The major histocompatibility complex and autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a complex disorder that appears to be caused by interactions between genetic changes and environmental insults during early development. A wide range of factors have been linked to the onset of ASD, but recently both genetic associations and environmental factors point to a central role for immune-related genes and immune responses to environmental stimuli. Specifically, many of the proteins encoded by the major histocompatibility complex (MHC) play a vital role in the formation, refinement, maintenance, and plasticity of the brain. Manipulations of levels of MHC molecules have illustrated how disrupted MHC signaling can significantly alter brain connectivity and function. Thus, an emerging hypothesis in our field is that disruptions in MHC expression in the developing brain caused by mutations and/or immune dysregulation may contribute to the altered brain connectivity and function characteristic of ASD. This review provides an overview of the structure and function of the three classes of MHC molecules in the immune system, healthy brain, and their possible involvement in ASD.

Figure 1. Schematic representations of MHC Class I and II molecules

MHCI molecules are trimeric proteins comprised of one transmembrane heavy chain (α1-3 domains; black), a β2-microglobulin light chain (β2m; light blue), and a peptide (pink star) that is bound within the groove of α1 and α2 of the heavy chain. The MHCI peptide is generated in the cytosol. Trimers are assembled in the endoplasmic reticulum and all three components are required for transport to the cell surface of cells. MHCII molecules consist of two transmembrane chains an α (green) and a β (dark blue); each chain contains two domains (α1-α2, and β1-β2). The peptide is bound for display in the groove of the α1 and β1 domains and is derived from extracellular pathogens. MHC Class III genes encode such a diversity of proteins that examples are not shown in this figure.

Figure 2. Genomic maps of the human, rat, and mouse MHC

This schematic identifies genes of MHC Class I classical (red) and non-classical (pink), MHC Class I pseudogenes (outlined in red), MHC Class II classical (dark blue) and non-classical (light blue), MHC Class III (black), and genes involved in processing and loading the MHC molecules. Classical MHC genes are typically polymorphic whereas the non-classical MHCI genes are not. These MHC genes are located on Chromosome 6, 20, and 17 in the human, rat, and mouse, respectively. The light chain of MHC Class I molecules, β2-microglobulin, is encoded on a separate chromosome (15 in humans, 3 in rats, and 2 in mice). Information for this figure was compiled from the UCSC Genome Browser on human Feb. 2009 (GRCh37/hg19), rat Mar. 2012 (RGSC 5.0/rn5), and mouse July 2007 (NCBI37/mm9) assemblies.