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1.
J Dermatol Sci ; 71(1): 12-21, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23702389

ABSTRACT

BACKGROUND: Recent studies provided insights into the recruitment and activation pathways of leukocytes in atopic dermatitis, however, the underlying mechanisms of tissue remodeling in atopic skin inflammation remain elusive. OBJECTIVE: To identify chemokine-mediated communication pathways regulating tissue remodeling during atopic skin inflammation. METHODS: Analysis of the chemokine receptor repertoire of human dermal fibroblasts using flow cytometry and immunofluorescence. Quantitative real-time polymerase chain reaction and immunohistochemical analyses of chemokine expression in atopic vs. non-atopic skin inflammation. Investigation of the function of chemokine receptor CCR3 on human dermal fibroblasts through determining intracellular Ca(2+) mobilization, cell proliferation, migration, and repair capacity. RESULTS: Analyses on human dermal fibroblasts showed abundant expression of the chemokine receptor CCR3 in vitro and in vivo. Among its corresponding ligands (CCL5, CCL8, CCL11, CCL24 and CCL26) CCL26 demonstrated a significant and specific up-regulation in atopic when compared to psoriatic skin inflammation. In vivo, epidermal keratinocytes showed most abundant CCL26 protein expression in lesional atopic skin. In structural cells of the skin, TH2-cytokines such as IL-4 and IL-13 were dominant inducers of CCL26 expression. In dermal fibroblasts, CCL26 induced CCR3 signaling resulting in intracellular Ca(2+) mobilization, as well as enhanced fibroblast migration and repair capacity, but no proliferation. CONCLUSION: Taken together, findings of the present study suggest that chemokine-driven communication pathways from the epidermis to the dermis may modulate tissue remodeling in atopic skin inflammation.


Subject(s)
Cell Communication , Dermatitis, Atopic/immunology , Fibroblasts/immunology , Receptors, CCR3/metabolism , Skin/immunology , Calcium Signaling , Case-Control Studies , Cell Proliferation , Cells, Cultured , Chemokine CCL26 , Chemokines, CC/metabolism , Chemotaxis , Dermatitis, Atopic/genetics , Dermatitis, Atopic/pathology , Fibroblasts/pathology , Humans , Inflammation Mediators/metabolism , Interleukin-13/metabolism , Interleukin-4/metabolism , Keratinocytes/immunology , Ligands , Receptors, CCR3/genetics , Signal Transduction , Skin/pathology , Th2 Cells/immunology , Time Factors , Up-Regulation , Wound Healing
2.
J Occup Environ Med ; 51(11): 1288-97, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19858747

ABSTRACT

OBJECTIVE: This article evaluates health-related quality of life (HRQoL) among patients with occupational rhinitis (OR), with an average of 10 years after diagnosis. METHODS: A cross-sectional questionnaire with general (RAND-36) and disease-specific (Rhinasthma) HRQoL questions was completed by 119 OR patients and 173 controls of the same age and locality. In addition, the patients compared their estimation of current occupational exposure level with that at the time of OR diagnosis. RESULTS: HRQoL was impaired among patients with continuing occupational allergen exposure in all Rhinasthma and several RAND-36 scores. The HRQoL among patients no longer exposed was mainly similar to that of the healthy controls. CONCLUSIONS: Among OR patients, continuous occupational exposure decreases QoL years after the diagnosis. To restore the well being of patients with OR, medication only is not sufficient; reduction or cessation of exposure is necessary.


Subject(s)
Occupational Exposure/adverse effects , Patients/psychology , Quality of Life , Rhinitis , Adult , Aged , Cross-Sectional Studies , Finland , Health Status , Humans , Middle Aged , Rhinitis/physiopathology , Surveys and Questionnaires
3.
Int Arch Allergy Immunol ; 147(1): 41-51, 2008.
Article in English | MEDLINE | ID: mdl-18446052

ABSTRACT

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease, for which no fundamental therapy exists. Immunostimulatory sequence CpG (ISS CpG) has potential in reducing susceptibility to allergic diseases and reversing established allergic reactions. OBJECTIVE: To investigate the effects of ISS CpG in the prevention and treatment of AD in an AD murine model. METHODS: BALB/c mice were epicutaneously exposed to ovalbumin (OVA) for 3 or 4 weeks with a 2-week resting period between each exposure week. ISS i.d. injection was given either on the 1st day of each exposure week (in the prevention experiment) or 3 days before and on the 1st, 4th and 7th day of the last exposure week (in the treatment experiment). Skin biopsy and blood were obtained at the end of the experiments. RESULTS: ISS CpG treatment increased drastically mRNA expression of proinflammatory and Th1-type cytokines and chemokines in OVA-treated skin both in the prevention and treatment experiments. The suppressing effect of ISS CpG on Th2-type cytokines and chemokines was weak and limited to IL-13 and CCL24 in the treatment experiment. No significant reduction in OVA-elicited infiltration of eosinophils and T cells in the skin was seen after ISS administration but infiltration of plasmacytoid dendritic cells was absent in ISS CpG-treated skin. In contrast, ISS injection elicited dramatic infiltration of F4/80+ and CCR5+ cells into the dermis and subcutaneous tissue. CONCLUSION: Due to unwanted side effects and minor beneficial effects in our model, administration of ISS CpG may not be suitable for the treatment of AD in humans.


