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1.  Associations of allergic sensitization and clinical phenotypes with innate immune response genes polymorphisms are modified by house dust mite allergen exposure 
Archives of Medical Science : AMS  2011;7(6):1029-1036.
Introduction
Polymorphisms within innate immunity genes are associated with allergic phenotypes but results are variable. These associations were not analyzed with respect to allergen exposure. We investigated associations of TLR and CD14 polymorphisms with allergy phenotypes in the context of house dust mite (HDM) exposure.
Material and methods
Children, aged 12-16 years (n=326), were recruited from downtown and rural locations and assessed by allergist. Skin prick tests, total and HDM-specific sIgE measurements were done. HDM allergen concentrations in dust were measured. Genetic polymorphisms were identified using restriction fragment length polymorphism (RFLP).
Results
Allergic rhinitis, asthma and atopy were more prevalent in urban area. Although HDM allergen concentrations were higher in rural households, sIgE were present more frequently in urban children. In the whole population no association was found between HDM exposure and sensitization. In children with CD14/−159CC, CD14/−159TT and TLR9/2848GA genotypes increased exposure to HDM was associated with reduced incidence of allergic rhinitis. Significant associations of increased HDM exposure with reduced incidence of atopy were found for the whole population and subjects with CD14/−159CC, CD14/−1359GT, TLR4/896AA and TLR9/2848GA genotypes. Among children with CD14/−159CC and CD14/−1359GG significant positive correlation between HDM allergen concentrations in household and sensitization to HDM was observed. In contrast, protective effect of high HDM allergen exposure against specific sensitization was seen in subjects with TLR4/896 AG.
Conclusions
Development of specific sensitization and allergy may be associated with innate immune response genes polymorphisms and is modified by allergen exposure.
doi:10.5114/aoms.2011.26616
PMCID: PMC3264996  PMID: 22328887
allergy; CD14; toll-like receptors; house dust mite exposure; polymorphism
2.  Association of House Dust Allergen Concentrations With Residential Conditions in City and in Rural Houses 
Background
The aim of the study was to evaluate the relationship between house dust mite, cat and dog allergen levels with household characteristics in the houses of children living in urban and rural areas in central Poland.
Methods
Dust samples were collected from 141 urban and 191 rural houses. Der f1 + Der p1, Can f 1, and Fel d1 levels were measured and associated with residential conditions and atopy-related health outcomes assessed by clinical examination and skin prick testing.
Results
Concentrations of mite allergens were lower, and cat and dog allergen levels were higher in urban houses. Fel d1 and Can f1 levels depended on the presence of a respective animal in the house. In urban houses, Der p1 + Der f1 concentration was lower in households with central heating, whereas Can f1 concentration was related to building age. Multivariate analyses revealed that the concentrations of house dust mite and dog allergens were associated with relative humidity, number of people in the household, and the presence of a dog at home. There was no significant association between allergen level and sensitization or atopic diseases.
Conclusions
Concentrations of indoor allergens in urban and rural houses differ significantly, and residential conditions associated with allergen levels seem to be different in both environments.
doi:10.1097/WOX.0b013e3182447fa8
PMCID: PMC3488928  PMID: 23268467
allergen concentration; house dust mite; cat allergen; dog allergen; allergy; residential conditions
3.  142 The Immune Response Against Respiratory Pathogens in Patients with Chronic Rhinosinusitis/Nasal Polyps and Asthma with or without Sensitivity to Aspirin 
Background
Viral and bacterial infections can modulate the ongoing inflammation in both upper and lower airways of patients with chronic rhinosinusitis with nasal polyps (CRS/NP) and asthma. It was not clear if the protective immune response to pathogens may differ depending on the disease severity.
Object: To compare serum IgG immune response against respiratory pathogens in patients with chronic airway disease (CRS/NP and asthma) with and without sensitivity to aspirin, and to refer the sensitization to severity of chronic rhinosinusitis.
