Was Thomas Wharton Jones FRS, assistant to the infamous Dr Knox, the first to recognise the blood eosinophil?

Thomas Wharton Jones (1808-91), described as a 'genius' by his famous pupil Thomas Henry Huxley, was an Edinburgh medical graduate. At the age of 19 years he was appointed anatomy demonstrator to the infamous Dr Robert Knox so unwittingly becoming caught up in the Burke and Hare scandal. Escaping to Glasgow, and then to Cork and London, Jones eventually became an outstanding physiologist and ophthalmologist.

Paul Ehrlich and the Early History of Granulocytes.

Paul Ehrlich's techniques, published between 1879 and 1880, for staining blood films using coal tar dyes, and his method of differential blood cell counting, ended years of speculation regarding the classification of white cells. Acidic and basic dyes had allowed him to recognize eosinophil and basophil granules, respectively, work that was a direct continuation of his discovery of the tissue mast cell described in his doctoral thesis. Ehrlich went on to develop neutral dyes that identified epsilon granules in neutrophils ("cells with polymorphous nuclei").

Landmarks in Allergy during the 19th Century.

There were remarkable achievements in the 19th century in our understanding of the cells of the allergic response, the clear descriptions of hay fever and asthma, as well as the role of pollen in seasonal rhinitis. Although allergy as a concept was not developed until well into the 20th century, the foundations of our present understanding of these diseases were laid in the 1800s. The outstanding physicians and scientists of this time included Paul Ehrlich (who described mast cells, eosinophils and basophils), John Bostock (who provided the first detailed account of hay fever), Charles Blackley (who showed that pollen was the cause of hay fever), Morrill Wyman (who demonstrated that autumnal catarrh was due to ragweed pollen), Henry Hide Salter (who made the first classic description of asthma) and Henri Laënnec (the inventor of the stethoscope).

CCL17/thymus and activation-regulated chemokine induces calcitonin gene-related peptide in human airway epithelial cells through CCR4.

Background: Calcitonin gene-related peptide (CGRP) is a potent arterial and venous vasodilator. Increased airway epithelial cell expression of CGRP, together with increased CCL17 expression, was previously observed in a model of provoked asthma in atopic human subjects.

Objective: We sought to determine whether CCL17 induces CCR4-dependent CGRP synthesis and secretion by human airway epithelial cells.

Allergen-induced expression of IL-25 and IL-25 receptor in atopic asthmatic airways and late-phase cutaneous responses.

Background: IL-25 is thought to participate in allergic inflammation by propagating T(h)2-type responses.

Objective: To address the hypothesis that allergen provocation increases expression of IL-25 and its receptor IL-25R in the asthmatic bronchial mucosa and skin dermis of atopic subjects.

Methods: Sequential single and double immunostaining was used to evaluate the numbers and phenotypes of IL-25 and IL-25R immunoreactive cells in bronchial biopsies from mild atopic subjects with asthma (n = 10) before and 24 hours after allergen inhalation challenge and skin biopsies from atopic subjects (n = 10) up to 72 hours after allergen subepidermal injection.

Calcitonin gene-related peptide- and vascular endothelial growth factor-positive inflammatory cells in late-phase allergic skin reactions in atopic subjects.

Background: Allergen-induced late-phase skin reactions are characterized by erythema and edema, but the vasoactive mediators involved remain unclear. Limited evidence from human studies suggests that calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF), potent vasodilator and permeability factors, respectively, are expressed by infiltrating inflammatory cells in certain allergic tissue reactions.

Objective: We sought to determine whether tissue swelling in allergen-challenged skin sites in atopic subjects is associated with the infiltration of CGRP(+) and VEGF(+) inflammatory cells.

Development and preliminary clinical evaluation of a peptide immunotherapy vaccine for cat allergy.

Background: Allergic sensitization to cat allergens is common and represents a major risk factor for asthma. Specific immunotherapy (SIT) is effective but cumbersome and associated with IgE-dependent adverse events. Immunotherapy targeting allergen-specific T cells, with synthetic peptides representing T-cell epitopes, might improve safety and reduce the duration of treatment.

Expression of functional receptor activity modifying protein 1 by airway epithelial cells with dysregulation in asthma.

Background: Epithelial cell expression of calcitonin gene-related peptide (CGRP) is a feature of provoked asthma. Receptor activity modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor combine to form the CGRP1 receptor.

Objective: To determine whether functional RAMP1 is expressed by airway epithelial cells and whether there are alterations in asthma.

Bone morphogenetic protein (BMP)-4 and BMP-7 regulate differentially transforming growth factor (TGF)-beta1 in normal human lung fibroblasts (NHLF).

Background: Airway remodelling is thought to be under the control of a complex group of molecules belonging to the transforming growth factor (TGF)-superfamily. The bone morphogenetic proteins (BMPs) belong to this family and have been shown to regulate fibrosis in kidney and liver diseases. However, the role of BMPs in lung remodelling remains unclear.

Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma.

Background: Both transforming growth factor (TGF)-beta(1) and activin-A have been implicated in airway remodeling in asthma, but the modulation of their specific signaling pathways after disease activation remains undefined.

