The cause and pathogenesis of rheumatoid arthritis (RA) are influenced by environmental and genetic risk factors. Shared epitope-coding human leukocyte antigen (HLA)-DRB1 alleles increase RA risk and severity; however, the underlying mechanisms of action remain unclear. In contrast, several other DRB1 alleles protect against RA. Additionally, genome-wide association studies suggest that RA associates with other, HLA and non-HLA, genes; but the relative contributions of such risk loci to RA are incompletely understood. Future research challenges include integrating the epidemiologic and genomic data into validated arthritogenic pathways and determining the mechanisms of interaction between RA risk genes and environmental influences.
Certain human leukocyte antigen (HLA) alleles have been found to be associated with immune mediated or autoimmune diseases, but the underlying mechanisms are largely unknown.
Rheumatoid arthritis (RA) strongly associates with HLA-DRB1 alleles that encode a sequence motif called shared epitope (SE), and there is variability in the strength of RA-SE association among ethnic and racial populations.
The SE shows interaction with environmental factors (tobacco exposure) and together significantly amplify the disease risk.
In contrast to RA risk-conferring SE-coding alleles, there are several other DRB1 alleles that protect against the disease.
Genome-wide association studies discovered many non-HLA RA risk loci, but their aggregate contribution to RA risk is outweighed by that of the SE.
Rheumatoid arthritis (RA) is a common inflammatory disease in which both genetic and environmental factors play a role in disease development. Based on twin studies, the heritability of the disease was estimated at around 60%. Among all the genetic risk factors found to date, the human leukocyte antigen (HLA) locus is the most significant one. A particularly strong association between RA and HLA-DRB1 alleles that encode an HLA-DRβ chain containing a 5 amino acid sequence motif called the shared epitope (SE) has long been documented. Here the authors review salient immunogenetic, clinical, and mechanistic features of RA association with the HLA locus, focusing primarily on the SE.
Human Leukocyte Antigen Genes and Their Products
The immune system is composed of various cells that work together to protect the host against invading pathogens without harming its own tissues. Therefore, the host has to recognize which antigens are self and which are foreign. To discriminate between such self- and foreign antigens, the major histocompatibility complex (MHC) antigens, known in humans as HLA, have evolved. MHC molecules have the ability to recognize and present foreign antigens to the immune system but at the same time disregard self-antigens. This ability to discriminate between self and foreign is established through a process called “MHC restriction.” During the development of T cells in the thymus, T cells that react to self-antigens are eliminated, whereas those that respond to foreign antigens that are presented by a self-HLA molecule are preserved. This selection results in CD4 + and CD8 + T cells that only respond to foreign antigens that are presented by self-HLA molecules. Despite their ability to selectively recognize and respond to foreign antigens, many HLA alleles have been found to confer susceptibility to various diseases, most of which involve dysregulated immunity or autoimmunity.
The HLA locus is located on the short arm of chromosome 6 and covers a 7.6-Mb region that contains more than 250 highly polymorphic genes. The region is organized in 3 subregions: class I, class II, and class III, which all have different functions. Both class I and II regions encode for glycoproteins that are expressed as cell surface receptors, whereas the class III region contains genes that encode for a variety of secreted immune system proteins, including complement factors and cytokines.
The class I region encodes for 3 main subsets of HLA molecules: HLA-A, HLA-B, and HLA-C. Class I HLA molecules are composed of an HLA-coded heavy α-chain and an invariant light chain, beta-2 microglobulin, which is essential for functional expression of the HLA molecule at the cell surface. The α-chain is folded to form a peptide-binding cleft that is closed and can accommodate short antigenic peptides, typically 8 to 10 amino acids long. These class I molecules are expressed on all nucleated cells and specialize in presentation of intracellular antigens, including viral antigens, to cytotoxic (CD8 + ) T cells. Genes in the class II region encode for HLA-DR, HLA-DP, and HLA-DQ molecules as well as a few other related proteins. Class II HLA molecules are composed of an α-chain and a β-chain, both coded by the HLA class II region. Unlike the class I molecules, the peptide-binding cleft of class II molecules are open, which allows the accommodation of larger peptides of 15 to 20 amino acids long. Class II molecules are initially expressed on the cell surface of immune cells, in particular antigen-presenting cells, such as macrophages or dendritic cells, as well as B cells and activated T cells. These molecules present antigens from outside the cell to (CD4 + ) T cells, which in turn stimulate B cells to produce antibodies toward that specific antigen, resulting in an antigen-specific immune response. After activation of the immune system, the HLA class II molecules can be expressed on other cells.
Human Leukocyte Antigen–Associated Diseases
The HLA locus is a highly polymorphic region. Its high gene density, presence of clusters of genes with related functions, enormous polymorphism, and a strong linkage disequilibrium (LD) between alleles, renders it difficult to unravel the comprehensive HLA functions. During the last several decades, various conditions, such as infectious diseases, cancer, or autoimmune diseases, have been found to be more prevalent in individuals who carry certain HLA alleles. Most HLA-associated diseases can be classified as autoimmune or immune-mediated disease and have been observed with merely HLA class I alleles (eg, ankylosing spondylitis [AS]) or merely class II alleles (eg, seropositive RA). Additionally, some autoimmune diseases have been found to be influenced by both HLA class I and class II genes (eg, diabetes mellitus type I). In addition to HLA alleles that predispose to disease, there are also several HLA alleles that are protective against disease.
How certain HLA alleles predispose to or protect against (autoimmune) diseases and what the underlying molecular mechanisms are is currently unclear. The hypotheses that have been proposed over the years commonly implicate atypical presentation of self-antigens, an immune response to altered self-antigens or cross-reactivity with foreign or self-antigens. These hypotheses may seem plausible based on HLA function and their role in the immune response. However, despite their plausibility, the mechanistic and epidemiologic evidence that is currently available is difficult to reconcile with presentation of specific antigens being the underlying mechanism for HLA-disease association.
Several examples of HLA alleles are associated with more than one disease with completely different target tissues and pathogeneses, which defies the notion that antigen presentation should be specific for both the antigen and the presenting HLA molecule. Examples of such HLA alleles are HLA-DRB1*04:01 , which is associated with both RA and type 1 diabetes, and HLA-DQB1*03:02 , which is associated with both type 1 diabetes and celiac disease. In addition, there are certain HLA alleles that predispose to one disease but protect against another; for example, HLA-DRB1*04:02 has been found to confer susceptibility to pemphigus vulgaris (PV) but at the same time protect against RA (discussed later).
Furthermore, the most significant HLA-disease association to date has been found for a brain disorder (narcolepsy), which is not known to involve antigen presentation. Also, certain HLA molecules have been found to have functions unrelated to antigen presentation, including cognition, olfaction, and the activation of innate immune signaling (reviewed in Ref. ).
In addition, some disease-associated alleles have been shown to demonstrate cross-species susceptibility; for example, HLA-DRB1*04:01 associates with human RA and also confers susceptibility to inflammatory arthritis in mice.
Moreover, despite extensive efforts to identify target antigens in autoimmune diseases, they have only been identified for a very small number of diseases. Also, presence of T-cell clonality, a phenomenon that can be expected in case of the presence of a specific antigen, has not been convincingly demonstrated in HLA-associated diseases.
Lastly, RA disease severity has been shown to correlate with HLA allele dose, that is, two allele copies confer greater susceptibility, severity, and penetrance compared with one copy (discussed later). Such allele-dose impact on RA disease severity cannot be explained by antigen presentation–based hypotheses.