Skewed Th1 Responses Caused by Excessive Expression of Txk, a Member of the Tec Family of Tyrosine Kinases, in Patients with Behcet's Disease

Abstract

Behcet's disease (BD) is characterized by recurrent attacks of uveitis, oral aphtha, genital ulcers and skin lesions.The etiology and pathogenesis of BD are largely unknown. It has been reported that excessive Th1 cell function is involved in the pathogenesis of BD. Previously, we found that Txk, a member of the Tec family of tyrosine kinases, acts as a Th1 cell-specific transcription factor that is involved in the effector function of Th1 cells.Thus, we studied Th1 cytokine production and Txk expression of T-lymphocytes in patients with BD. Peripheral blood lymphocytes produced excessive Th1-associated cytokines including interferon-γ (IFN-γ) and interleukin (IL)-12 in patients with BD. Circulating CD3+ and purified CD4+ T cells expressed excessive Txk protein.The extent of IFN-γ production by the lymphocytes correlated with the expression of Txk protein in the immunoblotting analysis. The majority of cells infiltrating into the skin lesions of patients with BD expressed IFN-γ. IL-12 and IL-18 were found in the mononuclear cell aggregates in the skin and intestinal lesions of those with BD. Lymphocytes accumulating in the skin and intestinal lesions expressed higher levels of Txk as compared with other Th2-associated diseases. IFN-γ, IL-18 and IL-12 detected in skin lesions may induce preferential development of Th1 cells in patients with BD. Collectively,Th1 cells expressing Txk and Th1-associated cytokines may play a critical role in the development of skin and intestinal lesions in patients with BD. This review may serve as a reminder of the importance of excessive Th1 cell function in the pathogenesis of BD and may contribute to the discovery of new molecular targets for the development of a specific therapeutic strategy for BD.

Selective Expression Rather than Specific Function of Txk and Itk Regulate Th1 and Th2 Responses

“…3d). Therefore the Txk transgene does not appear to lead to enhanced T H 1 differentiation or IFN-γ production, nor does it block T H 2 differentiation as would be observed if Txk were a T H 1-inducing kinase (12-16). Higher levels of IL-13 mRNA but not protein were also observed in the Tg(CD2-Txk)Itk −/− mice in comparison to WT.…”

“…Indeed, in some cases, Itk-deficient mice have been found to mount T H 1 responses to T H 2-inducing pathogens. In contrast, overexpression of Txk has been associated with increased expression of IFN-γ, a T H 1 cytokine (12-15). Txk has been found to bind directly to a sequence in the IFN-γ promoter, suggesting a direct role for Txk in driving IFN-γ transcription and T H 1 responses (16).…”

Expression of Th-17 and RORgammat mRNA in Behçet’s Disease

“…and herpes simplex virus, have been postulated [2]. Behçet’s disease is an inflammatory disease characterized by local tissue injury caused by immunocompetent cells, in particular CD4 + T lymphocytes, that are involved in the pathogenesis of this syndrome via the production of distinctive sets of cytokines like IFN-γ, IL-6, TNF-α, TGF-β [3–5]. The results from a cytokine production and gene profile analysis in different autoimmune/inflammatory diseases identified a population of in vivo differentiated retinoid-related orphan receptor γ-expressing T cells, producing high levels of IL-17 that can represent up to 30% of infiltrating T lymphocytes [6].…”

Mollaret Meningitis may be Caused by Reactivation of Latent Cerebral Toxoplasmosis

“…In active Behçet uveitis, aqueous humor levels of TNF-α, IFN-γ , and IL-15 were higher compared with patients without uveitis. Mege et al, 1993;Sakane, Takeno, Suzuki, & Inaba, 1999;Frassanito, Dammacco, Cafforio, & Dammacco, 1999;Hamzaoui et al, 2002;Aridogan et al, 2003;Suzuki, Nara, & Suzuki, 2006;Ahn, Yu, Chung, & Park, 2006;Shukla et al, 2006 (Continued on next page) …”