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Upon inhalation, house dust mite (HDM) allergens are deposited at the nasal and oral mucosa, where IgA is produced abundantly. IgA subclasses have been linked to protection against respiratory allergy previously. It is currently not known whether and how the human IgA subclasses IgA1 and IgA2 contribute to the clinical status of house dust mite-allergic patients. Saliva and serum samples were collected, and HDM-specific, IgE, IgG4, IgA1 and IgA2 levels were determined. HDM-specific levels of IgA in serum were similar to levels measured in nonallergic controls, but HDM-specific levels of IgA2 in saliva were decreased in allergic subjects. HDM-allergic patients who suffered from rhinitis and eczema showed a significant decrease in IgA2-levels compared to patients who suffered from rhinitis only. Taken together, our findings indicate that HDM-specific IgA2, but not IgA1, levels in serum and saliva are reduced in HDM-allergic patients suffering from eczema.

Cow's milk proteins cause allergic symptoms in 2-3% of all infants. In these individuals, the tolerogenic state of the intestinal immune system is broken, which can lead to sensitization against antigens and eventually to allergic responses. Although a true treatment for food allergy is not available, symptoms can be avoided by providing the infants with hydrolyzed proteins. Hydrolyzed proteins are proteins that are enzymatically degraded. They lack typical allergenic IgE-binding epitopes but are also thought to play a pertinent role in other mechanisms inducing hypoallergenic effects. This review discusses the mechanisms and evidence for immunomodulating properties of cow's milk hydrolysates. Hydrolysates are found to strengthen the epithelial barrier, modulate T-cell differentiation, and decrease inflammation. Some studies suggest a role for hydrolysates in manipulating pathogen recognition receptors signaling as underlying mechanism. Peptides from hydrolysates have been shown to bind to TLR2 and TLR4 and influence cytokine production in epithelial cells and macrophages. Current insight suggests that hydrolysates may actively participate in modulating the immune responses in subjects with cow's milk allergy and those at risk to develop cow's milk allergy. However, more research is required to design effective and reproducible means to develop targeting strategies to modulate the immune response.

Oral cholera vaccination is used to induce immune responses in the intestines to protect against cholera infection. However, oral vaccination may also affect immune responses in other mucosal tissues. To study this, tissue-specific homing potential and kinetics of B-cell responses were characterized after oral cholera vaccination. Healthy adult volunteers received two doses of Dukoral® and blood, saliva, nasal wash, and fecal samples were collected over time to detect vaccine-specific antibodies. Additionally, homing potential of lymphocytes to small intestine, colon, airways, skin, and periphery was measured by expression of Integrin β1 and β7, CCR9, CCR10, CCR7, and CLA. After vaccination, antibody responses to cholera toxin B (CTB) and Dukoral® were detected in serum and nasal wash. CTB-specific memory B cells in peripheral blood and tissue homing profiles of memory B cells peaked at day 18. IgA+ memory B cells expressed markers that enable homing to the airways and colon, while IgA− memory B cells primarily expressed small-intestine-homing markers. These data show that oral cholera vaccination has a differential effect on immune responses in various mucosal sites, including the respiratory tract.

Children that grow up on farms have fewer allergies than children growing up in city environments. This protection against the development of allergy is associated with the consumption of raw farm milk. Heated farm milk does not have this effect, indicating that (non-denatured) milk proteins are responsible for this effect. The consumption of normal bovine colostrum protects immunocompromised people against infections. Bovine milk proteins have immunological effects on human cells. Currently, raw milk is not commercially available and cannot be used for controlled intervention studies because of the potential presence of pathogenic microorganisms. Alternative milk-processing technologies are needed to preserve immune active milk proteins that can improve immunity in children.

