Evolution of airway inflammation in preschoolers with asthma : results of a two-year longitudinal study

Fractional exhaled nitric oxide (FeNO) is a non-invasive marker for eosinophilic airway inflammation and has been used for monitoring asthma. Here, we assess the characteristics of FeNO from preschool to school age, in parallel with asthma activity. A total of 167 asthmatic children and 66 healthy, age-matched controls were included in the 2-year prospective PreDicta study evaluating wheeze/asthma persistence in preschool-aged children. Information on asthma/rhinitis activity, infections and atopy was recorded at baseline. Follow-up visits were performed at 6-month intervals, as well as upon exacerbation/cold and 4-6 weeks later in the asthmatic group. We obtained 539 FeNO measurements from asthmatics and 42 from controls. At baseline, FeNO values did not differ between the two groups (median: 3.0 ppb vs. 2.0 ppb, respectively). FeNO values at 6, 12, 18 and 24 months (4.0, CI: 0.0-8.6; 6.0, CI: 2.8-12.0; 8.0, CI: 4.0-14.0; 8.5, CI: 4.4-14.5 ppb, respectively) increased with age (correlation p <= 0.001) and atopy (p = 0.03). FeNO was non-significantly increased from baseline to the symptomatic visit, while it decreased after convalescence (p = 0.007). Markers of disease activity, such as wheezing episodes and days with asthma were associated with increased FeNO values during the study (p < 0.05 for all). Age, atopy and disease activity were found to be important FeNO determinants in preschool children. Longitudinal and individualized FeNO assessment may be valuable in monitoring asthmatic children with recurrent wheezing or mild asthma

Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) drives the resolution of allergic asthma

RANTES is implicated in allergic asthma and in T cell-dependent clearance of infection. RANTES receptor family comprises CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with respiratory viruses like Rhinovirus cause induction of RANTES production by epithelial cells. Here, we studied the role of RANTES in the peripheral blood mononuclear cells in cohorts of children with and without asthma and validated and extended this study to the airways of adults with and without asthma. We further translated these studies to a murine model of asthma induced by house dust mite allergen in wild-type RANTES and CCR5-deficient mice. Here we show an unpredicted therapeutic role of RANTES in the resolution of allergen-induced asthma by orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils as well as increased IL-10 production in the lung

Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1.Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1.Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques. Physicochemical properties were investigated by gel electrophoresis, size exclusion chromatography, circular dichroism spectroscopy, reverse-phase high-performance liquid chromatography and mass spectrometry. Allergenicity was assessed by ImmunoCAP inhibition and basophil histamine release assay, immunogenicity by immunization of laboratory animals and stimulation of patients' peripheral blood mononuclear cells (PBMCs). Reference molecules were purified wild-type Cyp c 1 (natural and/or recombinant). GMP-compliant alum-adsorbed mCyp c 1 was tested for acute toxicity in mice and rabbits and for repeated-dose toxicity in mice. Accelerated and real-time protocols were used to evaluate stability of mCyp c 1 as drug substance and drug product.Purified mCyp c 1 behaves as a folded and stable molecule. Using sera of 26 double-blind placebo-controlled food-challenge-proven fish-allergic patients, reduction in allergenic activity ranged from 10- to 5,000-fold (1,000-fold on average), but with retained immunogenicity (immunization in mice/rabbits) and potency to stimulate human PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH)3-adsorbed drug product demonstrated at least 20 months of stability.The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine.info:eu-repo/grantAgreement/EC/FP7/20187

Immune-related adverse reactions as a result of therapy with check-point inhibitors

