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.
Highlights
The major histocompatibility complex (MHC), known in humans as Human leukocyte antigens (HLA) is a cluster of genes nested in three regions, designated as Class I, Class II and Class III
Using short synthetic peptides corresponding to this cusp region, we have demonstrated that these antigen presentation (AP)-incompetent peptides activated transcriptomes that are consistent with antiinflammatory (M2) macrophage polarization
Using two emblematic HLA-DRB1 alleles known to associate with autoimmune disease susceptibility or protection, DRB1*04:01; DRB1:04:02, we have shown that APincompetent ligands - peptide sequences unable to perform antigen presentation - corresponding to the cusp regions of these alleles trigger disease-relevant transcriptional, signaling, cell activation and disease phenomes [14, 15, 19, 21–23]
Summary
The major histocompatibility complex (MHC), known in humans as HLA (human leukocyte antigen) is a cluster of genes nested in three regions, designated as Class I, Class II and Class III. Under certain environmental and background gene conditions, these cusp-ligands can interact with non-major histocompatibility complex (MHC) receptors thereby activating aberrant cell signaling events that cause disease development” [9]. The SE was found to promote increased production of interleukin (IL)-6 and tumor necrosis factor alpha (TNF-a), and enhanced the differentiation of receptor activator of NF-kB ligand (RANKL)-expressing IL-17 producing T cells, causing Th17 cellmediated pro-osteoclastogenic effects independent of antigen presentation [15] Our studies with this cusp ligand have provided a mechanistic basis for the long-observed association between RA, cigarette smoking and carriage of SE-coding alleles [117], by demonstrating that in the presence of aryl hydrocarbon receptor (AhR) agonists - environmental pollutants found in cigarette smoke - the activation potency of the SE-mediated pathway is amplified synergistically with resultant augmented inflammatory response and bone erosive damage that lead to more severe experimental arthritis in mice [21].
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