Histamine and its receptors (H1R–H4R) play a crucial and significant role in the development of various allergic diseases. Mast cells are multifunctional bone marrow-derived tissue-dwelling cells that are the major producer of histamine in the body. H1R are expressed in many cells, including mast cells, and are involved in Type 1 hypersensitivity reactions. H2R are involved in Th1 lymphocyte cytokine production. H3R are mainly involved in blood–brain barrier function. H4R are highly expressed on mast cells where their stimulation exacerbates histamine and cytokine generation. Both H1R and H4R have important roles in the progression and modulation of histamine-mediated allergic diseases. Antihistamines that target H1R alone are not entirely effective in the treatment of acute pruritus, atopic dermatitis, allergic asthma, and other allergic diseases. However, antagonists that target H4R have shown promising effects in preclinical and clinical studies in the treatment of several allergic diseases. In the present review, we examine the accumulating evidence suggesting novel therapeutic approaches that explore both H1R and H4R as therapeutic targets for histamine-mediated allergic diseases.

Background In atopic individuals, food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays critical roles in this response and genetic polymorphisms in its components have been linked to allergy. Objective To test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen. Methods F709 mice, in which the IL-4Rα immuno-tyrosine inhibitory motif (ITIM) motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses including antibody production and Th2 responses were assessed. Results F709 mice, but not wild-type (WT) controls, sensitized by gavage with OVA and either cholera toxin (CT) or Staphylococcal enterotoxin B (SEB), displayed mast cell activation and systemic anaphylaxis upon enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic Th2 responses and intestinal mast cell hyperplasia as compared with WT mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high affinity receptor for IgE (FcεRI). Conclusion Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE-dependent.

Atopic dermatitis (AD) is a common allergic inflammatory skin disease caused by a combination of intense pruritus, scratching, and epicutaneous (e.c.) sensitization with allergens. To explore the roles of IL-21 and IL-21 receptor (IL-21R) in AD, we examined skin lesions from patients with AD and used a mouse model of allergic skin inflammation. IL-21 and IL-21R expression was upregulated in acute skin lesions of AD patients and in mouse skin subjected to tape stripping, a surrogate for scratching. The importance of this finding was highlighted by the fact that both Il21r -/-mice and WT mice treated with soluble IL-21R-IgG2aFc fusion protein failed to develop skin inflammation after e.c. sensitization of tape-stripped skin. Adoptively transferred OVA-specific WT CD4 + T cells accumulated poorly in draining LNs (DLNs) of e.c. sensitized Il21r -/-mice. This was likely caused by both DC-intrinsic and nonintrinsic effects, because trafficking of skin DCs to DLNs was defective in Il21r -/-mice and, to a lesser extent, in WT mice reconstituted with Il21r -/-BM. More insight into this defect was provided by the observation that skin DCs from tape-stripped WT mice, but not Il21r -/-mice, upregulated CCR7 and migrated toward CCR7 ligands. Treatment of epidermal and dermal cells with IL-21 activated MMP2, which has been implicated in trafficking of skin DCs. These results suggest an important role for IL-21R in the mobilization of skin DCs to DLNs and the subsequent allergic response to e.c. introduced antigen.

Background Signaling by IL-4 and IL-13 via the IL-4 receptor alpha chain (IL-4Rα) plays a critical role in the pathology of allergic diseases. The IL-4Rα is endowed with an immunoreceptor tyrosine-based inhibitory motif (ITIM), centered on tyrosine 709 (Y709) in the cytoplasmic domain, that binds a number of regulatory phosphatases. The function of the ITIM in the in vivo regulation of IL-4R signaling remains unknown. Objective To determine the in vivo function of the IL-4Rα ITIM using mice in which the ITIM was inactivated by mutagenesis of the tyrosine Y709 residue into phenylalanine (F709). Methods F709 ITIM mutant mice were derived by knockin mutagenesis. Activation of intracellular signaling cascades by IL-4 and IL-13 was assessed by intracellular staining of phosphorylated signaling intermediates and by gene expression analysis. In vivo responses to allergic sensitization were assessed using models of allergic airway inflammation. Results The F709 mutation increased STAT6 phosphorylation by IL-4 and, disproportionately, by IL-13. This was associated with exaggerated Th2 polarization, enhanced alternative macrophage activation by IL-13, augmented basal and antigen-induced IgE responses and intensified allergen-induced eosinophilic airway inflammation and hyperreactivity. Conclusions These results point to a physiologic negative regulatory role for the Y709 ITIM in signaling via IL-4Rα, especially by IL-13.

