Identification of Highly Expressed Genes in Peripheral Blood T Cells from Patients with Atopic Dermatitis

Matsumoto, Yoshiko; Oshida, Tadahiro; Obayashi, Izumi; Imai, Yukiho; Matsui, Kazuaki; Yoshida, Ning Lu; Nagata, Naoko; Ogawa, Katsuhiro; Obayashi, Masaya; Kashiwabara, Tomoko; Gunji, Shigemichi; Nagasu, Takeshi; Sugita, Yuji; Tanaka, Toshio; Tsujimoto, Gozoh; Katsunuma, Toshio; Akasawa, Akira; Saito, Hirohisa

doi:10.1159/000067589

Cited by 57 publications

(53 citation statements)

References 25 publications

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“…Also, the immunological symptoms of allergic asthma are attenuated in ItkϪ/Ϫ mice, and lung inflammation, eosinophil infiltration, and mucous production are drastically reduced in response to challenge with the allergen OVA (8). Furthermore, the Itk gene is reported to be more highly expressed in peripheral blood T-cells from patients with moderate or severe atopic dermatitis than in controls or patients with mild atopic dermatitis (9).…”

mentioning

confidence: 99%

Crystal Structures of Interleukin-2 Tyrosine Kinase and Their Implications for the Design of Selective Inhibitors

Brown

Long

Vial

et al. 2004

Journal of Biological Chemistry

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Interleukin-2 tyrosine kinase, Itk, is an important member of the Tec family of non-receptor tyrosine kinases that play a central role in signaling through antigen receptors such as the T-cell receptor, B-cell receptor, and Fc⑀. Selective inhibition of Itk may be an important way of modulating many diseases involving heightened or inappropriate activation of the immune system. In addition to an unliganded nonphophorylated Itk catalytic kinase domain, we determined the crystal structures of the phosphorylated and nonphosphorylated kinase domain bound to staurosporine, a potent broad-spectrum kinase inhibitor. These structures are useful for the design of novel, highly potent and selective Itk inhibitors and provide insight into the influence of inhibitor binding and phosphorylation on the conformation of Itk.The Tec kinases are a family of five non-receptor tyrosine kinases that play a central role in signaling through antigenreceptors such as the T-cell receptor (TCR), 1 B-cell receptor, and Fc⑀ (1) and are essential for T-cell activation. Three members of the family, Itk, Rlk, and Tec, are activated downstream of antigen receptor engagement in T-cells and transmit signals to downstream effectors, including PLC-␥. A fourth member, Btk, appears to act independently of T-cell signaling and is essential for B-cell development and activation. Btk-deficient murine mast cells have reduced degranulation and decreased production of proinflammatory cytokines following Fc⑀RI crosslinking (2). Btk deletion in mice has a profound effect on B-cell proliferation induced by anti-IgM and inhibits immune responses to thymus-independent type II antigens (3, 4). A biological role for the final member of this family, Bmx, has not been identified.Itk is a key member of this family, and a number of factors point to the importance of this kinase in immune disease.Deletion of Itk in mice results in reduced TCR-induced proliferation and secretion of the cytokines IL-2, IL-4, IL-5, IL-10, and interferon-␥ (5-7). Also, the immunological symptoms of allergic asthma are attenuated in ItkϪ/Ϫ mice, and lung inflammation, eosinophil infiltration, and mucous production are drastically reduced in response to challenge with the allergen OVA (8). Furthermore, the Itk gene is reported to be more highly expressed in peripheral blood T-cells from patients with moderate or severe atopic dermatitis than in controls or patients with mild atopic dermatitis (9).In certain cell types, the role of Itk may be intricately linked with other members of the family. For example, in mast cells, Btk and Itk are both expressed and activated by Fc⑀RI crosslinking (10). Splenocytes from RlkϪ/Ϫ mice secrete half the IL-2 produced by wild type animals in response to TCR engagement (5), whereas the combined deletion of Itk and Rlk in mice leads to a profound inhibition of TCR-induced responses, including proliferation and production of the cytokines IL-2, IL-4, IL-5, and interferon-␥ (5, 7). Furthermore, intracellular signaling following TCR engagement is affected in Itk...