Subject(s)
Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/immunology , Inflammation/immunology , Oligodeoxyribonucleotides/therapeutic use , Th1 Cells/immunology , Animals , Antigens, Differentiation/metabolism , Cytokines/biosynthesis , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Gene Expression , Immunoglobulin E/blood , Immunoglobulin G/blood , Immunohistochemistry , Inflammation/chemically induced , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Oligodeoxyribonucleotides/immunology , Ovalbumin/immunology , Polymerase Chain Reaction , RNA, Messenger/analysis , Skin/immunology
4.
Am J Rhinol ; 22(1): 38-46, 2008.
Article in English | MEDLINE | ID: mdl-18284858

ABSTRACT

BACKGROUND: Evaluations of rhinitis reactions in inhalation challenges (ICs) are sparse compared with research on nasal challenges. This study evaluates the outcome of IC tests in assessing occupational rhinitis (OR). It presents the largest rhinologic IC data in the literature, analyzing the exposure method of various agents causing OR and their relation to asthma. METHODS: Challenge tests performed on 829 individuals with suspected cases of OR were reviewed. Results from both exposures with occupational agents (n = 1229) and placebo (n = 838) were evaluated. RESULTS: A total of 10% of the occupational ICs (n = 123) were positive, suggesting OR, and 13% (n = 161) showed asthmatic reaction in the same challenge. In control challenges 2% showed rhinitis and 6% showed asthma symptoms. The most common agents tested were molds (160 tests), flours, and animal fodders (115 tests) and formaldehyde (122 tests). Obeche wood dust and latex produced positive nasal reactions the most frequently, followed by acid anhydrides. CONCLUSION: Although IC is a resource-intensive methodology, the evaluation of nasal symptoms and signs together with bronchial reactions saves time and expense compared with the organization of multiple individual challenges. We encourage the simultaneous evaluation of both nasal and bronchial reactions in IC tests.


Subject(s)
Allergens , Bronchial Provocation Tests/methods , Occupational Diseases/diagnosis , Occupational Exposure/adverse effects , Rhinitis/diagnosis , Administration, Inhalation , Adolescent , Adult , Aged , Allergens/administration & dosage , Diagnosis, Differential , Follow-Up Studies , Forced Expiratory Volume , Humans , Middle Aged , Occupational Diseases/etiology , Occupational Diseases/physiopathology , Peak Expiratory Flow Rate , Reproducibility of Results , Retrospective Studies , Rhinitis/etiology , Rhinitis/physiopathology , Severity of Illness Index
5.
Int J Biol Sci ; 3(7): 477-85, 2007 Nov 24.
Article in English | MEDLINE | ID: mdl-18071588

ABSTRACT

This study investigates the role of Smad3 signalling for the T-helper2 (Th2) cytokine homeostasis in normal lungs and in a mouse model of asthma. We used mice deficient for Smad3, a central part of the major signal transduction pathway for TGF-beta and other related cytokines, and a mouse model for allergic asthma with ovalbumin (OVA) as the antigen. Compared to wild type mice, naive (unmanipulated) Smad3-/- mice exhibited significantly increased levels of proinflammatory cytokines and IL-4 as well as the Th2 associated transcription factor GATA-3 in the lung tissue and bronchoalveolar lavage (BAL). In the asthma model, mucin secretion and airway hyperresponsiveness (AHR) after allergen exposure was significantly increased in the Smad3-/- mice as compared to wild type (WT) mice. IL-4 levels in Smad3-/- were similar to those encountered in WT mice but IL-13 levels were decreased in the airways of OVA sensitized Smad3-/- mice compared to corresponding WT mice. The results indicate that a lack of Smad3 dependent signalling in the normal state will lead to an increase in the GATA-3 levels and as a result of this the levels of IL-4 increase. However, the lack of Smad3 also seems to inhibit expression of some cytokines, especially IL-13. Our results also indicate that in the inflammatory state TGF-beta or related cytokines functions to counterbalance the effects of IL-4 rather than to critically regulate its expression.