The development of IgE-mediated allergic diseases is influenced by many factors, including genetic and environmental factors such as pollution and farming, but also by nutrition. In the last decade, substantial progress has been made in our understanding of the impact that nutrition can have on allergic diseases. Many studies have addressed the effect of breastfeeding, pre-, pro- and synbiotics, vitamins and minerals, fiber, fruit and vegetables, cow’s milk, and n-3 fatty acids, on the development of allergies. In addition, nutrition can also have indirect effects on allergic sensitization. This includes the diet of pregnant and breastfeeding women, which influences intrauterine development, as well as breastmilk composition. These include the diet of pregnant and breastfeeding women that influences intrauterine development as well as breastmilk composition, effects of food processing that may enhance allergenicity of foods, and effects via modulation of the intestinal microbiota and their metabolites. This editorial review provides a brief overview of recent developments related to nutrition and the development and management of allergic diseases.

It is well established that both the production of IgE by B lymphocytes and the maturation and recruitment of eosinophils in late-phase reactions are dependent on the activation of allergen-specific type-2 T-helper cells. What is less well known is the fact that efficient activation of allergen-specific T cells upon low-dose exposure to allergens is critically dependent on IgE-mediated or -facilitated allergen presentation. In fact, changes in the level of IgE-mediated allergen presentation may account for many of the immunological effects described for specific immunotherapy or anti-IgE treatment. This review aims to summarize the current knowledge, and will discuss the clinical relevance of blocking IgG antibodies induced by specific immunotherapy and anti-IgE monoclonal antibodies that both interfere with IgE-mediated allergen presentation.

Background The role of allergen-specific CD4+ T lymphocytes in the pathophysiology of atopic disease is well established. Previous studies on allergen-specific T-cell responses have focused on the recognition of single major allergens to identify T-cell epitopes. Objective However, it is not clear whether immune responses to allergen extracts are exclusively targeted at major allergens or whether additional proteins are recognized. Methods Here we describe the Phleum pratense-specific immunoglobulin E (IgE) and T-cell responses of six allergic rhinitis patients. Reactivity was measured to size-separated fractions of a P. pratense extract as well as to the purified major allergens Phl p 1, Phl p 2/3 and Phl p 5. Results The specificity of the patients' serum IgE, measured in a fluid phase assay, was restricted to one or two of the major allergens. Even though the majority of the patients had IgE antibodies reactive with a single major allergen, one patient reacted with both Phl p 5 and with Phl p 2/3. Analysis of the T-cell repertoire with P. pratense-specific T-cell lines (TCLs) and CD4+ T-cell clones (TCCs) revealed that at least six different proteins were recognized, including the three major allergens, most notably Phl p 5. Simultaneous production of IL-5 and interferon (IFN) -γ was detected in supernatants of the TCLs stimulated with P. pratense extract and the major allergens. Conclusion These results indicate that allergic rhinitis patients have a large pool of circulating allergen-specific CD4+ T cells that recognize many different proteins in an allergenic extract, whereas only a small number of these proteins are recognized by serum IgE.

Background The involvement of CD4+ T cells in the pathophysiology of atopic disease is well established. Objective To gain further insight into the activation requirements for allergen-specific T cells, we characterized epitope specificity, HLA restriction and T-cell receptor (TCR) usage for T cells specific to Phl p 5, the group 5 major allergen of the grass Phleum pratense. Methods To identify the T-cell epitopes of Phl p 5, three Phl p 5-specific T-cell lines (TCLs) and 15 T-cell clones (TCCs) generated from the peripheral blood of three grass-allergic patients were tested with recombinant truncated Phl p 5a fragments and synthetic Phl p 5b peptides representing these two different recombinant Phl p 5 isoallergens. Additional activation experiments with HLA-subtyped antigen-presenting cells and flow cytometry analysis with TCR V-specific mAb were performed to further characterize the activation requirements for Phl p 5-specific TCCs. Results At least nine distinct T-cell specificities were identified and the T-cell epitopes recognized differed considerably among the three patients. Most of the epitopes found were isoform-specific, whereas three epitopes were shared between Phl p 5a and 5b. Several human leucocyte antigen (HLA) class II molecules were involved in the recognition of Phl p 5. Different HLA restriction specificities were even found among TCCs specific to the same epitope region. All TCCs were TCR-alpha/beta positive, and an overrepresentation of TCR Vbeta 3.1+ clones among TCCs specific to Phl p 5 appear to exists as 31% (4/13) of the TCCs expressed TCR Vbeta 3.1 (compared with 5% TCR Vbeta 3.1+ T cells in human peripheral blood) with no correlation with epitope specificity or HLA restriction. Conclusion The T-cell reactivity of the three grass-allergic patients investigated shows that isoallergen-specific T-cell epitopes are found throughout the peptide backbone of Phl p 5a and Phl p 5b, and dominant T-cell epitopes of Phl p 5 were not identified. This indicates that a mixture of at least full-length rPhl p 5a and rPhl p 5b may be required to target the total Phl p 5-specific T-cell response of atopic patients.

