Regulation Of Allergic Responses Research Articles

S100A4 Is Critical for a Mouse Model of Allergic Asthma by Impacting Mast Cell Activation.

BackgroundThe calcium-binding protein S100A4 demonstrates important regulatory roles in many biological processes including tumorigenesis and inflammatory disorders such as allergy. However, the specific mechanism of the contribution of S100A4 to allergic diseases awaits further clarification.ObjectiveTo address the effect of S100A4 on the regulation of mast cell activation and its impact on allergy.MethodsBone marrow-derived cultured mast cells (BMMCs) were derived from wild-type (WT) or S100A4-/- mice for in vitro investigation. WT and S100A4-/- mice were induced to develop a passive cutaneous anaphylaxis (PCA) model, a passive systemic anaphylaxis (PSA) model, and an ovalbumin (OVA)-mediated mouse asthma model.ResultsFollowing OVA/alum-based sensitization and provocation, S100A4-/- mice demonstrated overall suppressed levels of serum anti-OVA IgE and IgG antibodies and proinflammatory cytokines in serum, bronchoalveolar lavage fluid (BALF), and lung exudates. S100A4-/- mice exhibited less severe asthma signs which included inflammatory cell infiltration in the lung tissue and BALF, and suppressed mast cell recruitment in the lungs. Reduced levels of antigen reencounter-induced splenocyte proliferation in vitro were recorded in splenocytes from OVA-sensitized and challenged mice that lacked S100A4-/-. Furthermore, deficiency in the S100A4 gene could dampen mast cell activation both in vitro and in vivo, evidenced by reduced β-hexosaminidase release and compromised PCA and PSA reaction. We also provided evidence supporting the expression of S100A4 by mast cells.ConclusionS100A4 is required for mast cell functional activation, and S100A4 may participate in the regulation of allergic responses at least partly through regulating the activation of mast cells.

The role of CD23 in the regulation of allergic responses.

IgE, the key molecule in atopy has been shown to bind two receptors, FcεRI, the high‐affinity receptor, and FcεRII (CD23), binding IgE with lower affinity. Whereas cross‐linking of IgE on FcεRI expressed by mast cells and basophils triggers the allergic reaction, binding of IgE to CD23 on B cells plays an important role in both IgE regulation and presentation. Furthermore, IgE‐immune complexes (IgE‐ICs) bound by B cells enhance antibody and T cell responses in mice and humans. However, the mechanisms that regulate the targeting of the two receptors and the respective function of the two pathways in inflammation or homeostasis are still a matter of debate. Here, we focus on CD23 and discuss several mechanisms related to IgE binding, as well as the impact of the IgE/antigen‐binding on different immune cells expressing CD23. One recent paper has shown that free IgE preferentially binds to FcεRI whereas IgE‐ICs are preferentially captured by CD23. Binding of IgE‐ICs to CD23 on B cells can, on one hand, regulate serum IgE and prevent effector cell activation and on the other hand facilitate antigen presentation by delivering the antigen to dendritic cells. These data argue for a multifunctional role of CD23 for modulating IgE serum levels and immune responses.

The role of regulatory B cells in allergen immunotherapy.

Allergen immunotherapy (AIT) is currently the only curative treatment available for allergic diseases, and has been used in clinical practice for over a century. Induction and maintenance of immune tolerance to nonhazardous environmental and self-antigens is essential to maintain homeostasis and prevent chronic inflammation. Regulatory B (BREG) cells are immunoregulatory cells that protect against chronic inflammatory responses primarily through production of anti-inflammatory cytokines such as IL-10, transforming growth factor-β, and IL-35. The importance of BREG cells has been extensively demonstrated in the context of autoimmune diseases. Data showing their role in the regulation of allergic responses are slowly accumulating. This review summarizes recent findings relevant to the topic of BREG cells and their potential role in AIT. BREG cells support AIT in models of allergic airway inflammation and intestinal inflammation through induction of regulatory T (TREG) cells. In humans BREG frequency increases during venom immunotherapy while the phenotype of allergen-specific B cells changes. Mechanisms of BREG-mediated tolerance to allergens include IL-10-mediated suppression of effector T cell, including TH2 responses, induction of TREG cells, IL-10-mediated inhibition of Dendritic cell maturation, modulation of T follicular helper responses, and production of anti-inflammatory IgG4 antibodies. Current evidence supports a potential role for BREG cells in induction and maintenance of allergen tolerance during AIT. A better understanding of the role of B cells and BREG cells in AIT could open potential new windows for developing targeted therapies specifically focused on promoting BREG responses during AIT.

