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Clinical heterogeneity in multiple sclerosis is the rule. Evidence suggests that HLA-DRB1*15 may play a role in clinical outcome. Spinal cord pathology is common and contributes significantly to disability in the disease. The influence of HLA-DRB1*15 on multiple sclerosis spinal cord pathology is unknown. A post-mortem cohort of pathologically confirmed multiple sclerosis cases (n=108, 34 males) with fresh frozen material available on which to do genetic analyses and fixed material on which to do pathology was used. HLA-DRB1 alleles were genotyped to select a subset of age- and sex-matched HLA-DRB1*15 positive (n=21) and negative (n=26) cases for detailed pathologic analyses. For each case, transverse sections from 3 SC levels (cervical, thoracic and lumbar) were stained for myelin, axons, and inflammation. The influence of HLA-DRB1*15 on pathologic outcome measures was evaluated. Carriage of HLA-DRB1*15 significantly increased the extent of demyelination (global measure: 15+: 23.7% vs. 15-: 12.16%, p=0.004), parenchymal (cervical, p<0.01; thoracic, p<0.05); lumbar, p<0.01) and lesional inflammation (border, p=0.001; periplaque white matter, p<0.05) in the multiple sclerosis spinal cord. HLA-DRB1*15 influenced demyelination through controlling the extent of parenchymal inflammation. Meningeal inflammation correlated significantly with small fibre axonal loss in the lumbar spinal cord (r=-0.832, p<0.001) only in HLA-DRB1*15 positive cases. HLA-DRB1*15 significantly influences pathology in the multiple sclerosis spinal cord. This study casts light on the role of HLA-DRB1*15 in disease outcome and highlights the powerful approach of using microscopic pathology to clarify the way in which genes and clinical phenotypes of neurological diseases are linked.


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multiple sclerosis, spinal cord, genetics, pathology, outcome