Depletion of CD4+CD25+ T cells switches the whey-allergic response from immunoglobulin E- to immunoglobulin free light chain-dependent (original) (raw)
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Journal of Allergy and Clinical Immunology, 2010
Background: Cow's milk allergy (CMA) affects 2.5% of young infants. In previous murine studies it was observed that allergic sensitization to the major cow's milk allergens casein and whey led, respectively, to IgE-independent and IgE-dependent clinical responses. Objectives: In this study the involvement of immunoglobulin free light chains (Ig-fLCs) in the hypersensitivity response to cow's milk proteins was explored in mice, and Ig-fLC serum levels were determined in children affected by CMA or atopic dermatitis (AD). Methods: Mice were orally sham, casein, or whey sensitized. Acute allergen-specific skin responses were determined, and serum immunoglobulin and Ig-fLC concentrations were measured. Ig-fLC dependency was validated by using the Ig-fLC blocker F991 in actively and passively sensitized mice. Ig-fLC serum concentrations were measured in a cohort of infants with CMA and infants with AD. Results: After sensitization, no specific IgE was detectable in sera of casein-sensitized mice, whereas specific IgE levels were enhanced in whey-sensitized mice. Instead, Ig-fLC levels were increased in sera from casein-sensitized mice. Furthermore, blocking Ig-fLCs strongly diminished the allergic skin responses not only in casein-sensitized mice but also in mice transferred with splenocyte supernatants of casein-sensitized mice. In both patients with CMA and patients with AD, serum Ig-fLC concentrations were significantly enhanced. Conclusions: This study indicates that sensitization with cow's milk proteins can lead to both IgE-dependent and Ig-fLCdependent allergic hypersensitivity responses. Also, in children affected with CMA or AD, serum Ig-fLC concentrations were increased, implying the relevance of Ig-fLC measurements in the diagnoses of human allergic disease. (J Allergy Clin Immunol 2010;125:1308-14.)
Journal of Allergy and Clinical Immunology, 1996
In cow's milk allergy (CMA) with intestinal symptoms, peripheral blood mononuclear cells' (PBMCs) secrete tumor necrosis factor-a (TNF-cO, altering intestinal function. However, the type of cow's milk protein (CMP) that triggers symptoms (intact or intestinally processed) is not known, and neither is the minimal amount required. Methods: PBMCs were isolated from infants with active CMA or cured infants just before a new challenge and stimulated with intact or intestinally processed CMP. Supernatants were tested for cytokine content and for their ability to perturb intestinal barrier capacity, measured in Ussing chambers in HT29-19A intestinal cells. Results: PBMCs from infants with active CMA secreted more TNF-~, when they were stimulated with intact rather than intestinally ptvcessed CMPs, and more TNF-e~ than PBMCs from cured infants. Accordingly, supernatants from PBMCs stimulated with intact but not intestinally processed CMPs significantly increased intestinal permeability. The CMP concentration required to trigger TNF-a secretion capable of altering intestinal function was very small in infants with active CMA (~-2 t~g/ml), but about 300 times higher in cured infants. Conclusion: Intact rather than intestinally' processed proteins stimulate PBMCs to release TNF-c~ and alter intestinal barrier capacity. The threshold for PBMC reactivity to milk antigens drops considerably during active CMA with intestinal symptoms. (J Allergy Clin Immunol 1996;98:781-9.)
Management of Cow’s Milk Allergy from an Immunological Perspective: What Are the Options?
Nutrients
The immunological mechanism underlying Immunoglobuline E (IgE)-mediated cow’s milk allergy has been subject to investigations for many years. Identification of the key immune cells (mast cells, B cells) and molecules (IgE) in the allergic process has led to the understanding that avoidance of IgE-crosslinking epitopes is effective in the reduction of allergic symptoms but it cannot be envisioned as a treatment. For the treatment and prevention of IgE-mediated cow’s milk allergy, it is thought that the induction of a sustained state of immunological tolerance is needed. In this review, we will discuss various approaches aimed at achieving immunological tolerance and their success. Furthermore, we will speculate on the involved immunological mechanism.
