Allergic sensitization: host-immune factors (original) (raw)
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The Immune Response to Intrinsic and Extrinsic Allergens: Determinants of Allergic Disease
International Archives of Allergy and Immunology, 2002
A central role for Th2 effector cells in IgE-mediated allergic disease is well established. However, the question of why some individuals develop allergic disease and others do not remains largely unanswered. Until recently, the prevailing view was that the allergic response reflected a shift in the Th1/Th2 ‘balance’ to favor production of Th2 cytokines and IgE antibody isotype switching. Evidence is now emerging to suggest that distinct allergic responses cannot be distinguished simply on the basis of type 1 and type 2 cytokine profiles. For example, delayed-type hypersensitivity responses to intrinsic allergens derived from the dermatophyte fungus Trichophyton are associated with a paradoxical increase in Th2 cytokines compared with immediate hypersensitivity responses. In contrast, analysis of ‘tolerant’ responses to extrinsic allergens which are induced by specific immunotherapy or high-dose natural exposure to inhaled allergen (the modified Th2 response) supports a role for bot...
Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites
Mucosal Immunology, 2014
Antigen-mediated cross-linking of Immunoglobulin E (IgE) bound to mast cells/basophils via FceRI, the high affinity IgE Fc-receptor, is a well-known trigger of allergy. In humans, but not mice, dendritic cells (DCs) also express FceRI that is constitutively occupied with IgE. In contrast to mast cells/basophils, the consequences of IgE/FceRI signals for DC function remain poorly understood. We show that humanized mice that express FceRI on DCs carry IgE like non-allergic humans and do not develop spontaneous allergies. Antigen-specific IgE/FceRI cross-linking fails to induce maturation or production of inflammatory mediators in human DCs and FceRI-humanized DCs. Furthermore, conferring expression of FceRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting antiinflammatory IgE/FceRI signals. Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FceRI cross-linking on papain or lipopolysaccharide-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines. Migration assays confirm that the IgE-dependent decrease in cytokine production results in diminished recruitment of mast cell progenitors; providing a mechanistic explanation for the reduced mast celldependent allergic phenotype observed in FceRI-humanized mice. Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation.
Cytokine Pathways in Allergic Disease
Toxicologic Pathology, 2012
Cytokines are critical in allergic intercellular communication networks, and they contribute to disease pathology through the recruitment and activation of pro-inflammatory leukocytes and in chronic disease to pro-fibrotic/remodeling events. Th2 cytokines predominate primarily in mild to moderate allergic asthma, although clinical trials with inhibitors of IL-4 and IL-5 have not provided the robust efficacy observed in animal models of allergy. These results not only highlight the complexity of allergic disease, but they also point to the importance of other cytokine networks in driving pathology. The heterogeneous nature of the disease is emphasized by the fact that the Th2/Th1/Th17 cytokine balance can be influenced by the initiating allergic trigger. For example, the house dust mite allergen Der p 2 mimics the activity of MD-2 by presenting lipopolysaccharide to Toll-like receptor-4 for the activation of inflammatory genes including innate-type cytokines. Here we discuss the functions of the novel cytokine players, thymic stromal lymphopoetin (TSLP), IL-33, IL-25, and IL-9 and delineate nonredundant roles for IL-4 and IL-13 in allergic disease. Persistent efforts in the characterization of these and other cytokine networks will be essential for understanding the complex pathogenic mechanisms that underpin allergic disease and for guiding targeted therapeutic interventions.
Mechanisms of allergy and clinical immunology
Background: Regulatory dendritic cell (DC) markers, such as C1Q, are upregulated in PBMCs of patients with grass pollen allergy exhibiting clinical benefit during allergen immunotherapy (AIT). Objectives: We sought to define markers differentially expressed in human monocyte-derived DCs differentiated toward a proallergic (DCs driving the differentiation of T H 2 cells [DC2s]) phenotype and investigate whether changes in such markers in the blood correlate with AIT efficacy. Methods: Transcriptomes and proteomes of monocyte-derived DCs polarized toward DCs driving the differentiation of T H 1 cells (DC1s), DC2s, or DCs driving the differentiation of regulatory T cells (DCreg cells) profiles were compared by using genome-wide cDNA microarrays and label-free quantitative proteomics, respectively. Markers differentially regulated in DC2s and DCreg cells were assessed by means of quantitative PCR in PBMCs from 80 patients with grass pollen allergy before and after 2 or 4 months of sublingual AIT in parallel with rhinoconjunctivitis symptom scores. Results: We identified 20 and 26 new genes/proteins overexpressed in DC2s and DCreg cells, respectively. At an individual patient level, DC2-associated markers, such as CD141, GATA3, OX40 ligand, and receptor-interacting serine/ threonine-protein kinase 4 (RIPK4), were downregulated after a 4-month sublingual AIT course concomitantly with an upregulation of DCreg cell-associated markers, including complement C1q subcomponent subunit A (C1QA), FcgRIIIA, ferritin light chain (FTL), and solute carrier organic anion transporter family member 2B1 (SLCO2B1), in the blood of clinical responders as opposed to nonresponders. Changes in such markers were better correlated with clinical benefit than alterations of allergen-specific CD4 1 T-cell or IgG responses. Conclusions: A combination of 5 markers predominantly expressed by blood DCs (ie, C1Q and CD141) or shared with lymphoid cells (ie, FcgRIIIA, GATA3, and RIPK4) reflecting changes in the balance of regulatory/proallergic responses in peripheral blood can be used as early as after 2 months to monitor the early onset of AIT efficacy. (J Allergy Clin Immunol 2016;137:545-58.)
Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β
Genes and Immunity, 2014
The prevalence of allergic diseases has significantly increased in industrialized countries. Allergen-specific immunotherapy (AIT) remains as the only curative treatment. The knowledge about the mechanisms underlying healthy immune responses to allergens, the development of allergic reactions and restoration of appropriate immune responses to allergens has significantly improved over the last decades. It is now well-accepted that the generation and maintenance of functional allergen-specific regulatory T (Treg) cells and regulatory B (Breg) cells are essential for healthy immune responses to environmental proteins and successful AIT. Treg cells comprise different subsets of T cells with suppressive capacity, which control the development and maintenance of allergic diseases by various ways of action. Molecular mechanisms of generation of Treg cells, the identification of novel immunological organs, where this might occur in vivo, such as tonsils, and related epigenetic mechanisms are starting to be deciphered. The key role played by the suppressor cytokines interleukin (IL)-10 and transforming growth factor (TGF)-b produced by functional Treg cells during the generation of immune tolerance to allergens is now well established. Treg and Breg cells together have a role in suppression of IgE and induction of IgG4 isotype allergen-specific antibodies particularly mediated by IL-10. Other cell types such as subsets of dendritic cells, NK-T cells and natural killer cells producing high levels of IL-10 may also contribute to the generation of healthy immune responses to allergens. In conclusion, better understanding of the immune regulatory mechanisms operating at different stages of allergic diseases will significantly help the development of better diagnostic and predictive biomarkers and therapeutic interventions.
Journal of Experimental Medicine, 2004
The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4 ϩ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-␥ -, interleukin (IL)-4-, and IL-10-producing allergen-specific CD4 ϩ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1-like cells, respectively. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4-secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF- as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy.
The paradigm of type 1 and type 2 antigen-presenting cells. Implications for atopic allergy
Clinical & Experimental Allergy, 1999
Optimal clearance of the various pathogen types encountered by the human body requires the selective activation of particular cellular and/or humoral immune responses. The orchestration of the types of effector responses is directed by Th cells through the production of type 1 (Th1 cell-associated) and type 2 (Th2 cell-associated) cytokines. The way in which the Th cell cytokine profile is matched to the type of invading pathogen, and why these profiles sometimes derail and lead to disease, is not well understood. Here, we will discuss the concept that antigen-presenting cells (APC) provide Th cells not only with antigen and costimulatory signals, but also with a polarizing signal (signal 3). This signal can be mediated by many APC-derived factors, but IL-12 and PGE 2 seem to be of major importance. The Th2-biased responses in atopic allergy appeared to be associated with monocytes with a decreased IL-12/PGE 2 ratio and, consequently, with the down-regulation of type 1 cytokine production in Th cells. As for Th cells, APC can be functionialy polarized. In vitro experiments with monocyte-derived dendritic cells (DC) showed that the presence of IFN-g during activation of immature DC primes for mature DC with the ability of high IL-12 production and, consequently, a Th1-driving capacity (APC1 or DC1). In contrast, PGE 2 primes for a low IL-12 production ability and a Th2-driving capacity (APC2 or DC2). These findings suggest that pathogens provoke either Th1-or Th2-cell development by inducing the production of a certain pattern of inflammatory DC-polarizing mediators (e.g. IFN-g and PGE 2) at the site of infection. The type of immune polarization will not only depend on the type of pathogen, but also varies with the type of infected tissue, i.e. that different tissues produce different mediators in response to the same pathogen. In the case of atopic allergy, this concept implies that the Th2-cell bias may be related to low levels of cross-regulatory infections, to Th1 cell-inducing pathogens, or to an aberrant function of stromal cells in peripheral tissues.