HLA-G and the MHC Cusp Theory

Abstract

Human leukocyte antigens (HLA) are significant genetic risk factors in a long list of diseases. However, the mechanisms underlying these associations remain elusive in many cases. The best-characterized function of classical major histocompatibility complex (MHC) antigens is to allow safe presentation of antigenic peptides via a self/non-self-discrimination process. Therefore, most hypotheses to date have posited that the observed associations between certain HLA molecules and human diseases involve antigen presentation (AP). However, these hypotheses often represent inconsistencies with current knowledge. To offer answers to the inconsistencies, a decade ago we have invoked the MHC Cusp theory, postulating that in addition to its main role in AP, the MHC codes for allele-specific molecules that act as ligands in a conformationally-conserved cusp-like fold, which upon interaction with cognate receptors can trigger MHC-associated diseases. In the ensuing years, we have provided empirical evidence that substantiates the theory in several HLA-Class II-associated autoimmune diseases. Notably, in a recent study we have demonstrated that HLA-DRB1 alleles known to protect against several autoimmune diseases encode a protective epitope at the cusp region, which activates anti-inflammatory signaling leading to transcriptional and functional modulatory effects. Relevant to the topic of this session, cusp ligands demonstrate several similarities to the functional effects of HLA-G. The overall goal of this opinion article is to delineate the parallels and distinctive features of the MHC Cusp theory with structural and functional aspects of HLA-G molecules.

Association of the HLA-G rs66554220 variant with non-segmental vitiligo and its clinical features in Northwestern Mexico population

“…The HLA-G expression can be upregulated by interferons, interleukin-10 and other factors such as miRNAs under certain pathological conditions prompting anti-inflammatory and Th2-response [ 27 ]. Primordially, it is recognized as a tolerogenic molecule [ 28 ], normally absent on healthy tissues except for trophoblast, cornea, and thymus [ 29 , 30 ].…”

Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases

“…One of the hypotheses put forward to explain the link between HLA alleles and disease pathogenesis has been the major histocompatibility complex (MHC) cusp theory, which states that in addition to presenting antigens, “HLA molecules encode ligands in one of their hypervariable regions, designated a “cusp” based on its three-dimensional cusp-like conformation. Under certain environmental and background gene conditions, these cusp-ligands can interact with non- MHC receptors thereby activating aberrant cell signaling events that cause disease development” [ 89 , 90 ]. In a recent study considering the cusp theory, the transcriptional effects of three allelic epitopes in the HLA-DR cusp region (residues 65-79 of the DRβ chain) were explored in human (THP-1) and mouse (RAW 264.7) macrophages [ 91 ].…”

Distributions of the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 alleles and haplotype frequencies of 1763 stem cell donors in the Colombian Bone Marrow Registry typed by next-generation sequencing

“…The HLA system has the highest density of genes in the human genome which are highly polymorphic. HLA alleles and haplotype frequencies vary widely between different populations, and even in the same territory may be conditioned by ethnicities and geographical regions ( 19 – 24 ).…”