PATHOPHYSIOLOGY OF BEHCET'S DISEASE.


Abstract: The etiology and pathogenesis of Behcet's disease (BD) are still unknown. As for other autoimmune disorders, in a special genetic background an exogenous or endogenous antigen acts as trigger in up-regulating and presenting the pathogenic epitope. The immune system reacts in an abnormal way, in the presence of a probable neuro-endocrine dysfunction(hyperprolactinemia?), by an exaggerated inflammatory response leading to the lesions of the disease. Genetic background: On the basis of chromosomal mapping and association analysis, the critical region for BD in the human MHC could be pinpointed to a 46-kb segment between the MIC-A (MHC class I chain-related gene A) and HLA-B gene. The major susceptibility gene is the HLA-B*51 allele itself. The increase of MIC-A009 allele in BD patients is secondary to the strong linkage disequilibrium with B51. Antigen: Some exogenous or endogenous antigen(s) such as bacteria (streptococcal strains), virus (herpes simplex virus), or host cross-reactive antigens may trigger the BD onset. A common denominator to these agents might be the heat shock protein (HSP). Specific immune responses in BD were found to be stimulated by shared epitopes within human 60-kD HSP (peptide 336­-351) and mycobacterial 65-kD HSP. Altered immune response: There is accumulating evidences that the disease is T cell mediated: a) In premature phases, there is a switch in the normal ratio of CD4/CD8. b) Increased T cell proliferation to the pathogenic epitope (notably T cells bearing Y /б receptors). c) Low threshold of T cells to produce large amounts of pro inflammatory cytokines such as INF- Y and TNF- α , when stimulated by superantigens. d) T cell aberration from the angle of Th1/Th2 pattern, secreting immunosuppressive cytokines, resulting an immunoregulation between these cells. Neutrophil (PMN) hyperfunction is one of the most characteristic features in BD. PMN are capable of promoting their own recruitment leading to an abnormal accumulation in the site of inflammation and the production of pro­inflammatory cytokines (IL-12, IL-18) and overproduction of O2 free radicals, which seems to be B51 related. Cell adhesion molecules are essential for PMN to reach the involved tissue, while TNF- α helps the accumulation by reducing the PMN spontaneous apoptosis.