Details

Autor(en) / Beteiligte

• Pisa, Marco
• Watson, Joseph L.
• Spencer, Jonathan I.
• Niblett, Guy
• Mahjoub, Yasamin
• Lockhart, Andrew
• Yates, Richard L.
• Yee, Sydney A.
• Hadley, Gina
• Ruiz, Jennifer
• Esiri, Margaret M.
• Kessler, Benedict
• Fischer, Roman
• DeLuca, Gabriele C.

Titel

A role for vessel‐associated extracellular matrix proteins in multiple sclerosis pathology

Ist Teil von

• Brain pathology (Zurich, Switzerland), 2024-11, Vol.34 (6), p.e13263-n/a

Ort / Verlag

Switzerland: John Wiley & Sons, Inc

Erscheinungsjahr

2024

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• Multiple sclerosis (MS) is unsurpassed for its clinical and pathological hetherogeneity, but the biological determinants of this variability are unknown. HLA‐DRB1*15, the main genetic risk factor for MS, influences the severity and distribution of MS pathology. This study set out to unravel the molecular determinants of the heterogeneity of MS pathology in relation to HLA‐DRB1*15 status. Shotgun proteomics from a discovery cohort of MS spinal cord samples segregated by HLA‐DRB*15 status revealed overexpression of the extracellular matrix (ECM) proteins, biglycan, decorin, and prolargin in HLA‐DRB*15‐positive cases, adding to established literature on a role of ECM proteins in MS pathology that has heretofore lacked systematic pathological validation. These findings informed a neuropathological characterisation of these proteins in a large autopsy cohort of 41 MS cases (18 HLA‐DRB1*15‐positive and 23 HLA‐DRB1*15‐negative), and seven non‐neurological controls on motor cortical, cervical and lumbar spinal cord tissue. Biglycan and decorin demonstrate a striking perivascular expression pattern in controls that is reduced in MS (−36.5%, p = 0.036 and − 24.7%, p = 0.039; respectively) in lesional and non‐lesional areas. A concomitant increase in diffuse parenchymal accumulation of biglycan and decorin is seen in MS (p = 0.015 and p = 0.001, respectively), particularly in HLA‐DRB1*15‐positive cases (p = 0.007 and p = 0.046, respectively). Prolargin shows a faint parenchymal pattern in controls that is markedly increased in MS cases where a perivascular deposition pattern is observed (motor cortex +97.5%, p = 0.001; cervical cord +49.1%, p = 0.016). Our findings point to ECM proteins and the vascular interface playing a central role in MS pathology within and outside the plaque area. As ECM proteins are known potent pro‐inflammatory molecules, their parenchymal accumulation may contribute to disease severity. This study brings to light novel factors that may contribute to the heterogeneity of the topographical variation of MS pathology. Shotgun proteomic and confirmatory immunohistochemical characterisation of post‐mortem tissue showed region‐specific and HLA‐DRB*15 influenced alteration in extracellular matrix proteins expression between MS and controls. In particular, we shows that non‐neurological controls have a perivascular‐predominant expression pattern of these proteins that is disrupted in MS where instead a marked parenchymal deposition pattern is seen. Our study provides unequivocal evidence for a role of extracellular matrix proteins and the vasculature being key contributors to MS pathology within and outside the plaque area.