Store-operated Ca 2+ entry (SOCE) is the principal Ca 2+ entry mechanism in nonexcitable cells. Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum Ca 2+ sensor that triggers SOCE activation. However, the role of STIM1 in regulating cancer progression remains controversial and its clinical relevance is unclear. Here we show that STIM1-dependent signaling is important for cervical cancer cell proliferation, migration, and angiogenesis. STIM1 overexpression in tumor tissue is noted in 71% cases of early-stage cervical cancer. In tumor tissues, the level of STIM1 expression is significantly associated with the risk of metastasis and survival. EGF-stimulated cancer cell migration requires STIM1 expression and EGF increases the interaction between STIM1 and Orai1 in juxta-membrane areas, and thus induces Ca 2+ influx. STIM1 involves the activation of Ca 2+ -regulated protease calpain, as well as Ca 2+ -regulated cytoplasmic kinase Pyk2, which regulate the focal-adhesion dynamics of migratory cervical cancer cells. Because of an increase of p21 protein levels and a decrease of Cdc25C protein levels, STIM1-silencing in cervical cancer cells significantly inhibits cell proliferation by arresting the cell cycle at the S and G2/M phases. STIM1 also regulates the production of VEGF in cervical cancer cells. Interference with STIM1 expression or blockade of SOCE activity inhibits tumor angiogenesis and growth in animal models, confirming the crucial role of STIM1-mediated Ca 2+ influx in aggravating tumor development in vivo. These results make STIM1-dependent signaling an attractive target for therapeutic intervention.

Background: House dust mites (HDMs) are among the most important allergen sources containing many different allergenic molecules. Analysis of patients from a double-blind, placebocontrolled allergen-specific immunotherapy (AIT) study indicated that patients may benefit from AIT to different extents depending on their molecular sensitization profiles. Objective: Our aim was to investigate in a real-life setting whether stratification of patients with HDM allergy according to molecular analysis may enhance AIT success. Methods: Serum and nasal secretion samples from patients with HDM allergy (n 5 24) (at baseline, 7, 15, 33, and 52 weeks) who had received 1 year of treatment with a well-defined subcutaneous AIT form (Alutard SQ 510) were tested for IgE and IgG reactivity to 15 microarrayed HDM allergen molecules with ImmunoCAP Immuno-solid-phase Allergen Chip technology. IgG subclass levels to allergens and peptides were determined by ELISA, and IgG blocking was assessed by basophil activation. In vitro parameters were related to reduction of symptoms determined by combined symptom medication score and visual analog scale score. Results: Alutard SQ 510 induced protective IgG mainly against Dermatophagoides pteronyssinus (Der p) 1 and Der p 2 and to a lesser extent to Der p 23, but not to the other important allergens such as Der p 5, Der p 7, and Der p 21, showing better clinical efficacy in patients sensitized only to Der p 1 and/or Der p 2 as compared with patients having additional IgE specificities. Conclusion: Stratification of patients with HDM allergy according to molecular sensitization profiles and molecular monitoring of AIT-induced IgG responses may enhance the success of AIT.

Background: Inthehousedustmite(HDM)Dermatophagoides pteronyssinus,Derp 1,2,5,7,21,and23havebeenidentifiedasthemostimportantallergens.Theaimof thisstudywastodefinehypoallergenicpeptidesderivedfromthesequencesofthe sixallergensandtousethepeptidesandthecompleteallergenstostudyantibody, Tcell,andcytokineresponsesinsensitizedandnonsensitizedsubjects. Methods: IgE reactivity of HDM-allergic and non-HDM-sensitized individuals to 15 HDM allergens was established using ImmunoCAP ISAC technology. Thirtythree peptides covering the sequences of the six HDM allergens were synthesized. Allergens and peptides were tested for IgE and IgG reactivity by ELISA and ImmunoCAP,respectively.Allergenicactivitywasdeterminedbybasophilactivation. CD4+TcellandcytokineresponsesweredeterminedinPBMCculturesbyCFSEdilu-tionandLuminextechnology,respectively. Results: HousedustmiteallergicsshowedIgEreactivityonlytocompleteallergens, whereas 31 of the 33 peptides lacked relevant IgE reactivity and allergenic activity.IgGantibodiesofHDM-allergicandnonsensitizedsubjectsweredirectedagainst peptideepitopesandhigherallergen-specificIgGlevelswerefoundinHDMallergics. PBMCfromHDM-allergicsproducedhigherlevelsofIL-5whereasnon-HDM-sensitized individuals mounted higher levels of IFN-gamma, IL-17, pro-inflammatory cytokines,andIL-10. Conclusion: IgG antibodies in HDM-allergic patients recognize peptide epitopes whicharedifferentfromtheepitopesrecognizedbyIgE.Thismayexplainwhynaturallyoccurringallergen-specificIgGantibodiesdonotprotectagainstIgE-mediated allergicinflammation.AmixofhypoallergenicpeptidescontainingTcellepitopesof themostimportantHDMallergenswasidentified. K E Y W O R D Sallergen,housedustmiteallergy,recombinantallergen,syntheticpeptide,Tcellepitope ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercialLicense,whichpermitsuse,distributionandreproduction inanymedium,providedtheoriginalworkisproperlycitedandisnotusedforcommercialpurposes.

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House dust mites (HDMs) induce allergic asthma in sensitized individuals, although how HDMs activate immature mucosal dendritic cells (DCs) to render the T helper cell type 2 (Th2)-mediated immune response is unclear. In this study, our results showed a significant calcium-dependent lectin binding of Dermatophagoides pteronyssinus (Der p) extracts to DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), the C-type lectin receptors (CLRs) of DCs. Moreover, monocyte-derived DCs (MDDCs) of Der p-sensitized asthmatics (AS) exhibited decreased expression of DC-SIGN, increased endocytosis, and impaired differentiation of DC precursors. The Der p-induced downregulation of DC-SIGN expression in the differentiation of immature MDDCs may be because of the internalization of Der p-DC-SIGN complex. MDDCs of AS produced more interleukin (IL)-6 and less IL-12p70 cytokines when stimulated with lipopolysaccharide (LPS) or Der p than those of nonallergic controls (NC). In the co-culture experiments, MDDCs pretreated with Der p induced GATA-3 expression and IL-4 cytokine productions in naive CD4(+) T cells. These effects of Der p on the differentiation and function of MDDCs could be partially blocked by anti-DC-SIGN antibodies. In conclusion, our results suggest a critical step of allergen sensitization that involves CLRs in the innate immune response of DCs, which may provide a therapeutic or preventive potential for allergic asthma.