A tryptophan metabolite, kynurenine, promotes mast cell activation through aryl hydrocarbon receptor

Tryptophan metabolites have been suggested to play a role in immune modulation, wherein those have recently been shown to be endogenous ligands of aryl hydrocarbon receptor (AhR; a unique cellular chemical sensor). However, the involvement of tryptophan metabolites and AhR in modulating mast cell function remains to be fully defined. We therefore investigated that the functional impacts of tryptophan metabolites on human and mouse mast cell responses in vitro and their functional importance in vivo. Three tryptophan metabolites, kynurenine (KYN), kynurenic acid (KA) and quinolinic acid (QA), were examined in terms of their effect on IgE-mediated responses in mouse bone marrow-derived mast cells (BMMCs) and in human peripheral blood-derived cultured mast cells (HCMCs) and on in vivo anaphylactic responses. For evaluation of AhR involvement, we examined the responses of mast cells from AhR-null or AhR-wild-type mice with the use of a known AhR antagonist, CH223191. Kynurenine, but not KA and QA, enhanced IgE-mediated responses, including degranulation, LTC4 release, and IL-13 production in BMMCs through the activation of PLCγ1, Akt, MAPK p38, and the increase of intracellular calcium. KYN also enhanced cutaneous anaphylaxis in vivo. These enhancing effects of KYN were not observed in AhR-deficient BMMCs and could be inhibited by CH223191 in BMMCs. Further, KYN had similar enhancing effects on HCMCs, which were inhibited by CH223191. The AhR-KYN axis is potentially important in modulating mast cell responses and represents an example of AhR's critical involvement in the regulation of allergic responses.

IKKβ in intestinal epithelial cells regulates allergen-specific IgA and allergic inflammation at distant mucosal sites.

Regulation of allergy responses by intestinal epithelial cells remain poorly understood. Using a model of oral allergen sensitization in the presence of cholera toxin as adjuvant and mice with cell-specific deletion of IKKβ in intestinal epithelial cells IECs (IKKβΔIEC), we addressed the contribution of IECs to allergic sensitization to ingested antigens and allergic manifestations at distant mucosal site of the airways. Cholera toxin induced higher proinflammatory responses and altered the profile of the gut microbiota in IKKβΔIEC mice. Antigen-specific IgE responses were unaltered in IKKβΔIEC mice, but their IgA Abs, Th1 and Th17 responses were enhanced. Upon nasal antigen challenge, these mice developed lower levels of allergic lung inflammation, which correlated with higher levels of IgA Abs in the airways. The IKKβΔIEC mice also recruited a higher number of gut-sensitized T cells in the airways after nasal antigen challenge and developed airway hyper-responsiveness, which were suppressed by treatment with anti-IL-17A. Fecal microbiota transplant during allergic sensitization reduced Th17 responses in IKKβΔIEC mice, but did not affect IgA Ab responses. In summary, we show that IKKβ in IECs shapes the gut microbiota and immune responses to ingested antigens and influences allergic responses in the airways via regulation of IgA Ab responses.

475 The Candidate Peptides in IgE for Allergy Vaccine Design

BackgroundThe World Allergy Organization in 2011 estimated that 30 to 40% of the world population is now affected by one or more allergic conditions. Since the IgE plays a central role in the expansion and regulation of allergic response that seems the IgE elimination is the best approach in the control of asthma and allergic diseases. Now, an anti-IgE antibody as a drug (Xolair) is available and efficient but is expensive with short half-life. As good and more efficient substitution IgE peptide-based vaccines has been proposed.MethodsIn this study, we analyzed all potential antigenic peptides on the constant region of the Ig epsilon chain (Fcε). For determination of B cell immunodominant epitope, we used the antibody epitope prediction tools. In continuing candidate peptides were done BlastP to avoid nonspecific antibody reactions with other human proteins in the NCBI database. And then, to preparation of vaccines, peptides were synthesized and conjugated by Tetanus toxoid (TT). To immunogenicity analysis of vaccines, the rats are being immunized with vaccines or TT as control.ResultsBy Kolaskar and Tongaonkar antigenicity algorithms 20 peptides with putative epitopes were selected. Homologous sequences and also previous studies peptides were excluded, 13 peptides remained that used for vaccine preparation. The produced vaccines are being analyzed for their effect on induction of anti-IgE antibody production. Peptides based on antibody production or not, were divided in 2 groups.ConclusionsActive immunization by IgE peptide based vaccines can be triggering production antibodies against self-IgE that are effective in preventing and control of IgE levels as an important factor in asthma and allergic diseases.

