Intracellular signaling mechanisms regulating the activation of human?eosinophils by the novel Th2 cytokine IL-33: implications for allergic?inflammation

The novel interleukin (IL)-1 family cytokine IL-33 has been shown to activate T helper 2 (Th2) lymphocytes, mast cells and basophils to produce an array of proinflammatory cytokines, as well as to mediate blood eosinophilia, IgE secretion and hypertrophy of airway epithelium in mice. In the present study, we characterized the activation of human eosinophils by IL-33, and investigated the underlying intracellular signaling mechanisms. IL-33 markedly enhanced eosinophil survival and upregulated cell surface expression of the adhesion molecule intercellular adhesion molecule (ICAM)-1 on eosinophils, but it suppressed that of ICAM-3 and L-selectin. In addition, IL-33 mediates significant release of the proinflammatory cytokine IL-6 and the chemokines CXCL8 and CCL2. We found that IL-33-mediated enhancement of survival, induction of adhesion molecules, and release of cytokines and chemokines were differentially regulated by activation of the nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathways. Furthermore, we compared the above IL-33 activities with two structurally and functionally related cytokines, IL-1β and IL-18. IL-1β, but not IL-18, markedly upregulated cell surface expression of ICAM-1. IL-1β and IL-18 also significantly enhanced eosinophil survival, and induced the release of IL-6 and chemokines CXCL8 and CCL2 via the activation of the NF-κB, p38 MAPK and ERK pathways. Synergistic effects on the release of IL-6 were also observed in combined treatment with IL-1β, IL-18 and IL-33. Taken together, our findings provide insight into IL-33-mediated activation of eosinophils via differential intracellular signaling cascades in the immunopathogenesis of allergic inflammation.     

Relation of early antibiotic use to childhood asthma: confounding by indication?

Background Findings from studies of the relation between early antibiotic use and subsequent asthma have been inconsistent, which may be attributable to methodologic issues. Objective Our objective was to assess the impact of confounding by indication on the relation of early antibiotic use to childhood asthma through age 5 in a non‐selected birth cohort (n=424). Methods Oral antibiotic use was assessed by frequent nurse interviews in the first 9 months of life. Physician‐diagnosed active asthma and eczema were assessed by questionnaire at 1, 2, 3, and 5 years, and were considered as ever asthma or ever eczema if positive at any age. Allergen‐specific IgE was assessed in plasma at 1, 2, 3, and 5 years. Confounding by indication was investigated by considering the relation of asthma to antibiotic use while controlling for the number of illness visits to a physician in early life. Results There was no statistically significant relation of early antibiotic use with physician‐diagnosed eczema or allergen‐specific IgE. A dose–response relation was evident for antibiotic use with ever asthma (odds ratio [OR]=1.5, P=0.047). Ever asthma also increased significantly with the number of illness visits to a physician (P<0.001). After adjustment for number of illness visits, antibiotic use showed no relation with asthma. Conclusions The relation of asthma to antibiotics in this cohort appears to be an artefact of the strong relation of number of physician visits for illness with both antibiotic use and risk for asthma. Cite this as: Y. Su, J. Rothers, D. A. Stern, M. Halonen and A. L. Wright, Clinical & Experimental Allergy, 2010 (40) 1222–1229.     

Treatments for food allergy: how close are we?

Food allergy continues to be a challenging health problem, with prevalence continuing to increase and anaphylaxis still an unpredictable possibility. While improvements in diagnosis are more accurately identifying affected individuals, treatment options remain limited. The cornerstone of treatment relies on strict avoidance of the offending allergens and education regarding management of allergic reactions. Despite vigilance in avoidance, accidental ingestions and reactions continue to occur. With recent advances in the understanding of humoral and cellular immune responses in food allergy and mechanisms of tolerance, several therapeutic strategies for food allergies are currently being investigated with the hopes of providing a cure or long-term remission from food allergy.     

β2-Agonists for asthma

Inhaled beta-agonists are commonly prescribed for the treatment of wheezing disorders in infants and children. Despite this, there are concerns that these medications have potentially detrimental effects on lung health and symptoms. We will review the ontogeny of beta-agonist receptor and smooth muscle development from fetal life through infancy and childhood as well as the evidence supporting the clinical utility of beta-agonists in wheezing infants and asthmatic children. Finally, the potential detrimental effects of long- and short-acting beta-agonists in infants and children are discussed.     

