The Journal of immunology : official journal of the American Association of Immunologists
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Alemtuzumab (anti-CD52 mAb) provides long-lasting disease activity suppression in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to characterize the immunological reconstitution of T cell subsets and its contribution to the prolonged RRMS suppression following alemtuzumab-induced lymphocyte depletion. The study was performed on blood samples from RRMS patients enrolled in the CARE-MS II clinical trial, which was recently completed and led to the submission of alemtuzumab for U. ⋯ A gradual increase in serum IL-7 and IL-4 and a decrease in IL-17A, IL-17F, IL-21, IL-22, and IFN-γ levels were detected following treatment. In vitro studies have demonstrated that IL-7 induced an expansion of CD4(+)CD25(+)CD127(low) regulatory T cells and a decrease in the percentages of Th17 and Th1 cells. In conclusion, our results indicate that differential reconstitution of T cell subsets and selectively delayed CD4(+) T cell repopulation following alemtuzumab-induced lymphopenia may contribute to its long-lasting suppression of disease activity.
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Leukotriene C4 (LTC4) and its extracellular metabolites, LTD4 and LTE4, mediate airway inflammation. They signal through three specific receptors (type 1 cys-LT receptor [CysLT1R], CysLT2R, and GPR99) with overlapping ligand preferences. In this article, we demonstrate that LTC4, but not LTD4 or LTE4, activates mouse platelets exclusively through CysLT2R. ⋯ LTC4 potentiated airway inflammation in a platelet- and CysLT2R-dependent manner. Thus, CysLT2R on platelets recognizes LTC4 with unexpected selectivity. Nascent LTC4 may activate platelets at a synapse with granulocytes before it is converted to LTD4, promoting mediator generation and the formation of leukocyte-platelet complexes that facilitate inflammation.
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Activation of TLR4 by the endotoxin LPS is a critical event in the pathogenesis of Gram-negative sepsis. Caveolin-1, the signaling protein associated with caveolae, is implicated in regulating the lung inflammatory response to LPS; however, the mechanism is not understood. In this study, we investigated the role of caveolin-1 in regulating TLR4 signaling in endothelial cells. ⋯ Exogenous expression of phosphorylation-deficient Y14F caveolin-1 mutant in cav-1(-/-) mouse pulmonary vasculature rendered the mice resistant to LPS compared with reintroduction of wild-type caveolin-1. Thus, caveolin-1 Y14 phosphorylation was required for the interaction with TLR4 and activation of TLR4-MyD88 signaling and sepsis-induced lung inflammation. Inhibiting caveolin-1 Tyr(14) phosphorylation and resultant inactivation of TLR4 signaling in pulmonary vascular endothelial cells represent a novel strategy for preventing sepsis-induced lung inflammation and injury.
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Liver sinusoidal endothelial cells (LSECs) are unique organ-resident APCs capable of Ag cross-presentation and subsequent tolerization of naive CD8(+) T cells. Under certain conditions, LSECs can switch from a tolerogenic to an immunogenic state and promote the development of T cell immunity. However, little is known about the mechanisms of LSECs to induce T cell immunity. ⋯ P3C stimulation did not induce programmed death ligand 1 expression on LSECs, thereby favoring T cell proliferation and activation instead of suppression. Our data suggest that LSECs undergo maturation exclusively in response to TLR1/2 ligand stimulation and that the immunological status of LSECs was dependent upon the balance between programmed death ligand 1 and IL-12 expression. These results have implications for our understanding of liver-specific tolerance and autoimmunity and for the development of strategies to overcome T cell tolerance in situations such as chronic viral liver infections or liver cancer.
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Chronic debilitating pruritus is a cardinal feature of atopic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. ⋯ Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from healthy subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1(+) dermal afferent nerves and TRPA1(+) mast cells in a Th2-dominated inflammatory environment.