Behcet's disease (BD) is a systemic inflammatory disease, characterized by recurrent signs and symptoms of oral aphthosis, genital ulcers, skin lesions, and uveitis. It is well known that BD is prevalent along the Silk Route, but BD patients are occasionally found in other regions of the world.
The etiology of BD is largely unknown and skewed T-cell responses are associated with development and maintenance of BD [1
]. Excessive cytokine productions by T helper type 1 (Th1) cells were reported using immunohistochemistry [2
] and intracellular cytokine staining [4
]. Th1 dominance was observed in BD uveitis [6
] and stomatitis as well [7
]. We reported excessive Th1 cell infiltration in BD skin and intestinal lesions [8
Immune responses against microbes and microbial antigens were thought to play an important role in the pathogenesis of BD. Regional differences of the disease distribution [11
] suggested association of disease development with locally prevalent microbes. Oral health was often impaired in patients with BD and was correlated well with BD disease severity [12
]. Streptococcus sanguinis
is a commensal oral bacterium and often forms dental plaque. S. sanguinis
was found frequently in oral flora in patients with BD and the strain showed uncommon serotype (KTH1) compared with the standard ATCC strains [13
]. T cells and peripheral blood mononuclear cells (PBMCs) from patients with BD responded to KTH1 antigens and produced interferon γ
) and interleukin (IL)-12 [14
]. Skin tests of streptococcal antigens caused various systemic reactions, such as fever, ocular attack, and genital and oral ulcer in patients with BD [15
]. Accumulation of indirect evidence suggested participation of bacteria (or associated antigens) in the pathogenesis of BD.
Pathergy reaction is a cutaneous phenomenon where a minor injury, such as a needle prick, causes major skin lesions, such as ulcerations, panniculitis, and pyoderma, and positive pathergy reaction is included in the diagnostic criteria for BD proposed by the International Study Group [16
]. Massive neutrophil infiltration and subsequent T-cell infiltration were frequently observed pathologically in the lesion caused by the reaction, even without any exogenous microbes [2
]. The underlying mechanisms of the reaction remain largely unknown. On the other hand, it was suggested that skin florae and some skin self-antigens played a role because bacterial sterilization of skin reduced the reaction [17
Heat shock proteins (HSPs) function as an intracellular chaperonin for other proteins, and significant sequence homology is found between mammalian HSP and microbial HSP (). For example, mycobacterial and streptococcal HSP65 have more than 90% homology, and mycobacterial HSP65 and human HSP60 have 42% homology [18
]. HSP60/65 were thought to be a major cause of the autoimmunity in patients with BD because of the molecular mimicry between human and microbial HSP. In this paper, we summarize current understanding of T-cell responses against HSP in patients with BD.
Table 1 Comparison of the amino acid sequences of human, Chinese hamster (C) HSP60, Escherichia coli (E), and Mycobacterium leprae (M) HSP65 .