Background: Pollinosis, caused by grasses of the Poaceae family, is a problem worldwide. The relative importance of grass groups 1 and 5 major allergens is well established. However, not much is known about the recognition of these allergens by T cells and whether this T-cell reactivity correlates with skin reactivity and serum IgE levels. Objectives: The aim of this study was to characterize the cross-reactive, grass allergen–specific T-cell responses from patients allergic to grass and nonatopic individuals and to investigate whether these responses correlate with grass-specific IgE and skin reactivity. Methods: Skin prick test wheal areas and grass-specific serum IgE levels were determined in all patients ( n = 21) and nonallergic control donors ( n = 20). Peripheral blood mononuclear cells were isolated and stimulated with grass allergen extracts (Phleum pratense, Poa pratensis, Lolium perenne) and immunoaffinity-purified group 5 allergens, and the production of type 1 and type 2 cytokines was determined in the patient group. Results: Donors allergic to grass showed increased T-cell–proliferative responses to grass allergens compared with nonatopic control subjects. We find it interesting that the magnitude of the patients' T-cell responses could not be correlated with the individual skin prick test areas and specific serum IgE levels, and several patients with allergies to grass had group 5–specific T-cell responses in the absence of group 5–specific IgE. The absence of a correlation between T-cell proliferation and IgE levels or skin prick test results may in part be explained by the finding that patients predominantly produced IL-5 in response to Phl p 5, the major allergen, and predominantly IFN-γ in response to Phl p extract. In general, all donors responded equally well to all three grasses. Additional experiments with Phl p 5–specific T-cell lines indicated that the equal proliferation of peripheral blood mononuclear cells to all three species is the direct result of cross-reactivity. Conclusions: Grass allergen–specific T-cell responses are highly cross-reactive, and patients with allergies exhibit higher responses than nonallergic donors, suggesting that T cells are involved in the allergic reaction to grass group 5 allergens. However, group 5–specific T-cell responses are also found in donors without group 5–specific IgE, and the patients' grass-specific T-cell responses and cytokine production do not correlate to skin reactivity or to concentrations of grass-specific IgE. (J Allergy Clin Immunol 1998;101:241-9.)

Summary Background Allergen-specific T lymphocytes play an important role in the pathophysiology of atopic disease. Detailed studies of their epitope-specificity and crossreactivity are required for the development of novel approaches for specific immunotherapy. Objectives The aim of the study was to characterize the fine specificity of Bet v 1-specific T cells from allergic donors. Methods Polyclonal T-cell lines (TCL) and T-cell clones (TCC), specific for Bet v 1, the major birch (Betula verrucosa) pollen allergen, were isolated from the peripheral blood of three birch-allergic patients. Their epitope-specificity was studied using overlapping synthetic peptides, and crossreactivity with other tree pollen allergens of the Fagales order was evaluated. In addition, the Bet v 1-specific TCC were studied for their phenotype and cytokine production. Results All isolated Bet v 1-specific TCC (19/21 CD4+, 2/21 CD8+) reacted with affinity purified Bet v 1, but showed different reactivities with recombinant Bet v 1 (rBet v 1), and with group 1 allergens from other Fagales species. Epitope mapping of rBet v 1-reactive TCC with synthetic peptides of Bet v 1 showed the presence of four T-cell epitopes. Polyclonal T-cell lines reacted with 13 different peptides, and displayed even broader crossreactivity with group 1 pollen allergens from other Fagales members. Conclusion This study demonstrates that apart from T-cell epitopes of rBet v 1, many other crossreactive or Bet v 1 isoallergen-specific epitopes exist. This indicates that isoallergenic variation plays an important role in the induction of Bet v 1-specific and crossreactive T-cell responsiveness to allergens.

