5. Conclusions
Two genes in the MHC II complex were decreased in expression in brain and lymphoblast cell lines, most strongly in bipolar disorder and schizophrenia. This supports some shared immune alterations in brain for bipolar disorder and schizophrenia, and the observed strong genetic association of SZ to the MHC region [18] supports a role of HLA-DPA1 as a potential susceptibility gene. In MDD, there was decreased MHC II gene expression in brain, but not lymphoblast cell lines. In addition, a significant eQTL for HLA-DPA1 was validated in brain expression. The functions of the MHC Class II genes in the brain are unknown, and the role of these novel alternatively spliced HLA-DPA1 gene products found in the present study require further investigation. It has been shown that decreased HLA-DPA1 expression could be peripherally associated with HBV viral susceptibility. MHC Class II antigen presentation could act in brain to mark cells for immune attack by cells such as natural killer cells or macrophages that invade the blood−brain barrier. It has also been suggested that MHC and complement genes could alter synaptic plasticity such as pruning in brain circuits [24,39,40]; these findings may apply to our finding of a general reduction of MHC Class II expression in brain samples from patients with neuropsychiatric disorders. Our findings also support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.
Besides a purely genetic mechanism that might decrease MHC Class II expression, an increased cortisol level which has been previously shown to be elevated in psychiatric disorders could lower MHC Class II expression. This first report on MHC Class II genes across multiple brain regions opens the door for study of epigenetic and environmental regulatory effects. The strong eQTL in brain is in linkage disequilibrium with an irrefutable association with schizophrenia, demonstrating that alterations in immune expression in brain circuits during development may play a role in the pathophysiology of schizophrenia.