Immunoglobulin E (IgE) activates mast cells (MCs). It remains unknown whether IgE also activates other inflammatory cells, and contributes to the pathogenesis of abdominal aortic aneurysms (AAAs). This study demonstrates that CD4+ T cells express IgE receptor FcεR1, at much higher levels than do CD8+ T cells. IgE induces CD4+ T-cell production of IL6 and IFN-γ, but reduces their production of IL10. FcεR1 deficiency (Fcer1a−/−) protects apolipoprotein E-deficient (Apoe−/−) mice from angiotensin-II infusion-induced AAAs and reduces plasma IL6 levels. Adoptive transfer of CD4+ T cells (but not CD8+ T cells), MCs, and macrophages from Apoe−/− mice, but not those from Apoe−/− Fcer1a−/− mice, increases AAA size and plasma IL6 in Apoe−/− Fcer1a−/− recipient mice. Biweekly intravenous administration of an anti-IgE monoclonal antibody ablated plasma IgE and reduced AAAs in Apoe−/− mice. Patients with AAAs had significantly higher plasma IgE levels than those without AAAs. This study establishes an important role of IgE in AAA pathogenesis by activating CD4+ T cells, MCs, and macrophages and supports consideration of neutralizing plasma IgE in the therapeutics of human AAAs.

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IntroductionThe tyrosine kinase Itk, a member of the Tec family of nonreceptor tyrosine kinases, is expressed in T cells and regulates signaling via the T-cell receptor. 1 On T-cell receptor activation, Itk phosphorylates and activates phospholipase-␥1, leading to calcium influx, as well as activation of nuclear factor-B, nuclear factor of activated T cell, and Ras-dependent signaling pathways. Signals regulated by Itk control the development of ␣␤ T cells such that positive and negative selection is affected in the absence of Itk. In addition, Itk also controls the development of populations of T cells that have a naive phenotype (CD62L hi /CD44 lo ), such that, in its absence, nonconventional CD4 ϩ and CD8 ϩ T cells carrying a memory phenotype (CD62L lo /CD44 hi ) and exhibiting innate function predominate. [2][3][4][5] Itk signals also regulate the development of Th2 cells such that, in its absence, T cells from Itk null mice have defects in the production of Th2 cytokines, and these mice have defects in generating Th2 response in several infection and allergic asthma models. [6][7][8][9] Despite this defect in the generation of effective Th2 responses and secretion of Th2 cytokines, Itk null mice paradoxically exhibit increased class switch in B cells to IgE and elevated levels of serum IgE. 10,11 What is not clear is the source of cytokines that could drive the increase in class switch to IgE.T cells are divided into ␣␤ T cells and ␥␦ T cells according to their TCR expression. Both ␣␤ and ␥␦ T cells arise from the most immature CD4 Ϫ CD8 Ϫ double-negative (DN) thymocytes in the thymus. DN thymocytes are divided into 4 developmental stages according to the surface expression of CD25 and CD44, from most immature DN1 to more mature DN4 cells. ␥␦ T cells separate from ␣␤ T cells at DN stages, although the exact time point and the mechanisms involved in this process are still elusive. 12,13 Several studies have shown that the strength of the TCR signal is important for T-cell lineage commitment. Stronger TCR signals favor the development of ␥␦ T cells, whereas the weaker signals favor the development of ␣␤ T cells. 14-16 Studies on ␥␦ TCR transgenic mice have demonstrated that negative selection occurs during the development of ␥␦ T cells in adult thymus, but whether positive selection is necessary is still controversial.␥␦ T cells can produce Th1, Th2, and Th17 cytokines thus having multiple functions in the modulating immune responses, such as host defense and tumor immunity. [17][18][19][20][21][22][23] Both murine and human ␥␦ T cells have been suggested to provide help to B cells, which is correlated with their production of the Th2 cytokine interleukin-4 (IL-4). [24][25][26] More interestingly, several studies showed that only the CD4 ϩ ␥␦ T cells are able to produce 21 We show here that mice lacking Itk have altered ␥␦ T-cell development such that they have more of these cells. We also show that the CD4 ϩ population of ␥␦ T cells is expanded in the absence of Itk and that this population can induce B cell...

