Alma Jildou Nauta

Early life: gut microbiota and immune development in infancy

The immune system of infants is actively downregulated during pregnancy and therefore the first months of life represent a period of heightened susceptibility to infection. After birth, there is an age-dependent maturation of the immune system. Exposure to environmental microbial components is suggested to play an important role in the maturation process. The gastrointestinal tract is the major site of interaction between the host immune system and microorganisms, both commensal as well as potentially pathogenic. It is well established that the mammalian immune system is designed to help protect the host from invading microorganisms and other danger signals. However, recent research is emerging in the field of host-microbe interactions showing that commensal microorganisms (microbiota) are most likely one of the drivers of immune development and, in turn the immune system shapes the composition of the microbiota. Specific early microbial exposure of the gut is thought to dramatically reduce the incidence of inflammatory, autoimmune and atopic diseases further fuelling the scientific view that microbial colonisation plays an important role in regulating and fine-tuning the immune system throughout life. Therefore, the use of pre-, pro- and synbiotics may result in a beneficial microbiota composition that might have a pivotal role on the prevention of several important diseases that develop in early life such as necrotizing enterocolitis and atopic eczema.

Cow Milk Allergy Symptoms Are Reduced in Mice Fed Dietary Synbiotics during Oral Sensitization with Whey

Cow milk allergy is the most common food allergy in children. So far, no effective treatment is available to prevent or cure food allergy. The purpose of this study was to compare effects of dietary supplementation with a prebiotic mixture (Immunofortis), a probiotic strain [Bifidobacterium breve M-16V], or a synbiotic diet combining both on the outcome of the allergic response when provided during oral sensitization with whey in mice. Mice were fed diets containing 2% (wt:wt) Immunofortis and/or the B. breve M-16V (n = 6/group). The acute allergic skin response was determined by measuring ear swelling. Antigen-induced anaphylaxis was scored. Furthermore, whey-specific serum immunoglobulins and mouse mast cell protease-1 (mMCP-1) were determined. In mice fed the synbiotic mixture, the allergic skin response and the anaphylactic reaction were strongly reduced compared with whey-sensitized mice fed the control diet (P < 0.01). Immunofortis or B. breve M-16V alone were significantly less effective in reducing the allergic skin response than the synbiotic diet and did not reduce the anaphylactic reaction. The whey-specific IgE and IgG(1) responses were not affected; however, IgG(2a) was greater in all treated groups than in the control group (P < 0.05). Serum mMCP-1 concentrations, reflecting mucosal mast cell degranulation, were lower in mice fed synbiotics compared with those fed the control diet (P < 0.01). Dietary supplementation with Immunofortis, B. breve M-16V, and particularly the synbiotic mixture, provided during sensitization, reduces the allergic effector response in a murine model of IgE-mediated hypersensitivity that mimics the human route of sensitization. This model shows the potential for dietary intervention with synbiotics in reducing the allergic response to food allergens.

Synbiotics prevent asthma-like symptoms in infants with atopic dermatitis

To cite this article: van der Aa LB, van Aalderen WMC, Heymans HSA, Henk Sillevis Smitt J, Nauta AJ, Knippels LMJ, Ben Amor K, Sprikkelman AB, the Synbad Study Group. Synbiotics prevent asthma‐like symptoms in infants with atopic dermatitis. Allergy 2011; 66: 170–177.

Mechanisms of allergy and asthma

Allergies are the result of an inappropriate reaction against innocuous environmental proteins. The prevalence and severity of allergic diseases has increased dramatically during the last decade in developed countries. Allergen-specific T helper (Th) cells play a pivotal role in the pathogenesis of allergic hypersensitivity reactions. These Th cells activate a complex immune reaction that triggers the release of potent mediators and enhances the recruitment of inflammatory cells, which in turn elicit an inflammatory response that leads to the clinical symptoms of allergic disease. The current therapies for allergic diseases focus primarily on control of symptoms and suppression of inflammation, without affecting the underlying cause. However, the knowledge about the pathophysiology of allergic diseases has substantially increased, offering new opportunities for therapeutic intervention. In this review, we will focus on current insights into the mechanism of allergic reactions.

Oral treatment with β-lactoglobulin peptides prevents clinical symptoms in a mouse model for cow's milk allergy.

