Udo Herz

The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo

The cytokine IL-6 acts via a specific receptor complex that consists of the membrane-bound IL-6 receptor (mIL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). In this study, we investigated the role of IL-6R components in asthma. We observed increased levels of sIL-6R in the airways of patients with allergic asthma as compared to those in controls. In addition, local blockade of the sIL-6R in a murine model of late-phase asthma after OVA sensitization by gp130-fraction constant led to suppression of Th2 cells in the lung. By contrast, blockade of mIL-6R induced local expansion of Foxp3-positive CD4+CD25+ Tregs with increased immunosuppressive capacities. CD4+CD25+ but not CD4+CD25- lung T cells selectively expressed the IL-6R alpha chain and showed IL-6-dependent STAT-3 phosphorylation. Finally, in an in vivo transfer model of asthma in immunodeficient Rag1 mice, CD4+CD25+ T cells isolated from anti-IL-6R antibody-treated mice exhibited marked immunosuppressive and antiinflammatory functions. IL-6 signaling therefore controls the balance between effector cells and Tregs in the lung by means of different receptor components. Furthermore, inhibition of IL-6 signaling emerges as a novel molecular approach for the treatment of allergic asthma.

Role of nerve growth factor in a mouse model of allergic airway inflammation and asthma

The role of nerve growth factor (NGF), a potent mediator acting in the development and differentitation of both neuronal and immune cells, was examined in a mouse model of allergic asthma. NGF‐positive cells were detected in the inflammatory infiltrate of the lung and enhanced levels of NGF were detected in serum and broncho‐alveolar lavage fluids. Mononuclear cells in inflamed airway mucosa as well as broncho‐alveolar macrophages were identified as one source of NGF production. Splenic mononuclear cells from allergen‐sensitized mice produced NGF in response to allergen. They responded to exogenously added NGF with a dose‐dependent increase in IL‐4 and IL‐5 production and augmented IgE and IgG1 synthesis. In contrast, IFN‐γ and IgG2a levels remained unaffected. The effects were NGF specific, since they could be blocked by an anti‐NGF‐antibody. Nasal application of anti‐NGF to allergen‐sensitized mice significantly reduced IL‐4 and prevented development of airway hyperreactivity. These results show that allergic airway inflammation is accompanied by enhanced local NGF production that acts as an amplifier for Th2 effector functions and plays an important role in the development of airway hyperreactivity. Therefore it is suggested that NGF may serve as a link between the immune and nerve system.

BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model

BACKGROUND Epidemiologic studies suggest an inverse correlation between infections and development of atopy. The purpose of this study was to test the hypothesis whether a preexisting Th1-type immune response elicited by BCG immunization could suppress allergic sensitization and airway hyperreactivity in an animal model. METHODS BALB/c mice were immunized with BCG and/or sensitized to ovalbumin. RESULTS BCG immunization alone resulted in cutaneous type-IV hypersensitivity reactions to tuberculin and granulomatous lesions in the liver. Splenic mononuclear cells (MNCs) produced increased levels of IFN-gamma after activation by Concanavalin A (ConA). Ovalbumin sensitization alone resulted in increased production of IL-4 after activation by ConA. Ovalbumin-sensitized animals also demonstrated markedly elevated anti-ovalbumin IgE/IgG1 serum antibody titers and increased airway reactivity after allergen challenges by means of the airways. BCG immunization 14 days before the start of ovalbumin sensitization markedly hindered the development of allergic responses as indicated by (1) increased IFN-gamma and normalized IL-4 and IL-10 production by splenic MNCs after activation with ConA, (2) a reduced proliferation rate of splenic MNCs after ovalbumin restimulation, (3) partial prevention of ovalbumin-specific IgE/IgG1 serum antibody titers but elevated (nonallergic) anti-ovalbumin IgG2a serum antibody titers, (4) prevention of airway responsiveness, (5) reduced eosinophilic influx into the airway lumen, and (6) reduced levels of IL-4 and IL-5 in broncho alveolar lavage fluids. CONCLUSION In this model BCG immunization established a Th1-type immune response that hinders allergic sensitization and the development of increased airway reactivity.

