Developmental changes in interleukin-12-producing ability by monocytes and their relevance to allergic diseases

BACKGROUND: The T helper type-2 (Th2)-dominated situation can be observed in allergic diseases such as asthma or atopic dermatitis. A reduced ability to produce IL-12, which is a key cytokine for the induction of Th1 responses, has been proposed to lead to aberrant Th2 development in these disease conditions. OBJECTIVE: This study was intended to examine how IL-12-producing ability might associate with allergic diseases as a function of age. METHODS: IL-12 production by monocytes at various ages was assessed in patients with bronchial asthma and/or atopic dermatitis (n = 100) in comparison with non-allergic control subjects (n = 144). Whole blood cells were stimulated with lipopolysaccharide (LPS) after priming with IFN-gamma, then intracellular cytokine expression of IL-12 and IL-8 as a control cytokine of CD14-positive cells was assessed by flow cytometric analysis. RESULTS: In the control subjects, the ability of monocytes to produce IL-12 was negligible at birth and gradually increased with advancing age, whereas IL-8 production was intense throughout the human life. At more than 7 years of age, IL-12 production of patients with allergic diseases was significantly lower compared with that of control subjects. The unexpected finding was that infants and children below 6 years of age with allergic diseases tended to produce more IL-12 compared with age-matched controls. In this young group, it was noted that enhanced IL-12 production by monocytes was especially observed in allergic patients with specific IgE antibodies against some food allergens. Significant inverse relationships between serum IgE levels and IL-12-producing ability were found in the teenage and adult groups, but not in the younger children. CONCLUSION: IL-12 appeared to play different roles in the pathogenesis of allergic diseases between younger and older ages.     

Langerin+ dendritic cells are responsible for LPS-induced reactivation of allergen-specific Th2 responses in postasthmatic mice

Allergic asthma is a T cell-dependent inflammatory lung disease that results from complex interactions between genetic predisposition and environmental factors, including exposure to lipopolysaccharide (LPS). In this study, we have shown that airway LPS exposure was sufficient to induce airway hyperreactivity (AHR) and eosinophil recruitment in mice that had previously experienced an acute episode of allergic asthma. LPS-induced disease reactivation depended on the activation of allergen-specific CD4(+) T cells by a subset of lung langerin(+) dendritic cells (DCs) that retained the allergen. Upon LPS exposure, migration of langerin(+) DCs from lungs to draining lymph nodes increased and LPS-exposed langerin(+) DCs instructed CD4(+) T cells toward a T helper (Th) 2 response. Selective depletion of langerin(+) DCs prevented LPS-induced eosinophil recruitment and T-cell activation, further demonstrating a critical role for langerin(+) DCs in disease reactivation. This finding provides a possible explanation for the subclinical worsening of asthmatics following exposure to low-dose LPS.     

Search of a novel diagnostic marker for allergic diseases by the microarray approach

It is well known that Th2-type immune response is important for the pathogenesis of allergic diseases, such as bronchial asthma, allergic rhinitis, and atopic dermatitis. However, the pathogenesis of allergic diseases is heterogeneous, in that various cells and mediators are involved. If a relevant marker to discriminate the pathogenesis of allergic diseases in each individual could be found, such a marker would be beneficial to carry out personalized therapy for allergic diseases. We have recently found that squamous cell carcinoma antigens 1 and 2, which are now widely used as biomarkers to diagnose squamous cell carcinomas, are downstream molecules of interleukin-4 and interleukin-13, Th2-type cytokines, by the microarray approach. We furthermore found that these molecules are relevant biomarkers for bronchial asthma and atopic dermatitis. It is hoped that the measurement of squamous cell carcinoma antigens will be useful to diagnose allergic patients to apply agents targeting interleukin-4 or interleukin-13 in the future.     

