Behçet's disease (BD), also known as the Silk Road disease, is a blinding inflammatory disorder of young adults found predominantly between the Mediterranean basin and the Orient, and is strongly associated with the major histocompatibility complex (MHC) antigen HLA-B51. In this article we review the history of Behçet's disease since its first description by Hippocrates, the development of the trading routes collectively known as the Silk Road and the effect of population movement on the distribution of HLA-B51. The global distribution of this antigen among healthy control populations bears a striking similarity both to the ancient trading routes and the distribution of Behçet's disease, suggesting a genetic risk that migrated in parallel with population movement between the Mediterranean and Asia. However, certain indigenous Amerindian peoples have a high prevalence of HLA-B51 but no reported cases of BD. Furthermore, a clear genealogical relationship exists between eastern, but not central, Siberian populations with the Amerindians. Since a high level of recombination within the MHC is known to have occurred in these eastern populations before their migration into Beringia, we suggest that disruption of genetic loci in linkage disequilibria with HLA-B51 may be one reason for the absence of disease in these high HLA-B51-bearing populations. However, a contributory influence of environmental factors is not excluded by this data, and the wide variation that exists in relative risk of HLA-B51 even within Europe would support other non-genetic risk factors on the Silk Road which may be absent, or non-contributory to disease, in the Americas.

The role of HLA-B*51 and other major histocompatibility complex (MHC) genes in Behçet's disease (BD) remains unknown. We have performed HLA and tumour necrosis factor (TNF) polymorphism analysis in BD and evaluated their contribution to ocular disease. In this study, 102 patients and 115 controls of Middle Eastern descent were investigated by HLA and B*51 subtyping using novel primers, and by LT alpha NCo 1 and TNF 308 promoter polymorphism analysis. The frequency of the HLA-B*51 family of alleles was raised in patients compared to controls (66% vs. 15%, Pc=2.5x10(-12), OR=10.9). The odds ratio (OR) of this group of alleles for subgroups of patients was as follows: non-ocular patients 7.8, all ocular patients 12.6, blind patients >22. HLA-B*51 subtyping detected B*5101, 07, 08 and 09 alleles, with a similar frequency among patients and controls. HLA-Cw*1602 was associated with B*5108, but was not an independent risk factor for disease. The LT alpha (TNFB*2) allele was associated with HLA-B*51 among patients and the frequency of this allele was significantly higher among completely blind patients compared to both non-ocular patients (P=0.048, OR >3.6) and to healthy controls (P=0.022, OR >4.3). The rare TNF-2 polymorphism at the TNF -308 promoter position was associated with HLA-B*50 (not B*51), and was not associated with BD. Thus, in this population the HLA*B51 family of alleles is a strong risk factor for BD, and in particular the development of ocular disease. HLA-B*51 subtyping did not define new markers for BD. A primary role for TNF gne polymorphisms in BD was not identified, but co-expression of the TNFB*2 allele with HLA-B*51 may contribute to severity of ocular disease.

Purpose Hyperhomocysteinaemia has been linked to macrovascular disease. Our aim was to investigate whether there is a relationship between fasting plasma total homocysteine levels and retinal vascular disease.Methods We measured the homocysteine levels in 70 patients with arterial or venous retinal vessel occlusion and compared them with the levels in 85 controls without evidence of ischaemic heart disease. Homocysteine levels were determined by high-performance liquid chromatography with electrochemical detection and compared after logarithmic transformation.Results Homocysteine levels were found by univariate analysis (unpaired two-tailed t-test) to be significantly higher in the group with retinal artery occlusion than the group with retinal vein occlusion ( p = 0.045) and in both groups compared with controls (18.4 and 13.8 vs 9.5 fLmol/l; p = 0.0002 and < 0.0001, respectively).The controls, however, were significantly younger than the subjects (51.5 ± 15.4 vs 66.2 ± 11.9 years; p < 0.0001), but analysis of the results by age revealed significant differences between the groups and controls for the seventh decade Conclusions We conclude that homocysteine may be a risk factor for retinal vascular disease and could be simply and cheaply treated with folate and vitamins B6 and Bu.

Aim: The potential causes of the optic nerve injury as a result of blunt object trauma, were investigated using a computer model. Methods: A finite element model of the eye, the optic nerve, and the orbit with its content was constructed to simulate blunt object trauma. We used a model of the first phalanx of the index finger to represent the blunt body. The trauma was simulated by impacting the blunt body at the surface between the globe and the orbital wall at velocities between 2-5 m/s, and allowing it to penetrate 4-10 mm below the orbital rim. Results: The impact caused rotations of the globe of up to 5000˚/s, lateral velocities of up to 1 m/s, and intraocular pressures (IOP) of over 300 mm Hg. The main stress concentration was observed at the insertion of the nerve into the sclera, at the side opposite to the impact. Conclusions:The results suggest that the most likely mechanisms of injury are rapid rotation and lateral translation of the globe, as well as a dramatic rise in the IOP. The strains calculated in the study should be sufficiently high to cause axonal damage and even the avulsion of the nerve. Finite element computer modelling has therefore provided important insights into a clinical scenario that cannot be replicated in human or animal experiments.A nterior traumatic optic neuropathy and optic nerve avulsion may result from a blunt injury where a foreign object intrudes between the globe and the orbital wall.

Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms have been implicated in the susceptibility to inflammatory diseases, including multiple sclerosis and inflammatory bowel disease. The expression of both soluble and tissue ICAM-1 is increased in Behçet's disease (BD) but the contribution of ICAM-1 gene polymorphisms to this disease remains unknown. Associations with BD have been reported for genes within the MHC, including HLA-B51, TNF and MICA, but the role of non-MHC genes in BD remains largely unexplored. We have investigated the frequency of the R/G 241 and K/E 469 ICAM-1 gene polymorphisms in 83 patients with BD disease and 103 healthy controls, all of Palestinian and Jordanian descent, and demonstrated an association between BD and the ICAM-1 E469 allele (Pc = 0.046, OR = 2.1). Among patients, no association was found between the presence of ocular disease and ICAM-1 polymorphisms. While the functional correlate of this polymorphism remains unclear, this finding indicates that a genetic polymorphism in the ICAM-1 gene domain, which is independent of the MHC, may contribute to disease.