To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation. Copyright © ILSI Europe 2013.

Basophils account for only 0.1-1% of all peripheral blood leukocytes. They were considered to be a redundant cell type for a long time. However, several findings show a non-redundant role for basophils in type 2 T-helper cell (Th2) immune responses in helminth infections, allergy and autoimmunity. Both immunoglobulin-E-dependent and -independent pathways have been described to contribute to basophil activation. In addition, several recent studies reported that basophils can function as antigen-presenting cells and are important in the initiation of Th2 immune responses. However, there are also conflicting studies that do not corroborate the importance of basophils in Th2 immune responses. This review discusses the role of basophils in Th2 immune responses in view of these recent findings. Copyright (c) 2012 S. Karger AG, Basel

The probiotic properties of commensal bacteria including lactobacilli and bifidobacteria are likely to be determined at least in part by their effects on dendritic cells. Like traditional immune stimulants such as lipopolysaccharides (LPS), probiotic bacteria promote maturation of cultured human dendritic cells (DC) by inducing elevated expression of MHC-II and co-stimulatory molecules. Different effects have been reported on cytokine induction, especially of major regulatory cytokines such as TNF-α, IL-12 and IL-10. Yet, these previous analyses have failed to reveal consistent differences between such effects of probiotics on the one hand, and of LPS on the other. Selective response markers for probiotics, however, would be important for our understanding of their biological properties and for a rational selection of strains for in vivo studies. In this study, we compared in detail both early and late effects on cultured human DC of 4 different probiotics with those of LPS. At the early stages of stimulation, all stimuli induced qualitatively very similar responses in DC at the level of surface markers and secretion of cytokines and chemokines. A lower immune stimulatory effect was observed by Bifidobacterium animalis BB-12 as compared to lactobacilli. Late responses, on the other hand, tended to diverge. Microarray transcript profiling for 268 cytokines, chemokines, growth factors and their receptors after 2 days of culture revealed various transcripts to be selectively induced by certain probiotics but not LPS. Our data indicate that late rather than early DC responses may be helpful to clarify the divergent biological effects of probiotics on human innate immune responses.

Background: As a result of the very efficient capture of allergens by IgE that focuses to CD23 on B cells or FcΕRI on dendritic cells, allergen-specific T cells can be activated after exposure to very low levels of allergens. This IgE-mediated allergen presentation is 100- to 1,000-fold more efficient than fluid phase endocytosis. The aim of the present study was to determine whether humanized anti-IgE mAb Hu-901 can prevent the activation of allergen-specific T cells by inhibiting IgE-mediated allergen presentation. Methods: A house dust mite major allergen Der p 1-specific T cell line was generated from an allergic asthma patient, and a model was set up to show IgE-facilitated allergen presentation via CD23 on EBV-transformed B cells. In addition, experiments were performed by FACS analysis, detecting the presence of IgE-allergen complexes bound to EBV-B cells by polyclonal FITC-labeled anti-IgE antisera. Results: The anti-IgE mAb Hu-901 inhibited proliferation of allergen-specific T cells at low allergen concentrations. Inhibition was dose-dependent. This effect could be explained by Hu-901 inhibition of binding of allergen-IgE complexes to CD23 expressed on EBV-transformed B lymphocytes. Conclusions: These data clearly indicate that anti-IgE antibodies for the treatment of allergy exert their effect not only by inhibiting mast cell/basophil degranulation, but also by preventing T cell activation, which possibly explains the effect of anti-IgE treatment on late-phase reactions noted in clinical studies.