Methods
We recruited 73 patients with CRS/NP and asthma with (43 patients) and without (30 patients) hypersensitivity to aspirin. The extent of mucosal hypertrophy in paranasal sinuses was assessed by CT scans and the sense of smell was valuated with “sniffing smell” test. Serum IgG immunoglobulin levels against respiratory pathogens: Respiratory Syncytial Virus (RSV), Adenowirus (ADV), Parainfluenza virus (PIV) and Mycoplasma pneumoniae were determined by ELISA.
Results
Patients with ASA-hypersensitivity had history of significantly more nasal polypectomies (P = 0.002), lower smell test score (P = 0.03) and higher mean paranasal CT score (P = 0.03) as compared to ASA-tolerant patients, reflecting higher severity of the upper airway disease. The percentage of positive serological testing to respiratory pathogens was very high in the whole group of patients with CRS/NP and asthma (RSV, 95.8%; ADV, 95.9%; PIV, 84.9% and Mycoplasma pneumonieae, 100% patients) without any difference between ASA-sensitive and ASA-tolerant subjects. Patients with ASA-sensitivity had significantly lower concentrations of PIV- specific IgG (mean 188.67 ± 34.46 U/mL versus 207.56 ± 30.036 U/mL; P < 0.04) as compared to ASA-tolerant subjects. There was a significant trend (P < 0.048) for lower PIV–specific IgG concentrations with increased number of polypectomies. No correlation of IgG immunoglobulin concentrations for other pathogens with the number of polypectomies, paranasal sinuses CT score or presences of smell were observed.
Conclusions
Patients with CRS/NP and asthma had high frequency of IgG immunoglobulin against common respiratory pathogens. Serum IgG immune response to paramyxoviruses may be related to the recurrence of nasal polyps and the presence of aspirin sensitivity.
doi:10.1097/01.WOX.0000411887.21654.e0
PMCID: PMC3512738
4.  72 The Choice of Hypoallergens for Fish and Peach to Develop Food Allergy Specific Immunotherapy (TheFAST Project) 
Background
Classical allergen-specific immunotherapy (SIT), using subcutaneous injections with food extracts, may be effective but dangerous due to anaphylactic side-effects. The FAST project (Food Allergy Specific Immunotherapy) aims at the development of safe and effective treatment of food allergies, targeting persistent and severe allergy to fish (cod) and fruit (peach). Both are caused by a single major allergen, parvalbumin (Cyp c 1) and lipid transfer protein (Pru p 3), respectively. FAST will apply hypo-allergenic recombinant major allergens for SIT.
Methods
Two approaches were evaluated for achieving hypo-allergenicity, i.e. site-directed mutagenesis and chemical modification. Wildtype (wt) natural and recombinant allergens and the hypo-allergens were extensively purified and characterized physico-chemically. Their stability was tested and allergenicity was compared by CAP-inhibition and histamine release experiments while immunogenicity was tested in T-cell proliferation experiments and rabbit and mice immunizations.
Results
For Cyp c 1, the mutant without calcium-binding site showed up to a 1000 times reduced allergenicity, while secondary fold and immunogenicity (tested in human PBMC stimulations and by immunization of laboratory animals) were retained. Chemically modified Cyp c 1 demonstrated a reduced capacity to stimulate T-cells and showed less immunogenicity in rabbits. The calcium-binding mutant has been produced under GMP conditions.
For Pru p 3, 5 potential hypoallergens were compared. The allergenicity was reduced to a similar extent (∼1000-fold) for both variants in which disulfide bridges were disrupted, i.e. either by mutagenesis or by reduction/alkylation. The modification resulted in loss of alpha-helical secondary structure. However, unexpectedly, the immunogenicity was also significantly lowered/absent.
Conclusions
For the Cyp c 1 calcium-binding mutant we are preparing to enter Phase I clinical trials. For Pru p 3, we need to evaluate new molecules to generate a hypoallergenic mutant that retains immunogenicity.
doi:10.1097/01.WOX.0000411817.24011.93
PMCID: PMC3513097
5.  141 Abnormal Immune Response Against Respiratory Pathogens in Olympic Athletes 
Background
Viruses and bacteria are important contributors to asthma exacerbations. Exercise at competitive level is believed to increase susceptibility to respiratory infections. The study aimed at investigation of the anti-infectious immune response in athletes in the context of exercise intensity, atopy and allergic diseases.
