Behçet's Disease: A Comprehensive Review on the Role of HLA-B*51, Antigen Presentation, and Inflammatory Cascade

Abstract

Behçet's disease (BD) is a complex, recurring inflammatory disorder with autoinflammatory and autoimmune components. This comprehensive review aims to explore BD's pathogenesis, focusing on established genetic factors. Studies reveal that HLA-B*51 is the primary genetic risk factor, but non-HLA genes (ERAP1, IL-10, IL23R/IL-12RB2), as well as innate immunity genes (FUT2, MICA, TLRs), also contribute. Genome-wide studies emphasize the significance of ERAP1 and HLA-I epistasis. These variants influence antigen presentation, enzymatic activity, and HLA-I peptidomes, potentially leading to distinct autoimmune responses. We conducted a systematic review of the literature to identify studies exploring the association between HLA-B*51 and BD and further highlighted the roles of innate and adaptive immunity in BD. Dysregulations in Th1/Th2 and Th17/Th1 ratios, heightened clonal cytotoxic (CD8+) T cells, and reduced T regulatory cells characterize BD's complex immune responses. Various immune cell types (neutrophils, γδ T cells, natural killer cells) further contribute by releasing cytokines (IL-17, IL-8, GM-CSF) that enhance neutrophil activation and mediate interactions between innate and adaptive immunity. In summary, this review advances our understanding of BD pathogenesis while acknowledging the research limitations. Further exploration of genetic interactions, immune dysregulation, and immune cell roles is crucial. Future studies may unveil novel diagnostic and therapeutic strategies, offering improved management for this complex disease.

Keywords: Behçet’s disease; ERAP; HLA-B*51; T cell receptor; antigens; pathogenesis.

Figure 1

Flowchart of study selection according to PRISMA guidelines.

Figure 2

Schematic illustrates the process of HLA class I presentation of peptides containing 8–10 amino acids to the T cell receptor of CD8+ T cells. Anchor amino acids play a definitive role in peptide binding to HLA class I molecules. While T cell receptors exhibit polyspecificity, the specific contact residues on the peptide are of utmost importance in dictating the recognition. (Created using BioRender.com, accessed on 8 June 2023).

Figure 3

Schematic illustration of pathogenesis in Behçet’s disease: This schematic provides an illustration of the genetic determinants and potential triggering antigens that activate an immune cascade when self-peptides, mimicking environmental antigens, are presented to CD8 T cells. This activation is further triggered by the release of IL-23. Immune dysregulation leads to the release of cytokines by various immune cells such as Tc17, Th17, NKT, and NK cells. The dominant cytokines involved in this process, including IL-23, IL-17, TNF-alpha, IFN-gamma, and IL-8, play a pivotal role in activating neutrophils, generating reactive oxygen species, and triggering the formation of neutrophilic extracellular traps. Subsequently, this immune response can lead to tissue damage. (Created using BioRender.com, accessed on 14 May 2023).