Subject(s)
Asthma/metabolism , Cytokines/metabolism , Lung/metabolism , Smad3 Protein/metabolism , Th2 Cells/metabolism , Animals , Asthma/immunology , Asthma/physiopathology , Bronchial Hyperreactivity/metabolism , Gene Deletion , Homeostasis/physiology , Inflammation/metabolism , Lung/immunology , Lung/physiopathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction/physiology , Smad3 Protein/genetics
6.
J Invest Dermatol ; 127(8): 1923-9, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17429443

ABSTRACT

Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by itchy, dry, and inflamed skin. Transforming growth factor (TGF)-beta is an important fibrogenic and immunomodulatory factor that regulates cellular processes in the injured and inflamed skin. This study examines the role of the TGF-beta-Smad signaling pathway using Smad3-deficient mice in a murine model of AD. Dermatitis was induced in mice by epicutaneous application of ovalbumin (OVA) applied in a patch to tape-stripped skin. OVA-specific IgE and IgG2a antibody levels were measured by ELISA. Skin biopsies from sensitized skin areas were used for RNA isolation, histology, and immunohistochemical examination. The thickness of dermis was significantly reduced in OVA-sensitized skin of Smad3-/- mice. The defect in the dermal thickness was accompanied by a decrease in the expression of mRNA for proinflammatory cytokines IL-6 and IL-1beta in the OVA-sensitized skin. In contrast, the number of mast cells was significantly increased in OVA-sensitized skin of Smad3-/- mice, which also exhibited elevated levels of OVA-specific IgE. These results demonstrate that the Smad3-pathway regulates allergen-induced skin inflammation and systemic IgE antibody production in a murine model AD. The Smad3 signaling pathway might be a potential target in the therapy of allergic skin diseases.


Subject(s)
Dermatitis, Atopic/etiology , Immunoglobulin E/biosynthesis , Signal Transduction/physiology , Smad3 Protein/physiology , Transforming Growth Factor beta/physiology , Animals , Collagen/biosynthesis , Dermatitis, Atopic/immunology , Interleukin-1beta/biosynthesis , Interleukin-6/biosynthesis , Mast Cells/physiology , Mice , Mice, Knockout , Ovalbumin/immunology , Skin/pathology
7.
J Allergy Clin Immunol ; 119(6): 1470-80, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17337293

ABSTRACT

BACKGROUND: As clinical and histological features of allergic and irritant contact dermatitis share common characteristics, the differentiation between them in the preclinical and clinical evaluations of chemicals remains difficult. OBJECTIVE: To identify the differences in the underlying immunological mechanisms of chemical-induced allergic or irritant skin responses. METHODS: We systematically studied the involvement of chemokines in both diseases by quantitative real-time polymerase chain reaction in mice and humans. The cellular origin of relevant chemokines and receptors was determined using immunohistochemistry; functional relevance was demonstrated in vitro by transwell chemotaxis and in vivo by adoptive transfer experiments using a model of hapten-induced murine contact hypersensitivity. RESULTS: Independent of overall skin inflammation, chemical-induced allergic and irritant skin responses showed distinct molecular expression profiles. In particular, chemokine genes predominantly regulated by T-cell effector cytokines demonstrated differential upregulation in hapten-specific skin inflammation. Notably, the expression of CXCR3 ligands, such as CXCL9 (Mig) and CXCL10 (IP-10), was upregulated in chemical-induced allergic skin responses when compared with irritant skin responses. Furthermore, we showed that inflammatory chemokines such as CXCL10 prime leukocytes to respond to CXCL12 (SDF-1), increasing their recruitment both in vitro and in vivo. CONCLUSION: We provide important insights into the molecular basis of chemical-induced allergic and irritant contact dermatitis, identify novel markers suitable for their differentiation, and demonstrate the cooperation of inflammatory and homeostatic chemokines in the recruitment of pathogenic leukocyte subsets. CLINICAL IMPLICATIONS: Molecular differences between both diseases represent the basis for new approaches to diagnostics and therapy.


Subject(s)
Chemokines/biosynthesis , Chemokines/genetics , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/immunology , Dermatitis, Irritant/diagnosis , Dermatitis, Irritant/immunology , Immunologic Memory , T-Lymphocyte Subsets/immunology , Animals , Biomarkers/metabolism , Cell Movement/immunology , Cells, Cultured , Chemokines/physiology , Dermatitis, Allergic Contact/pathology , Dermatitis, Irritant/metabolism , Disease Models, Animal , Female , Humans , Mice , Mice, Inbred BALB C , T-Lymphocyte Subsets/metabolism
8.
J Allergy Clin Immunol ; 117(2): 411-7, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16461142

