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 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/μm(2) neuronal membrane versus control: 0.348 ± 0.009 synapses/μm(2) neuronal membrane, p = 0.005). Neurons expressing inhibitory synapses were 24% smaller in MS cases compared to the control (MS: 403 ± 15 μm(2) versus control: 531 ± 29 μm(2), p = 0.001), a finding driven by HLA‐DRB1*15+ cases (15+: 376 ± 21 μm(2) vs. 15−: 432 ± 22 μm(2), 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.