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mentioning

confidence: 99%

Crystal Structures of Interleukin-2 Tyrosine Kinase and Their Implications for the Design of Selective Inhibitors

Brown

Long

Vial

et al. 2004

Journal of Biological Chemistry

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“…This secretion of hsp60 may originate either from lymphocytes themselves, from other cutaneous cells like keratinocytes and fibroblasts, or from other sources such as nerves or vessels (De Maio 2011). Also, next to hsp60, other proteins involved in inflammation, including proteins from other hsp families, may be involved in AD pathogenesis Ghoreishi 2000;Ishibashi et al 2009;Matsumoto et al 2002;Park et al 2008). This is the first study to demonstrate that hsp60 is present at the site of inflammation and that it induces specific proinflammatory T cell responses in children with AD.…”

Section: Discussionmentioning

confidence: 99%

Recognition of self-heat shock protein 60 by T cells from patients with atopic dermatitis

Kapitein

Aalberse

Klein

et al. 2013

Cell Stress and Chaperones

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Heat shock protein 60 (hsp60) is a highly conserved stress protein and target of self-reactive T cells in various inflammatory diseases. Not much is known about a possible role in atopic disease. As atopic diseases are considered to be the result of a disturbance in the balance between T helper cells type 2 and regulatory T cells, it is of interest to know whether hsp60 acts as a bystander antigen in atopic disease. Our aim was to investigate whether hsp60 is involved in the chronicity of inflammation of atopic dermatitis (AD). We studied the expression of hsp60 in skin tissue of adults with AD by immunohistochemistry. Peripheral blood mononuclear cells (PBMC) of children with AD were cultured with hsp60 and proliferative responses, cytokine secretion, surface markers, and functional assays were compared to responses of PBMC of healthy controls (HC). Hsp60 was detected more in lesional skin of AD patients compared to nonlesional skin. Furthermore, PBMC of children with AD proliferated more strongly in response to hsp60 compared to HC. hsp60-reactive T cells of atopic children produced high levels of IFNγ and low levels of IL-10. In vitro activation with hsp60 leads to the induction of CD4 + CD25 bright T cells expressing FOXP3 in both HC as well as in atopic children. However, despite their regulatory phenotype, hsp60-induced CD4 + CD25bright CD127− FOXP3 + T cells of AD patients were incapable of suppressing effector T cells in vitro. hsp60 is recognized by proinflammatory (IFNγ high, IL-10 low) T cells in atopic patients and is more present in lesional AD skin. This suggests that hsp60-specific T cell responses contribute to local inflammation in AD.

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“…Patients with allergic disease and healthy individuals were recruited for participation in the study. Patient profiles and clinical parameters have previously been described in detail (1). Patients with ad were diagnosed according to the criteria of Hanifin (3).…”

Section: Methodsmentioning

confidence: 99%

“…The methods for the dd analysis of human peripheral blood T cells from allergic patients have previously been described in detail (1). A slightly modified version of the fluorescent DD method described by ito et al was used in this study (5).…”

Section: Methodsmentioning

confidence: 99%

“…The analysis of genes differentially expressed between ad patients and normal individuals and between the different phases of ad may provide information on the molecular pathogenesis of the disease. To identify the genes involved in allergic diseases, we analyzed transcription profiles in peripheral blood immune cells from patients with allergic diseases, and found many genes that were differentially expressed between patients and healthy individuals (1,2). during differential display (dd) gene expression studies on peripheral blood cd3+ T cells from ad patients, we observed that the level of expression of a gene later designated coiledcoil domain containing 132, transcript variant 1 (CCDC132) was markedly higher in ad patients than in normal controls.…”

Section: Introductionmentioning

confidence: 99%

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CCDC132 is highly expressed in atopic dermatitis T cells

Matsumoto

Imai²,

Sugita³

et al. 2009

Mol Med Rep

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Identification of Highly Expressed Genes in Peripheral Blood T Cells from Patients with Atopic Dermatitis

Cited by 57 publications

References 25 publications

Crystal Structures of Interleukin-2 Tyrosine Kinase and Their Implications for the Design of Selective Inhibitors

Crystal Structures of Interleukin-2 Tyrosine Kinase and Their Implications for the Design of Selective Inhibitors

Recognition of self-heat shock protein 60 by T cells from patients with atopic dermatitis

CCDC132 is highly expressed in atopic dermatitis T cells

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