IL-10 is a key pleiotropic cytokine that can both promote and curb Th2-dependent allergic responses. Herein we demonstrate a novel role for IL-10 in promoting mast cell expansion and the development of IgE-mediated food allergy. Oral ovalbumin challenge in sensitized BALB/c mice resulted in a robust intestinal mast cell response accompanied by allergic diarrhea, mast cell activation, and a predominance of Th2 cytokines, including enhanced IL-10 expression. In contrast, the development of intestinal anaphylaxis including diarrhea, mast cell activation, and Th2 cytokine production was significantly attenuated in IL-10−/− mice compared to WT controls. IL-10 also directly promoted the expansion, survival, and activation of mast cells, increased FcɛRI expression on mast cells, and enhanced the production of mast cell cytokines. IL-10−/− mast cells had reduced functional capacity, which could be restored by exogenous IL-10. Similarly, attenuated passive anaphylaxis in IL-10−/− mice could be restored by IL-10 administration. The adoptive transfer of WT mast cells restored allergic symptoms in IL-10−/− mice, suggesting that the attenuated phenotype observed in these animals is due to a deficiency in IL-10-responding mast cells. Lastly, transfer of WT CD4 T cells also restored allergic diarrhea and intestinal mast cell numbers in IL-10−/− mice, suggesting that the regulation of IL-10-mediated intestinal mast cell expansion is T cell-dependent. Our observations demonstrate a critical role for IL-10 in driving mucosal mast cell expansion and activation, suggesting that in its absence, mast cell function is impaired, leading to attenuated food allergy symptoms.

Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα–dependent signaling.

Studies performed using cultured cells indicate that IgE functions not only to trigger degranulation of mast cells following allergen exposure, but also to enhance their survival. Such an influence of IgE on mast cell homeostasis during allergic responses in vivo has not been established. In this study, we show that inhalation of Aspergillus fumigatus extract in mice induced a dramatic rise in IgE accompanied by an increase in airway mast cells. These had an activated phenotype with high levels of FcεRI. Plasma mast cell protease-1 was also increased, indicating an elevated systemic mast cell load. In addition, enhanced levels of IL-5 and eosinophils were observed in the airway. Both mast cell expansion and activation were markedly attenuated in IgE−/− animals that are incapable of producing IgE in response to A. fumigatus. The recruitment of eosinophils to the airways was also reduced in IgE−/− mice. Analyses of potential cellular targets of IgE revealed that IgE Abs are not required for the induction of mast cell progenitors in response to allergen, but rather act by sustaining the survival of mature mast cells. Our results identify an important role for IgE Abs in promoting mast cell expansion during allergic responses in vivo.

Background Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are skin disorders triggered by epicutaneous sensitization (EC) with protein antigens and contact sensitization (CS) with haptens, respectively. Skin is colonized with bacteria, which are a source of Toll-like receptor 2 (TLR2) ligands. Objective To examine the role of TLR2 in murine models of AD and ACD. Methods TLR2-/- mice and WT littermates were EC sensitized with ovalbumin (OVA) or contact sensitized with oxazolone (OX). Skin histology was assessed by H&E staining and immunohistochemistry. Ear swelling was measured with a micrometer. Cytokine mRNA expression was examined by quantitative RT-PCR. Antibody levels and splenocyte secretion of cytokines in response to OVA stimulation were measured by ELISA. Dendritic cells (DCs) were examined for their ability to polarize TCR-OVA transgenic naïve T cells to Th1 and Th2. Results In response to OVA sensitization, TLR2-/- mice developed skin infiltration with eosinophils and CD4+ cells as well as upregulation of Th2 cytokine mRNAs that were comparable to WT littermates. In contrast, epidermal thickening, IFN-γ expression in the skin, IFN-γ production by splenocytes and IgG2a anti-OVA antibody levels were impaired in TLR2-/- mice. Following OX ear challenge, contact sensitized TLR2-/- mice exhibited defective ear swelling with impaired cellular infiltration, decreased epidermal thickening and local IFN-γ expression and impaired OX-specific IgG2a responses. DCs from TLR2-/- mice induced significantly lower production of IFN-γ, but normal IL-4 and IL-13 production, in naïve T cells. Conclusions These results indicate that TLR2 promotes the IFN-γ response to cutaneously introduced antigens.