The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing
Richard L Yates1, Jonathan Pansieri1, Qizhu Li2
1Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
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/microm2 neuronal membrane versus control: 0.348 ± 0.009 synapses/microm2 neuronal membrane, p = 0.005). Neurons expressing inhibitory synapses were 24% smaller in MS cases compared to the control (MS: 403 ± 15 microm2 versus control: 531 ± 29 microm2 , p = 0.001), a finding driven by HLA-DRB1*15+ cases (15+: 376 ± 21 microm2 vs. 15-: 432 ± 22 microm2 , 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.
Insights
The HLA-DRB1*15 genotype influences how inflammation and neurodegeneration interact in multiple sclerosis (MS) cortical tissue. This genetic factor affects the relationship between microglia, synapses, and neuron density in MS.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Cortical tissue injury is a significant factor in multiple sclerosis (MS) and is linked to disability progression.
- Previous research indicated a correlation between HLA-DRB1*15 genotype and the extent of cortical inflammatory pathology in MS.
Purpose of the Study:
- To investigate the influence of the HLA-DRB1*15 genotype on the interplay between inflammation and neurodegeneration in the MS cortex.
- To examine how microglial activity, synaptic loss, and neuronal density are modulated by HLA-DRB1*15 status in MS.
Main Methods:
- Utilized post-mortem human brain tissue from MS cases (n=47) and controls (n=10).
- Performed immunohistochemical staining for microglia, lymphocytes, astrocytes, and neurons.
- Assessed inhibitory synaptic loss using double-labeling for neurofilament and GAD65/67 in a subset of cases.
Main Results:
- Microglial protein expression positively correlated with neuron density in MS cases without the HLA-DRB1*15 genotype.
- A 14% reduction in inhibitory synapses was observed in MS cases compared to controls.
- Neurons with inhibitory synapses were smaller in MS cases, particularly in those with the HLA-DRB1*15 genotype.
Conclusions:
- The HLA-DRB1*15 genotype plays a crucial role in modulating the relationship between microglial inflammation, inhibitory synapses, and neuronal density in the MS cortex.
- Findings suggest a specific genetic influence on neuroinflammatory and neurodegenerative pathways in MS.
