The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter.
Brain Pathol
; 32(4): e13041, 2022 07.
Article
in En
| MEDLINE
| ID: mdl-34904300
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
HLA-DRB1 Chains
/
Multiple Sclerosis
Limits:
Humans
Language:
En
Journal:
Brain Pathol
Journal subject:
CEREBRO
/
PATOLOGIA
Year:
2022
Document type:
Article
Affiliation country:
United kingdom