Etiology Pathogenesis

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BS appears to be a disorder of complex etiology in which the interaction of unknown environmental triggers and genetic susceptibility jointly influences the course and clinical expression of disease (Sakane et al., 1999). The unifying feature of the inflammation observed in BS is a nonspecific inflammatory hyperreactivity with vasculitis as its main clinical consequence (Gul, 2001a). Conceptually, BS may result from an inappropriate and exaggerated inflammatory response to an unknown antigen that is, in part, genetically determined.

The family studies have provided evidence of a genetic predisposition to BS. The sibling recurrence risk ratio (Is) in Turkey has been estimated to be between 11 and 53, implying a strong genetic influence on disease expression (Gul et al., 2000). Although multicase familial studies have suggested a multifactorial mode of inheritance, an autosomal recessive pattern of inheritance has been implicated in childhood BS (Molinari et al., 2003).

HLA B51 has been the most consistently reported HLA-association in BS (Ohno et al., 1982), however, the mechanism whereby HLA B51 confers susceptibility to BS is not known. A HLA B51-related peptide might function as a cross-reactive antigen, such as in the proposed role played by the retinal S antigen and HLA B27 in the pathogenesis of ankylosing spondylitis (Kurhan-Yavuz et al., 2000). A neutrophil hyper-reactivity reported in BS has been tied up with HLA B51 as determined by the detection of excessive neutrophil responses to f-Met-Leu-Phe (fMLP) stimulation in HLA B51 transgenic mice as well as in HLA B51-positive healthy individuals (Takeno et al., 1995). The specificity of the neutrophil hyperreactivity, however has been challenged (Tuzun et al., 1999).

HLA B51 may account for no more than 20% of the sibling relative risk (Gul et al., 2001b), which supports the view that, in addition to potential environmental triggers for disease onset, susceptibility is dependent on other genetic loci. Among these, suggestive evidence of linkage was detected on chromosomes 6p22-23 (Gul et al., 2001c). A preliminary whole-genome screening also provided evidence of non-major histocompati-bility complex (MHC) genetic-susceptibility loci in BS (Karasneh et al., 2005).

Histologically, (CD4 + ) T lymphocytes seem to be major cell-type in inflammatory infiltrates (Lakhanpal et al., 1985; Ben Ahmed et al., 2004) and peripheral T cells have a predominant Th1-type cytokine pattern (Frassanito et al., 1999). These suggest T-cell-mediated immune response in pathogenesis. However, heterogenity is evident by different histologic. Features of various lesions, the presence of neutrophil-predominating inflammatory infiltrates which, are also capable of causing identically appearing skin lesions, suggest immune complex-dependent inflammation responsible for tissue damage (Mangelsdorf et al., 1996). It is not clear whether these reflect different path-ophysiologic mechanisms operating in tissue damage of BS. The nature of infiltrate may obviously depend on the timing of the biopsy in relation to the age of the lesions.

A unifying feature of the inflammation observed in BS is the presence of pathergy phenomenon where traumatic insult or various types of inflammatory stimuli to the tissue is followed by an enhanced inflammatory response. In clinical practice, skin pathergy reaction (SPR), is induced by needle prick leading to the development of papule or pustule at 48 h. Pathogenetically, SPR shows features in common with T-cell-mediated immune response (Gul et al., 1995) and the results of recent, study suggested that injury to the skin of BS patients elicits a T helper 1 (TH1)-cell response owing to interleukin (IL)-12-mediated production of interferon (IFN)-g by CD4+ T cells (Melikoglu et al., 2002). It has been suggested that pathergy phenomenon might provide insights into the dysregulated immunity underlying other affected organ systems in BS. Not only nonspecific trauma may elicit an important disease but there is evidence at the cellular level as demonstrated by spontaneous or induced over-production of proinflammatory cytokines from T cells (Gul et al., 2001a), monocytes and neutrophils (Mege et al., 1993) which might prime the immune system for an enhanced T-cell response observed in BS.

Present evidence suggests that BS is an immu-nologically mediated disease, however, little is known about the cellular and molecular mechanisms responsible for tissue damage at related tissue sites. Increasing evidence led to the current view that Th1-type T cells are the main cell type responsible for tissue destruction; however, the possibility that it is caused by specific or nonspecific T-cell activation is still a matter of debate. The former possibility is indicated by the evidence for the presence of the increased susceptibility to infectious triggers (Kaneko et al., 2003), the upregulation of heat-shock protein (hsp60) expression in mucosal lesions of BS (Ergun et al., 2001), a strong oligoclonal T-cell response to human hsp60 or other antigens from different strains of stre-ptoccocci or other microbial agents (Esin et al., 1997; Pervin et al., 1993) suggesting the participation of potential antigenic stimuli in disease process. In this context, one attractive hypothesis is the involvement of HSP in disease pathogenesis which can mediate Thl-type immune response without requiring specific TCR engagement, and therefore link the innate immune system to T-cell immunity (Direskeneli and Saruhan-Direskeneli, 2003). The other possibility that T cells expand in response to nonspecific mechanisms is exemplified by a model that essential proinflammatory cyto-kines are overproduced by innate immune cells of BS (Mege et al., 1993; Zierhut et al., 2003) that would, in turn, overstimulate mononuclear cells, thereby amplifying the inflammatory T-cell response in BS.

