XLP is caused by mutations affecting SAP, an adaptor that recruits Fyn to SLAM family receptors. SAP-deficient mice recapitulate features of XLP, including increased T cell activation and decreased humoral responses post-infection. SAP-deficient T cells also show increased TCR-induced IFN-gamma and decreased T(H)2 cytokine production. We demonstrate that the defect in IL-4 secretion in SAP-deficient T cells is independent of increased IFN-gamma production. SAP-deficient cells respond normally to polarizing cytokines, yet show impaired TCR-mediated induction of GATA-3 and IL-4. Examination of TCR signaling revealed normal Ca(2+) mobilization and ERK activation in SAP-deficient cells, but decreased PKC-theta recruitment, Bcl-10 phosphorylation, IkappaB-alpha degradation, and nuclear NF-kappaB1/p50 levels. Similar defects were observed in Fyn-deficient cells. SLAM engagement amplified PKC-theta recruitment in wt but not SAP- or Fyn-deficient cells, arguing that a SAP/Fyn-mediated pathway enhances PKC-theta/NF-kappaB1 activation and suggesting a role for this pathway in T(H)2 regulation.
Background Stabilization after a pelvic fracture can be accomplished with an anterior external fixator. These devices are uncomfortable for patients and are at risk for infection and loosening, especially in obese patients. As an alternative, we recently developed an anterior subcutaneous pelvic internal fixation technique (ASPIF).Questions/purposes We asked if the ASPIF (1) allows for definitive anterior pelvic stabilization of unstable pelvic injuries; (2) is well tolerated by patients for mobility and comfort; and (3) has an acceptable complication rate. Methods We retrospectively reviewed 91 patients who incurred an unstable pelvic injury treated with an anterior internal fixator and posterior fixation at four Level I trauma centers. We assessed (1) healing by callous formation on radiographs and the ability to weightbear comfortably; (2) patient function by their ability to sit, stand, lie on their sides, and how well they tolerated the implants; and (3) complications during the observation period. The minimum followup was 6 months (mean, 15 months; range, 6-40 months). Results All 91 patients were able to sit, stand, and lie on their sides. Injuries healed without loss of reduction in 89 of 91 patients. Complications included six early revisions resulting from technical error and three infections. Irritation of the lateral femoral cutaneous nerve was reported in 27 of 91 patients and resolved in all but one. Heterotopic ossification around the implants, which was asymptomatic in all cases, occurred in 32 of 91 patients. Conclusions The anterior internal fixator provided high rates of union for the anterior injury in unstable pelvic fractures. Patients were able to sit, stand and ambulate
The Tec family kinase Itk is an important regulator of Ca2+ mobilization and is required for in vivo responses to Th2-inducing agents. Recent data also implicate Itk in TCR-induced regulation of the actin cytoskeleton. We have evaluated the requirements for Itk function in TCR-induced actin polarization. Reduction of Itk expression via small interfering RNA treatment of the Jurkat human T lymphoma cell line or human peripheral blood T cells disrupted TCR-induced actin polarization, a defect that correlated with decreased recruitment of the Vav guanine nucleotide exchange factor to the site of Ag contact. Vav localization and actin polarization could be rescued by re-expression of either wild-type or kinase-inactive murine Itk but not by Itk containing mutations affecting the pleckstrin homology or Src homology 2 domains. Additionally, we find that Itk is constitutively associated with Vav. Loss of Itk expression did not alter gross patterns of Vav tyrosine phosphorylation but appeared to disrupt the interactions of Vav with SLP-76. Expression of membrane-targeted Vav, Vav-CAAX, can rescue the small interfering RNA to Itk-induced phenotype, implicating the alteration in Vav localization as directly contributing to the actin polarization defect. These data suggest a kinase-independent scaffolding function for Itk in the regulation of Vav localization and TCR-induced actin polarization.
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