Background
Local tissue eosinophilia and Th2 cytokines are characteristic features of seasonal allergic rhinitis. Airway remodelling is a feature of asthma whereas evidence for remodelling in ...allergic rhinitis (AR) is conflicting.
Objective
By use of a novel human repetitive nasal allergen challenge (RAC) model, we evaluated the relationship between allergic inflammation and features of remodelling in AR.
Methods
Twelve patients with moderate–severe AR underwent 5 alternate day challenges with diluent which after 4 weeks were followed by 5 alternate day challenges with grass pollen extract. Nasal symptoms, Th1/Th2 cytokines in nasal secretion and serum were evaluated. Nasal biopsies were taken 24 hours after the 1st and 5th challenges with diluent and with allergen. Sixteen healthy controls underwent a single challenge with diluent and with allergen. Using immunohistochemistry, epithelial and submucosal inflammatory cells and remodelling markers were evaluated by computed image analysis.
Results
There was an increase in early and late‐phase symptoms after every allergen challenge compared to diluent (both P < .05) with evidence of both clinical and immunological priming. Nasal tissue eosinophils and IL‐5 in nasal secretion increased significantly after RAC compared to corresponding diluent challenges (P < .01, P = .01, respectively). There was a correlation between submucosal mast cells and the early‐phase clinical response (r = 0.79, P = .007) and an association between epithelial eosinophils and IL‐5 concentrations in nasal secretion (r = 0.69, P = .06) in allergic rhinitis. No differences were observed after RAC with regard to epithelial integrity, reticular basement membrane thickness, glandular area, expression of markers of activation of airway remodelling including α‐SMA, HSP‐47, extracellular matrix (MMP7, 9 and TIMP‐1), angiogenesis and lymphangiogenesis for AR compared with healthy controls.
Conclusion
Novel repetitive nasal allergen challenge in participants with severe persistent seasonal allergic rhinitis resulted in tissue eosinophilia and increases in IL‐5 but no structural changes. Our data support no link between robust Th2‐inflammation and development of airway remodelling in AR.
Background
Chronic rhinosinusitis with nasal polyps (NP) and allergic rhinitis (AR) is characterized by local Th2 inflammation and up‐regulation of IgE; however, IgE in NP is ‘polyclonal’ and ...allergen specific, whereas IgE in AR is ‘oligoclonal’ and allergen specific. Germinal center (GC) reactions occur in AR, while only the formation of GC‐like structures in NP is described. The aim of this study was to investigate the involvement of local IgE production, class switch recombination, and receptor revision in NP.
Methods
We compared the levels of local IgE, germline gene transcripts, and mature Ig mRNA expression, recombination activating gene (RAG1 and RAG2), key markers of Th2 inflammation, and GC reactions in NP tissue vs AR and control tissue. Nasal mucosa was immunostained for the co‐expression of RAG1 and RAG2 in B cells, plasma cells, and T cells, using dual or triple immunofluorescence (IF).
Results
In NP, local IgE level and key markers of local class switching are increased compared with AR and normal controls (NC). In NP, switch circle transcripts reveal ongoing local class switch recombination to IgE. Up to 30% of B cells, plasma cells, and T cells in nasal polyps re‐express both RAG1 and RAG2, required for receptor revision. RAG1 and RAG2 mRNA concentrations are increased in NP and correlated with the magnitude of inflammation and the presence of S. aureus enterotoxin (superantigen)‐specific IgE in the nasal polyp mucosa.
Conclusion
Our results provide the first evidence of local receptor revision and class switching to IgE, and B‐cell differentiation into IgE‐secreting plasma cells in NP.
Background Regulatory T (Treg) cells play an important role in controlling allergic inflammation. The transcription factor Foxp3 regulates the development and function of natural and adaptive CD4+ ...CD25+ Treg cells. Objectives We sought to examine the effect of grass pollen injection immunotherapy on the numbers of Foxp3+ CD4+ and Foxp3+ CD25+ T cells in and out of season and their expression of IL-10 in the nasal mucosa of patients with hay fever. Methods Nasal biopsy specimens were obtained from untreated patients with hay fever, participants with grass pollen allergy who had received 2 years of immunotherapy, and healthy control subjects. Dual-immunofluorescence microscopy was used to enumerate and colocalize Foxp3 expression to CD4+ and CD25+ T cells in the nasal mucosa. Triple staining was performed to colocalize Foxp3+ cells to CD3+ CD25+ and CD3+ IL-10–expressing cells. Results At peak season, numbers of Foxp3+ CD25+ ( P = .02) and Foxp3+ CD4+ ( P = .03) cells were significantly increased in the nasal mucosa of immunotherapy-treated patients compared with numbers before treatment. Foxp3+ CD25+ ( P = .03) and Foxp3+ CD4+ ( P = .04) cells were also greater in immunotherapy-treated patients out of season compared with those in untreated patients with hay fever. Within the immunotherapy-treated group, 20% of CD3+ CD25+ cells expressed Foxp3, and 18% of Foxp3+ CD3+ cells were IL-10 positive. Conclusion The presence of local Foxp3+ CD25+ CD3+ cells in the nasal mucosa, their increased numbers after immunotherapy, and their association with clinical efficacy and suppression of seasonal allergic inflammation support a putative role for Treg cells in the induction of allergen-specific tolerance in human subjects.