Objective: To define the expression kinetics of TGF-beta(1), activin-A ligands, and follistatin (a natural activin inhibitor), their type I and type II receptors (activin-like kinase[ALK]-1, ALK-5, ALK-4, TbetaRII, and ActRIIA/RIIB) and activation of signaling (via phosphorylated (p) Smad2), in the asthmatic airway after allergen challenge.

Methods: Immunohistochemistry was performed on bronchial biopsies from 15 mild atopic patients with asthma (median age, 25 years; median FEV(1)% predicted, 97%) at baseline and 24 hours after allergen inhalation.

Peptide immunotherapy in allergic asthma generates IL-10-dependent immunological tolerance associated with linked epitope suppression.

Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other ("linked") epitopes within the same molecule.

Eosinophils: biological properties and role in health and disease.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, the biology of eosinophils is summarized, focusing on transcriptional regulation of eosinophil differentiation, characterization of the growing properties of eosinophil granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of eosinophil degranulation. New views on the role of eosinophils in homeostatic function are examined, including developmental biology and innate and adaptive immunity (as well as their interaction with mast cells and T cells) and their proposed role in disease processes including infections, asthma, and gastrointestinal disorders.

Basal expression of bone morphogenetic protein receptor is reduced in mild asthma.

Rationale: Despite increasing recognition of bone morphogenetic protein (BMP) signaling in tissue remodeling, the expression pattern of ligands and signaling pathways remain undefined in the asthmatic airway.

Objectives: To determine expression of BMP ligands (BMP-2, BMP-4, and BMP-7) and type I and type II receptors (ALK-2, ALK-3, ALK-6, and BMPRII) as well as evidence for activation of BMP signaling via detection of phosphorylated Smad1/5 (pSmad1/5) expression in asthmatic airways at baseline (compared with nonasthmatic controls), and after allergen challenge.

Methods: Bronchial biopsies were obtained from 6 nonasthmatic control volunteers, and 15 atopic patients with asthma (median age, 25 yr; median FEV(1)% predicted, 97%) at baseline, then at 24 hours and 7 days after allergen challenge.

Airway hyperresponsiveness and bronchial mucosal inflammation in T cell peptide-induced asthmatic reactions in atopic subjects.

Background: Subjects with allergic asthma develop isolated late asthmatic reactions after inhalation of allergen-derived T cell peptides. Animal experiments have shown that airway hyperresponsiveness (AHR) is CD4+ cell-dependent. It is hypothesised that peptide inhalation produces increases in non-specific AHR and a T cell-dominant bronchial mucosal inflammatory response.

Remodeling and airway hyperresponsiveness but not cellular inflammation persist after allergen challenge in asthma.

Rationale: Airway hyperresponsiveness (AHR) increases up to 2 weeks after allergen inhalational challenge of subjects with asthma who show a late-phase asthmatic reaction (dual responders). Cellular inflammation and airway remodeling are increased 24 hours after allergen challenge.

Objectives: To determine whether persistence of increased AHR is associated with persistent activation of remodeling and enhanced inflammation.

The role of T lymphocytes in asthma.

There is now overwhelming evidence to support a major role for T cells in asthma, in particular the involvement of T helper type 2 (Th2) cells in atopic allergic asthma as well as nonatopic and occupational asthma. There may also be a minor contribution from T cytotoxic type 2 CD8+T cells. Several Th2 cytokines have potential to modulate airway inflammation, in particular interleukin-13 which induces airway hyperresponsiveness independently of IgE and eosinophilia in animal models.

Anti-IgE (omalizumab) inhibits late-phase reactions and inflammatory cells after repeat skin allergen challenge.

Background: Anti-IgE (omalizumab) inhibited early and late asthmatic reactions and infiltration of inflammatory cells in asthmatic bronchial biopsies at baseline. The effect of chronic allergen exposure on these outcomes is unknown. Repeat allergen challenge in human skin represents a suitable model to address this question.

The role of eosinophils in the pathogenesis of asthma.

Two recent papers have addressed the ever-intriguing question of the role of eosinophils in asthma. Both groups used experimental models of airway inflammation in mice that were gene targeted to selectively ablate the eosinophil lineage. One group found that eosinophils were required for both airway hyperresponsiveness and mucus accumulation.

T cell epitope immunotherapy induces a CD4+ T cell population with regulatory activity.

Background: Synthetic peptides, representing CD4(+) T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils.

Methods And Findings: In this study we address the mechanism of action of peptide immunotherapy (PIT) in cat-allergic, asthmatic patients.

Anti-interleukin-5 therapy for asthma and hypereosinophilic syndrome.

Interleukin 5 (IL-5) is a key cytokine in the regulation of eosinophilia and eosinophil activation in humans. Monoclonal antibodies to anti-IL-5 have become available for use in clinical studies in humans. This article discusses the rationale for the use of anti-IL-5 therapy in asthma and hypereosinophilic syndrome and summarizes the available clinical data on the use of anti-IL-5 to treat these disorders.