The effector immune mechanisms underlying peanut-induced anaphylaxis remain to be fully elucidated. We investigated the relative contribution of Igs, mast cells (MCs), and FcεRI in the elicitation of anaphylaxis in a murine model. Assessment of peanut hypersensitivity reactions was performed clinically and biologically. Our data show that wild-type (WT; C57BL/6 strain) mice consistently developed severe anaphylaxis (median clinical score: 3.5/5), an ∼8°C drop in core body temperature, and significantly increased plasma levels of histamine and leukotrienes. CD40 ligand- and B cell-deficient mice presented evidence of allergic sensitization as demonstrated by production of Th2-associated cytokines by splenocytes and a late-phase inflammatory response that were both indistinguishable to those detected in WT mice. However, CD40 ligand- and B cell-deficient mice did not exhibit any evidence of anaphylaxis. Our data also show that MC-deficient (KitW/KitW-v) mice did not suffer, unlike their littermate controls, anaphylactic reactions despite the fact that serum levels of peanut-specific Igs were similarly elevated. Finally, FcεRI-deficient mice experienced anaphylactic responses although to a significantly lesser degree than those observed in WT mice. Thus, these data demonstrate that the presence of peanut-specific Abs along with functional MCs comprise a necessary and sufficient condition for the elicitation of peanut-induced anaphylaxis. That the absence of FcεRI prevented the development of anaphylaxis only partially insinuates the contribution of an IgE-independent pathway, and suggests that strategies to impair MC degranulation may be necessary to improve the efficacy of anti-IgE therapy.

Objective-We recently identified HSP27 as an atheroprotective protein that acts extracellularly to prevent foam cell formation and atherogenesis in female but not male mice, where serum levels of HSP27 were increased and inversely correlated with degree of lesion burden. In the current study we sought to determine whether estrogens are required for the observed atheroprotective benefits of HSP27 as well as its extracellular release. Methods and Results-In vitro estrogens prompted the release of HSP27 from macrophages in an ER␤ specific manner that involved exosomal trafficking. Ovariectomy nullified the previously recognized attenuation in aortic lesion area in HSP27 o/e apoE Ϫ/Ϫ mice compared to apoE Ϫ/Ϫ mice. Supplementation with 17␤-estradiol resulted in a Ͼ15ϫ increase in uterine weight and attenuation of atherogenesis in all mice, although HSP27o/e apoE Ϫ/Ϫ had 34% less lesion burden compared to apoE Ϫ/Ϫ mice. Mice treated with the ER␤-specific agonist, DPN had no effect on uterine weight but a 28% decrease in aortic lesion area in HSP27o/e apoE Ϫ/Ϫ compared to apoE Ϫ/Ϫ mice. HSP27 serum levels showed a similar gradual increase with E2 and DPN replacement treatment but did not change in untreated mice. Key Words: heat shock Ⅲ proteins Ⅲ estrogen Ⅲ receptors Ⅲ athersclerosis P reviously, we showed in human coronary arteries that Heat Shock Protein 27 (HSP27) expression is lower in atherosclerotic plaques compared to lesion-free arterial segments, suggesting higher levels of this protein may confer protection from disease. 1 More recently, we demonstrated that HSP27 is an atheroprotective protein that acts in the extracellular space to reduce foam cell formation and atherogenesis by binding scavenger receptor-A on the surface of macrophages and preventing the uptake of acLDL as well as inflammatory cytokine release. Moreover, when fed a highfat diet for 4 weeks apoE null (apoE Ϫ/Ϫ ) mice that overexpress HSP27 (HSP27 o/e apoE Ϫ/Ϫ ) show a reduction in aortic atherosclerotic plaque area-however, only in female and not male mice. 2 Interestingly, female HSP27 overexpressing mice have significantly higher levels of serum HSP27 than do their male counterparts, and serum HSP27 levels show a strong inverse correlation with atherosclerotic lesion area. These sex-specific effects of HSP27 hint that the function or release of this intriguing protein may in some way be hormonally modulated. Conclusions-TheGiven our previous observations that estrogens cause HSP27 secretion, and that HSP27 physically associates with ER␤ but not ER␣, 3 we sought to determine the role for these receptors in the release of HSP27 both in vitro and in vivo. As described herein, we now report that the release of HSP27 from macrophages is preferentially induced via specific ER␤ stimulation (not ER␣) and induction of HSP27 release in vivo via the ER␤-specific modulator DPN increases serum HSP27 levels to a level comparable to 17␤-estradiol (E2)-yet unlike E2 attenuates atherogenesis without causing unwanted uterine hypertrophy. Materials and Me...

GSKi improves the functional profile of EPCs and is associated with improved re-endothelialization and reduced neointima formation following injury.

It is becoming increasingly evident that the compartmentalization of immune responses is governed, in part, by tissue-selective homing instructions imprinted during T cell differentiation. In the context of allergic diseases, the fact that “disease” primarily manifests in particular tissue sites, despite pervasive allergen exposure, supports this notion. However, whether the original site of Ag exposure distinctly privileges memory Th2 immune-inflammatory responses to the same site, while sparing remote tissue compartments, remains to be fully investigated. We examined whether skin-targeted delivery of plasmid DNA encoding OVA via gene-gun technology in mice could generate allergic sensitization and give rise to Th2 effector responses in the skin as well as in the lung upon subsequent Ag encounter. Our data show that cutaneous Ag priming induced OVA-specific serum IgE and IgG1, robust Th2-cytokine production, and late-phase cutaneous responses and systemic anaphylactic shock upon skin and systemic Ag recall, respectively. However, repeated respiratory exposure to aerosolized OVA failed to instigate airway inflammatory responses in cutaneous Ag-primed mice, but not in mice initially sensitized to OVA via the respiratory mucosa. Importantly, these contrasting airway memory responses correlated with the occurrence of Th2 differentiation events at anatomically separate sites: indeed cutaneous Ag priming resulted in Ag-specific proliferative responses and Th2 differentiation in skin-, but not thoracic-, draining lymph nodes. These data indicate that Ag exposure to the skin leads to Th2 differentiation within skin-draining lymph nodes and subsequent Th2 immunity that is selectively manifested in the skin.