Allergy, Anaphylaxis and Non-Allergic Hypersensitivity: IgE, Mast Cells and Beyond

International audienceIgE-mediated type I hypersensitivity reactions have many reported beneficial functions in the immune defense against parasites, venoms, toxins etc. However, they are best-known for their role in allergy affecting nowadays almost one third of the population worldwide. IgE-mediated allergic diseases result from a maladaptive type 2 immune response that promotes the synthesis of IgE antibodies directed to a special class of antigens called allergens. IgE antibodies bind to type I high affinity IgE receptors (FcepsilonRI) on mast cells and basophils licensing them to get triggered in a subsequent encounter with the cognate allergen. This promotes the release of a whole set of inflammatory mediators including histamine responsible for the symptoms of immediate hypersensitivity. The development of type 2 driven allergies are dependent on a complex interplay of genetic and environmental factors at barrier surfaces including the host microbiome that builds up during early life. While without doubt IgE-mediated immediate hypersensitivity reactions are at the origin of the majority of allergies it has become clear that similar responses and symptoms can be triggered by other types of adaptive immune responses mediated via IgG or complement involving other immune cells and mediators. Likewise, various innate triggers via receptors expressed on mast cells have been found either to directly launch an allergic reaction and/or to amplify existing IgE-mediated responses. This review summarizes recent findings on both IgE-dependent and IgE-independent mechanisms in the development of allergies and provides an update on allergy diagnosis

Pulmonary Hypoplasia Associated with Congenital Heart Diseases: A Fetal Study

<div><p>Background</p><p>Abnormalities of the fetal pulmonary vasculature may affect lung morphogenesis. Postnatal studies have suggested that pulmonary hypoplasia (PH) may be associated with congenital heart diseases (CHDs).</p><p>Objective</p><p>To determine the prevalence of PH associated with CHDs, and to evaluate whether CHDs with right outflow obstruction were associated with the highest risk of lung growth impairment.</p><p>Methods</p><p>Between January 2006 and December 2010, fetuses with CHD obtained following the termination of pregnancies due to fetal abnormalities were examined in a prospective manner for the detection of heart and lung defects. CHDs were classified into five pathophysiological groups. Lung weight (LW), body weight (BW), and LW/BW ratio were analyzed for each case. The expression of CD31 and VEGF in the lung was evaluated by immunohistochemistry.</p><p>Results</p><p>Fetuses with CHDs and right outflow obstruction had significantly lower LW for a given BW, and significantly lower LW/BW ratios for a given gestational age. When defining PH as a fetal LW/BW ratio <0.015 before 28 weeks, and <0.012 after 28 weeks, PH was detected in 15 of the 119 fetuses analyzed (13%). It was significantly associated with CHD with right outflow obstruction, independently of chromosomal abnormalities and associated extracardiac abnormalities (<i>p</i><0.03). Right outflow obstruction was detected in 60% of the fetuses with CHD and PH, but in only 32% of those with CHD but no PH. In fetuses with right outflow obstruction, no difference was observed between those with PH and those without PH, in terms of the ratio of pulmonary artery diameter to aortic diameter, lung CD31 expression, or lung VEGF expression.</p><p>Conclusion</p><p>CHDs with right outflow obstruction are a significant risk factor for prenatally acquired PH. The occurrence of fetal PH is not correlated with abnormalities of the pulmonary vasculature, suggesting the involvement of perfusion-independent mechanisms.</p></div

Characteristics of the fetuses, assigned to two subgroups according to the association of PH with CHD.

<p>Values are medians (IQR) or <i>n</i> (% of each subgroup). BW: body weight; LW: lung weight.</p><p>*<i>P</i> value<0.05;</p><p>**<i>P</i> value<0.0001.</p

Univariate and multivariate analyses assessing the risk of PH as a function of CHD category, presence of an abnormal karyotype and the presence of a malformation likely to interfere with lung growth (IUGR, renal hypoplasia, omphalocele, thoracic dystrophy, or hydrothorax).

<p>Univariate and multivariate analyses assessing the risk of PH as a function of CHD category, presence of an abnormal karyotype and the presence of a malformation likely to interfere with lung growth (IUGR, renal hypoplasia, omphalocele, thoracic dystrophy, or hydrothorax).</p

Characteristics of fetuses with CHD and PH.

<p>Characteristics of fetuses with CHD and PH.</p

Individual PA/Ao values.

<p>Values were available for 35 fetuses with CHD and right outflow obstruction, and 45 fetuses with CHDs of other types. Horizontal bar: median value in each subgroup. Dashed horizontal line: expected normal AP/Ao value (i.e. 1.2). <i>p</i><0.0001 for comparisons between subgroups.</p

CHD diagnosis (<i>n</i> = 119).

<p>CHD diagnosis (<i>n</i> = 119).</p

VEGF immunohistochemistry.

<p>Original magnification×10, and ×40 magnification of the area identified by a rectangle. VEGF (brown) and counterstaining with hematoxylin. Fetuses with PH (A, C, E) were compared withfetusesof a similar gestational age without PH (B, D, F). A: Fetus with right ventricular hypoplasia and a septal defect, 18 weeks, LW/BW = 0.010; B: Fetus with pulmonary atresia and a septal defect, 16 weeks, LW/BW = 0.024; C: Fetus with tetralogy of Fallot, 22 weeks, LW/BW = 0.005; D: Fetus with atrioventricular septal defect, 17 weeks, LW/BW = 0.027; E: Fetus with pulmonary atresia and tricuspid atresia, 36 weeks, LW/BW = 0.009; F: Fetus with tetralogy of Fallot, 33 weeks, LW/BW = 0.029.</p

Individual residual values.

<p>Fetuses are classified into four categories on the basis of the CHD. Values are deviations of each observation from the sample mean. Horizontal bar: median value in each subgroup. Kruskal-Wallis test: <i>p</i> = 0.008. *<i>p</i><0.05 for the comparison between subgroups.</p

TLR4 Receptor Induces 2-AG–Dependent Tolerance to Lipopolysaccharide and Trafficking of CB2 Receptor in Mast Cells

International audienceMast cells (MCs) contribute to the control of local inflammatory reactions and become hyporesponsive after prolonged TLR4 activation by bacterial LPS. The molecular mechanisms involved in endotoxin tolerance (ET) induction in MCs are not fully understood. In this study, we demonstrate that the endocannabinoid 2-arachidonoylglycerol (2-AG) and its receptor, cannabinoid receptor 2 (CB2), play a role in the establishment of ET in bone marrow-derived MCs from C57BL/6J mice. We found that CB2 antagonism prevented the development of ET and that bone marrow-derived MCs produce 2-AG in a TLR4-dependent fashion. Exogenous 2-AG induced ET similarly to LPS, blocking the phosphorylation of IKK and the p65 subunit of NF-κB and inducing the synthesis of molecular markers of ET. LPS caused CB2 receptor trafficking in Rab11-, Rab7-, and Lamp2-positive vesicles, indicating recycling and degradation of the receptor. 2-AG also prevented LPS-induced TNF secretion in vivo, in a MC-dependent model of endotoxemia, demonstrating that TLR4 engagement leads to 2-AG secretion, which contributes to the negative control of MCs activation. Our study uncovers a functional role for the endocannabinoid system in the inhibition of MC-dependent innate immune responses in vivo