1.3. MHC Class II Genes
The purpose of the current study was to examine immune gene expression focusing on CD74, HLA-DRB1, and HLA-DPA1, which are integral components of the MHC Class II pathway (Figure 1). Using a cohort of postmortem brain tissue, we compared three diagnoses (schizophrenia, bipolar disorder type I, and major depressive disorder) to controls.
The three MHC Class II genes of relevance for this paper share well-described molecular functions within the immune system of antigen processing and presentation (Figure 1). CD74 has multiple roles in the immune system: it is a transmembrane protein that associates to MHC Class II α and β chains, and is a receptor of the proinflammatory cytokine macrophage migration inhibitory factor which modulates macrophage and monocyte activation. HLA-DPA1 dimers associate with CD74 trimers forming a heterononamer from NCBI RefSeq. The level of HLA-DRB1 gene expression is complex due to the multiple alleles and involvement of polymorphisms of the HLA-DRB1 promoter. Susceptibility to rheumatoid arthritis (RA) is associated with defined HLA-DRB1 alleles that are related to expression, and there is thought to be a negative correlation between incidences of RA and schizophrenia [21,22].
HLA-DPA1 SNPs, in particular rs3077, are associated with risk for persistent infection with the hepatitis B and C viruses, first noted in [23] and then subsequently replicated in multiple reports. Presumably, carriers of HLA-DPA1 coding variants along with variants in HLA-DPB and HLA-DRB have different sensitivities to viral antigen binding, clearing the virus by altering the antigen-presenting capabilities, and building effective immune response.
Taken together, the MHC Class II genes have multiple alleles and tissue-specific expression patterns which have not been described, and these transcripts have been quantitatively assessed in brain. Previously, MHC Class I genes were shown to be localized to neurons [24], while the expression of MHC Class II molecules in human brain has been found on microglia cells using OX-6 immunohistochemistry. Thus, we focused an investigation on members of the MHC Class II genes in multiple brain regions and disorders.
The MHC Class II are heterodimers composed of α and β transmembrane chains, such as HLA-DPA1 and HLA-DPB1, the latter a dimer that associates with the invariant chain of CD74 which forms a trimer in the endoplasmic reticulum. The trimer traffics to the Golgi compartment and then is transported to the late endosomic compartments, thereby loading the antigen peptide [25]. CD74 acts as a chaperone that regulates antigen presentation. Invariant chain of CD74 involves binding to the HLA-DPA1 and HLA-DPB1 dimers. After trafficking and targeting antigen, the invariant chain is released from MHC-II and then the antigen peptide binds [26,27]. The antigen-bound MHC-II complex moves to the plasma membrane. The plasma membrane-bound antigen-MHC II (pMHCII) interacts with T-cell receptor (TCR). TCR recognizes the antigen only when presented by foreign MHC molecules. TCR activates the pMHCII complex, and facilitate CD4 T-cell stimulation on the cell surface [28]. Crystal structure shows the ternary model of CD4-pMHCII-TCR that appears V-shaped with pMHC II at apex, but CD4 and TCR do not have direct contact. The signaling of CD4 and TCR is coordinated around the pMHCII [29]. Therefore, MHCII genes play an essential role in immune responses.