The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter

Cortical tissue injury is common in multiple sclerosis (MS) and associates with disability progression. We have previously shown that HLA-DRB1*15 genotype status associates with the extent of cortical inflammatory pathology. In the current study, we sought to examine the influence of HLA-DRB1*15 on...

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Asıl Yazarlar: Yates, RL, Pansieri, J, Li, Q, Bell, JS, Yee, SA, Palace, J, Esiri, MM, DeLuca, GC
Materyal Türü: Journal article
Dil:English
Baskı/Yayın Bilgisi: Wiley 2021
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author Yates, RL
Pansieri, J
Li, Q
Bell, JS
Yee, SA
Palace, J
Esiri, MM
DeLuca, GC
author_facet Yates, RL
Pansieri, J
Li, Q
Bell, JS
Yee, SA
Palace, J
Esiri, MM
DeLuca, GC
author_sort Yates, RL
collection OXFORD
description Cortical tissue injury is common in multiple sclerosis (MS) and associates with disability progression. We have previously shown that HLA-DRB1*15 genotype status associates with the extent of cortical inflammatory pathology. In the current study, we sought to examine the influence of HLA-DRB1*15 on relationships between inflammation and neurodegeneration in MS. Human post-mortem MS cases (n = 47) and controls (n = 10) were used. Adjacent sections of motor cortex were stained for microglia (Iba1+, CD68+, TMEM119+), lymphocytes (CD3+, CD8+), GFAP+ astrocytes, and neurons (NeuN+). A subset of MS cases (n = 20) and controls (n = 7) were double-labeled for neurofilament and glutamic acid decarboxylase 65/67 (GAD+) to assess the extent of the inhibitory synaptic loss. In MS cases, microglial protein expression positively correlated with neuron density (Iba1+: r = 0.548, p < 0.001, CD68+: r = 0.498, p = 0.001, TMEM119+ r = 0.437, p = 0.003). This finding was restricted to MS cases not carrying HLA-DRB1*15. Evidence of a 14% reduction in inhibitory synapses in MS was detected (MS: 0.299 ± 0.006 synapses/μm2 neuronal membrane versus control: 0.348 ± 0.009 synapses/μm2 neuronal membrane, p = 0.005). Neurons expressing inhibitory synapses were 24% smaller in MS cases compared to the control (MS: 403 ± 15 μm2 versus control: 531 ± 29 μm2, p = 0.001), a finding driven by HLA-DRB1*15+ cases (15+: 376 ± 21 μm2 vs. 15−: 432 ± 22 μm2, p = 0.018). Taken together, our results demonstrate that HLA-DRB1*15 modulates the relationship between microglial inflammation, inhibitory synapses, and neuronal density in the MS cortex.
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spelling oxford-uuid:3a342ba8-ee8d-4ac2-ac45-c718d42537f92022-09-05T13:58:30ZThe influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matterJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3a342ba8-ee8d-4ac2-ac45-c718d42537f9EnglishSymplectic ElementsWiley2021Yates, RLPansieri, JLi, QBell, JSYee, SAPalace, JEsiri, MMDeLuca, GCCortical tissue injury is common in multiple sclerosis (MS) and associates with disability progression. We have previously shown that HLA-DRB1*15 genotype status associates with the extent of cortical inflammatory pathology. In the current study, we sought to examine the influence of HLA-DRB1*15 on relationships between inflammation and neurodegeneration in MS. Human post-mortem MS cases (n = 47) and controls (n = 10) were used. Adjacent sections of motor cortex were stained for microglia (Iba1+, CD68+, TMEM119+), lymphocytes (CD3+, CD8+), GFAP+ astrocytes, and neurons (NeuN+). A subset of MS cases (n = 20) and controls (n = 7) were double-labeled for neurofilament and glutamic acid decarboxylase 65/67 (GAD+) to assess the extent of the inhibitory synaptic loss. In MS cases, microglial protein expression positively correlated with neuron density (Iba1+: r = 0.548, p < 0.001, CD68+: r = 0.498, p = 0.001, TMEM119+ r = 0.437, p = 0.003). This finding was restricted to MS cases not carrying HLA-DRB1*15. Evidence of a 14% reduction in inhibitory synapses in MS was detected (MS: 0.299 ± 0.006 synapses/μm2 neuronal membrane versus control: 0.348 ± 0.009 synapses/μm2 neuronal membrane, p = 0.005). Neurons expressing inhibitory synapses were 24% smaller in MS cases compared to the control (MS: 403 ± 15 μm2 versus control: 531 ± 29 μm2, p = 0.001), a finding driven by HLA-DRB1*15+ cases (15+: 376 ± 21 μm2 vs. 15−: 432 ± 22 μm2, p = 0.018). Taken together, our results demonstrate that HLA-DRB1*15 modulates the relationship between microglial inflammation, inhibitory synapses, and neuronal density in the MS cortex.
spellingShingle Yates, RL
Pansieri, J
Li, Q
Bell, JS
Yee, SA
Palace, J
Esiri, MM
DeLuca, GC
The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter
title The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter
title_full The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter
title_fullStr The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter
title_full_unstemmed The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter
title_short The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter
title_sort influence of hla drb1 15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter
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