Role of osteopontin, a multifunctional protein, in allergy and asthma

Osteopontin (OPN) is an extracellular matrix protein and immune modulator with a wide range of functions. OPN is recognized as a key cytokine in Th1 immune responses, yet its potential involvement in allergic/asthmatic responses has been investigated only recently. Current data from molecular and cellular studies and studies of OPN-deficient mice provide evidence that OPN plays multiple roles in the regulation of allergic responses, including regulation of IgE response, inflammatory cell migration, and the development of airway fibrosis and angiogenesis. These results suggest that OPN is a pleiotropic cytokine that functions both systemically and locally in tissue mucosa. Notably, OPN is able to exert its effects through different functional domains, and the secreted and intracellular forms of OPN may have distinct functions. Future research to elucidate all aspects of OPN function is needed to ultimately establish its role in the regulation of immune responses and various disease processes, including those critically involved in the development of allergies and asthma.

Depletion of CD4+CD25+ T cells switches the whey‐allergic response from immunoglobulin E‐ to immunoglobulin free light chain‐dependent

Symptoms of allergy are largely attributed to an IgE-mediated hypersensitivity response. However, a considerable number of patients also exhibit clinical features of allergy without detectable systemic IgE. Previous work showed that Ig-free light chains (IgLC) may act as an alternate mechanism to induce allergic responses. CD4+CD25+ T cells are crucial in the initiation and regulation of allergic responses and compromised function might affect the response to allergens. To examine the contribution of CD4+CD25+ T cells and IgLC towards the whey-allergic response. Mice were sensitized orally with whey using cholera toxin as an adjuvant. CD25+ T cells were depleted in vivo using a CD25 mAb. The acute allergic skin response to whey and ex vivo colon reactivity was measured in the presence or absence of F991, a specific inhibitor of IgLC. Serum whey-specific antibodies and IgLC in serum and mesenteric lymph node (MLN) supernatants were measured. Depletion of CD4+CD25+ T cells was confirmed in the spleen. Anti-CD25 treatment strongly reduced whey-specific antibody levels and resulted in a partial depletion of effector T cells and a major depletion of Foxp3(+) regulatory T cells. Surprisingly, despite the abolished specific IgE response, the acute allergic skin response to whey was not affected. IgLC levels were enhanced in the serum and MLN supernatants of CD25-depleted sensitized mice. F991 inhibited the acute skin response and colon hyperreactivity in anti-CD25-treated mice, indicating that these responses were mainly IgLC dependent. Depletion of CD4+CD25+ T cells resulted in a switch from an IgE- to an IgLC-dependent acute skin response and functional hyperresponsiveness of the colon. Our data suggest that CD25+ T cells play a crucial role in balancing cow's milk allergy between IgE and IgE-independent responses and both mechanisms might play a role in allergic responses to the same allergen.

The E3 ubiquitin ligase Itch regulates Foxp3 expression and airway inflammation via enhancing TIEG1 function

Transforming growth factor (TGF)‐b signaling in naïve T cells induces expression of transcription factor Foxp3, a master regulator in the regulatory T cells (Tregs). However, the molecular mechanisms leading to Foxp3 induction remain unclear. Here we show that Itch−/− T cells are resistant to TGF‐b treatment with reduced Foxp3 expression. The E3 ubiquitin ligase Itch associates with and promotes ubiquitin conjugation to TGF‐b inducible early gene1 product (TIEG1). More importantly, Itch cooperates with TIEG1 to induce Foxp3 expression, which is reversed by TIEG1 deficiency. Functionally TGF‐b‐converted Tregs generated from TIEG1−/− mice are unable to inhibit naïve T cell proliferation in vitro and suppress airway inflammation in vivo. The results suggest an ubiquitin‐dependent non‐proteolytic pathway that is critical for Foxp3 expression and regulation of allergic responses.