Food allergy promotes a Th2/Th17 response that drives house dust mite-induced allergic airway inflammation in humanized mice

Food allergy is related to increasing risk of the development of allergic asthma, but the precise interplay between sensitization to different allergens in different compartments of the body is not fully understood. The aim of this study was to develop a novel humanized murine model of mixed food and respiratory allergy that recapitulates the human anaphylactic response and to more clearly understand the impact of food allergies on asthma. Immunodeficient mice transferred with peripheral blood mononuclear cells (PBMCs) from donors with peanut and house dust mite (HDM) allergy were exposed and challenged to peanut. Between peanut exposure and challenge, mice were intranasally treated to HDM. Allergic parameters were analyzed. Allergen-specific immunoglobulin (Ig)E in sera could only be measured in mice treated with peripheral blood mononuclear cells (PBMCs) plus allergen. A preceding peanut exposure increased IgE levels, histamine release, bronchial hyper-responsiveness and lung inflammation. Recruitment of inflammatory cells to the airways was aggravated associated with an enhanced T helper type 2 (Th2)/Th17 cytokine secretion when the two allergies were present. A preceding peanut exposure amplifies allergic asthma in this humanized model, which may contribute to the understanding of underlying immunological mechanism of polysensitization occurring in allergic individuals and evaluation of therapeutic interventions.     

Prior Bordetella pertussis infection modulates allergen priming and the severity of airway pathology in a murine model of allergic asthma

BACKGROUND: It has been proposed that T helper (Th)2-driven immune deviation in early life can be countered by Th1 inducing childhood infections and that such counter-regulation can protect against allergic asthma. OBJECTIVE: To test whether Th1-inducing infection with Bordetella pertussis protects against allergic asthma using well-characterized murine models. METHODS: Groups of mice were sensitized to ovalbumin (OVA) in the presence or absence of B. pertussis, a well-characterized Th1 inducing respiratory infection. Immunological, pathological and physiological parameters were measured to assess the impact of infection on immune deviation and airway function. RESULTS: We demonstrate that OVA sensitization does not affect the development of B. pertussis-specific immune responses dominated by IgG2a and IFN-gamma and does not impair Th1-mediated clearance of airway infection. In contrast, B. pertussis infection at the time of sensitization modulated the response to OVA and significantly reduced total serum and OVA-specific IgE. The pattern of cytokine responses, in particular OVA-specific IL-5 responses in the spleen was also modulated. However, B. pertussis did not cause global suppression as IL-10 and IL-13 levels were enhanced in OVA-stimulated spleen cell cultures and in lavage fluid from infected co-sensitized mice. Histopathological examination revealed that B. pertussis infection prior to OVA sensitization resulted in increased inflammation of bronchiolar walls with accompanying hyperplasia and mucous metaplasia of lining epithelia. These pathological changes were accompanied by increased bronchial hyper-reactivity to methacholine exposure. CONCLUSION: Contrary to the above premise, a Th1 response induced by a common childhood infection does not protect against bronchial hyper-reactivity, but rather exacerbates the allergic asthmatic response, despite modulation of immune mediators.     

Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation

Background:  As Th2 type lymphocytes orchestrate the cardinal features of allergic asthma, inhibiting their recruitment to the lungs could be of therapeutic benefit. Although human Th2 cells express the CCR4 chemokine receptor and increased production of CCR4 ligands has been found in asthmatic airways, studies in animals have reached contradictory conclusions on whether blocking this pathway would be beneficial.
Objective:  As a lack of efficacy might be due to differences between mouse and man, we readdressed this question using a humanized severe combined immunodeficiency model of asthma.
Methods:  Mice received peripheral blood mononuclear cells from house dust mite (HDM) allergic asthmatic patients and then underwent bronchial challenge with HDM.
Results:  This resulted in marked allergic inflammation and bronchial hyper-reactivity. Administration of CCR4 blocking antibody abolished the airway eosinophilia, goblet cell hyperplasia, IgE synthesis and bronchial hyperreactivity. In this chimeric system, human CD11c+ dendritic cells (DCs) were the predominant source of CCR4 ligands, suggesting that DC-derived chemokines attract Th2 cells. In separate experiments using human DCs, in vitro exposure to HDM of DCs from HDM allergic patients but not healthy controls caused CCL17 and CCL22 release that resulted in chemoattraction of polarized human Th2 cells in a CCR4-dependent way.
Conclusions:  Taken together, our data provide proof of concept that CCR4 blockade inhibits the salient features of asthma and justify further clinical development of CCR4 antagonists for this disease.     