Check-point inhibitors are becoming a chance for patients with neoplasmatic disorders. The inhibitors of PD-1/PD1L and CTLA4 pathway are used in treatment of such neoplasmatic disorders as melanoma or lung cancer. Unfortunately interference with signaling between antigen presenting cells and T-Lymphocytes can lead to deregulation of immune system, loss of autotolerance and results in occurence of autoimmune diseases symptoms. Immune-related adverse drug reactions affects even 25% of treated patients and in 6% the observed reactions are severe. The most common clinical manifestation of these reactions include cutaneous symptoms, endocrine disturbances, complaints from gastrointestinal and respiratory systems and renal involvement as well. In the recent years it is reported that also “rheumatologic symptoms” like arthritis, polymyalgia or sicca symptoms are often observed in patients treated with check-point inhibitors. The aim of the article is to present the current knowledge on pathogenesis, clinical pattern, prevalence and treatment of immune-related adverse drug reactions evoked by check-point inhibitors.Inhibitory punktów kontrolnych układu immunologicznego (check-point inhibitors) stanowią dużą szansę dla pacjentów z chorobami nowotworowymi. Leki hamujące szlak PD1-PD1L oraz szlak CTLA4 znalazły zastosowanie w terapii licznych nowotworów złośliwych np. czerniaka czy raka płuc. Niestety ingerencja w przekazywanie sygnałów między komórkami prezentującymi antygen a limfocytami T może prowadzić do deregulacji układu immunologicznego, utraty tolerancji własnych antygenów i tkanek oraz pojawienia się objawów klinicznych chorób autoimmunologicznych. Działania niepożądane związane z układem immunologicznym (immune related adverse drug reaction, irAEs) dotyczą nawet 25% pacjentów leczonych, a u 6% pacjentów rozwijają się ciężkie reakcje. Najczęstsze reakcje niepożądane to objawy skórne, endokrynologiczne, objawy ze strony przewodu pokarmowego i oddechowego oraz ze strony nerek. W ostatnich latach pojawia się coraz więcej doniesień o pojawianiu się objawów reumatycznych takich jak zapalenie stawów, zespoły suchości, objawy polimialgii, wywołanych przez terapię. Celem poniższego artykułu jest przedstawienie obecnej wiedzy na temat patogenezy, diagnostyki i postępowania w przypadku wystąpienia działań niepożądanych związanych z układem immunologicznym w przebiegu terapii inhibitorami punktu kontrolnego ze szczególnym uwzględnieniem objawów reumatycznych

Psoriatic arthritis – can trauma cause the inflammation

Łuszczycowe zapalenie stawów jest chorobą autoimmunologiczną, przewlekłą i niejednokrotnie prowadzącą do niepełnosprawności. Dotyczy ona 44 tys. osób w Polsce i stanowi 24-41% wszystkich pacjentów z łuszczycą skóry. Z reguły łuszczyca poprzedza wystąpienie ŁZS. Objawami ŁZS są sztywność poranna ustępująca po aktywności fizycznej oraz ból stawów obwodowych i kręgosłupa. W odróżnieniu do innych chorób reumatycznych w ŁZS obserwuje się objaw dactylitis, tzn. objaw palca kiełbaskowatego oraz zapalenie przyczepów ścięgnistych. Etiologia powstawania ŁZS nie jest do końca poznana. Sugeruje się, iż wystąpienie ŁZS może być spowodowane podatnością genetyczną, silnym stresem, zakażeniem bakteryjnym lub wirusowym oraz urazem mechanicznym. Od lat w doniesieniach naukowych udowadniany jest wpływ mikrourazu i urazu na rozwinięcie ŁZS. Poniższa praca ma na celu przegląd najnowszej literatury w poszukiwaniu badań potwierdzających powyższą tezę oraz zebranie opisów przypadków pacjentów, u których prawdopodobnym czynnikiem wywołującym chorobę był uraz.Psoriatic arthritis is an autoimmune, chronic disease, which often leading to disability. It affects 44 thousand people in Poland and constitute 24-41% of all patients with psoriasis. Usually, psoriasis precedes the occurrence of PsA. Psoriatic arthritis symptoms are joint stiffness in the morning which disappears after physical activity and pain in joints and spine. The difference between PsA and other rheumatic diseases is tendonitis and dactylitis. The etiology of the psoriatic arthritis is not fully understood. It is suggested that the onset of PsA may be caused by genetic susceptibility, severe stress, bacterial or viral infections or mechanical trauma. For years, the impact of microtrauma and trauma on the onset of PsA has been proven in research. The aim of this study was to review the latest literature to confirm the thesis, that trauma can cause the psoriatic arthritis and to collect case reports in which trauma was the probable factor causing the PsA

