A Critical Role for Syk in Signal Transduction and Phagocytosis Mediated by Fcγ Receptors on Macrophages

Receptors on macrophages for the Fc region of IgG (FcγR) mediate a number of responses important for host immunity. Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after FcγR cross-linking. Macrophages derived from Syk-deficient (Syk−) mice were defective in phagocytosis of particles bound by FcγRs, as well as in many FcγR-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases. In contrast, Syk− macrophages exhibited normal responses to another potent macrophage stimulus, lipopolysaccharide. Phagocytosis of latex beads and Escherichia coli bacteria was also not affected. Syk− macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by FcγRs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked FcγR-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for FcγR-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family of kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon FcγR engagement, accompanied by a delay in FcγR-mediated phagocytosis. These observations demonstrate that Syk is critical for FcγR-mediated phagocytosis, as well as for signal transduction in macrophages. Additionally, our findings provide evidence to support a model of sequential tyrosine kinase activation by FcγR's analogous to models of signaling by the B and T cell antigen receptors

Utility of Huntington's disease assessments by disease stage: floor/ceiling effects

Introduction: An understanding of the clinimetric properties of clinical assessments, including their constraints, is critical to sound clinical study and trial design. Utilizing data from Enroll-HD—a global, prospective HD observational study and clinical research platform—we examined several well-established HD clinical assessments across all stages of disease for evidence of instrument constraints, specifically floor/ceiling effects, to inform selection of appropriate instruments for use in future studies/trials and identify gaps in instrument utility over the life-course of the disease. Material and Methods: Analyzing publicly available data from 6,614 HD gene-expansion carriers (HDGECs), we grouped participants into deciles based on baseline CAP score, which ranged from 26 to 229. We used descriptive statistics to characterize data distribution for 25 outcome measures (encompassing motor, function, cognition, and psychiatric/behavioral domains) in each CAP decile. A skewness statistic threshold of ±2 was defined a priori to indicate floor/ceiling effects. Results: We found evidence of floor/ceiling effects in the early premanifest stages of disease for most motor and function assessments (e.g., TMS, TFC) and select cognitive tasks (MMSE, Trail Making tests). Other cognitive assessments, and the HADS-SIS scales, performed well ubiquitously, with no evidence of floor/ceiling effects at any disease stage. Floor/ceiling effects were evident at every disease stage for certain assessments, including PBA-s measures. Ceiling effects were apparent for DCL from onset stages onwards, as expected. Discussion: Developing instruments sensitive to subtle differences in performance at the earlier stages of the disease spectrum, particularly in motor and function domains, is warranted