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

Wahid Boukouaci,Mohamed Amin Bencharif,Ryad Tamouza,Arij Ben Chaaben,Caroline Barau,Jihène Bouassida,Soumia Naamoune,Philippe Le Corvoisier,Ching-Lien Wu,Mohamed Lajnef,Jean-Romain Richard,Marianne Foiselle,Céline Straczek,Esma Mezouad,Ismail Rafik,Sofiane Salah,Marion Leboyer

doi:10.1038/s41598-021-99732-9

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.

Highlights

Schizophrenia (SZ) and bipolar disorders (BD) are severe mental illnesses that lack reliable biomarkers to guide diagnosis and management
We first observed that circulating soluble isoform of human leucocyte antigen (HLA)-E molecules (sHLA-E) levels were significantly higher in SZ and in BD patients as compared to healthy controls (HC), a finding that could implicate the functional properties of the soluble form of the HLA-E molecule in SZ and BD
High levels of sHLA-E were observed both in periphery and in the cerebrospinal fluid (CSF) of relapsing–remitting multiple sclerosis (MS) patients as compared to non-MS, non-inflammatory neurological controls, similar to that observed in non-MS inflammatory neurological patients

Summary

Introduction

Schizophrenia (SZ) and bipolar disorders (BD) are severe mental illnesses that lack reliable biomarkers to guide diagnosis and management. Schizophrenia (SZ) and Bipolar Disorders (BD) are complex groups of severe and chronic psychiatric disorders associated with reduced psychosocial functioning and with an approximately 20 year decrease in life expectancy[1,2,3] Their management still relies on clinical assessments as there are no biomarkers to guide diagnosis, prognosis, or disease course. A broad body of replicated data indicates that immune dysfunction contributes to the pathogenesis of both disorders, at least for a significant subset of patients This provides a direction to clarify disease pathophysiology and novel treatment t argets[4]. Hosted by the major histocompatibility complex (MHC), the HLA system encodes molecules pivotal for mounting pro-inflammatory processes. This can arise due to the extreme polymorphism of classical HLA alleles that condition antigen-presentation function. HLA-E molecules exist as a soluble circulating isoform, soluble HLA-E (sHLA-E), which result from the shedding of membrane bound HLA-E molecules induced by stressful events, such as infections and/or inflammation[18]

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Conclusion