Assessment of musculoskeletal symptoms in patients with psoriasis

Introduction. Psoriasis is a chronic autoimmune disease of skin which may affect around 2% of population and 20-40% of psoriatic patients develop psoriatic arthritis (PsA). It is estimated that cutaneous symptoms are present for about 10 years ahead of the musculoskeletal symptoms. Early diagnosis of arthritis and implementation of treatment are crucial for achieving remission and improved prognosis. Aim. The aim of the study was to assess the musculoskeletal symptoms in patients with psoriasis. Material and methods. 180 subjects with psoriasis of the skin and/ or nails were enrolled in the study. The screening questionnaire was developed to assess the frequency of musculoskeletal symptoms and their character. The symptoms reported by the patients were compared with the CASPAR classification criteria and with the screening questionnaire PEST. Results. More than 90% of respondents declared complaints from musculoskeletal system. In 70% of the surveyed, the symptoms were present at the time of completing the questionnaire and in 40% the reported symptoms fulfilled the criteria of inflammatory arthritis. 43% of the surveyed patients reported Achilles tendon pain and 42% reported dactylitis. The examined patients rarely reported back pain of inflammatory character (11%). In the study group nearly 40% of the patients were diagnosed with psoriatic arthritis. About 23% respondents (16/70) who reported symptoms fulfilling the criteria for psoriatic arthritis had not been previously diagnosed with rheumatic disease, and in patients reporting inflammatory back pain this figure amounted to 55% (10/18). Conclusions. Musculoskeletal complaints are frequent among patients with psoriasis. The significant percentage of patients treated by dermatologists do not have any diagnosis of inflammatory joint disease despite the presented symptoms.Wprowadzenie. Łuszczyca jest przewlekłą chorobą zapalną dotyczą- cą około 2% populacji. Spośród pacjentów z łuszczycą skóry 20-40% choruje na łuszczycowe zapalenie stawów (ŁZS). U większości osób zmiany skórne wyprzedzają objawy stawowe nawet o 10 lat. Wczesne rozpoznanie zapalenia stawów i zastosowanie leczenia jest kluczowe dla osiągnięcia remisji choroby i poprawy rokowania. Cel pracy. Celem pracy była ocena objawów ze strony układu mię- śniowo-szkieletowego wśród pacjentów z łuszczycą. Materiał i metody. Do badania włączono 180 osób z łuszczycą skóry i/lub paznokci. Opracowano ankietę oceniającą częstość występowania dolegliwości stawowych, a także ich natężenie i charakter. Zgłaszane przez chorych objawy zestawiono z kryteriami klasyfikacyjnymi CASPAR oraz ankietą przesiewową PEST. Wyniki. Ponad 90% osób ankietowanych zgłaszało dolegliwości bó- lowe ze strony układu mięśniowo-szkieletowego, u 70% występowały one w momencie badania, a u prawie 40% osób spełniały kryteria bólu zapalnego stawów. Ból przyczepu ścięgnistego (ścięgna Achillesa) zgłaszało 43% pacjentów, a zapalenie palca 42% respondentów. Dość rzadko pacjenci zgłaszali dolegliwości o charakterze zapalnym ze strony kręgosłupa (11% pacjentów). W grupie badanej blisko 40% osób miało zdiagnozowane łuszczycowe zapalenie stawów. Około 23% (16/70) osób zgłaszających dolegliwości spełniające kryterium bólu zapalnego stawów, nie posiadało dotychczas diagnozy choroby reumatycznej, pośród chorych zgłaszających ból zapalny kręgosłupa odsetek ten wynosił aż 55% (10/18). Wnioski. Dolegliwości ze strony układu mięśniowo-szkieletowego są powszechne wśród pacjentów chorujących na łuszczycę. Istotny odsetek chorych pozostających pod opieką lekarza dermatologa i spełniających kryteria dolegliwości o charakterze zapalnym nie posiada rozpoznania choroby stawów mimo prezentowanych objawów

