The proper regulation of inducible costimulator (ICOS) and its ligand (ICOSL) have been shown to be essential for maintaining proper immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant antibody production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that ADAM10 is the primary physiological sheddase of ICOSL in both mouse and human. Using an in vivo system in which ADAM10 is deleted only on B cells (ADAM10B−/−), elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is deleted from human B cell lines. Identification of the primary sheddase has allowed the characterization of a novel mechanism of ICOS regulation. In wildtype (WT) mice, interaction of ICOSL/ICOS results in ADAM10 induced shedding of ICOSL on B cells and moderate ICOS internalization on T cells. When this shedding is blocked, excessive ICOS internalization occurs. This results in severe defects in T follicular helper (TFH) development and TH2 polarization, seen in a house dust mite exposure model. In addition, enhanced TH1 and TH17 immune responses are seen in experimental allergic encephalomyelitis. Blockade of ICOSL rescues T cell ICOS surface expression and at least partially rescues both TFH numbers and the abnormal antibody production previously reported in these mice. Overall, we propose a novel regulation of the ICOS/ICOSL axis, with ADAM10 playing a direct role in regulating ICOSL as well as indirectly regulating ICOS, thus controlling ICOS/ICOSL-dependent responses.
BackgroundAlthough cardiac injury has been reported in patients with various neurological conditions, few data report cardiac injury in patients with traumatic brain injury (TBI). The aim of this work is to report the incidence of cardiac injury in patients with TBI and its impact on patient outcome.MethodsA prospective observational study was conducted on a cohort of 50 patients with severe TBI. Only patients with isolated severe TBI defined as Glascow coma scale (GCS) < 8 were included in the study. Acute physiology and chronic health evaluation (APACHE) II score, GCS, hemodynamic data, serum Troponin I, electrocardiogram (ECG), and echocardiographic examination, and patients’ outcome were recorded. A neurogenic cardiac injury score (NCIS) was calculated for all patients (rising troponin = 1, abnormal echocardiography = 1, hypotension = 1). Univariate and multivariate analyses for risk factors for mortality were done for all risk factors.Results and discussionFifty patients were included; age was 31 ± 12, APACHE II was 21 ± 5, and male patients were 45 (90 %). Troponin I was elevated in 27 (54 %) patients, abnormal echocardiography and hypotension were documented in 14 (28 %) and 16 (32 %) patients, respectively. The in-hospital mortality was 36 %. Risk factors for mortality by univariate analysis were age, GCS, APACHE II score, serum troponin level, NCIS, and hypotension. However, in multivariate analysis, the only two independent risk factors for mortality were APACHE II score (OR = 1.25, 95 % confidence interval: 1.02–1.54, P = 0.03) and NCIS score (OR = 8.38, 95 % confidence interval: 1.44–48.74, P = 0.018).ConclusionsCardiac injury is common in patients with TBI and is associated with increased mortality. The association of high NCIS and poor outcome in these patients warrants a further larger study.
Dendritic cells are an important link between innate and adaptive immune response. The role of dendritic cells in bone homeostasis, however, is not understood.Osteoporosis medications that inhibit osteoclasts have been associated with osteonecrosis, a condition limited to the jawbone, thus called medication-related osteonecrosis of the jaw. We propose that disruption of the local immune response renders the oral microenvironment conducive to osteonecrosis. We tested whether zoledronate (Zol) treatment impaired dendritic cell (DC) functions and increased bacterial load in alveolar bone in vivo and whether DC inhibition alone predisposed the animals to osteonecrosis. We also analyzed the role of Zol in impairment of differentiation and function of migratory and tissue-resident DCs, promoting disruption of T-cell activation in vitro. Results demonstrated a Zol induced impairment in DC functions and an increased bacterial load in the oral cavity. DC-deficient mice were predisposed to osteonecrosis following dental extraction. Zol treatment of DCs in vitro caused an impairment in immune functions including differentiation, maturation, migration, antigen presentation, and T-cell activation. We conclude that the mechanism of Zolinduced osteonecrosis of the jaw involves disruption of DC immune functions required to clear bacterial infection and activate T cell effector response. K E Y W O R D S alveolar bone healing, dendritic cells, osteonecrosis 2596 | ELSAYED Et AL.
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