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Thymic t cells syk

Fabian Hauck, Britta Blumenthal, Sebastian Fuchs, Christelle Lenoir, Emmanuel Martin, Carsten Speckmann, Thomas Vraetz, Wilma Mannhardt-Laakmann, Nathalie Lambert, Marine Gil, Stephan Borte, Marie Audrain, Klaus Schwarz, Annick Lim, Wolfgang W Schamel, Alain Fischer, Stephan Ehl, Anne Rensing-Ehl, Capucine Picard, Sylvain Latour
Autosomal recessive human ZAP70 deficiency is a rare cause of combined immunodeficiency (CID) characterized by defective CD4 T cells and profound CD8 T cell lymphopenia. Herein, we report two novel patients that extend the molecular genetics, the clinical and functional phenotypes associated with the ZAP70 deficiency. The patients presented as infant-onset CID with severe infections caused by varicella zoster virus and live vaccines. Retrospective TCR excision circle newborn screening was normal in both patients...
December 2015: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Luis A Pedroza, Vipul Kumar, Keri B Sanborn, Emily M Mace, Harri Niinikoski, Kari Nadeau, Dewton de Moraes Vasconcelos, Elena Perez, Soma Jyonouchi, Harumi Jyonouchi, Pinaki P Banerjee, Olli Ruuskanen, Antonio Condino-Neto, Jordan S Orange
BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a complex immunologic disease caused by mutation of the autoimmune regulator (AIRE) gene. Autoimmunity in patients with APECED syndrome has been shown to result from deficiency of AIRE function in transcriptional regulation of thymic peripheral tissue antigens, which leads to defective T-cell negative selection. Candidal susceptibility in patients with APECED syndrome is thought to result from aberrant adaptive immunity...
February 2012: Journal of Allergy and Clinical Immunology
Kathryn E Hulse, Amanda J Reefer, Victor H Engelhard, James T Patrie, Steven F Ziegler, Martin D Chapman, Judith A Woodfolk
BACKGROUND: The molecule H22-Fel d 1, which targets cat allergen to FcgammaRI on dendritic cells (DCs), has the potential to treat cat allergy because of its T-cell modulatory properties. OBJECTIVE: We sought to investigate whether the T-cell response induced by H22-Fel d 1 is altered in the presence of the T(H)2-promoting cytokine thymic stromal lymphopoietin (TSLP). METHODS: Studies were performed in subjects with cat allergy with and without atopic dermatitis...
January 2010: Journal of Allergy and Clinical Immunology
Emil H Palacios, Arthur Weiss
The spleen tyrosine kinase (Syk) and zeta-associated protein of 70 kD (ZAP-70) tyrosine kinases are both expressed during early thymocyte development, but their unique thymic functions have remained obscure. No specific role for Syk during beta-selection has been established, and no role has been described for ZAP-70 before positive selection. We show that Syk and ZAP-70 provide thymocytes with unique and separable fitness advantages during early development. Syk-deficient, but not ZAP-70-deficient, thymocytes are specifically impaired in initial pre-TCR signaling at the double-negative (DN) 3 beta selection stage and show reduced cell-cycle entry...
July 9, 2007: Journal of Experimental Medicine
Yanhong Zhu, Ellen Herlaar, Esteban S Masuda, Gary R Burleson, Andrew J Nelson, Elliott B Grossbard, George R Clemens
Spleen tyrosine kinase (Syk) is a novel pharmaceutical target for treatment of allergic, autoimmune, and neoplastic disorders. Previous studies have indicated that Syk signaling plays critical roles in regulating the lymphohematopoietic system. These observations prompted us to investigate whether inhibition of Syk would promote immunotoxicity. In a series of studies, rats were treated orally with R406, at dose levels up to and including 100 mg/kg/day (or its prodrug R788 at dose levels up to and including 100 mg/kg/day, reduced to 50 mg/kg/day for females as MTD was exceeded), a potent Syk inhibitor, twice daily for 28 days...
June 15, 2007: Toxicology and Applied Pharmacology
Corinne Barat, Chenqi Zhao, Marc Ouellette, Michel J Tremblay
Leishmaniasis is an important opportunistic disease among patients infected with human immunodeficiency virus (HIV)-1. The pentavalent antimony compound sodium stibogluconate is a drug of choice for the treatment of leishmaniasis. Because sodium stibogluconate acts as an inhibitor of phosphotyrosyl phosphatases and such inhibitors can promote HIV-1 replication, we tested the effect of this compound on virus gene expression. Using pseudotyped reporter viruses and fully infectious laboratory-adapted and clinical strains of HIV-1, we report that sodium stibogluconate induces an increase in HIV-1 transcription and virus replication in primary CD4(+) T cells and in thymic histocultures...
January 15, 2007: Journal of Infectious Diseases
Michela Pozzobon, Teresa Marafioti, Martin-Leo Hansmann, Yasodha Natkunam, David Y Mason
We have investigated whether intracellular signal transduction molecules can be used as immunohistological markers of normal and neoplastic human leucocytes in routine tissue sections. We obtained selective labelling of white cells for eight such molecules (the 'linker' molecules SLP-76 and BLNK, the Src family kinases Lyn, Fyn, Syk and Hck, and the phospholipases PLC-gamma1 and PLC-gamma2). Antibodies to SLP-76 and PLC-gamma1 selectively labelled T cells, and antibodies to BLNK, Lyn, Fyn, Syk and PLC-gamma2 labelled B cells (although Fyn immunostaining was restricted to mantle zone B cells)...