Prostatein or steroid binding protein (PSBP) induces experimental autoimmune prostatitis (EAP) in NOD mice

Antigen-pulsed dendritic cells (DCs) have been used extensively as cellular vaccines to induce a myriad of protective immune responses. Adoptive transfer of antigen-pulsed DCs is especially effective at generating Th1 and CD8 immune responses. However, recently this strategy has been shown to induce Th2 cells when DCs are administered locally into the respiratory tract. We sought to address whether systemic rather than local antigen-pulsed DC administration could induce Th2 experimental allergic asthma. We found that OVA-pulsed splenic DCs injected intraperitoneally induced polarized Th2 allergic lung disease upon secondary OVA aerosol challenge. Disease was characterized by eosinophilic lung inflammation, excess mucus production, airway hyperresponsiveness, and OVA-specific IgG1 and IgE. In addition, unusual pathology characterized by macrophage alveolitis and multinucleated giant cells was observed. These data show that systemic administration of antigen-pulsed DCs and subsequent aeroantigen challenge induces Th2 immunity. These findings have important implications for the development of DC-based vaccines.     

Differential control of CD4+ T‐cell subsets by the PD‐1/PD‐L1 axis in a mouse model of allergic asthma

Studies examining the role of PD‐1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD‐1/PD‐L1 has distinct influences on different CD4⁺ T‐cell subsets. PD‐1/PD‐L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2‐type immune response, but by allowing the development of a concomitant Th17‐type immune response. Supporting differential CD4⁺ T‐cell responsiveness to PD‐1‐mediated inhibition, naïve PD‐1^?/? mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD‐1 in WT cells limited cytokine production by in vitro polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro polarized Th2 cells. Furthermore, PD‐1 ligation enhanced Th2 cytokine production by naïve T cells cultured under nonpolarizing conditions. These data demonstrate that different CD4⁺ T‐cell subsets respond differentially to PD‐1 ligation and may explain some of the variable results observed in control of allergic asthma by the PD‐1 family members. As the PD‐1/PD‐L1 axis limits asthma severity by constraining Th17 cell activity, this suggests that severe allergic asthma may be associated with a defective PD‐1/PD‐L1 regulatory axis in some individuals.     

Atopic disorders: a vaccine around the corner?

The incidence and severity of atopic disorders, in particular asthma, is steadily increasing at an alarming rate. Furthermore, no primary prevention measure exists to date. However, recent results obtained from numerous animal studies suggest that primary prevention in humans might be possible in the near future. The most promising approaches include the induction of systemic or local allergen-dependent or -independent T helper 1 (Th1) immune responses, through the use of killed bacteria (or components derived from them), CpG oligodeoxynucleotides or plasmid DNA, and the induction of allergen-specific T-cell tolerance. Here, we review the data showing that animals can be protected from developing allergic Th2 responses by vaccination. Possible future use in humans and potential side-effects of the described vaccination strategies are discussed also.     

IL-10 serum levels in children with moderate asthma

Levels of an interleukin 10 (IL-10) are reduced in asthmatic patients in comparison to healthy subjects. Fact, that IL-10 is produced by Th1 and that inhibits cytokine production by Th2 lymphocytes has led to the concept that IL-10 might be beneficial in mitigating allergic inflammation. The purpose of this study was to define the effect of 4 week monotherapy with triamcinolone acetonide or nedocromil sodium on the serum level of IL-10, bronchial hyperresponsiveness and clinical parameters in atopic asthma children. It was an 8 week, randomised, double-blind trial of 37 children with moderate asthma allergic to house dust mite. Patients were randomly allocated to receive 200 mcg triamcinolone twice daily (n = 18), or 0.004 g nedocromil four times daily (n = 19). Thirty children completed the study. After treatment with triamcinolone the level of IL-10 in blood serum significantly increased, bronchial hyperreactivity significantly decreased, and all clinical parameters improved. Mean IL-10 levels in serum before and after treatment with triamcinolone were 7.5 pg/ml with 95%CI 6.79%-8.22% and 14.21 pg/ml with 95%CI 11.33%-17.09% respectively (p < 0.001). After treatment with nedocromil, clinical symptoms improved significantly, IL-10 serum levels and bronchial hyperreactivity did not change significantly (p = 0.094 and p = 0.09 respectively). This study demonstrates that one possible way by which triamcinolone contribute to inhibition of inflammation is by effect on IL-10.     