Epithelial tissues covering the external and internal surface of a body are constantly under physical, chemical or biological assaults. To protect the epithelial tissues and maintain their homeostasis, multiple layers of immune defense mechanisms are required. Besides the epithelial tissue-resident immune cells that provide the first line of defense, circulating immune cells are also recruited into the local tissues in response to challenges. Chemokines and chemokine receptors regulate tissue-specific migration, maintenance and functions of immune cells. Among them, chemokine receptor CCR10 and its ligands chemokines CCL27 and CCL28 are uniquely involved in the epithelial immunity. CCL27 is expressed predominantly in the skin by keratinocytes while CCL28 is expressed by epithelial cells of various mucosal tissues. CCR10 is expressed by various subsets of innate-like T cells that are programmed to localize to the skin during their developmental processes in the thymus. Circulating T cells might be imprinted by skin-associated antigen-presenting cells to express CCR10 for their recruitment to the skin during the local immune response. On the other hand, IgA antibody-producing B cells generated in mucosa-associated lymphoid tissues express CCR10 for their migration and maintenance at mucosal sites. Increasing evidence also found that CCR10/ligands are involved in regulation of other immune cells in epithelial immunity and are frequently exploited by epithelium-localizing or -originated cancer cells for their survival, proliferation and evasion from immune surveillance. Herein, we will review current knowledge on roles of CCR10/ligands in regulation of epithelial immunity and diseases and speculate on related important questions worth further investigation.

Background Traffic-related particulate matter (PM) has been linked to heightened incidence of asthma and allergic diseases. However, molecular mechanisms by which PM exposure promote allergic diseases remain elusive. Objective We sought to determine the expression, function and regulation of pathways involved in the promotion by PM of allergic airway inflammation. Methods We employed gene expression transcriptional profiling, in vitro culture assays, and vivo murine models of allergic airway inflammation. Results We identified genes of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells (DCs). PM, especially ultrafine particles (UFP), upregulated T helper cytokine, IgE production and allergic airway inflammation in mice in a Jag1 and Notch-dependent manner especially in the context of the pro-asthmatic IL-4 receptor allele Il4raR576. PM-induced Jag1 expression was mediated by the aryl hydrocarbon receptor (AhR), which bound to and activated AhR response elements in the Jag1 promoter. Pharmacological antagonism of AhR or its lineage-specific deletion in CD11c+ cells abrogated the augmentation of airway inflammation by PM. Conclusion PM activate an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with pro-asthmatic alleles.

Objectives Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown. Methods and Results Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days post-perfusion. CatK deficiency significantly reduced lesion CD4+ T-cellcontent, total lesion and medial cell proliferation and apoptosis, medial smooth-muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but did not affect AAA lesion Mac-3+ macrophage accumulation or CD31+ microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4+ T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMC and endothelial cells, but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice. Conclusion This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation, and by affecting vascular cell protease expression and activities.

Background The interplay between the immune system and abnormal metabolic conditions sustains and propagates a vicious feedback cycle of chronic inflammation and metabolic dysfunction that is critical for atherosclerotic progression. It is well established that abnormal metabolic conditions, such as dyslipidemia and hyperglycemia, cause various cellular stress responses that induce tissue inflammation and immune cell activation, which in turn exacerbate the metabolic dysfunction. However, molecular events linking these processes are not well understood. Methods and Results Tissues and organs of humans and mice with hyperglycemia and hyperlipidemia were examined for expression of ligands for NKG2D, a potent immune activating receptor expressed by several types of immune cells, and the role of NKG2D in atherosclerosis and metabolic diseases was probed using mice lacking NKG2D or by blocking NKG2D with monoclonal antibodies. NKG2D ligands were upregulated in multiple organs, particularly atherosclerotic aortae and inflamed livers. Ligand upregulation was induced in vitro by abnormal metabolites associated with metabolic dysfunctions. Using ApoE-/- mouse models we demonstrated that preventing NKG2D functions resulted in a dramatic reduction in plaque formation, suppressed systemic and organ inflammation mediated by multiple immune cell types, and alleviated abnormal metabolic conditions. Conclusions The NKG2D/ligand interaction is a critical molecular link in the vicious cycle of chronic inflammation and metabolic dysfunction that promotes atherosclerosis and might be a useful target for therapeutic intervention in the disease.

UFP exacerbate allergic airway inflammation by promoting a Jag1-Notch 4-dependent interaction between AM and allergen-specific T cells, leading to augmented T cell differentiation.