Biomedical subjects

Christopher J Corrigan

Publications and source records attributed to Christopher J Corrigan.

7 recordsLinked to original sources

PubMed2007

Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic patients with asthma.

BACKGROUND: Class switching from IgM/IgG/IgA to IgE is required for B cells to express IgE. This requires class switch recombination in the Ig heavy-chain gene locus. It is generally believed that class switch recombination occurs in lymphoid tissue, but it was recently shown that class switching to IgE occurs in the nasal mucosa in allergic rhinitis. OBJECTIVE: We aimed to determine whether class switching to IgE also occurs in the bronchial mucosa in asthma, and to look for possible differences/similarities between atopic and nonatopic asthma. METHODS: We have used RT-PCR to examine epsilon immunoglobulin heavy-chain germline gene transcripts (GLTs; epsilonGLTs), epsilon circle transcripts (CTs; Ivarepsilon-Cmu CT or Ivarepsilon-Cgamma CT), and mRNA encoding the heavy chain of IgE (epsilon mRNA) and activation-induced cytidine deaminase (AID) in bronchial biopsies from atopic patients with asthma, nonatopic patients with asthma, atopic controls without asthma, and nonatopic controls without asthma (10 subjects in each group). RESULTS: The varepsilonGLT and AID mRNA were detectable in the bronchial mucosa of subjects in all 4 groups. In contrast, Iepsilon-Cmu CT, Ivarepsilon-Cgamma CT, and epsilon mRNA were detectable in the bronchial mucosa of the majority of both atopic and nonatopic patients with asthma, but rarely in the controls without asthma. CONCLUSION: The bronchial mucosa is a site primed in all individuals for class switching to IgE, because of B-cell expression of epsilonGLT and AID mRNA. However, it is only in patients with asthma, regardless of atopic status, that class switching to IgE occurs. CLINICAL IMPLICATIONS: Our findings reveal prospects for local targeting of the Ig class switch mechanism in the management of atopic and nonatopic asthma.

Adult↗

PubMed2006

Germinal-centre reactions in allergic inflammation.

Primary and secondary immune responses in the germinal centres of lymphoid organs have been studied in the past. There is now compelling evidence of a third stage in the immune response, in 'tertiary lymphoid organs' that develop at sites of chronic inflammation in response to persistent local antigen challenge. Germinal-centre-like reactions are well-documented in the target organs of autoimmune diseases. Here, we review recent evidence that they also occur at sites of allergic inflammation.

Animals↗

PubMed2006

Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis.

BACKGROUND: Specific immunotherapy is widely used to treat allergic rhinitis, but few large-scale clinical trials have been performed. OBJECTIVE: We sought to assess the efficacy and safety of specific immunotherapy with 2 doses of Alutard grass pollen in patients with moderately severe seasonal allergic rhinitis inadequately controlled with standard drug therapy. METHODS: We performed a double-blind, randomized, placebo-controlled study of 410 subjects (203 randomized to 100,000 standardized quality units [SQ-U] maintenance, 104 to 10,000 SQ-U, and 103 to placebo). Three hundred forty-seven (85%) completed treatment. Groups were well matched for demographics and symptoms. RESULTS: Across the whole pollen season, mean symptom and medication scores were 29% and 32% lower, respectively, in the 100,000-SQ-U group compared with those in the placebo group (both P < .001). Over the peak pollen season, mean symptom and medication scores were 32% and 41% lower, respectively, than those in the placebo group. The 10,000-SQ-U group had 22% less symptoms than the placebo group over the whole season (P < .01), but medication scores reduced by only 16% (P = .16). Quality-of-life measures confirmed the superiority of both doses to placebo. Local and delayed side effects were common but generally mild. Clinically significant early and delayed systemic side effects were confined to the 100,000-SQ-U group, but no life-threatening reactions occurred. CONCLUSIONS: One season of immunotherapy with Alutard grass pollen reduced symptoms and medication use and improved the quality of life of subjects with moderately severe hay fever. The 100,000-SQ-U regimen was more effective, but the 10,000-SQ-U regimen caused fewer side effects.

Adolescent↗

PubMed2005

Interleukin-10-secreting "regulatory" T cells induced by glucocorticoids and beta2-agonists.

Greater clinical benefit in controlling the symptoms of asthma is frequently observed through combining moderate doses of inhaled glucocorticoids together with long-acting beta(2)-agonists, as compared with increasing glucocorticoid dosage alone. To address in vitro whether glucocorticoids plus beta(2)-agonists, compared with glucocorticoids alone, have greater inhibitory activity on CD4+ T cell responses to allergen, peripheral blood CD4+ T cell responses to allergen were compared in the presence or absence of the glucocorticoid fluticasone proprionate and the short- and long-acting beta(2)-agonists salbutamol and salmeterol, respectively. Fluticasone proprionate inhibited interleukin (IL)-5 and IL-13 and enhanced IL-10 synthesis in allergen-stimulated cultures in a concentration-dependent manner. Salmeterol, but not salbutamol, inhibited IL-5 and IL-13 and enhanced IL-10 synthesis in these cultures. When used in combination the two drugs demonstrated an additive effect on this pattern of cytokine production. Allergen-specific T cell lines induced in the presence of salmeterol and fluticasone proprionate inhibited IL-5 and IL-13 production by allergen-specific Th2 cell lines in an IL-10-dependent manner. Thus fluticasone proprionate and salmeterol increased IL-10 and reduced Th2 cytokine synthesis additively in allergen stimulated human CD4+ T cells.