Journal of Allergy and Clinical Immunology, 1997
Objective: Allergic reactions to food are characterized by enhanced allergen-specific IgE serum levels and the activation of intestinal mast cells. Here we describe a murine model for the onset of food allergy and the role of cytokines in the regulation of food-induced IgE responses. Methods: Mice were primed systemically with low doses of alum-precipitated ovalbumin. Subsequent intragastric challenge led to enhanced sensitization. Results: Compared with baseline ovalbumin-specific IgE levels before challenge (0.23 ± 0.06 optical density [OD] units), ovalbumin-challenged mice showed significantly elevated IgE levels (0.86 ± 0.23 OD units) after intragastric challenge, which were not observed in control animals (0.29 ± 0.06 OD units). IgE levels mirrored intestinal mast cell activation, measured by decreased histamine levels in duodenal specimens, in ovalbumin-challenged mice (92.6 ± 7.9 ng/0.1 gm tissue weight) but not in saline-challenged mice (135.4 ± 18.3 ng/0.1 gm tissue weight), compared with baseline levels (141.1 ± 4.1 ng/0.1 gm tissue weight). Changes in IgE and histamine levels after intragastric challenge could be blocked by treating the animals with neutralizing antibodies against IL-4 or IL-10. Although it is generally accepted that ingestion of food allergens leads to a state of immunologic unresponsiveness (i.e., oral tolerance), it is shown here that low-dose systemic priming followed by intragastric challenge leads to sensitization instead of unresponsiveness. Conclusions: Our murine model shows an important correlation between Th2 cytokines, IgE production, and histamine release. Hence, this in vivo model provides a useful tool with which the complex mechanism underlying sensitization to food allergens can be studied. (J Allergy Clin Immunol 1997;99:94-9.)
Differences between normal and milk allergic subjects in their immune responses after milk ingestion
Archives of Disease in Childhood, 1983
In order to understand why non-atopic people do not have adverse symptoms to food antigens which enter the circulation after eating, 8 non-atopic and 10 atopic eczema- and milk-allergic subjects were challenged with milk, and the types of circulating immune complexes formed were analysed. Although the amount of beta-lactoglobulin incorporated into complexes did not differ statistically between the groups, the type of immune complex did. Of the non-atopic individuals, 5 formed IgA and 2 IgG complexes. Of the milk-allergic group, all showed a rise in at least one type; 5 formed IgA, 7 IgG, 6 IgE, and 6 formed C1q-binding complexes. Our data suggest that serum IgA is concerned in safe food antigen handling in non-atopic people, and that the differences in the type of immune complexes formed in response to antigen challenge may underlie the systemic symptoms of food allergy.
Clinical & Experimental Allergy, 2007
Background The central role of specific IgE in cow's milk allergy (CMA) is well documented. However, less is known about the function of other immunoglobulin isotypes in allergy and tolerance to cow's milk proteins (CMPs). Objective To determine differences in the antibody responses that are associated with allergy and tolerance to cow's milk in allergic, atopic and non-atopic individuals of different age groups. Methods Nineteen infants (o1 year), 18 children (6-14 years) and 41 adults (21-68 years) were included. Each age group was comprised of subjects with CMA, atopic individuals without a history of CMA and non-atopic subjects. Levels of specific IgE, IgG4, IgG1 and IgA to whole cow's milk and the six most abundant individual CMPs were determined in plasma by ELISA. For comparison, specific IgE and IgG4 were measured to ovomucoid and house dust mite (HDM) in individuals allergic for the respective allergens, and in atopic and non-atopic subjects without allergy. Results In infants and children with CMA, as1-casein and b-lactoglobulin induced the highest specific IgE response, whereas as1-casein was the most allergenic CMP in adult patients. Specific IgG4 and IgG1 responses were the highest to as1-casein and b-lactoglobulin in all age groups, while k-casein and a-lactalbumin induced the highest levels of IgA. CMP-specific IgG4 was higher in atopic children and adults without CMA, as compared with non-atopic individuals. A similar difference between tolerant atopic and non-atopic subjects was observed for IgG4 specific to ovomucoid, whereas HDM-specific IgG4 was not detectable in these subjects. Conclusion Maintenance of tolerance to cow's milk in atopic children and adults without CMA is associated with elevated levels of specific IgG4, in combination with low specific IgE. The up-regulation of specific IgG4 in tolerant atopic individuals may be related to the type of allergen and its regular dose of exposure.