Background Carbohydrate moieties are frequently encountered in food and can elicit IgE responses, the clinical significance of which has been unclear. Recent work, however, has shown that IgE antibodies to galactose-α-1,3-galactose (α-gal), a carbohydrate commonly expressed on nonprimate mammalian proteins, are capable of eliciting serious, even fatal, reactions. Objective We sought to determine whether IgE antibodies to α-gal are present in sera from patients who report anaphylaxis or urticaria after eating beef, pork, or lamb. Methods Detailed histories were taken from patients presenting to the University of Virginia Allergy Clinic. Skin prick tests (SPTs), intradermal skin tests, and serum IgE antibody analysis were performed for common indoor, outdoor, and food allergens. Results Twenty-four patients with IgE antibodies to α-gal were identified. These patients described a similar history of anaphylaxis or urticaria 3 to 6 hours after the ingestion of meat and reported fewer or no episodes when following an avoidance diet. SPTs to mammalian meat produced wheals of usually less than 4 mm, whereas intradermal or fresh-food SPTs provided larger and more consistent wheal responses. CAP-RAST testing revealed specific IgE antibodies to beef, pork, lamb, cow’s milk, cat, and dog but not turkey, chicken, or fish. Absorption experiments indicated that this pattern of sensitivity was explained by an IgE antibody specific for α-gal. Conclusion We report a novel and severe food allergy related to IgE antibodies to the carbohydrate epitope α-gal. These patients experience delayed symptoms of anaphylaxis, angioedema, or urticaria associated with eating beef, pork, or lamb.

No abstract

Sepsis is an often-deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control. Here, we identify the ER-resident protein Sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock. Mice lacking S1R succumb quickly to hypercytokinemia induced by a sub-lethal challenge in two models of acute inflammation. Mechanistically, we find that S1R restricts the endonuclease activity of the ER stress sensor IRE1 and cytokine expression, but does not inhibit the classical inflammatory signaling pathways. These findings could have substantial clinical implications, as we further find that fluvoxamine, an anti-depressant therapeutic with high affinity for S1R, protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes. Our data reveal the contribution of S1R to the restraint of the inflammatory response, and place S1R as a possible therapeutic target to treat bacterial-derived inflammatory pathology.

No abstract

Although high dose exposure to inhaled cat allergen (Fel d 1) can cause a form of tolerance (modified Th2 response), the T cell mechanism for this phenomenon has not been studied. T cell responses to Fel d 1 were characterized in both allergic (IgEpos) and modified Th2 (IgEnegIgGpos) responders as well as serum Ab-negative controls (IgEnegIgGneg). Fel d 1 stimulated high levels of IL-10 in PBMC cultures from all individuals, with evidence of Th2 and Th1 cytokine skewing in allergic and control subjects, respectively. Using overlapping peptides, epitopes at the N terminus of Fel d 1 chain 2 were shown to stimulate strong T cell proliferation and to preferentially induce IL-10 (peptide 2:1 (P2:1)) or IFN-γ (P2:2) regardless of the allergic status of the donor. Injection of cat extract during conventional immunotherapy stimulated expansion of IL-10- and IFN-γ-producing chain 2 epitope-specific T cells along with increased Fel d 1-specific serum IgG and IgG4 Ab. Six of 12 modified responders expressed the major HLA-DRB1 allele, *0701, and both P2:1 and P2:2 were predicted ligands for this allele. Cultures from DR7-positive modified responders produced the highest levels of IL-10 to P2:1 in addition to other major and minor epitopes within chains 1 and 2. In the presence of anti-IL-10 mAb, both T cell proliferation and IFN-γ production were enhanced in a Fel d 1- and epitope-specific manner. We conclude that IL-10-producing T cells specific for chain 2 epitopes are relevant to tolerance induction, and that DR7-restricted recognition of these epitopes favors a modified Th2 response.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex etiology that is dependent upon interactions between the host and the environment. Acute skin lesions exhibit the features of a Th2-driven inflammatory disorder and many patients are highly atopic. The skin barrier plays key roles in immune surveillance and homeostasis, and in preventing penetration of microbial products and allergens. Defects that compromise the structural integrity, or else the immune function of the skin barrier play a pivotal role in the pathogenesis of AD. This article provides an overview of the array of molecular building blocks that are essential to maintaining healthy skin. The basis for structural defects in the skin is discussed in relation to AD, with an emphasis on filaggrin and its genetic underpinnings. Aspects of innate immunity, including the role of anti-microbial peptides and proteases are also discussed.

No abstract

The hygiene hypothesis states that a reduced exposure to allergens in early life is solely implicated in the growing propensity for allergy sensitization. Important elements of the hypothesis include helminth infection, exposure to endotoxins, exposure to pets and growing up on a farm. However, the hygiene hypothesis alone does not provide an adequate explanation for the observed increase in allergic disease. For example, in North American inner cities, asthma is increasing among children who live in very poor housing, which might be assumed to be somewhat dirty. In order to explain the increase in asthma, we need to take a broader view and also consider alterations related to the adoption of a western lifestyle. It has been suggested that lifestyle changes related to obesity (e.g. a change in diet) are associated with asthma. Other changes include a progressive decrease in physical activity. This lifestyle factor seems to correlate best with the recent increase in asthma. Clearly, the link between physical activity and asthma needs to be investigated in more detail.