Prevalence and role of serum IgE antibodies to the StaphylococcuS aureus–derived superantigens SEA and SEB in children with atopic dermatitis

BACKGROUND The skin of patients with atopic dermatitis exhibits a striking susceptibility to colonization and infection with Staphylococcus aureus. In this context it has been previously shown that S aureus-derived superantigens could function as classic allergens, inducing production of functionally relevant specific IgE antibodies. OBJECTIVE The aim of this study was to determine the prevalence and the role of circulating staphylococcal enterotoxin A (SEA)- and staphylococcal enterotoxin B (SEB)-specific IgE antibodies in children with atopic dermatitis. METHODS In a cross-sectional study of 58 children with atopic dermatitis, the presence of IgE antibodies to SEA and SEB was correlated with the severity of the disease and the total and other unrelated allergen-specific IgE titers and density of colonization with S aureus strains on atopic skin and episodes of superficial S aureus skin infections. RESULTS Twenty of 58 children (34%) were sensitized to superantigens (45% to SEB, 10% to SEA, 45% to SEA and SEB). In this group, severity of atopic dermatitis and levels of specific IgE to food and air allergens were significantly higher. The degree of disease severity correlated to a higher extent with the presence of SEA/SEB-specific antibodies than with total serum IgE levels. Density of colonization with superantigen-secreting S aureus strains was higher in the superantigen IgE-positive group. Sixty-three percent of these children experienced repeated episodes of superficialS aureus skin infections. CONCLUSIONS Sensitization to S aureus-derived superantigens may be involved in disease exacerbation. The presence of SEA/SEB-specific antibodies had additional explanatory value for disease severity and therefore may be helpful in the characterization of children with severe atopic dermatitis.

Role of T Cells in Atopic Dermatitis

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease. Influx of activated T cells into the skin lesions represents a hallmark in AD. Recent results indicate a dynamic T-cell-derived cytokine production in AD. In addition to the well-known TH-2 component, chronic lesions and late-phase allergic responses are characterized by an TH-1/TH-0 cytokine pattern. Although there is no doubt that aeroallergens can contribute to the elicitation of acute- and late-phase allergic responses in AD, their role in the immunopathogenesis is controversally discussed. Recent attention has been given to the long-known phenomenon of persistent colonization of AD skin with S. aureus and the potential role of S. aureus-derived superantigens. Evidence from several in vitro and in vivo studies suggests that such bacterial superantigens have the potency to trigger chronic T-cell-mediated skin inflammation. Although these data are certainly suggestive, further clinical studies are required to elucidate the role of bacterial superantigens in initiation, maintenance and, especially, chronicity of skin inflammation.

Stress enhances airway reactivity and airway inflammation in an animal model of allergic bronchial asthma.

Objective Despite the long-standing clinical assumption that stress and asthma morbidity are associated, convincing experimental evidence on mechanisms has been unavailable. A wide range of immunological, endocrinological, and neuronal pathways are known to mediate and modulate a systemic stress response. Interestingly, most of these mediators play a crucial role in initiating and perpetuating symptoms associated with bronchial asthma. To explore potential mechanisms linking stress to asthma exacerbation we developed an animal model that combines allergic airway inflammation and exposure to stress. Methods CBA/J mice were sensitized by intraperitoneal injection of ovalbumin (OVA) and challenged with OVA aerosol via the airways. Additionally, some mice were stressed by exposure to an ultrasonic stressor. Airway hyperreactivity (AHR) was measured in vitro by electric field stimulation (EFS) of tracheal smooth muscle elements. Bronchoalveolar lavage fluid (BAL) was obtained and cell numbers determined. Cytokine levels of IL-4, IL-5, and IFN-&ggr; in BAL were determined by ELISA. Results Our findings demonstrate that exogenously applied stress dramatically enhances airway reactivity in OVA-sensitized and challenged mice. Further, stress significantly increases allergen-induced airway inflammation identified by increased leukocyte (ie, eosinophil) numbers in bronchoalveolar lavage fluids. Conclusions We found further evidence that stress can indeed exacerbate airway hyperreactivity and airway inflammation in an animal model of allergic bronchial asthma and now introduce a novel murine model to identify stress-triggered pathways, including mediators as neurohormones, neuropeptides, and markers of inflammation.