Another potential connection between the innate and adaptive immune system involves the interaction of MHC class I molecules with the killer-cell immunoglobulin-like receptors (KIRs), which are expressed by natural killer cells and T cells. A particular association between HLA B51 and KIR3DL1 or KIR3DS1 receptors on inflammatory cells has been reported in BS (Gul et al., 2002), however, the evidence for the significance of this interaction has been limited.

Increased B-cell reactivity a autoantibodies, is not part of BS. This is also true for ANCA (Tunc et al., 2001) and anticardiolipin antibodies (Tokay et al., 2001). However antibodies to Saccharo-myces cerevisiae, usually seen in Crohn's disease have also been reported in BS (Krause et al., 2002; Fresko et al., in print). Antibodies to alpha-tropomysin with an animal model for uveitis has also been described (Mahesh et al., 2005). Finally, the target antigen for the endothelial antibodies found in some patients has been described as alpha-enolase (Lee et al., 2003).

The thrombophlebitis of deep veins is the most frequent manifestation of large vessel involvement in BS (Kural-Seyahi et al., 2003). Several studies have been reported on inherited and acquired cause of thrombophilia that may contribute to the development of thrombosis complicating large vessel inflammation in BS. No single coagulation abnormality has been described apart from a decrease in fibrinolysis (Espinosa et al., 2002; Leiba et al., 2004). We have recently observed that a deficiency of tissue Plasminogen Activator (tPA) production in acute thrombosis of BS was associated with this decrease in fibriolysis (Yurdakul et al., in print). Coupled with the decreased nitric oxide (NO) production-related endothelial dysfunction (Chambers et al., 2001) these findings suggest that the primary pathology in thromboph-ilia of BS is in the vessel wall.

Premature atherosclerosis is part of many diseases that are associated with vasculitis. Our preliminary observations suggest that this probably is not the case for BS (Seyahi et al., 2004).

5. Clinical manifestations

Behcet's disease affects oral and genital integument, eye, joints, vascular and CNS.

5.1. Oral ulcers

The most frequent finding is the aphthous stomatitis which cannot be differentiated from idiopatic reccurrent aphthous stomatitis on clinical grounds. Some patients have oral ulcers for 6-8 years before other clinical findings appear (Gurler et al., 1997; Verpilleux et al., 1999; Bang et al., 1993). The ulcers are usually localized at the lips, buccal mucosa, gums, tongue, as well as the posterior parts of the mouth such as uvula and pharynx. The presence of posteriorly located oral ulcers occurring in crops of 5 or less, with a healing time of more than a week appear to be associated with BS (Ifeacho et al., 2004).

Oral ulceration of BS can be minor, major or herpetiform. Ulcers in minor form are round or oval, rather shallow and, less than 10 mm in diameter, with yellow-tan pseudomembrane which is surrounded by an erythematous halo (Fig. 1). They usually heal within 7-10 days without scarring.

Figure 1. Minor aphtous ulcers.

Major aphthous ulcers are seen less often. These ulcers are painful, larger (range from 1 to 3 cm in diameter), deeper and heal more slowly (15-30 days) and often with scarring. They can be localized in any part of the mouth and may cause pha-ryngeal stenosis, resulting in malnutrition. The herpetiform ulcers are rather uncommon and these ulcers present as multiple clusters of small ulcers, 2-3 mm in diameter, distrubuted throughout the oral cavity. In a recent study the frequency of oral ulcer type was studied (Cosgun et al., 2004). Minor aphthous ulcers were the most common presentation of BS (85%). The frequency of major aphthae was found to be 14% and it was more frequent among the females. Major and minor aphthae were equally distrubuted among both genders in recurrent apthous stomatitis group. Herpetiform aphthae were not observed.

In histologic specimens the oral aphthae of BS, the squamous epithelium is replaced by a necrotic and fibrinopurulent exudate. Inflammatory cells and regenerative changes in keratinocytes can be detected in the epithelium adjacent to the ulcer. Underlying mucosa is heavily infiltrated with ne-utrophils, lymphocytes, histiocytes and plasma cells. There is a prominent vascular proliferation, together with endothelial swelling. Partial occlusion of the lumen (Nazzaro, 1966) and rarely le-ukocytoclastic vasculitis (Chun et al., 1990) have also been reported in the aphthous lesions of BS. These findings are similar to other aphthous lesions, seen in idiopathic recurrent aphthous stomatitis (RAS).

It is interesting to note that in both BS and RAS, activated gammadelta T cells are present in peripheral blood. In BS, they are capable of producing IFN-gamma and tumor necrosis factor (TNF)-alpha, while in RAS they produce IFN-gamma, but not TNF-alpha (Freysdottir et al., 1999).

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