Atopy and bronchial reactivity in Australian and Melanesian populations

In order to compare the prevalence of atopy and bronchial hyperreactivity among Papua New Guinian (P.N.G.) and Australian populations, skin prick tests and methacholine bronchial challenge tests were performed. A civilian and an army population from each country were examined and those with past or present asthma, recent respiratory tract infection and chronic lung disease were excluded. No statistical difference in the prevalence of atopy was found between the four populations. In the P.N.G. population 40 and 49%, and in the Australian population 27 and 39%, were found to be atopic, without symptoms of past or present allergic disease. The house dust mites were the commonest allergens in all populations. In response to methacholine (0·3 mg), only 6% of subjects had falls in 1 sec forced expiratory volume (FEV₁) of more than 12% (upper limit of normal range) and only two were in the asthmatic range. There was no correlation between the degree of bronchial hyper-reactivity and atopic status; however, the degree of bronchial hyperreactivity was slightly greater in the New Guinea civilian than in the Australian civilian population. In the absence of asthma, atopic status does not appear to cause increased bronchial reactivity, suggesting that some factor other than atopy must be present for the development of bronchial hyperreactivity characteristic of asthma.     

IL‐5‐induced airway eosinophilia – the key to asthma?

Summary: Bronchial asthma is a chronic inflammatory airway disease defined by reversible airway obstruction and non-specific airway hyper-responsiveness (AHR). Although profound insights have been made into the pathophysiology of asthma, the exact mechanisms inducing and regulating the disease are still not fully understood. Yet, it is generally accepted that the pathological changes in asthma are induced by a chronic inflammatory process which is characterized by infiltration of the bronchial mucosa with lymphocytes and eosinophils, increased mucus production and submucosal edema. There is increasing evidence that an imbalance in the T-helper (Th) cell response of genetically predisposed individuals to common environmental antigens plays a pivotal role in the pathogenesis of allergic bronchial asthma and other atopic disorders. Following allergic sensitization, T cells from atopic patients tend to produce elevated levels of Th2-type cytokines, especially interleukin (IL)-4, IL-13, IL-5 and IL-6, which induce and regulate IgE production and eosinophil airway infiltration. In this review, the role of Th2-type cytokines, IgE and airway eosinophils in the induction of airway inflammation and AHR is discussed, and animal studies of asthma and AHR, mainly in rodents will be considered. A better understanding of the underlying mechanisms leading to asthma pathology may yield more specific immunological strategies for the treatment of this disease which is increasing worldwide.
I thank the many colleagues in the laboratory of Dr. E. W. Gelfand, National Jewish Research Center, Denver CO, USA, for continuous support and encouragement. E.H. is a fellow of the Deutsche Forschungsgemeinschaft (DFG Ha 2162/1-1 and 2-1).     

Possible reasons for lack of effect of allergen avoidance in atopy-prone infants and sensitive asthmatic patients

The basic paradigm that allergen exposure produces atopic sensitization, and that continued exposure leads to clinical asthma throughout the development of airway inflammation and bronchial hyperreactivity has been challenged. However, because it was observed that epidemiological evidence suggests that around 40% of asthma cases are attributable to atopy (even using restrictive criteria), the obvious corollary is that if allergen avoidance begins before the onset of sensitization (primary prevention), then it should be associated with a reduced number of new cases of the disease. However, there are conflicting results regarding the effect of allergen avoidance on primary prevention of atopic sensitization and asthma onset. Instead, more uniform and positive results are available from secondary prevention studies. Secondary prevention obviously is an attractive opportunity for pediatricians who may recognize the patients who might benefit from these interventions simply by screening for food allergy in young children with atopic dermatitis. The conflicting results of tertiary prevention are most frequently observed in adult patients and sometimes result from incomplete avoidance of allergens responsible for the sensitization.     

