Kerstin Gerhold

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.

The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment

RA is known to be associated with an increased risk of serious infection. Even more than 50 years ago, observational studies showed a greater than 2-fold increased risk of serious infection in RA. This was reinforced by various subsequent cohort studies. The elevated susceptibility of patients with RA can be explained by the pathobiology of the disease itself, the impact of chronic comorbid conditions, as well as sequelae of immunosuppressive treatment. It has been suggested that premature ageing of the immune system in RA contributes to weakened protection against infectious organisms. In addition, chronic comorbid conditions such as diabetes or chronic lung or kidney disease, disease-related functional disability, as well as lifestyle factors such as smoking, increase the risk in individual patients. For a long time glucocorticoids (GCs) have been used as potent immunosuppressive drugs in RA. There is evidence that they increase the risk of serious infections up to 4-fold in a dose-dependent manner. TNF-α inhibitors increase the serious infection risk up to 2-fold. They have, however, the potential to outweigh their risk when higher GC doses can be tapered down. If patients need higher dosages of GCs in addition to treatment with biologic agents, their risk of infection is substantial. This combination should be used carefully and, if possible, avoided in patients with additional risk factors such as older age or comorbid conditions.

Oral application of bacterial lysate in infancy decreases the risk of atopic dermatitis in children with 1 atopic parent in a randomized, placebo-controlled trial.

BACKGROUND Lower prevalence of atopy was found in children with continuous exposure to livestock and thus to microbial compounds. In animal models exposure to endotoxin (LPS) decreases allergic sensitization and airway inflammation. OBJECTIVE We sought to evaluate the effect of orally applied bacterial lysate in infancy on the prevalence of atopic dermatitis (AD) after the treatment phase at 7 months of age. METHODS This randomized, placebo-controlled trial included 606 newborns with at least single heredity for atopy. From week 5 until the end of month 7, infants were treated orally with bacterial lysate containing heat-killed gram-negative Escherichia coli Symbio and gram-positive Enterococcus faecalis Symbio or its placebo. Children were followed until 3 years of age. RESULTS There was no difference in the primary outcome between the active and placebo groups in the total study group. AD prevalence was significantly reduced at the end of the intervention phase (31 weeks of age) in the subgroup of infants with single heredity for atopy (relative risk, 0.52; 95% CI, 0.3-0.9). Ten percent (15/154) of infants in the active group had AD compared with 19% (27/145, P = .030) in the placebo group. This was more pronounced in the group of infants with paternal heredity for atopy (11% vs 32%, P = .004; relative risk, 0.34; 95% CI, 0.2-0.7). CONCLUSION Feeding of bacterial lysate might have prevented the development of AD, especially in children with paternal atopy, possibly indicating a preventive property only in subjects with a limited risk for atopy.

New insights into the hygiene hypothesis in allergic diseases: Mediation of sibling and birth mode effects by the gut microbiota

There is convincing evidence from both human and animal studies suggesting that the infant intestinal microbiota plays an important role in regulating immune responses associated with the development of allergic diseases. To date there are, however, still no definite bacterial taxa or particular subsets of the microbiota that have been consistently associated with allergic diseases, which is mainly attributable to the methodological dissimilarities between studies. As such there is a need to apply different methodological concepts to enhance a deeper and more refined understanding of the relationship between the gut microbiota and allergies. Within our recent studies we reported that colonization by clostridia in early infancy increased the risk of atopic dermatitis. Using subsequent mediation analysis, we demonstrated that birth mode and having older siblings strongly impacted the infant microbiota which in turn affected the risk of atopic dermatitis. The results of these mediation analyses contributed stronger evidence for a causal link of birth mode and birth order on allergy risk through modulation of the microbiota composition.

Health-related quality of life in patients with long-standing rheumatoid arthritis in the era of biologics: data from the German biologics register RABBIT

Objective. To compare the 24-month course of health-related quality of life (HRQoL) in patients with long-standing RA treated with a conventional synthetic (cs) or a first, second or third biologic (b) DMARD in daily rheumatological care. Methods. Patients enrolled in the German biologics register RABBIT who were observed over at least 12 months were stratified according to the nth bDMARD started at enrolment. HRQoL was captured by the SF36 health survey. Within strata of sequential bDMARD therapy, we examined patients’ HRQoL at baseline and at follow-ups in comparison with the general population, the 24-month course of HRQoL of different bDMARDs and the proportion of patients exceeding the minimal detectable improvement of physical and mental health sum scores. Results. All patients reported remarkably lower scores of physical and mental health than the general population at baseline and month 12. In each stratum of sequential bDMARD therapy, patients improved significantly by month 12 and remained stable until month 24. The improvement of HRQoL was not attributable to a particular bDMARD. The following proportions of patients exceeded the minimal detectable improvement of at least 17.85 Physical Component Scale scores or 22.18 Mental Component Scale score points: csDMARD (n = 1113) 31.1%/22.3%, first bDMARD (n = 1352) 39.9%/29.7%, second bDMARD (n = 730) 37.3%/26.2% and third bDMARD (n = 680) 34.2%/30.9%. Conclusion. Lasting improvement of both physical and mental health is achievable even for severely affected RA patients with a history of more than one bDMARD failure. Nevertheless, impairment of HRQoL in RA patients is enormous compared with the general population.