Murine models and cell lines for the investigation of pheochromocytoma: applications for future therapies?

Pheochromocytomas (PCCs) are slow-growing neuroendocrine tumors arising from adrenal chromaffin cells. Tumors arising from extra-adrenal chromaffin cells are called paragangliomas. Metastases can occur up to approximately 60% or even more in specific subgroups of patients. There are still no well-established and clinically accepted “metastatic” markers available to determine whether a primary tumor is or will become malignant. Surgical resection is the most common treatment for non-metastatic PCCs, but no standard treatment/regimen is available for metastatic PCC. To investigate what kind of therapies are suitable for the treatment of metastatic PCC, animal models or cell lines are very useful. Over the last two decades, various mouse and rat models have been created presenting with PCC, which include models presenting tumors that are to a certain degree biochemically and/or molecularly similar to human PCC, and develop metastases. To be able to investigate which chemotherapeutic options could be useful for the treatment of metastatic PCC, cell lines such as mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells have been recently introduced and they both showed metastatic behavior. It appears these MPC and MTT cells are biochemically and molecularly similar to some human PCCs, are easily visualized by different imaging techniques, and respond to different therapies. These studies also indicate that some mouse models and both mouse PCC cell lines are suitable for testing new therapies for metastatic PCC.     

TNF-blocking therapies: an alternative mode of action?

Despite expanding use of drugs blocking tumour necrosis factor (TNF), their precise mechanisms of action remain unclear. Early assumptions that they act by direct neutralization of the toxic inflammatory effects of TNF might be too simplistic because they explain neither the range of effects observed nor the varying properties of different TNF-blocking agents. Recent studies have demonstrated a key role for mast cell-derived TNF in the increase in lymph node size and the organizational complexity that accompanies a developing immune response. Regulation of this phenomenon might comprise a novel mode of action for TNF-directed therapy: by preventing this lymph node hyperplasia, TNF blockade could modulate immune responses, ameliorating pathology in autoimmune diseases, such as rheumatoid arthritis.     

Autoimmune disease: A role for new anti-viral therapies?

Many chronic human diseases may have an underlying autoimmune mechanism. In this review, the author presents a case of autoimmune CIU (chronic idiopathic urticaria) in stable remission after therapy with a retroviral integrase inhibitor, raltegravir (Isentress). Previous reports located using the search terms "autoimmunity" and "anti-viral" and related topics in the pubmed data-base are reviewed suggesting that novel anti-viral agents such as retroviral integrase inhibitors, gene silencing therapies and eventually vaccines may provide new options for anti-viral therapy of autoimmune diseases. Cited epidemiologic and experimental evidence suggests that increased replication of epigenomic viral pathogens such as Epstein-Barr Virus (EBV) in chronic human autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus Erythematosus (SLE), and multiple sclerosis (MS) may activate endogenous human retroviruses (HERV) as a pathologic mechanism. Memory B cells are the reservoir of infection of EBV and also express endogenous retroviruses, thus depletion of memory b-lymphocytes by monoclonal antibodies (Rituximab) may have therapeutic anti-viral effects in addition to effects on B-lymphocyte presentation of both EBV and HERV superantigens. Other novel anti-viral therapies of chronic autoimmune diseases, such as retroviral integrase inhibitors, could be effective, although not without risk.     

Immunoregulation via 'bystander suppression' needs minute amounts of substances--a basis for homeopathic therapy?

One of the main characteristics of homeopathic drugs is the low concentration of substances they contain. In most discussions this serves as the predominant argument against homeopathic treatments. The small amount of ingredients is in most instances considered not to be able to induce significant changes in classical pharmacological models. A few years ago researchers at the Harvard Medical School in Boston observed that the auto-reactivity ofT-cells is managed by the immune system in at least two different ways that obviously were dependent upon the concentration of the antigen they encounter: If they see high concentrations of a self-antigen they are deleted (killed), but when given low doses they undergo a special kind of active inhibition (called 'bystander suppression'). We feel that this type of regulation induced by very low substance concentrations could serve as a model to explain the way in which at least some homeopathic pharmaceuticals mediate their therapeutic effects.