Pathogenesis of Behçet’s disease: autoinflammatory features and beyond

Abstract

Behçet's disease (BD) is an inflammatory disorder of unknown aetiology characterised by recurrent attacks affecting the mucocutaneous tissues, eyes, joints, blood vessels, brain and gastrointestinal tract. It is a multifactorial disease classified as a variable vessel vasculitis, and several environmental triggers may induce inflammatory episodes in genetically susceptible individuals. BD has several autoinflammatory features including recurrent self-limited clinical manifestations overlapping with monogenic autoinflammatory disorders, significant host predisposition and abnormally increased inflammatory response, with a robust innate component. Human leukocyte antigen (HLA)-B*51 is the strongest susceptibility factor described so far affecting the disease risk and typical phenotype. Non-HLA genetic associations such as endoplasmic reticulum aminopeptidase 1 (ERAP1), interleukin 23 receptor (IL23R) and IL10 variations suggest that BD shares susceptibility genes and inflammatory pathways with spondyloarthritis. Although genomewide association studies revealed an increased risk associated with recessively inherited ERAP1 variations in HLA-B*51 positive patients, it is not clear yet whether certain peptide-HLA allele combinations result in an adaptive response by a self-antigen-directed cytotoxic response or an innate response by modulating an NK cell activity or causing an unfolded protein response. Understanding of major histocompatibility complex (MHC) Class I-driven inflammatory response is expected to provide insights for the development of better treatment and remission-induction options in BD as well as in ankylosing spondylitis (AS) and psoriasis.

CSF/serum matrix metallopeptidase‐9 ratio discriminates neuro Behçet from multiple sclerosis

“…A low percentage of T cells, B cells, and monocytes produce MMP9 (from 0.5% to 0.07%), whereas NK cells were MMP9‐positive for 1.9%. We identified NKs CD56 DIM subset as the key producers of MMP9, in agreement with previous findings that indicate NK CD56 DIM involved in inflammation of several autoimmune diseases, including Behçet 23, 24, 25. In Behçet, this NK subset was found depleted in blood during disease activity, probably because trafficking into disease active tissues and decreased during treatment with azathioprine 26.…”

Etiology, Immunopathogenesis and Biomarkers in Behçet’s disease

“…There are clear similarities and differences across different ethnic groups phenotypically and at a genetic or molecular level. So far, clinical data trials support the critical role of innate cytokines TNF, IL1, and IL6 in the development of inflammatory episodes of BD, and targeting T cells or B cells may provide favorable results [256]. In this era of personalized and precision medicine, collaborative efforts nationally or internationally are needed to assemble adequately powered cohorts to perform further population-or regional-based molecular and genetic studies.…”

Vascular Manifestations of Behçet’s Disease

“…However, it has an important genetic component due to its familial characteristics [48]. HLA-B51 is the strongest identified factor for genetic predisposition.…”

“…HLA-B51 may contribute to the pathogenesis of BD by both adaptive (presentation of some pathogenic peptides to CD8 T cells) and congenital mechanisms (activation with natural killer cells and by activating intracellular inflammatory pathways) affecting the immune system [48].…”

“…Regarding the site of occurrence, there have been some geographic variations in cohorts studied so far [47,48]. Reports from Turkey and Korea described the femoral artery and the abdominal aorta as the most common locations of aneurysm formation [49,50].…”