Methods
Questionnaire data were obtained from 219 Polish athletes (median age 26 years) preparing for Beijing Olympic Games during the multicenter study within the GA2LEN project (WP 2.8.2). Allergy Questionnaire for Athletes (AQUA) (Bonini et al 2009) was used to obtain data about symptoms and exercise pattern. Athletes were evaluated by allergist. Control group consisted of 77 healthy never-smokers (median age 29 years) not performing sport at competitive level. Serum IgG against parainfluenza virus 1,2 and 3 (PIV), respiratory syncytial virus (RSV), adenovirus and Mycoplasma pneumoniae were determined by ELISA.
Results
Percentage of athletes with positive serological testing was lower than percentage of HC in case of PIV (P < 0.0003), RSV (P = 0.01) and M. pneumoniae (P = 0.01). Analysis of IgG only in subjects with positive testing showed lower anti-PIV IgG levels in non-atopic athletes compared to HC (P < 0.001) and atopic athletes (P < 0.01) (median 66.0 vs 104.8 and 88.1 U/mL). In contrast, higher adenovirus IgG titres were found in atopic and non-atopic athletes as compared to HC (52.3 and 48.5 vs 36.6 EIU, P < 0.001). Positive anti-PIV serology test was most frequent in athletes with allergic rhinitis compared to asthmatic and healthy athletes (78.3 vs 50.0 and 46.8%; P = 0.002). For PIV and M. pneumoniae the difference was also seen when atopic and non-atopic athletes were compared separately with HC. Positive RSV serology was more frequent in atopic versus non-atopic athletes (76.3 vs 60.8%, P = 0.03) and in HC versus non-atopic athletes (84.4 vs 60.8%, P = 0.001) but no significant difference between atopic athletes and HC was seen. Positive RSV serology was associated with atopy (OR 2.89; 95% CI, 1.34-6.23; P = 0.007). No differences were observed with regard to exercise pattern (endurance vs non-endurance).
Conclusions
Competitive sport at Olympic level may be associated with altered immune response against respiratory pathogens. For some agents this response may be affected by the atopic status.
doi:10.1097/01.WOX.0000411886.44524.d9
PMCID: PMC3513113
6.  Oral and Nasal Steroids for Nasal Polyps 
doi:10.1007/s11882-011-0192-9
PMCID: PMC3087876  PMID: 21475992
7.  Stem cell factor and its soluble receptor (c-kit) in serum of asthmatic patients- correlation with disease severity 
Background
SCF (stem cell factor) is a pleiotropic cytokine exerting its role at different stages of bone marrow development and affecting eosinophil activation, mast cells and basophil chemotaxis and survival. The aim of the study was to assess concentration of SCF and its soluble receptor c-kit (sc-kit) in peripheral blood of patients with asthma referring it to asthma severity and phenotype.
Methods
The study involved 107 patients with bronchial asthma, well characterized with respect to severity and 21 healthy controls. Concentration of SCF and sc-kit in the patients serum were measured by ELISA method.
Results
Mean serum SCF level in the group of asthmatics (n = 88) was significantly higher as compared to healthy controls (1010 pg/ml ± 37 vs 799 ± 33; p < 0,001). The level of SCF was higher in patients with severe asthma as compared to patients with non-severe asthma (1054 +/- 41 pg/ml vs 819 +/- 50; p < 0,01) and correlated with dose of inhaled glucocorticosteroids taken by the patients to achieve asthma control (R = 0,28; p < 0,01). The mean sc-kit serum level did not differ between asthmatic patients and healthy controls, however the level of sc-kit in non-severe asthmatics was significantly higher as compared to patients with severe asthma and healthy controls. In asthmatic patients (n = 63) the level of sc-kit correlated positively with FEV1% predicted value (R = 0,45; p < 0,001) and MEF25% predicted value (R = 0,33; p < 0,01). The level of sc-kit inversely correlated with the dose of inhaled glucocorticosteroids taken by the patients (R = -0,26; p < 0,01).
