Behçet's disease: from Hippocrates to the third millennium

Abstract

Behçet's disease (BD) is characterised by recurrent episodes of orogenital aphthae, systemic vasculitis, and systemic and retinal venous thrombosis. An association between HLA-B51 and BD was first identified over 20 years ago, but recently identified gene associations implicate regions both within and without the MHC in the immunological events underlying the lesions in BD. These include allelic variants within the tumour necrosis factor gene region and within the MHC class I chain related gene region, the factor V Leiden mutation, which is associated with retinal vascular occlusion, and alleles of the intercellular adhesion molecule gene. No single causative gene for BD has emerged; the evidence indicates that the underlying immune events in BD are triggered by a microbial antigen and subsequently driven by genetic influences which control leucocyte behaviour and the coagulation pathways. Knowledge of these risk factors may permit a more accurate prognosis for a given patient, and identify new pathways for more targeted intervention than is currently available.

Figure 1

Spectrum of organ involvement in Behçet’s disease.

Figure 2

Anterior segment complications of retinal vein occlusion: retinal ischaemia with secondary rubeosis iridis.

Figure 3

Inflammatory retinal vein occlusion with associated vitritis and retinal vasculitis before (A) and after (B) treatment with high dose oral steroid.

Figure 4

(A) Acute branch retinal vein occlusion. (B) Total vascular obliteration and optic atrophy secondary to recurrent vascular occlusion.

Figure 5

Global distribution of HLA-B51 among healthy ethnic control groups with reference to the Silk Road and early demographic movements.

Figure 6

The human major histocompatibility complex (MHC) on the short arm of chromosome 6. TAP = transporter of antigenic peptides; 21-OH = steroid 21-hydroxylase enzyme; C4A and B = complement loci; Bf = properdin factor B of the alternate complement pathway; C2 = complement C2; TNF = tumour necrosis factor; MICA = MHC class I chain related gene; LT = lymphotoxin.

Figure 7

Behçet’s disease. Putative role of MICA molecules and HSP expressed on mucosal epithelial cells. *The MHC class I chain related (MIC) gene locus is situated adjacent to the HLA-B domain. MICA is of interest in Behçet’s disease because it is expressed at gastrointestinal epithelial surfaces in response to bacterial infection. γδ T cells and NK cells are upregulated in Behçet’s disease and are known to recognise and kill MICA transfected cells. Recently, MICA was shown to be a ligand for NKG2D which is also expressed on γδ T cells and NK cells. †Heat shock proteins (HSP) are expressed in response to cellular shock, and have been found on cells lining the gastointestinal tract. T cell responses to HSP derivatives are reported to be raised in patients, and the genetic promoter region for HSP expression is also known to control MICA expression.

Figure 8

Intracranial venous thrombosis. (A) Male patient presents with headaches and disc oedema. (B) Magnetic resonance imaging and (C) magnetic resonance angiography demonstrating superior sagittal sinus thrombosis.

Figure 9

Behçet’s disease. Factors affecting endothelial cell activation and leucocyte extravasation.

Figure 10

Behçet’s disease is associated with multiple hereditory and environmental risk factors.