Wpływ lipoksyny A4 na uwalnianie cytokin przez komórki jednojądrowe pacjentów chorych na łuszczycowe zapalenie stawów

Background: Up to 40% of patients with psoriasis suffer from psoriatic arthritis (PsA), an underrecognized inflammatory arthropathy of incompletely understood pathogenesis. PsA affects axial joints, surrounding ligaments, tendons and entheses. One hypothesis links repeated microinjuries with disorders of inflammation resolution mechanisms that lead to chronic inflammation, which spreads to surrounding tissues. An example of the mediators which lead to resolution of inflammation in physiological conditions are derivatives of arachidonic acid – lipoxins. Objectives: The aim of the study was to compare if the influence of lipoxin A4 on the synthesis of pro-inflammatory cytokines by peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood of patients with PsA and healthy individuals. Methods: 10 patients with PsA and 5 matching healthy controls were enrolled in the study. PBMSc were isolated by gradient-density centrifugation technique and incubated with lipopolysaccharide with or without the addition of lipoxin A4 for 24 hours. The levels of IL-1β, IFN-α, IFN-γ, TNFα, MCP-1, IL-6, IL-8, IL-10, IL-17, IL-12, IL-18, IL-23 and IL-33 in cell culture supernatants were quantified by cytometric bead array system. Results: Incubation of PBMCs with LPS, increased production of all cytokines assessed either in patients with psoriatic arthritis or in healthy controls. In PBMCs from healthy controls incubation of cells with lipoxine A4 decrease production of proinflammatory cytokines. However, in patients with psoriatic arthritis addition of lipoxine A4 did not inhibited LPS – induced proinflammatory cytokines release. Conclusions: The anti-inflammatory effect of lipoxin A4 is reversed in PsA PBMCs, supporting the hypothesis of defective resolution of inflammation in the pathogenesis of PsA.Wprowadzenie: Patogeneza łuszczycowego zapalenie stawów (ŁZS), które występuje u ok. 40% pacjentów chorych na łuszczycę, jest nie do końca poznana i wyjaśniona. ŁZS obejmuje stawy osiowe (kręgosłup i stawy krzyżowo-biodrowe), stawy obwodowe, więzadła, ścięgna i przyczepy ścięgniste. Jedna z hipotez mówi, że powtarzające się mikrourazy oraz upośledzenie mechanizmów rezolucji procesu zapalnego, prowadzi do przewlekłego zapalenia, które obejmuje otaczające tkanki. Do mediatorów, prowadzących do ustąpienia stanu zapalnego w warunkach fizjologicznych należą lipoksyny pochodzące z kwasu arachidonowego. Cel pracy: Celem pracy było porównanie wpływu lipoksyny A4 na syntezę cytokin prozapalnych przez komórki jednojądrowe krwi obwodowej (PBMC) izolowane z krwi obwodowej pacjentów chorych na ŁZS i osób zdrowych. Metody: Do badania włączono 10 pacjentów chorych na łuszczycowe zapalenie stawów oraz 5 osób zdrowych. Komórki jednojądrowe krwi obwodowej izolowano techniką wirowania w gradiencie gęstości, a następnie inkubowano z lipopolisacharydem Escherichia coli O111:B4 z dodatkiem lub bez lipoksyny A4 przez 24 godziny. Poziomy IL-1β, IFN-α, IFN-γ, TNFα, MCP-1, IL-6, IL-8, IL-10, IL-17, IL-12, IL-18, IL-23 i IL -33 w supernatantach hodowli komórkowej oznaczono metodą cytometrii przepływowej. Wyniki: Inkubacja PBMC z LPS zwiększała produkcję wszystkich cytokin zarówno u pacjentów z łuszczycowym zapaleniem stawów i osób zdrowych. W PBMC osób zdrowych inkubacja komórek z lipoksyną A4 zmniejszała wytwarzanie cytokin prozapalnych. Jednak u pacjentów z łuszczycowym zapaleniem stawów dodanie lipoksyny A4 nie hamowało indukowanego przez LPS uwalniania cytokin prozapalnych. Wnioski: Przeciwzapalne działanie lipoksyny A4 jest odwrócone w PBMC u chorych na ŁZS, co potwierdza hipotezę o zaburzeniach rezolucji zapalenia w patogenezie ŁZS