Oral administration of desloratadine prior to sensitization prevents allergen‐induced airway inflammation and hyper‐reactivity in mice

Background Histamine‐1‐receptor (H1R)‐antagonists were shown to influence various immunological functions on different cell types and may thus be employed for immune‐modulating strategies for the prevention of primary immune responses.

Endotoxins and allergy: lessons from the murine model.

Exposure early in life to organic dusts containing immunomodulatory components such as endotoxins and immunizing components such as aeroallergens may greatly influence whether subsequent encounters with allergens lead rather to sensitization or unresponsiveness. We investigated the effects of endotoxin in the context of allergen-mediated immune responses in a murine model of allergen sensitization. Systemic sensitization with ovalbumin induced high serum levels of allergen-specific IgE, predominant Th2-type cytokine production, eosinophilic airway inflammation and in vivo airway hyperreactivity. Endotoxins were either applied systemically prior to sensitization, or via the airways prior to airway challenges, or by repeated inhalation during the first weeks of life prior to subsequent sensitization. Different effects of endotoxins on allergen-induced immune responses may be attributed to differences in dosing, route of application, time relationship with allergen sensitization and the concurrent exposure to endotoxin and allergen. The results of these studies may help to define the effects of endotoxin on allergen-mediated immune reactions and to further delineate the important interrelationships between environment and disease development. Finally, this may lead to new strategies in the prevention and treatment of allergic diseases.

Prenatal allergen exposures prevent allergen‐induced sensitization and airway inflammation in young mice

Immune‐modulation such as tolerance induction appears to be an upcoming concept to prevent development of atopic diseases. Pregnancy might present a critical period for preventing allergic sensitization of the progeny. We investigated the effect of maternal allergen exposures during pregnancy on allergen‐induced sensitization and airway inflammation in the offspring in a murine model.

Intranasal delivery of whole influenza vaccine prevents subsequent allergen‐induced sensitization and airway hyper‐reactivity in mice

Background Infection with influenza virus has been associated with seemingly opposing effects on the development of asthma. However, there are no data about the effects of mucosal vaccination with inactivated influenza on the inception of allergic asthma.

Lipopolysaccharides modulate allergen-specific immune regulation in a murine model of mucosal tolerance induction.

Background: Farming has been widely reported to be associated with decreased risk of developing atopic disorders, but underlying immunomodulatory mechanisms are still not fully defined. We delineated T-cell functions after induction of mucosal tolerance in the context of intranasally delivered organic dust compounds, lipopolysaccharides (LPS). Methods: BALB/c mice were pretreated intranasally with ovalbumin (OVA) with or without LPS (Escherichia coli) three times (days –21, –14, –7) prior to systemic OVA sensitization (days 1 and 14) and airway allergen challenges (days 28–30). CD4+ spleen T cells from pretreated and sensitized donors were characterized for cytokine function, and transferred into naive recipients prior to subsequent OVA sensitization and challenges. Results: Intranasal OVA pretreatment suppressed Th2-mediated immune and inflammatory responses and enhanced frequency of regulatory T cells in OVA-sensitized and -challenged mice. Addition of LPS to OVA, but not LPS alone, inhibited development of allergen-induced sensitization and eosinophilic airway infiltration, and markedly enhanced allergen-specific IgG1 serum levels and frequencies of IL-10- and IFN-γ-producing CD4+ T cells. Transfer of CD4+ spleen T cells from OVA-pretreated animals protected naive recipients against subsequent allergen sensitization and airway disease, whereas transfer from LPS/OVA-pretreated animals only protected against allergen sensitization. Conclusion: Microbial LPS modulated mucosal tolerance by inducing allergen-specific IgG1 production and distinct effector CD4+ T cells with a mixed regulatory/Th1 phenotype. Organic dust components such as LPS might therefore be important immune modulators in naturally occurring or preventive allergen-specific tolerance induction.