Adrenergic beta-2 Receptor Agonists↗

PubMed2005

IL-4-expressing bronchoalveolar T cells from asthmatic and healthy subjects preferentially express CCR 3 and CCR 4.

BACKGROUND: The concept of the polarization of chemokine receptor expression by T(H)1 and T(H)2 cells provides an attractive mechanism for their differential recruitment to tissue, which could be subject to disease-specific therapeutic intervention. The paradigm that T(H)1 cells preferentially express CXCR 3 and CCR 5 and T(H)2 cells preferentially express CCR 3, CCR 4, and CCR 8 has been well established in the setting of in vitro polarized cell lines; however, the situation in vivo appears less clear-cut. OBJECTIVE: We sought to investigate whether this pattern of polarization can be demonstrated in human lung tissue. METHODS: We used single-cell analysis to investigate the relationship between chemokine receptor expression and cytokine production on peripheral blood and bronchoalveolar lavage fluid T cells in patients with asthma, a putative T(H)2 disease, as well as in healthy control subjects. RESULTS: We have found in both asthmatic and control subjects that IL-4-expressing blood and bronchoalveolar lavage fluid T cells are significantly more likely to express the T(H)2 type 2 chemokine receptors CCR 3 and CCR 4, with 10-fold and 2-fold differences in expression, respectively, compared with IFN-gamma-expressing cells. CONCLUSION: We have provided evidence that polarization of T(H)2-type chemokine receptors on IL-4-expressing cells can be demonstrated in an in vivo setting and therefore that these cells might indeed be susceptible to differential patterns of recruitment as a result of expression of the relevant chemokines at inflammatory sites.

Adult↗

PubMed2002

Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis.

BACKGROUND: Patients with asthma who have aspirin sensitivity have greater cysteinyl leukotriene production and greater airway hyperresponsiveness to the effects of inhaled cysteinyl leukotrienes than their aspirin-tolerant counterparts. We hypothesized that the latter effect reflects elevated expression of the cysteinyl leukotriene receptor CysLT1 on inflammatory cells in the target organ and that its expression is down-regulated by aspirin desensitization. METHODS: We obtained nasal-biopsy specimens from 22 aspirin-sensitive and 12 non-aspirin-sensitive patients with chronic rhinosinusitis and nasal polyps. Additional specimens were then obtained from subgroups of the aspirin-sensitive patients after intranasal application of lysine aspirin or placebo for two weeks (five and four patients, respectively) or for six months (five and four patients, respectively). The numbers of leukocytes expressing the CysLT1 and leukotriene B4 (LTB4) receptors per unit area of sections of the nasal submucosa were determined by immunohistochemistry. RESULTS: The absolute number of cells expressing the CysLT1 receptor was significantly higher in the aspirin-sensitive patients than in the non-aspirin-sensitive patients (median, 542 cells per square millimeter [range, 148 to 1390] vs. 116 cells per square millimeter [range, 40 to 259]; P<0.001). The percentage of CD45+ leukocytes expressing the CysLT1 receptor was also higher in the aspirin-sensitive subjects (25 percent of CD45+ leukocytes [range, 4 to 50] vs. 5 percent of CD45+ leukocytes [range, 2 to 11]; P<0.001); the percentage of CD45+ leukocytes expressing the LTB4 receptor did not differ significantly between these two groups. Desensitization was associated with a decrease in the numbers of inflammatory cells expressing CysLT1. CONCLUSIONS: The elevated numbers of nasal inflammatory leukocytes expressing the CysLT1 receptor in aspirin-sensitive patients with chronic rhinosinusitis as compared with their non-aspirin-sensitive counterparts and the down-regulation of receptor expression after desensitization to aspirin are probably fundamental in the pathogenesis of aspirin sensitivity and in the mechanism of aspirin desensitization.

Adult↗

PubMed2002

Glucocorticoid-resistant asthma.

Glucocorticoids are currently the most effective anti-inflammatory therapy for asthma. However, a small subset of asthma sufferers do not respond to clinically relevant doses of glucocorticoids and are termed "glucocorticoid resistant." These patients are characterized by increased bronchial hyperreactivity, lower morning peak expiratory flow rates, and a longer total duration of symptoms. The definition of glucocorticoid resistance is arbitrary, and a dosage and duration of oral glucocorticoid therapy that represent a completely adequate therapeutic trial have yet to be established. For research purposes, glucocorticoid-resistant asthma is defined on the basis of a lack of improvement in airway obstruction (FEV1) following a 2-week course of oral glucocorticoid therapy. Glucocorticoid resistance is associated with in vivo and in vitro alterations in cellular responses to exogenous glucocorticoids. We have implicated abnormal regulation of the activator protein I in the molecular mechanism of glucocorticoid resistance, a phenomenon that may be confined to T cells and monocytes. The identification of an alternatively spliced isoform of the glucocorticoid receptor (GR beta) has sparked interest in the functional role of this isoform and its potential involvement in the pathology of glucocorticoid resistance. Alternative therapies for this condition will have to await a better understanding of the mechanisms of glucocorticoid action.

Animals↗