Pathogenesis

Multiple aspects of the immune system have been shown to be abnormal in Adamantiades-Behget's, including lowered neutrophil and endothelial cell activation thresholds, abnormal T-cell responses (including yS T-cells), increased cytokine expression and immune complex formation, increased Fas-ligand expression, abnormal complement activation proteins, and disrupted coagulation pathways (4,6). The driving process behind these multiple abnormalities is unknown. Infections have been thought to lead to the disease, and various organisms have been implicated, including Staphylococcus, Streptococcus, and some Gram-negative bacterial species, as well as multiple viruses, including herpes simplex. In most models, infection would act as the initial trigger for disease, with downstream inflammation being caused by immune cross-reactivity (7). This model is attractive, but conclusive evidence for a pathogenic role of these or other organisms has not been found (7). Antibodies reactive against oral mucosa and antiendothelial cell antibodies have been found in patients with Adamantiades-Behget's, but they lack specificity for disease, although a subset of these antibodies directed against a-enolase in the vascular wall may prove to be fairly specific markers for Adamantiades-Behget's (6). Abnormalities of the clotting system, including elevated homocysteine levels, low levels of activated protein C, and antiphospholipid antibodies, also have been observed in patients with disease and are thought to lead to the endothelial damage and the thrombotic complications seen with this disease (8,9).

Adamantiades-Behget's does have a significant association with the class I human leukocyte antigens B51 and B52, although interestingly, the strength of these associations depends on the geographic region of disease, with a relative risk of disease of 13.3 in carriers of the HLA-B51 gene in Turkey versus a relative risk of 1.3 in carriers of the gene in the United States (4,10). It is thought that the HLA-B51 and -B52 molecules may act to present antigenic peptides to CD8+ T-cells, initiating the immune response seen in Adamantiades-Behget's; however, the specific peptide(s) has not been identified (7). HLA-B51 and -B52 molecules may also act as antigens themselves, becoming targets after similar proteins are released from immunologic sequestered sites in the body, perhaps by an initial infection (7). Other genes have also been implicated in disease, including polymorphisms in genes for intracellular adhesion molecule-1 (ICAM-1), endothelial nitric oxide synthase, pyrin, major histocompatibility complex class I (MICA), vascular endothelial growth factor (VEGF), interleukin-1A (IL-1A), and other proteins related to antigen processing, although further investigations are needed to define the pathways by which these specific genetic alterations lead to Adamantiades-Behget' s (4,11-13).

Histopathologic evaluation of early Adamantiades-Behget's mucocutaneous lesions shows a neutrophilic vascular process involving the small vessels. Its appearance is similar to leukocytoclastic vasculitis with neutrophilic infiltrates, nuclear dust, and extravasation of red blood cells, with immune complex deposition and endothelial and neutrophil activation thought to play a role in initiation of this process (6). In late mucocutaneous lesions, lymphocytic infiltrate may predominate. In larger-vessel disease, similar vasculitic changes of the vasa vasorum are seen, with lymphocytic infiltration of these vessel lesions likely representing more chronic inflammation (5). It is this larger-vessel vasculitis that can lead to vessel wall damage and aneurysms that are prone to rupture.

In sum, while the exact etiology of the disease is unknown, it appears that in the appropriate genetic and immunologic background, after a trigger by perhaps an initial infection, the signs and symptoms of Adamantiades-Behget's occur when trauma or other vascular injury, allows for the activation of already overly sensitive components of the innate immune system, including neutrophils, endothelial cells, and more primitive yS T-cells, with the resulting robust cytokine response and recruitment of T- and B-cells playing a role in continued inflammation and tissue injury.

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