Is Behçet's disease a ‘class 1-opathy’? The role of HLA-B*51 in the pathogenesis of Behçet's disease

Abstract

Summary The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the ‘MHC-I-opathies’. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8+ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies.

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

“…Importantly, in these conditions, ERAP is in epistasis with the risk alleles of MHC-I allele. However, not all patients with ankylosing spondylitis or Behçet's disease carry a MHC-I risk allele, an observation that has provoked discussions on this unifying concept [6,7] and whether it reflects shared underlying disease etiology.…”

TIM-3 genetic variants and risk of Behçet disease in the Iranian population

“…The role of dysregulated or abnormal immune responses in BD pathogenesis is well-defined and supports the theory that BD is an autoimmune disorder. 15 The initiation and development of BD as an autoimmune disease is the result of a multistep pathogenic process, involving various genetic alterations and environmental factors leading to breakdown of tolerance and induction of an immune response against components of the self.…”

Behçet’s syndrome: focus on pathogenetic background, clinical phenotypes and specific treatments

“…Since the first report by Ohno and colleagues [5], the Human Leukocyte Antigen-B51 (HLA-B*51) has been confirmed in different populations as the most strongly genetic risk factor for BS developing [6]. However, depending on the genetic ancestry, the frequency of HLA-B*51 varies, ranging from 15 to 60% of BS patients, thus not fully explaining the genetic susceptibility of this syndrome [7][8][9].…”