树突细胞与哮喘Th1/Th2失衡

特应性哮喘患者以Th2免疫反应为主,导致气道炎症,Th1／Th2失衡是特庆性哮喘重要的免疫病理机制,树突细胞（DCs）中肺部主要抗原递呈细胞,不但可以介志对吸入抗原初始的免疫反应,活化辅助性T细胞,而且在可以决定T细胞的分化方向,维持哮喘Th2免疫反应和Th1／Th2失衡机制中发挥重要作用而日益受到重视。本文就近年来对特应性哮喘免疫病理机制中DCs对Th1／Th2失衡影响认识作一综述。     

Characterization of T cell subpopulations involved in the pathogenesis of asthma and allergic diseases

Allergic asthma is a complex and heterogeneous disease which is characterized by intermittent reversible airway obstruction, chronic inflammation of the airways, bronchial hyperreactivity and an infiltration of lymphocytes and eosinophils into the airway submucosa. Animal models and clinical studies in humans have indicated an important role for T helper type 2 lymphocytes, producing IL-4, IL-5 and IL-13, in the pathogenesis of this disorder. However, although IL-4 and IL-13 have strong anti-inflammatory properties, the physiologic anti-inflammatory Th2 response does not seem to be operational in allergic asthma. Moreover, the induction of a Th1 response seems to aggravate, rather than ameliorate, its inflammatory character. This article will focus on the involvement of T lymphocyte subpopulations in the pathogenesis of allergic asthma and allergic diseases. In addition, a potential role of the subpopulation(s) of T regulatory cells in the induction and/or maintaince of the disease process will be discussed.     

Atopic march: link to upper airways

PURPOSE OF REVIEW: This review examines the role of the upper airways in the atopic march. Evidence examining the theory that allergic rhinitis precedes asthma will be discussed. In addition, the role of allergic rhinitis as an end point in the atopic march will be reviewed. RECENT FINDINGS: Ciprandi and colleagues found that nasal symptoms, airflow and markers of inflammation (eosinophils, cytokine levels) directly correlated with lower airway markers. This confirms previous studies finding that many patients with allergic rhinitis have lower airway hyperreactivity or bronchial hyperresponsiveness and the link between upper and lower airways. Leynaert and colleagues questioned over 90 000 individuals and found that patients with rhinitis have increased risk for asthma and lower airway reactivity compared with patients without rhinitis. In the German Multicenter Atopy Study, a longitudinal study of 1300 children, patients with atopic dermatitis were found to have increased risk for asthma at 7 years of age. Patients with atopic dermatitis and no wheezing in the first 3 years, however, did not have an increased risk for developing current wheezing or bronchial hyperresponsiveness at 7 years of age. It was proposed that atopic dermatitis and asthma are linked, but atopic dermatitis does not precede asthma. SUMMARY: Allergic rhinitis is a risk factor for asthma and can precede asthma in the atopic march.     

TLR4/MyD88-induced CD11b+Gr-1intF4/80+ non-migratory myeloid cells suppress Th2 effector function in the lung

In humans, environmental exposure to a high dose of lipopolysaccharide (LPS) protects from allergic asthma, the immunological underpinnings of which are not well understood. In mice, exposure to a high LPS dose blunted house dust mite-induced airway eosinophilia and T-helper 2 (Th2) cytokine production. Although adoptively transferred Th2 cells induced allergic airway inflammation in control mice, they were unable to do so in LPS-exposed mice. LPS promoted the development of a CD11b⁺Gr1^intF4/80⁺ lung-resident cell resembling myeloid-derived suppressor cells in a Toll-like receptor 4 and myeloid differentiation factor 88 (MyD88)-dependent manner that suppressed lung dendritic cell (DC)-mediated reactivation of primed Th2 cells. LPS effects switched from suppressive to stimulatory in MyD88^−/− mice. Suppression of Th2 effector function was reversed by anti-interleukin-10 (IL-10) or inhibition of arginase 1. Lineage^neg bone marrow progenitor cells could be induced by LPS to develop into CD11b⁺Gr1^intF4/80⁺cells both in vivo and in vitro that when adoptively transferred suppressed allergen-induced airway inflammation in recipient mice. These data suggest that CD11b⁺Gr1^intF4/80⁺ cells contribute to the protective effects of LPS in allergic asthma by tempering Th2 effector function in the tissue.     