The influence of infections on the development and severity of allergic disorders

The frequency and severity of atopic disorders are steadily increasing, particularly in developing countries. The reason for this observation is not clear. Recent studies indicate that infections with viruses and especially with bacteria early in life may help to inhibit allergic Th2 responses by skewing the immune system towards Th1 responses. However, infections can also lead to the exacerbation of atopic disorders.

Critical Role of Preconceptional Immunization for Protective and Nonpathological Specific Immunity in Murine Neonates

Expression of Th2 immunity against environmental Ags is the hallmark of the allergic phenotype and contrasts with the Th1-like pattern, which is stably expressed in healthy adults throughout life. Epidemiological studies indicate that the prenatal environment plays an important and decisive role in the development of allergy later in life. Since the underlying mechanisms were unclear, an animal model was developed to study the impact of maternal allergy on the development of an allergic immune response in early life. An allergic Th2 response was induced in pregnant mice by sensitization and aerosol allergen exposure. Both, IgG1 and IgG2a, but not IgE, Abs cross the placental barrier. Free allergen also crosses the placental area and was detected in serum and amniotic fluids of neonatal F1 mice. These F1 mice demonstrated a suppressed Th1 response, as reflected by lowered frequencies and reduced levels of IFN-γ production. Development of an IgE response against the same allergen was completely prevented early in life. This effect was mediated by diaplacental transfer of allergen-specific IgG1 Abs. In contrast, allergic sensitization against a different allergen early in life was accelerated in these mice. This effect was mediated by maternal CD4 and OVA-specific Th2 cells induced by allergic sensitization during pregnancy. These data indicate a critical role for maternal T and B cell response in shaping pre- and postnatal maturation of specific immunity to allergens.

Levels of Antibodies Specific to Tetanus Toxoid, Haemophilus influenzae Type b, and Pneumococcal Capsular Polysaccharide in Healthy Children and Adults

ABSTRACT Antibody levels specific for capsular polysaccharides of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) and for tetanus toxoid were measured in serum samples of 386 age-stratified subjects. The study group consists of healthy adult blood donors and hospitalized children undergoing elective surgery, excluding individuals with a history of infection. In children, anti-tetanus toxoid antibody levels displayed two peaks of 1.20 IU/ml (20.4 mg/liter) and 1.65 IU/ml (28.1 mg/liter) related to the schedule of routine childhood immunization in the first year and at 8 years of age. Eighty percent of the antibodies are of the immunoglobulin G1 (IgG1) isotype. For pneumococcal capsular polysaccharide (PCP), the specific antibody levels represent the acquisition of natural immunity. The initial concentration of 9.2 mg/liter was low in infancy (0.5 to 1 years of age) and remained low until 3 to 4 years of age (14.6 mg/liter). During this period PCP antibodies were almost 100% of the IgG2 subclass. Thereafter, IgG anti-PCP antibody titers increased steadily to adult levels (59.5 mg/liter). The data are intended to provide reference ranges to aid in the interpretation of specific antibody determinations in the clinical setting.

α-Melanocyte-Stimulating Hormone Inhibits Allergic Airway Inflammation

α-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide controlling melanogenesis in pigmentary cells. In addition, its potent immunomodulatory and immunosuppressive activity has been recently described in cutaneous inflammatory disorders. Whether α-MSH is also produced in the lung and might play a role in the pathogenesis of inflammatory lung conditions, including allergic bronchial asthma, is unknown. Production and functional role of α-MSH were investigated in a murine model of allergic airway inflammation. α-MSH production was detected in bronchoalveolar lavage fluids. Although aerosol challenges stimulate α-MSH production in nonsensitized mice, this rapid and marked stimulation was absent in allergic animals. Treatment of allergic mice with α-MSH resulted in suppression of airway inflammation. These effects were mediated via IL-10 production, because IL-10 knockout mice were resistant to α-MSH treatment. This study provides evidence for a novel function of α-MSH linking neuroimmune functions in allergic airway inflammation.