Prior exposure to partial whey hydrolysates has been shown to reduce the allergic response to whey in mice. This effect was more pronounced in combination with a diet containing non‐digestible oligosaccharides (scGOS/lcFOS/pAOS). It is unknown which fractions/epitopes are responsible for this effect. Therefore, the prophylactic ability of synthetic peptides of β‐lactoglobulin with/without a scGOS/lcFOS/pAOS‐containing diet to reduce the allergic response in a mouse model for cows milk allergy was investigated.

No detectable beneficial systemic immunomodulatory effects of a specific synbiotic mixture in infants with atopic dermatitis.

In a murine model of allergic inflammation, Bifidobacterium breve M‐16V has been shown to reduce IL‐4 and IgE by inducing IL‐10 and IFN‐γ. However, it remains unknown whether this strain has the same effect in humans with allergic disease.

Prebiotic‐supplemented partially hydrolysed cow's milk formula for the prevention of eczema in high‐risk infants: a randomized controlled trial

Prevention guidelines for infants at high risk of allergic disease recommend hydrolysed formula if formula is introduced before 6 months, but evidence is mixed. Adding specific oligosaccharides may improve outcomes.

Evidence-based benefits of specific mixtures of non-digestible oligosaccharides on the immune system.

Non-digestible carbohydrates (NDC) are natural constituents of many foods. They are mostly referred to as dietary fibre and are associated with many health benefits mostly connected to gut health. NDC have emerged as a promising nutritional concept to modulate immune function as well. In the world of immunology non-digestible carbohydrates are recognized now as key immunomodulating molecules. Both pharma and food industries realize the enormous potency of these immune active components. Although the mechanisms underlying the effects of NDC on the immune system are not totally clear yet many studies have reported beneficial effects on both mucosal and systemic immunity in humans. The aim of this review is to summarize the available evidence on the immune modulatory effects of specific mixtures of oligosaccharides. Both mechanistic in vitro and in vivo studies have been performed and will be discussed. Finally the potential use of these unique structures will be evaluated.

IgG Antibodies in Food Allergy Influence Allergen–Antibody Complex Formation and Binding to B Cells: A Role for Complement Receptors

Allergen–IgE complexes are more efficiently internalized and presented by B cells than allergens alone. It has been suggested that IgG Abs induced by immunotherapy inhibit these processes. Food-allergic patients have high allergen-specific IgG levels. However, the role of these Abs in complex formation and binding to B cells is unknown. To investigate this, we incubated sera of peanut- or cow’s milk–allergic patients with their major allergens to form complexes and added them to EBV-transformed or peripheral blood B cells (PBBCs). Samples of birch pollen-allergic patients were used as control. Complex binding to B cells in presence or absence of blocking Abs to CD23, CD32, complement receptor 1 (CR1, CD35), and/or CR2 (CD21) was determined by flow cytometry. Furthermore, intact and IgG-depleted sera were compared. These experiments showed that allergen–Ab complexes formed in birch pollen, as well as food allergy, contained IgE, IgG1, and IgG4 Abs and bound to B cells. Binding of these complexes to EBV-transformed B cells was completely mediated by CD23, whereas binding to PBBCs was dependent on both CD23 and CR2. This reflected differential receptor expression. Upon IgG depletion, allergen–Ab complexes bound to PBBCs exclusively via CD23. These data indicated that IgG Abs are involved in complex formation. The presence of IgG in allergen–IgE complexes results in binding to B cells via CR2 in addition to CD23. The binding to both CR2 and CD23 may affect Ag processing and presentation, and (may) thereby influence the allergic response.

Animal models of anaphylaxis.

Purpose of reviewIn this review we will focus on recent advances in the role of mast cells in the pathophysiology of insect allergy and the possible mechanisms of mast cell activation in anaphylaxis. Recent findingsAnaphylactic reactions in the mouse can be induced by several independent pathways involving immunoglobulin E, immunoglobulin free light chains, or immunoglobulin G. There is considerable evidence that mast cells play a central role in anaphylactic reactions to insect stings. Mast cells can be directly activated by components of insect venom or after allergic sensitization. Of interest is the observation that mast cells are not only effector cells in insect allergy, but may also play a protective role in preventing the development of severe anaphylactic responses or by controlling inflammatory reactions by modulation of antigen-specific T-cell responses. SummaryThe contribution of mast cells in anaphylactic responses to insect venom may be heterogeneous. On the one hand, activation of mast cells contributes to the pathology by the release of bioactive and tissue-damaging mediators. However, mast cell activation may neutralize constituents in insect venom and defend against the adverse effects of these toxins or they may modulate inflammation through downregulation of antigen-specific immune responses.