Conclusion
Serum levels of SCF and its soluble receptor c-kit seem to be reflect asthma severity suggesting a role for these molecules in asthmatic inflammation.
doi:10.1186/1471-2466-9-27
PMCID: PMC2701918  PMID: 19480722
8.  RANTES and Chemotactic Activity in Synovial Fluids From Patients With Rheumatoid Arthritis and Osteoarthritis 
Mediators of Inflammation  2005;2005(6):343-348.
A massive accumulation of inflammatory cells in synovial tissues is a major pathological feature of rheumatoid arthritis (RA). Neutrophiles dominate synovial fluid while rheumatoid synovium is infiltrated with mononuclear cells. Mechanisms regulating influx of particular subpopulations of leukocytes into articular cavity and synovium compartment are not completely defined. An increasing amount of data supports a crucial role of a C-C chemokine RANTES in the RA pathogenesis. Our objective is to evaluate chemotactic activity for neutrophils (NCA), lymphocytes (LCA), and monocytes (MoCA) in SFs obtained from patients with RA and osteoarthritis (OA). We also aimed to characterise the relation between chemotactic activity, RANTES, and percentage distribution of leukocytes in SF. SFs from 11 patients with RA and 6 with OA were included in the study. Modified microchamber Boyden method was employed to assess chemotactic activity. Cytological and biochemical analysis of SF was performed. RANTES was measured with ELISA. Rheumatoid SFs were rich in cells with predominance of neutrophiles while osteoarthritic fluids were lymphocytic. RA SFs were also characterised by increased lactoferrin level. Both NCA and LCA were higher in SF from patients with RA (62 ± 12 and 24 ± 6 cells/HPF, resp) as compared to patients with OA (23 ± 6; P < .05 and 6 ± 2 cells/HPF; P < 0.05). The chemoattractive effect of RA SF was more pronounced on neutrophiles than on lymphocytes. RA SF expressed high RANTES levels (145 ± 36 pg/mL), while OA SF was characterised by only trace amount of this chemokine (2 ± 1 pg/mL). We found positive correlation of RANTES with chemotactic activity for mononuclear cells (LCA+MoCA; R = 0.61; P < .05). Surprisingly, RANTES correlated also positively with neutrophiles number (R = 0.77; P < 0.001). Rheumatoid SF possesses strong chemotactic potency for leukocytes. RANTES is overexpressed in RA SF and is a potential mediator influencing intensity and composition of cellular infiltration in joints affected with inflammatory arthritis.
doi:10.1155/MI.2005.343
PMCID: PMC1533897  PMID: 16489254
9.  Tumour necrosis factor-alpha polymorphism as one of the complex inherited factors in pemphigus. 
Mediators of Inflammation  2003;12(5):303-307.
The aim of our study was to analyse a significance of tumour necrosis factor (TNF)-alpha promoter gene polymorphisms in relation to the HLA-DR locus in genetic predisposition to pemphigus. TNF-alpha gene polymorphisms in position -238 and -308 were identified using a modified polymerase chain reaction-restriction fragment length polymorphism method in 53 patients with pemphigus (38 with pemphigus vulgaris, 15 with pemphigus foliaceus) and 87 healthy controls. The HLA-DRB1 locus was typed using the polymerase chain reaction SSO method in all the patients and 152 population controls. Carriers of the TNF-alpha polymorphic -308 A allele were found to be more frequent in the pemphigus foliaceus group in comparison with the control group (odds ratio (OR) = 8.12; p = 0.0005). A significant association between HLA-DRB1*04 (OR = 3.86; pcor = 0.0001) and DRB1*14 (OR = 8.4; pcor = 0.0001) and pemphigus vulgaris was found. In this group of patients a decreased frequency of HLA-DRB1*07 (OR = 0.08; pcor = 0.006) was also identified. We have shown for the first time a positive association of TNF-alpha polymorphism in position -308 with pemphigus foliaceus.
PMCID: PMC1781627  PMID: 14760938
10.  Increased apoptosis of peripheral blood mononuclear cells in patients with perennial allergic asthma/rhinitis: relation to serum markers of apoptosis. 
Mediators of Inflammation  2002;11(4):225-233.