Allergy-Blocking Transmitters

The endocannabinoid system performs various regulatory functions and has been implicated in a growing number of physiological roles, both in the central and peripheral nervous systems and in peripheral organs. Karsak et al . now find that this influence extends to regulation of allergic response. Mice lacking the two known cannabinoid receptors showed a strong tendency toward developing cutaneous contact sensitivity in response to distinct allergens. Blocking the receptors with antagonists had a similar effect, whereas absence of the gene encoding an enzyme responsible for breaking down cannabinoids increased resistance of mice to contact sensitivity. The regulation of the endocannabinoids or their receptors might be useful in treating allergies, although their role in the wider context of human allergy needs to be explored. M. Karsak, E. Gaffal, R. Date, L. Wang-Eckhardt, J. Rehnelt, S. Petrosino, K. Starowicz, R. Steuder, E. Schlicker, B. Cravatt, R. Mechoulam, R. Buettner, S. Werner, V. Di Marzo, T. Tüting, A. Zimmer, Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316 , 1494-1497 (2007). [Abstract] [Full Text]

The Inhibitory Receptor IRp60 (CD300a) Is Expressed and Functional on Human Mast Cells

Mast cell-mediated responses are likely to be regulated by the cross talk between activatory and inhibitory signals. We have screened human cord blood mast cells for recently characterized inhibitory receptors expressed on NK cells. We found that IRp60, an Ig superfamily member, is expressed on human mast cells. On NK cells, IRp60 cross-linking leads to the inhibition of cytotoxic activity vs target cells in vitro. IRp60 is constitutively expressed on mast cells but is down-regulated in vitro by the eosinophil proteins major basic protein and eosinophil-derived neurotoxin. An immune complex-mediated cross-linking of IRp60 led to inhibition of IgE-induced degranulation and stem cell factor-mediated survival via a mechanism involving tyrosine phosphorylation, phosphatase recruitment, and termination of cellular calcium influx. To evaluate the role of IRp60 in regulation of allergic responses in vivo, a murine model of allergic peritonitis was used in which the murine homolog of IRp60, LMIR1, was neutralized in BALB/c mice by mAbs. This neutralization led to a significantly augmented release of inflammatory mediators and eosinophilic infiltration. These data demonstrate a novel pathway for the regulation of human mast cell function and allergic responses, indicating IRp60 as a candidate target for future treatment of allergic and mast cell-associated diseases.

Enhancement of the Stability and Skin Penetration of Vitamin C by Polyphenol

Background: It is necessary for human beings to uptake vitamin C through diet or supplements. It is also well-known that vitamin C plays an important role in the prevention of scurvy, enhancement of collagen synthesis and anti-tumor immune response. In addition, there are several recent reports regarding the effective role of vitamin C on the regulation of allergic responses, such as atopic dermatitis and asthma. However, the effective therapeutic and preventive measures using vitamin C are not established yet, since vitamin C is seriously unstable in aqueous solution. Therefore, we have investigated the best way to maintain the stability of vitamin C. Methods: After we making a mixture of polyphenol (0.001, 0.01, 0.1%) and vitamin C (1 mM), the mixtures were placed at room temperature both with/without light protection. And then the concentration of ascorbic acid was measured with HPLC. To analyze the in vivo effect of vitamin C on the regulation of skin allergic reaction, polyphenol (0.1%)-vitamin C (1 mM) mixture was applied to the skin and the production of histamine from mast cell was analyzed by Evans blue dye staining. Results: We have found that the polyphenol has preventive power of oxidation of vitamin C. In addition, the production of histamine was suppressed by the polyphenol (0.1%)-vitamin C (1 mM) mixture. Conclusion: We have reached the conclusion that our study suggests the research guideline for the therapy of atopic dermatitis through vitamin C. (Immune Network 2004;4(4): 250-254)

Emerging Concepts of T-Cell Regulation in Asthma and Allergy

Background: The focus of research into the etiology of allergic diseases has, over the past decade, been directed principally at CD4 T cell functions, within the general framework of the Th1/Th2 paradigm. Recent research has provided independent confirmation of the reciprocal nature of allergen-specific T cell immunity in atopics versus nonatopics, employing measures other than cytokines. However, it is also clear that the Th-memory patterns expressed in humans are more complex than predicted by earlier murine studies, suggesting the operation of a variety of T cell regulatory mechanisms. Ongoing research points to contributions from antigen presenting cells, populations of T-regulatory cells, and possibly cytokine and non-cytokine producing CD8 T cells. Methods/Data base: A review of the literature. Results/Conclusions: While the Th1/Th2 paradigm, as initially described in mice, has expanded our concepts of T cell mechanisms in asthma and allergy, it does not completely describe the human situation. Recent studies on transcription factors confirm that this paradigm is relevant to human immunology but that it does not describe the whole story. The sentinel role of DC in the initiation, maintenance and regulation of allergic responses, especially in the airways, in immunologically mature individuals is now recognised but we have not fully uncovered the role these cells play, particularly during primary allergic sensitization during the early postnatal period. Exciting new data are showing the potentially important role of Tr cells in early life and these may yet be one of the keys to understanding the increase in the prevalence of asthma and allergies in the developed world.