February 2004: British Journal of Haematology
Om Prakash, Zhen-Ya Tang, Xiaochang Peng, Roy Coleman, Javed Gill, Gist Farr, Felipe Samaniego
BACKGROUND: The K1 gene of human herpesvirus-8 (HHV-8; also known as Kaposi's sarcoma-associated herpesvirus) encodes a transmembrane signaling protein that elicits cellular activation events. To evaluate the potential role of K1 in HHV-8-associated pathogenesis, we produced transgenic mice expressing the HHV-8 K1 gene under the transcriptional control of the simian virus 40 promoter. METHODS: Three independent heterozygous transgenic K1 mouse lines were generated from founder mice...
June 19, 2002: Journal of the National Cancer Institute
F Colucci, D Guy-Grand, A Wilson, M Turner, E Schweighoffer, V L Tybulewicz, J P Di Santo
The Syk protein tyrosine kinase (PTK) is essential for B, but not T or NK, cell development, although certain T cell subsets (i.e., gamma delta T cells of intestine and skin) appear to be dependent on Syk. In this report, we have re-evaluated the role of Syk in T cell development in hematopoietic chimeras generated by using Syk-deficient fetal liver hematopoietic stem cells (FL-HSC). We found that Syk-/- FL-HSC were vastly inferior to wild-type FL-HSC in reconstituting T cell development in recombinant-activating gene 2 (RAG2)-deficient mice, identifying an unexpected and nonredundant role for Syk in this process...
May 15, 2000: Journal of Immunology: Official Journal of the American Association of Immunologists
D H Chu, N S van Oers, M Malissen, J Harris, M Elder, A Weiss
Thymocyte development proceeds through two critical checkpoints that involve signaling events through two different receptors, the TCR and the pre-TCR. These receptors employ two families of protein tyrosine kinases to propagate their signals, the Src and Syk families. Genetic and biochemical evidence has shown that the Src family kinases are critical for normal T cell maturation. ZAP-70, a Syk family kinase, has similarly been implicated as a critical component in thymocyte development. Although genetic evidence has suggested that Syk is involved during thymocyte development, a definitive study of Syk expression has not been performed...
September 1, 1999: Journal of Immunology: Official Journal of the American Association of Immunologists
D H Chu, C T Morita, A Weiss
The processes of T-cell development and activation employ similar immature and mature receptors as well as similar signal transduction pathways to achieve different outcomes. Many signaling molecules are shared between the receptor signaling pathways, including two families of cytoplasmic protein tyrosine kinases, the Src family and the Syk family. The two Syk family members expressed in T cells, Syk and ZAP-70, are structurally similar but are expressed at different times during thymic development and during T-cell activation...
October 1998: Immunological Reviews
V Pivniouk, E Tsitsikov, P Swinton, G Rathbun, F W Alt, R S Geha
The adaptor protein SLP-76 is expressed in T lymphocytes and myeloid cells and is a substrate for ZAP-70 and Syk. We generated a SLP-76 null mutation in mice by homologous recombination in embryonic stem cells to evaluate the role of SLP-76 in T cell development and activation. SLP-76-deficient mice exhibited subcutaneous and intraperitoneal hemorrhaging and impaired viability. Analysis of lymphoid cells revealed a profound block in thymic development with absence of double-positive CD4+8+ thymocytes and of peripheral T cells...
July 24, 1998: Cell
A C Chan, N S van Oers, A Tran, L Turka, C L Law, J C Ryan, E A Clark, A Weiss
TCR stimulation results in the tyrosine phosphorylation of a number of cellular substrates. We have recently identified a 70-kDa protein tyrosine kinase, ZAP-70, which associates with the human TCR zeta-chain after TCR stimulation. We report here the isolation and sequence of a cDNA clone that encodes murine ZAP-70. Murine and human ZAP-70 share 93% amino acid identity and are homologous to the 72-kDa protein tyrosine kinase Syk. Syk has been implicated in the signal transduction pathways of the B cell membrane Ig and high affinity IgE receptors, Fc epsilon RI...
May 15, 1994: Journal of Immunology: Official Journal of the American Association of Immunologists
E W Gelfand, K Weinberg, B D Mazer, T A Kadlecek, A Weiss
Recently, a severe combined immunodeficiency syndrome with a deficiency of CD8+ peripheral T cells and a TCR signal transduction defect in peripheral CD4+ T cells was associated with mutations in ZAP-70. Since TCR signaling is required in developmental decisions resulting in mature CD4 (and CD8) T cells, the presence of peripheral CD4+ T cells expressing TCRs incapable of signaling in these patients is paradoxical. Here, we show that the TCRs on thymocytes, but not peripheral T cells, from a ZAP-70-deficient patient are capable of signaling...
October 1, 1995: Journal of Experimental Medicine
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