BACKGROUND: The goal of our study was to examine spontaneous and stimulated apoptosis of peripheral blood MNC from allergic patients, sensitized to Der p I antigen as compared to cells from non-atopic subjects. Furthermore we aimed to investigate which populations of mononuclear cells (lymphocytes, monocytes) undergo the apoptosis and to determine relations between apoptosis and serum levels of sFas/APO-1, ICE/caspase-1 or TNF-alpha. METHODS: The study included 17 patients with perennial, allergic asthma and/or allergic rhinitis [6 male and 11 female; mean age 29,5 years; (range 15-49)]. Apoptosis was assessed by fluorescence technique and confirmed by flow-cytometric method and DNA ladder. Serum levels of sFas, ICE/caspase-1 or TNF-alpha were determined by immunoassays (ELISA). RESULTS: Apoptotic index of unfractionated mononuclear cells (MNC) and lymphocytes (but not monocytes) were significantly higher in allergic patients as compared to non-allergic subjects after 48 and 72 hours of culture (p<0.05). Incubation of cells with ConA (10 microg/ml) resulted in a significant increase in the proportion of apoptotic cells in all populations once the apoptotic index for MNC and lymphocytes (but not monocytes) was again significantly higher in allergic as compared to non-allergic subjects after 24, 48 and 72 hour of culture. In allergic patients, mean serum sFas level, was significantly lower then in non-allergic group (mean value 624.8 pg/ml +/- 25.67 versus 802.0 pg/ml +/- 31.91; p = 0.003) and in both groups sFas level correlated inversely with apoptosis of MNC. The mean ICE/caspase-1 concentration was significantly higher in sera of allergic patients as compared to non-allergic group (mean value 27.71 pg/ml +/- 3.79 vs 23.54 pg/ml respectively; p<0.01). ICE/caspase-1 levels in allergic patients correlated with apoptotic index of mononuclear cells (r = 0.57; p<0.001). CONCLUSIONS: An increased spontaneous and mitogen-induced apoptosis of MNC from peripheral blood of atopic patients as well as different serum levels of sFas and ICE/caspase-1 correlating with apoptosis, suggest different regulation of apoptotic process in peripheral blood mononuclear cells of patients with allergic asthma and/or rhinitis.
doi:10.1080/09629350290000087
PMCID: PMC1781668  PMID: 12396474
11.  FAST: towards safe and effective subcutaneous immunotherapy of persistent life-threatening food allergies 
The FAST project (Food Allergy Specific Immunotherapy) aims at the development of safe and effective treatment of food allergies, targeting prevalent, persistent and severe allergy to fish and peach. Classical allergen-specific immunotherapy (SIT), using subcutaneous injections with aqueous food extracts may be effective but has proven to be accompanied by too many anaphylactic side-effects. FAST aims to develop a safe alternative by replacing food extracts with hypoallergenic recombinant major allergens as the active ingredients of SIT. Both severe fish and peach allergy are caused by a single major allergen, parvalbumin (Cyp c 1) and lipid transfer protein (Pru p 3), respectively. Two approaches are being evaluated for achieving hypoallergenicity, i.e. site-directed mutagenesis and chemical modification. The most promising hypoallergens will be produced under GMP conditions. After pre-clinical testing (toxicology testing and efficacy in mouse models), SCIT with alum-absorbed hypoallergens will be evaluated in phase I/IIa and IIb randomized double-blind placebo-controlled (DBPC) clinical trials, with the DBPC food challenge as primary read-out. To understand the underlying immune mechanisms in depth serological and cellular immune analyses will be performed, allowing identification of novel biomarkers for monitoring treatment efficacy. FAST aims at improving the quality of life of food allergic patients by providing a safe and effective treatment that will significantly lower their threshold for fish or peach intake, thereby decreasing their anxiety and dependence on rescue medication.
doi:10.1186/2045-7022-2-5
PMCID: PMC3386014  PMID: 22409908
FAST; Food allergy; Specific immunotherapy; Subcutaneous; Sublingual; Fish; Peach; Hypoallergens
12.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
doi:10.1186/gm259
PMCID: PMC3221551  PMID: 21745417

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