Background
Myeloid (m) and plasmacytoid (p) dendritic cells (DCs) regulate immune responses to allergens, whereas it remains unclear whether abnormal DC function characterizes patients with airway ...allergy and whether putative dysfunction exists only in target organs. To evaluate DC function from patients with allergic rhinitis (AR), we assessed nasal, cutaneous as well as blood DCs after in vivo and in vitro allergen challenge, respectively.
Methods
DCs were immunostained in nasal and skin tissues, and cytokine expression was assessed by dual immunofluorescence. Cytokine production and regulation of cocultured peripheral CD4+ T cells were assayed by ELISA.
Results
In AR patients, local allergen challenge resulted in increases in pDC and mDC numbers at 8 h in the nasal mucosa and at 8–48 h in the skin. Defects in IL‐10 and IFN‐α were observed in both organs from AR. Blood mDCs from AR exhibited reduced IL‐10 and IL‐12 expression. The capacity of activated pDCs from AR to produce IFN‐α and to trigger IL‐10 by allogeneic CD4+ T cells was diminished, whereas mDCs from these patients supported Th2‐ and Th17‐cell differentiation.
Conclusion
In allergic rhinitis, DCs are altered not only locally but also in the systemic circulation. mDCs and pDCs increased in airway and skin tissues exposed to the allergen and displayed reduced production of IL‐10 and ‘type 1 signals’ (IL‐12, IFN‐α) both locally and in blood. Functional studies showed that this results in preferential Th2/Th17‐cell polarization and impaired generation by blood DCs of IL‐10+ T cells, linking systemic DC dysfunction and biased T‐cell responses.
Degenerative cervical myelopathy encompasses a spectrum of age-related structural changes of the cervical spine that result in static and dynamic injury to the spinal cord and collectively represent ...the most common cause of myelopathy in adults. Although cervical myelopathy is determined clinically, the diagnosis requires confirmation via imaging, and MRI is the preferred modality. Because of the heterogeneity of the condition and evolution of MRI technology, multiple techniques have been developed over the years in an attempt to quantify the degree of baseline severity and potential for neurological recovery. In this review, these techniques are categorized anatomically into those that focus on bone, ligaments, discs, and the spinal cord. In addition, measurements for the cervical spine canal size and sagittal alignment are also described briefly. These tools have resulted collectively in the identification of numerous useful parameters. However, the development of multiple techniques for assessing the same feature, such as cord compression, has also resulted in a number of challenges, including introducing ambiguity in terms of which methods to use and hindering effective comparisons of analysis in the literature. In addition, newer techniques that use advanced MRI are emerging and providing exciting new tools for assessing the spinal cord in patients with degenerative cervical myelopathy.
T regulatory cells and IL-10 have been implicated in the mechanism of immunotherapy in patients with systemic anaphylaxis following bee stings. We studied the role of IL-10 in the induction of ...clinical, cellular, and humoral tolerance during immunotherapy for local mucosal allergy in subjects with seasonal pollinosis. Local and systemic IL-10 responses and serum Ab concentrations were measured before/after a double-blind trial of grass pollen (Phleum pratense, Phl P) immunotherapy. We observed local increases in IL-10 mRNA-positive cells in the nasal mucosa after 2 years of immunotherapy, but only during the pollen season. IL-10 protein-positive cells were also increased and correlated with IL-10 mRNA(+) cells. These changes were not observed in placebo-treated subjects or in healthy controls. Fifteen and 35% of IL-10 mRNA signals were colocalized to CD3(+) T cells and CD68(+) macrophages, respectively, whereas only 1-2% of total CD3(+) cells and 4% of macrophages expressed IL-10. Following immunotherapy, peripheral T cells cultured in the presence of grass pollen extract also produced IL-10. Immunotherapy resulted in blunting of seasonal increases in serum allergen Phl p 5-specific IgE, 60- to 80-fold increases in Phl p 5-specific IgG, and 100-fold increases in Phl p 5-specific IgG4. Post-immunotherapy serum exhibited inhibitory activity, which coeluted with IgG4, and blocked IgE-facilitated binding of allergen-IgE complexes to B cells. Both the increases in IgG and the IgG "blocking" activity correlated with the patients' overall assessment of improvement. Thus, grass pollen immunotherapy may induce allergen-specific, IL-10-dependent "protective" IgG4 responses.