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 (

ummary Background The clinical efficacy of specific allergy vaccination (SAV), previously called specific immunotherapy is well documented. The working mechanism of this treatment is not completely known at present. Allergen-specific CD4+ T lymphocytes are activated at extremely low allergen concentrations in vivo possibly as a result of serum IgE-facilitated allergen presentation (S-FAP). Previously, we have shown that this process can be inhibited by long-term birch SAV sera. Methods In the present study, we have analysed sera from birch-allergic patients in a randomized double-blind, placebo-controlled clinical trial for their ability to mediate S-FAP. Birch-specific IgE levels were not changed after SAV. Bet v 1-specific IgE levels, however, were significantly decreased (P

Non-anaphylactogenic anti-IgE mAb have been developed over the past decade to treat atopic allergies. These antibodies neutralize circulating IgE molecules, and thus prevent IgE from binding to its receptors, FCERI and CD23. Efficacy of anti-IgE treatment has been shown in several clinical trials,and new, unanticipated, mechanisms by which anti-IgE exerts its clinical effect are being discovered. Here we summarize a number of studies on the immunological mechanisms underlying anti-IgE treatment.

Background: At present, recombinant allergens are considered for the diagnosis and treatment of atopic allergies. To evaluate the theoretical impact of isoallergen variation on the selection of isoallergens for specific allergy vaccination, we characterized the T–cell response of allergic patients to the Phleum pratense major allergen, Phl p 5, and five of its recombinant isoallergens. Methods: Phl p 5–specific T cell lines (TCLs) were isolated from the peripheral blood of 3 allergic rhinitis patients, and their reactivity patterns were studied in detail. Results: The TCLs were highly crossreactive with related grasses. The crossreactivity with Poa pratensis was more extensive than with Lolium perenne, directly reflecting the sequence identity between Phl p 5, Poa p 5, and Lol p 5. The TCLs produced IFN–γ and IL–4 simultaneously, resembling a Th0–like cytokine production profile. Interestingly, when T cell clones were tested with natural Phl p 5 and five rPhl p 5 isoallergens, a differential recognition pattern was found. One of the TCLs exclusively reacted with Phl p 5b, another reacted with all isoforms tested, and the third reacted strongly with native purified Phl p 5, but only weakly with all five recombinant isoallergens. Conclusion: These results indicate that Phl p 5–specific T cells are highly heterogeneous, and that they differentially recognize isoallergens. This indicates that when recombinant Phl p 5 is considered for allergy vaccination, a mixture of isoallergens representing the different isoallergen groups may clinically prove to be more effective than single isoallergens.