Prediction of murine MHC class I epitopes in a major house dust mite allergen and induction of T1-type CD8+ T cell responses.

The group I (Der p 1) allergen of Dermatophagoides pteronyssinus (house dust mite, HDM) contains several T helper (Th) epitopes recognized by C57BL/6 mice, with the peptide (111-139) containing a dominant MHC class II-restricted epitope (113-127). Since CD8+ T cells are thought to play a role in the regulation of allergic disease, we examined the Der p 1 sequence for potential MHC class I-binding motifs and observed that residues 111-119 (FGISNYCQI) contain motifs for H-2Db and Kb. Furthermore, immunization of C57BL/6 mice with unadjuvanted Ty virus-like particles (VLP) carrying Der p 1 (111-139), a method known to induce murine cytotoxic T lymphocyte (CTL) responses, primed Der p 1 (111-119)-specific Db-restricted CTL which produce high levels of IFN-gamma and low levels of IL-5 and IL-6 in vitro (T1-type CTL). VLP carrying the minimal epitope (FGISNYCQI) also induced a CTL response following immunization without adjuvant by various routes. Der p 1 (111-139)-VLP adjuvanted with alum did not prime CTL in C57BL/6 mice but were found to prime Th1-type CD4+ T cells that recognize the overlapping peptide (113-127) and native protein. The ability to successfully predict allergen-specific CD8+ T cell epitopes and prime CD8+ and/or CD4+ T cell responses provides an opportunity to dissect the relative roles of these T cells in the regulation of allergic responses and may offer therapeutic potential for reprogramming Th2-type allergic responses.

Evidence for a locus regulating total serum IgE levels mapping to chromosome 5.

Genetics studies of total serum IgE levels were performed since high IgE levels correlate with clinical expression of allergy and asthma. Families ascertained through a parent with asthma were genotyped for markers on 5q where there are multiple candidate genes that may influence the control of IgE and inflammation. Evidence for linkage of the IgE phenotype to 5q was obtained by both sib-pair and lod score analysis with evidence for recessive inheritance of high IgE levels from segregation analysis. These findings represent a major step in mapping genes important in the regulation of allergic responses and the pathogenesis of asthma.

IFN-gamma, but not IL-4, synthesis by antigen-primed murine T cells is IL-2 dependent. Differential requirements in de novo and established responses.

Ag-induced, CD4 T cell-dependent synthesis of IL-4 and IFN-gamma plays a critical role in the induction, maintenance, and regulation of allergic responses. The requirement for IL-2 and IL-4 in the initial induction of IL-4 T cell responses is well established. However, it remains unclear whether IL-2 is required for priming of IL-4 responses, IL-4 gene expression, or both. In this report, we dissociate the IL-2 dependence of developing and established IL-4 responses. The capacity of spleen cells from naive and allergen-immunized mice to synthesize IL-4 after Ag-specific vs polyclonal restimulation is examined in overnight cultures. Although de novo induction of IL-4 and IFN-gamma production obtained after in vitro activation of cells from naive animals with immobilized anti-CD3 is IL-2 dependent, Ag-driven IL-4 synthesis by CD4 T cells from OVA (alum)- or ragweed extract (alum)-immunized mice is independent of IL-2. The data demonstrate the IL-2 independence of CD4 T cell-derived IL-4 synthesis by allergen-primed cells, distinguishing IL-2-dependent from IL-2-independent stages of IL-4 responses. In contrast to the finding that IL-2 is not required for IL-4 gene expression by primed T cells in allergen-driven responses, both induction and expression of IFN-gamma responses are strictly IL-2 dependent. This differential requirement for IL-2 in IL-4 and IFN-gamma gene expression may be significant in the maintenance of IL-4-dominated responses in allergic individuals.

Regulation of allergic responses

Regulation of allergic responses

Regulation of Allergic Responses by Prostaglandins: A Review

Regulation of Allergic Responses by Prostaglandins: A Review