HLA-E circulating and genetic determinants in schizophrenia and bipolar disorder

Abstract

Schizophrenia (SZ) and bipolar disorders (BD) are severe mental illnesses that lack reliable biomarkers to guide diagnosis and management. As immune dysregulation is associated with these disorders, we utilized the immunoregulatory functions of the natural killer cell inhibitory HLA-E locus to investigate the relationships between HLA-E genetic and expression diversities with SZ and BD risk and severity. Four hundred and forty-four patients meeting DSM-IV criteria for SZ (N = 161) or BD (N = 283) were compared to 160 heathy controls (HC). Circulating levels of the soluble isoform of HLA-E molecules (sHLA-E) were measured and HLA-E*01:01 and HLA-E*01:03 variants genotyped in the whole sample. sHLA-E circulating levels were significantly higher in both SZ and in BD patients compared to HC (pc < 0.0001 and pc = 0.0007 for SZ and BD, respectively). High sHLA-E levels were also observed in stable SZ patients and in acute BD patients experiencing depressive episodes when comparisons were made between the acute and stable subgroups of each disorder. sHLA-E levels linearly increased along HLA-E genotypes (p = 0.0036). In conclusion, HLA-E variants and level may have utility as diagnostic biomarkers of SZ and BD. The possible roles of HLA diversity in SZ and BD etiology and pathophysiology are discussed.

Synapse-specific roles for microglia in development: New horizons in the prefrontal cortex

“… Genetic, environmental and microglial influences on synaptic connectivity in development and disease. (A,B) Immune and neuronal factors ( Gauthier et al, 2010 ; Marín, 2012 ; Nieto et al, 2013 ; Volk and Lewis, 2013 b; El-Ansary and Al-Ayadhi, 2014 ; McAllister, 2014 ; English et al, 2015 ; Estes and McAllister, 2015 ; Sinclair et al, 2016 ; Ishizuka et al, 2017 ; Gao et al, 2018 ; Jiang et al, 2018 ; Huang et al, 2019 ; Trossbach et al, 2019 ; Wiebe et al, 2019 ; Barbosa et al, 2020 ; Chen et al, 2020 ; Boukouaci et al, 2021 ) known to be altered in ASD and SZ. Purple text represents elements that are affected in both disorders.…”

“…While a large body of work has identified perturbations in neuronal genes and proteins that affect synaptic connectivity ( Figures 2A,B ; Gauthier et al, 2010 ; Marín, 2012 ; Nieto et al, 2013 ; Volk and Lewis, 2013 ; El-Ansary and Al-Ayadhi, 2014 ; McAllister, 2014 ; English et al, 2015 ; Estes and McAllister, 2015 ; Sinclair et al, 2016 ; Ishizuka et al, 2017 ; Gao et al, 2018 ; Jiang et al, 2018 ; Huang et al, 2019 ; Trossbach et al, 2019 ; Wiebe et al, 2019 ; Barbosa et al, 2020 ; Chen et al, 2020 ; Boukouaci et al, 2021 ), accumulating evidence indicates that microglia are also key loci of dysfunction in neurodevelopmental disorders ( Koyama and Ikegaya, 2015 ; Jin et al, 2017 ; Comer et al, 2020 ; Petrelli et al, 2020 ; Xu et al, 2020 ). In ASD and SZ, mPFC microglia have amoeboid morphology and increased cytokine production that is characteristic of an activated state ( Fillman et al, 2013 ; Momtazmanesh et al, 2019 ).…”