Both infants and elderly people have compromised immune systems. For infants human milk provides support for the immune system. Infants need immunological support, as their immune system needs time to develop. Furthermore, infants are faced with microbial colonisation and changed nutrition from breast milk towards solid food. In addition to commensal bacteria, infants are increasingly exposed to food- and airborne pathogens as well, which can cause infections in the intestine and airways. As especially, RSV and Influenza infections in the airways can be quite severe, it would be beneficial to improve airway immunity by dietary modulation. Next to this, the epithelial barrier of infants is not fully closed, especially just after birth. As a result intact food an microbial components can cross the epithelium into the mucosa. The infant should not develop allergies or anti-inflammatory immune responses towards these macronutrients and is supposed to induce oral tolerance against both food components as well as to commensal bacteria. Elderly people often suffer from non-communicable inflammation-related inflammatory diseases as a result of immunosenescence and inflammaging. Next to this, elderly respond less to vaccination and are more vulnerable to infections. The ageing population is growing worldwide and therefore the burden of age-related disease on the global health care system is increasing as well. Hence, it would be beneficial when people become older without developing these diseases, which is termed healthy ageing. The main objective of this project was to study the immunomodulatory effect of raw bovine milk and its ingredients in nutritional intervention, oral cholera vaccination and trained immunity and its possible relevance for different stages in life. Consumption of raw bovine milk is associated in epidemiological studies with a reduced incidence of asthma, allergies, rhinitis and respiratory tract infections, which are all related to immunity in the airways. However, not much is known about the mechanisms by which raw milk can exert this enhanced airway immunity. Therefore, the aim of this thesis was to investigate to which extent raw bovine milk can modulate immune responses to improve immunity in the airways. Chapter 2, 3, 4 and 5 are relevant for modulating the immune responses in children and adults, by raw bovine milk and it’s components. We started in this thesis by giving a literature overview of potential mechanisms by which milk components modulate immune function in the upper respiratory tract as well as the gastrointestinal tract (chapter 2). Furthermore, in chapter 3 we investigate the potential of raw bovine milk, milk fractions, lactoferrin and bovine IgG to induce trained immunity. We could demonstrate that raw bovine milk as well as isolated bovine IgG can induce trained immunity in human monocytes. This can serve as mechanistic concept for protection against infections. Next to this, we characterized the immune responses upon oral cholera vaccination in chapter 4, including expression of homing markers that enable homing towards the airways. Oral cholera vaccination induces a clear vaccination response in serum. Furthermore, oral cholera vaccination induces a homing marker expression profile consistent with homing to the large intestine and airways in IgA+ memory B cells. In IgA- memory B cells a homing marker expression profile towards the small intestine was induced. In chapter 5, we investigated the immunomodulatory effect of raw milk, pasteurized milk and ultra-heat treated milk on oral cholera vaccination responses in blood and mucosal tissues, including saliva and nasal wash in two vaccination studies. Oral cholera vaccination induces a clear vaccination response in serum, nasal wash, and saliva. Opposite results in modulatory capacity of milk on the oral cholera vaccination response were obtained for both MOSAIC studies. Hence, it cannot be concluded whether raw bovine milk is able to increase or decrease the production of vaccine-specific antibodies after oral cholera vaccination. We also compared homing potential towards the airways between the control and raw milk vaccine group. In the current experimental set-up, raw milk did not enhance an increase in airway homing potential. The aim of chapter 6 was to compare innate immune function towards TLR-mediated responses between elderly and young adult women. Elderly women were shown to have lower pDCs frequencies, comparable mDC frequencies, lower basal production of cytokines by pDCs and mDCs in steady state, and increased serum markers involved in inflammation, compared to young adult women. Especially after TLR 7/8 stimulation, reduced numbers of pDCs and mDCs positive for pro-inflammatory cytokines were observed in elderly compared to young adult women. This confirms the concept of both immunosenescence and inflammaging in elderly women. In chapter 7 we performed a double-blind placebo-controlled nutritional intervention study, to investigate the potential of bovine lactoferrin, galactooligosaccharides (GOS) and vitamin D to restore TLR responsiveness of pDCs and mDCs and to reduce inflammatory cytokines in serum in elderly women. Nutritional supplementation with bLF, GOS and vitamin D is safe and enhances responses to TLR stimuli in elderly women in both pDCs and mDCs. No clear effects on pro-inflammatory markers in serum were observed, probably due to the group size in this study that was set up to study pDC responses as primary outcome. Especially TLR7-mediated responses in pDCs were enhanced after bLF supplementation compared to placebo, suggesting that bLF may contribute to protection against viral infections in elderly women. In chapter 8 I discuss the main outcomes of our research and their relevance by placing the results in a broader perspective. I will focus on four themes: 1). Induction of trained immunity by diet; 2). Modulation of respiratory immunity by raw bovine milk; 3). Immunomodulation in elderly by bovine milk components; 4). The potential role of trained immunity throughout life.