The immunogenetics of Behçet's disease: A comprehensive review

Abstract

Behçet's disease is a chronic multisystem inflammatory disorder characterized mainly by recurrent oral ulcers, ocular involvement, genital ulcers, and skin lesions, presenting with remissions and exacerbations. It is thought that both environmental and genetic factors contribute to its onset and development. Although the etiology of Behçet's disease remains unclear, recent immunogenetic findings are providing clues to its pathogenesis. In addition to the positive association of HLA-B*51, which was identified more than four decades ago, and which has since been confirmed in multiple populations, recent studies report additional independent associations in the major histocompatibility complex class I region. HLA-B*15, -B*27, -B*57, and -A*26 are independent risk factors for Behçet's disease, while HLA-B*49 and -A*03 are independent class I alleles that are protective for Behçet's disease. Genome-wide association studies have identified associations with genome-wide significance (P < 5 × 10(-8)) in the IL23R-IL12RB2, IL10, STAT4, CCR1-CCR3, KLRC4, ERAP1, TNFAIP3, and FUT2 loci. In addition, targeted next-generation sequencing has revealed the involvement of rare nonsynonymous variants of IL23R, TLR4, NOD2, and MEFV in Behçet's disease pathogenesis. Significant differences in gene function or mRNA expression associated with the risk alleles of the disease susceptibility loci suggest which genes in a disease-associated locus influence disease pathogenesis. These genes encompass both innate and adaptive immunity and confirm the importance of the predominant polarization towards helper T cell (Th) 1 versus Th2 cells, and the involvement of Th17 cells. In addition, epistasis observed between HLA-B*51 and the risk coding haplotype of the endoplasmic reticulum-associated protease, ERAP1, provides a clue that an HLA class I-peptide presentation-based mechanism contributes to this complex disease.

Keywords: Behçet's disease; Disease-associated genetic variants; ERAP1; GWAS; HLA-B*51.

Figure 1. The MHC class I molecule, HLA-B, showing BD-associated amino acid positions

A 3D model of the HLA-B molecule drawn by PyMol using 1E27, protein data of HLA-B*51:01 from the Protein Data Bank. The pink line shows a peptide antigen in the antigen-binding groove of the HLA-B molecule. Red indicates amino acids with genome-wide significant association (P < 5 × 10⁻⁸) with BD from [43].

Figure 2. Immunogenetic findings and the pathogenesis of Behçet’s disease

Reported susceptibility genes and functions of risk alleles were described [42, 43, 56, 57, 59, 62, 63, 85]. CTL: cytotoxic T cell, DC: dendritic cell, NK: natural killer cell, Treg: regulatory T cell.