Long-Term Clinical Efficacy of Grass-Pollen Immunotherapy Durham, Stephen R; Walker, Samantha M; Varga, Eva-Maria ...
New England journal of medicine/The New England journal of medicine,
08/1999, Letnik:
341, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Despite advances in pharmacotherapy for grass-pollen allergy, there has been a marked increase in the prevalence of summer hay fever in countries with a Western lifestyle.
1
Although topical nasal ...corticosteroids and the new nonsedating antihistamines are highly effective in treating hay fever,
2
there remains a group of patients who have a poor response to these treatments and for whom immunotherapy is currently recommended.
3
An important question is whether allergen immunotherapy exerts a prolonged effect after it is discontinued. Such an effect would make this form of therapy attractive for prophylaxis and for early intervention.
We previously demonstrated the usefulness of . . .
Summary
Background
The mechanisms of sublingual immunotherapy (SLIT) are less well understood than those of subcutaneous immunotherapy (SCIT).
Objectives
To determine the effects of grass‐pollen SLIT ...on oral mucosal immune cells, local regulatory cytokines, serum allergen‐specific antibody subclasses and B cell IgE‐facilitated allergen binding (IgE‐FAB).
Methods
Biopsies from the sublingual mucosa of up to 14 SLIT‐treated atopics, nine placebo‐treated atopics and eight normal controls were examined for myeloid dendritic cells (mDCs) (CD1c), plasmacytoid dendritic cells (CD303), mast cells (AA1), T cells (CD3) and Foxp3 using immunofluorescence microscopy. IL‐10 and TGF‐β mRNA expression were identified by in situ hybridization. Allergen‐specific IgG and IgA subclasses and serum inhibitory activity for binding of allergen‐IgE complexes to B cells (IgE‐FAB) were measured before, during and on the completion of SLIT.
Results
Foxp3+ cells were increased in the oral epithelium of SLIT‐ vs. placebo‐treated atopics (P=0.04). Greater numbers of subepithelial mDCs were present in placebo‐treated, but not in SLIT‐treated, atopics compared with normal controls (P=0.05). There were fewer subepithelial mast cells and greater epithelial T cells in SLIT‐ compared with placebo‐treated atopics (P=0.1 for both). IgG1 and IgG4 were increased following SLIT (P<0.001). Peak seasonal IgA1 and IgA2 were increased during SLIT (P<0.05). There was a time‐dependent increase in serum inhibitory activity for IgE‐FAB in SLIT‐treated atopics.
Conclusions
SLIT with grass pollen extract is associated with increased Foxp3+ cells in the sublingual epithelium and systemic humoral changes as observed previously for SCIT.
Cite this as: G. W. Scadding, M. H. Shamji, M. R. Jacobson, D. I. Lee, D. Wilson, M. T. Lima, L. Pitkin, C. Pilette, K. Nouri‐Aria and S. R. Durham, Clinical & Experimental Allergy, 2010 (40) 598–606.
Background: Regulatory T (Treg) cells play an important role in controlling allergic inflammation. The transcription factor Foxp3 regulates the development and function of natural and adaptive ...CD4+CD25+ Treg cells. Objectives: We sought to examine the effect of grass pollen injection immunotherapy on the numbers of Foxp3+CD4+ and Foxp3+CD25+ T cells in and out of season and their expression of IL-10 in the nasal mucosa of patients with hay fever. Methods: Nasal biopsy specimens were obtained from untreated patients with hay fever, participants with grass pollen allergy who had received 2 years of immunotherapy, and healthy control subjects. Dual-immunofluorescence microscopy was used to enumerate and colocalize Foxp3 expression to CD4+ and CD25+ T cells in the nasal mucosa. Triple staining was performed to colocalize Foxp3+ cells to CD3+CD25+ and CD3+ IL-10expressing cells. Results: At peak season, numbers of Foxp3+CD25+ (P = .02) and Foxp3+CD4+ (P = .03) cells were significantly increased in the nasal mucosa of immunotherapy-treated patients compared with numbers before treatment. Foxp3+CD25+ (P = .03) and Foxp3+CD4+ (P = .04) cells were also greater in immunotherapy-treated patients out of season compared with those in untreated patients with hay fever. Within the immunotherapy-treated group, 20% of CD3+CD25+ cells expressed Foxp3, and 18% of Foxp3+CD3+ cells were IL-10 positive. Conclusion: The presence of local Foxp3+CD25+CD3+ cells in the nasal mucosa, their increased numbers after immunotherapy, and their association with clinical efficacy and suppression of seasonal allergic inflammation support a putative role for Treg cells in the induction of allergen-specific tolerance in human subjects.
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