Toll-Like Receptor Agonists Modulate Wound Regeneration in Airway Epithelial Cells

Background: Impaired regeneration of airway epithelium may lead to persistence of inflammation and remodelling. Regeneration of injured epithelium is a complex phenomenon and the role of toll-like receptors (TLRs) in the stimulation of respiratory virus products in this process has not been established. Objective: This study was undertaken to test the hypothesis that the wound repair process in airway epithelium is modulated by microbial products via toll-like receptors. Methods: Injured and not-injured bronchial epithelial cells (ECs) (BEAS-2B line) were incubated with the TLR agonists poly(I:C), lipopolisacharide (LPS), allergen Der p1, and supernatants from virus-infected epithelial cells, either alone or in combination with TLR inhibitors. Regeneration and immune response in injured and not-injured cells were studied. Results: Addition of either poly(I:C) or LPS to ECs induced a marked inhibition of wound repair. Supernatants from RV1b-infected cells also decreased regeneration. Preincubation of injured and not-injured ECs with TLR inhibitors decreased LPS and poly(I:C)-induced repair inhibition. TGF-&beta; and RANTES mRNA expression was higher in injured ECs and IFN-&alpha;, IFN-&beta;, IL-8, and VEGF mRNA expression was lower in damaged epithelium as compared to not-injured. Stimulation with poly(I:C) increased IFN-&alpha; and IFN-&beta; mRNA expression in injured cells, and LPS stimulation decreased interferons mRNA expression both in not-injured and injured ECs. Conclusion: Regeneration of the airway epithelium is modulated by microbial products via toll-like receptors

Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients

Purpose In order to gain an insight into determinants of reported variability in immune responses to respiratory viruses in human bronchial epithelial cells (HBECs) from asthmatics, the responses of HBEC to viral infections were evaluated in HBECs from phenotypically heterogeneous groups of asthmatics and in healthy controls. Methods HBECs were obtained during bronchoscopy from 10 patients with asthma (6 atopic and 4 non-atopic) and from healthy controls (n=9) and grown as undifferentiated cultures. HBECs were infected with parainfluenza virus (PIV)-3 (MOI 0.1) and rhinovirus (RV)-1B (MOI 0.1), or treated with medium alone. The cell supernatants were harvested at 8, 24, and 48 hours. IFN-α, CXCL10 (IP-10), and RANTES (CCL5) were analyzed by using Cytometric Bead Array (CBA), and interferon (IFN)-β and IFN-λ1 by ELISA. Gene expression of IFNs, chemokines, and IFN-regulatory factors (IRF-3 and IRF-7) was determined by using quantitative PCR. Results PIV3 and RV1B infections increased IFN-λ1 mRNA expression in HBECs from asthmatics and healthy controls to a similar extent, and virus-induced IFN-λ1 expression correlated positively with IRF-7 expression. Following PIV3 infection, IP-10 protein release and mRNA expression were significantly higher in asthmatics compared to healthy controls (median 36.03-fold). No differences in the release or expression of RANTES, IFN-λ1 protein and mRNA, or IFN-α and IFN-β mRNA between asthmatics and healthy controls were observed. However, when asthmatics were divided according to their atopic status, HBECs from atopic asthmatics (n=6) generated significantly more IFN-λ1 protein and demonstrated higher IFN-α, IFN-β, and IRF-7 mRNA expressions in response to PIV3 compared to non-atopic asthmatics (n=4) and healthy controls (n=9). In response to RV1B infection, IFN-β mRNA expression was lower (12.39-fold at 24 hours and 19.37-fold at 48 hours) in non-atopic asthmatics compared to atopic asthmatics. Conclusions The immune response of HBECs to virus infections may not be deficient in asthmatics, but seems to be modified by atopic status. Keywords: Asthma; bronchial epithelial cells; interferon; parainfluenza virus; rhinoviru