ABSTRACT

BACKGROUND: IL-31 is a novel T-cell-derived cytokine that induces severe pruritus and dermatitis in transgenic mice, and signals through a heterodimeric receptor composed of IL-31 receptor A and oncostatin M receptor. OBJECTIVE: To investigate the role of human IL-31 in pruritic and nonpruritic inflammatory skin diseases. METHODS: The expression of IL-31 was analyzed by quantitative real-time PCR in skin samples of healthy individuals and patients with chronic inflammatory skin diseases. Moreover, IL-31 expression was analyzed in nonlesional skin of atopic dermatitis patients after allergen or superantigen exposure, as well as in stimulated leukocytes. The tissue distribution of the IL-31 receptor heterodimer was investigated by DNA microarray analysis. RESULTS: IL-31 was significantly overexpressed in pruritic atopic compared with nonpruritic psoriatic skin inflammation. Highest IL-31 levels were detected in prurigo nodularis, one of the most pruritic forms of chronic skin inflammation. In vivo, staphylococcal superantigen rapidly induced IL-31 expression in atopic individuals. In vitro, staphylococcal enterotoxin B but not viruses or T(H)1 and T(H)2 cytokines induced IL-31 in leukocytes. In patients with atopic dermatitis, activated leukocytes expressed significantly higher IL-31 levels compared with control subjects. IL-31 receptor A showed most abundant expression in dorsal root ganglia representing the site where the cell bodies of cutaneous sensory neurons reside. CONCLUSION: Our findings provide a new link among staphylococcal colonization, subsequent T-cell recruitment/activation, and pruritus induction in patients with atopic dermatitis. Taken together, these findings show that IL-31 may represent a novel target for antipruritic drug development.


Subject(s)
Dermatitis, Atopic/immunology , Interleukins/metabolism , Pruritus/immunology , T-Lymphocytes/immunology , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/physiopathology , Ganglia, Spinal/metabolism , Humans , Lymphocyte Activation , Prurigo/immunology , Prurigo/metabolism , Pruritus/metabolism , Pruritus/physiopathology , Psoriasis/immunology , Psoriasis/metabolism , Receptors, Interleukin/metabolism , Staphylococcus aureus/immunology , Superantigens/immunology , Up-Regulation
9.
Contact Dermatitis ; 50(4): 218-21, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15186376

ABSTRACT

Topical corticosteroids are usually banned on test areas prior to patch testing. The previous literature on the effect of topical corticosteroids is conflicting. Patients allergic to nickel sulfate were patch tested on 4 sites with nickel on day (D) 0. Intracutaneous betamethasone was injected to test sites on D-1, D0 and D1. NaCl injection on D-1 was control. The patch test reactions were evaluated clinically and with laser Doppler. There were no differences in patch test reaction intensities on sites treated with intracutaneous betamethasone as compared to control. A single local dose of potent corticosteroid does not suppress allergic patch reactions to nickel. The current practice of avoiding topical corticosteroid use prior to patch testing should be re-evaluated.


Subject(s)
Allergens/adverse effects , Betamethasone/administration & dosage , Dermatitis, Allergic Contact/diagnosis , Glucocorticoids/administration & dosage , Nickel/adverse effects , Patch Tests/methods , Dermatitis, Allergic Contact/etiology , False Negative Reactions , Humans , Injections, Subcutaneous
10.
Nat Med ; 8(2): 157-65, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11821900

ABSTRACT

The skin-associated chemokine CCL27 (also called CTACK, ALP and ESkine) and its receptor CCR10 (GPR-2) mediate chemotactic responses of skin-homing T cells in vitro. Here we report that most skin-infiltrating lymphocytes in patients suffering from psoriasis, atopic or allergic-contact dermatitis express CCR10. Epidermal basal keratinocytes produced CCL27 protein that bound to extracellular matrix, mediated adhesion and was displayed on the surface of dermal endothelial cells. Tumor necrosis factor-alpha and interleukin-1beta induced CCL27 production whereas the glucocorticosteroid clobetasol propionate suppressed it. Circulating skin-homing CLA+ T cells, dermal microvascular endothelial cells and fibroblasts expressed CCR10 on their cell surface. In vivo, intracutaneous CCL27 injection attracted lymphocytes and, conversely, neutralization of CCL27-CCR10 interactions impaired lymphocyte recruitment to the skin leading to the suppression of allergen-induced skin inflammation. Together, these findings indicate that CCL27-CCR10 interactions have a pivotal role in T cell-mediated skin inflammation.


Subject(s)
Chemokines, CC/immunology , Inflammation/immunology , Receptors, Chemokine/immunology , Skin/immunology , T-Lymphocytes/immunology , Animals , Cell Adhesion/immunology , Chemokine CCL27 , Endothelium, Vascular/immunology , Extracellular Matrix/immunology , Humans , Mice , Microscopy, Confocal , Receptors, CCR10 , Receptors, Lymphocyte Homing/immunology , Skin/pathology , T-Lymphocytes/pathology
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