Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis-From Research to Clinical Practice

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease with an unclear pathogenic mechanism. However, it has been proven that the key underlying risk factor is a genetic predisposition. Association studies of the HLA-DRB1 gene clearly indicate its importance in RA morbidity. This review presents the current state of knowledge on the impact of HLA-DRB1 gene, functioning both as a component of the patient's genome and as an environmental risk factor. The impact of known HLA-DRB1 risk variants on the specific structure of the polymorphic HLA-DR molecule, and epitope binding affinity, is presented. The issues of the potential influence of HLA-DRB1 on the occurrence of non-articular disease manifestations and response to treatment are also discussed. A deeper understanding of the role of the HLA-DRB1 gene is essential to explore the complex nature of RA, which is a result of multiple contributing factors, including genetic, epigenetic and environmental factors. It also creates new opportunities to develop modern and personalized forms of therapy.

Keywords: HLA-DRB1; polymorphisms; rheumatoid arthritis.

Figure 1

Human leukocyte antigen (HLA) molecules are encoded by three classes of genes located on short arm of chromosome 6 at positions 6p21.1–21.3. Within the DR subregion there is an outstandingly polymorphic HLA-DRB1 gene, which is of key importance in the pathogenesis of rheumatoid arthritis (RA).

Figure 2

Various biological effects of anti-citrullinated protein antibodies (ACPA). The production of ACPA reflects break of immune tolerance and is dependent on the occurrence of both genetic, epigenetic and environmental factors. Genetic factors are: shared epitopes (SEs), protein tyrosine phosphatase non-receptor type 22 (PTPN22), α1-antitrypsin, type I interferons. Epigenetic modifications are: DNA methylation, histone acetylation and deacetylation, miRNA expression. Environmental factors include: noxious agents, influence of pathogens such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans (Aa) and Epstein–Barr virus (EBV). Interaction between genetic and environmental factors led to the activation of antigen presenting cells (APCs), such as dendritic cells, macrophages or B cells. Additionally, various noxious agents have a potential to activate toll-like receptors (TLRs). Triggering the innate immune response activate Ca^2+-mediated peptidyl-arginine-deiminase (PAD) of granulocytes and macrophages, which catalyze citrullination of the target proteins located in the immune cells. The formation of neutrophil extracellular traps (NETs) may be induced by pathogens and reactive oxygen species (ROS). NETosis contributes to ACPA production by the externalization of citrullinated autoantigens and releasing of activated PAD, which form a pool of autoantigens that fuels autoimmunity. ACPA biologic effects rely on complement activation, osteoclasts stimulation, as well as direct macrophages and neutrophils activation. Joint pain may precede synovial inflammation and may be induced by ACPA via both osteoclast activation and direct Fc receptor binding [25].

Figure 3

The HLA class II beta chains are much more polymorphic than the alpha chains. The most polymorphic HLA class II locus is HLA-DRB1-2690 alleles of this gene have been identified. Source: adapted from http://hla.alleles.org/nomenclature/stats.html; accessed on 21 April 2020.

Figure 4

HLA-DRB1 gene is encoded by six exons. Exon 1 encodes the leader peptide, Exons 2 and 3 encode the two extracellular domains, Exon 4 encodes the transmembrane domain, and Exon 5 encodes the cytoplasmic tail. Amino acid motifs forming the first hypervariable region (HVR1) are encoded by Exon 1, the major HVR3, and shared epitope motifs are encoded by Exon 2.

Figure 5

HLA-DRB1 interactions leading to the development of RA. By contributing to autoimmunity, the HLA-DRB1 SE alleles may interact with environmental factors such as smoking, Epstein–Barr virus (EBV), Porphyromonas gingivalis infection, as well as other susceptibility loci.

Figure 6

Potential HLA-DRB1 causal variants influencing specific treatment responses. Classical synthetic disease-modifying antirheumatic drugs (csDMARDs) include methotrexate, sulfasalazine, leflunomide, antimalarial drugs (chloroquine, hydroxychloroquine); CsA = cyclosporine; ADA = adalimumab; ABA = abatacept.