IgE-mediated regulation of IL-10 and type I IFN enhances rhinovirus-induced Th2 differentiation by primary human monocytes

Rhinovirus (RV) infections are linked to the development and exacerbation of allergic diseases including allergic asthma. IgE, another contributor to atopic disease pathogenesis, has been shown to regulate DC antiviral functions and influence T cell priming by monocytes. We previously demonstrated that IgE-mediated stimulation of monocytes alters multiple cellular functions including cytokine secretion, phagocytosis, and influenza-induced Th1 development. In this study, we investigate the effects of IgE-mediated stimulation on monocyte-driven, RV-induced T cell development utilizing primary human monocyte-T cell co-cultures. We demonstrate that IgE crosslinking of RV-exposed monocytes enhances monocyte-driven Th2 differentiation. This increase in RV-induced Th2 development was regulated by IgE-mediated inhibition of virus-induced type I IFN and induction of IL-10. These findings suggest an additional mechanism by which two clinically significant risk factors for allergic disease exacerbations—IgE-mediated stimulation and rhinovirus infection—may synergistically promote Th2 differentiation and allergic inflammation.     

Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations

BACKGROUND: Early exposure to microbial matter such as LPS may influence the development of asthma and allergies by activation of innate immunity pathways as indicated by studies in farming environments. Recently, polymorphisms in caspase recruitment domain containing protein 15 (CARD15), an intracellular LPS receptor protein, have been associated with Crohn's disease. Because these polymorphisms lead to changes in LPS recognition, they may affect the development of asthma and allergies. OBJECTIVE: We genotyped a large population of German schoolchildren (N = 1872) from East and West Germany for 3 functional relevant CARD15 polymorphisms for their role in the development of asthma and allergy. METHODS: By use of parental questionnaires, skin prick testing, pulmonary function tests, bronchial challenge tests, and measurements of serum IgE levels, children were phenotyped for the presence of atopic diseases. Genotyping was performed with PCR-based restriction enzyme assays. To assess associations between atopic phenotypes and genotypes standard statistical procedures were applied. RESULTS: Children with the polymorphic allele C2722 had a more than 3-fold risk to develop allergic rhinitis (P <.001) and an almost 2-fold risk for atopic dermatitis (P <.05). Furthermore, the T2104 allele was associated with an almost 2-fold risk for allergic rhinitis (P <.05). When a C insertion at position 3020 was present, the risk of atopy increased by 50% (P <.05) and serum IgE levels were elevated (P <.01). CONCLUSION: The shared genetic background between Crohn's disease and atopy may indicate that an impaired recognition of microbial exposures results in an insufficient downregulation of excessive immune responses, giving rise to either T(H)2 dominated allergies or T(H)1 related Crohn's disease.     

Innate and adaptive type 2 immunity in lung allergic inflammation

Allergic inflammation is a type 2 immune disorder classically characterized by high levels of immunoglobulin E (IgE) and the development of Th2 cells. Asthma is a pulmonary allergic inflammatory disease resulting in bronchial hyper-reactivity. Atopic asthma is defined by IgE antibody-mediated mast cell degranulation, while in non-atopic asthma there is no allergen-specific IgE and more involvement of innate immune cells, such as basophils, group 2 innate lymphoid cells (ILC2), and eosinophils. Recently, protease allergens were shown to cause asthmatic responses in the absence of Th2 cells, suggesting that an innate cell network (IL-33/TSLP-basophil-ILC2-IL-5/IL-13 axis) can facilitate the sensitization phase of type 2 inflammatory responses. Recent evidence also indicates that in the chronic phase, these innate immune cells directly or indirectly contribute to the adaptive Th2 cell responses. In this review, we discuss the role of Th2 cytokines (IL-4 and IL-13) and innate immune cells (mast cells, basophils, ILC2s, and dendritic cells) in the cross-talk between innate and adaptive inflammatory responses.