the extent of demyelination in younger MS cases, and influences relationships between motor cortical and SC pathology.
Insights
The HLA-DRB1*15 gene influences multiple sclerosis (MS) motor cortex pathology, increasing inflammation and demyelination in younger patients. This genetic factor also affects the relationship between motor cortex and spinal cord damage in MS.
Area of Science:
- Neurology
- Immunogenetics
- Pathology
Background:
- Multiple sclerosis (MS) is a complex CNS inflammatory demyelinating disease with heterogeneous clinical outcomes.
- The HLA-DRB1 locus is implicated in MS, and cortical pathology, particularly motor dysfunction, is a significant aspect of disease progression.
- The specific impact of the HLA-DRB1*15 allele on motor cortex pathology in MS remains largely unexplored.
Purpose of the Study:
- To investigate the influence of the HLA-DRB1*15 allele on pathological changes within the motor cortex in multiple sclerosis.
- To correlate HLA-DRB1*15 status with the extent and distribution of demyelination and inflammation in the MS motor cortex.
- To examine the relationship between motor cortical pathology and spinal cord pathology in HLA-DRB1*15 positive and negative MS cases.
Main Methods:
- Analysis of a post-mortem cohort of MS patients, matched for age and sex, stratified by HLA-DRB1*15 positivity (n=21) versus negativity (n=26).
- Detailed pathological examination of motor cortex sections, including myelin and inflammation staining, to assess pathology extent and distribution.
- Comparison of motor cortical pathology with available spinal cord pathology data in a subset of cases (n=42).
Main Results:
- Motor cortical demyelination was more severe in younger MS cases, particularly those carrying the HLA-DRB1*15 allele.
- HLA-DRB1*15 positive MS cases exhibited significantly increased parenchymal, perivascular, and meningeal T-cell inflammation in the motor cortex.
- HLA-DRB1*15 status strongly influenced microglial burden in both normal-appearing gray matter and lesions within the MS motor cortex.
- Relationships between motor cortical and spinal cord pathology were observed, primarily driven by HLA-DRB1*15 positive cases.
Conclusions:
- The HLA-DRB1*15 allele is significantly associated with increased inflammation in the MS motor cortex.
- HLA-DRB1*15 status correlates with more severe demyelination in younger MS patients.
- This genetic factor modulates the interplay between motor cortical and spinal cord pathology in multiple sclerosis.
