title: Casting light on multiple sclerosis heterogeneity: the role of HLA-DRB1 on spinal cord pathology.
abstract: 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 cases with multiple sclerosis (n = 108, 34 males) with fresh frozen material available for genetic analyses and fixed material for 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 pathological analyses. For each case, transverse sections from three spinal cord levels (cervical, thoracic and lumbar) were stained for myelin, axons and inflammation. The influence of HLA-DRB1*15 on pathological outcome measures was evaluated. Carriage of HLA-DRB1*15 significantly increased the extent of demyelination (global measure 15+: 23.7% versus 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 = 0.003) 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.
authors.affiliation: Nuffield Department of Clinical Neurosciences (Neuropathology) Level 1, West Wing, John Radcliffe Hospital Headley Way, Headington, Oxford, OX3 9DU, UK. gabriele.deluca@ndcn.ox.ac.uk
authors.forename: Gabriele C
authors.initials: GC
authors.lastname: DeLuca
authors.forename: Rose
authors.initials: R
authors.lastname: Alterman
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Martin
authors.forename: Arunesh
authors.initials: A
authors.lastname: Mittal
authors.forename: Samkeliso
authors.initials: S
authors.lastname: Blundell
authors.forename: Shannon
authors.initials: S
authors.lastname: Bird
authors.forename: Harry
authors.initials: H
authors.lastname: Beale
authors.forename: Lai San
authors.initials: LS
authors.lastname: Hong
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Esiri
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology*; D014015:Tissue Banks
chemical_list: D059811:HLA-DRB1 Chains