Serum Immunoglobulin G and Risk of Exacerbations and Hospitalizations in Chronic Obstructive Pulmonary Disease

Publication date: Available online 27 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Fernando Sergio Leitao Filho, Seung Won Ra, Andre Mattman, Robert S. Schellenberg, Nick Fishbane, Gerard J. Criner, Prescott G. Woodruff, Stephen C. Lazarus, Richard Albert, John E. Connett, Meilan K. Han, Fernando J. Martinez, Janice M. Leung, S.F. Paul Man, Shawn D. Aaron, Robert M. Reed, Don D. Sin

Teaser

Hypogammaglobulinemia (total IgG levels < 7.0 g/L) is present in 1 in 4 patients with moderate to severe COPD and is associated with 50% to 100% increase in the risk of exacerbations and hospitalizations.


http://ift.tt/2qhCccl

Protein Tyrosine Phosphatase Conjugated with a Novel Transdermal Delivery Peptide, AP-rPTP Alleviates both Atopic Dermatitis-like and Psoriasis-like Dermatitis

Publication date: Available online 26 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Won-Ju Kim, Ja-Hyun Koo, Hyun-Jung Cho, Jae-Ung Lee, Ji Yun Kim, Hong-Gyun Lee, Sohee Lee, Jong Hoon Kim, Mi Seon Oh, Minah Suh, Eui-Cheol Shin, Joo Yeon Ko, Myung Hyun Sohn, Je-Min Choi
BackgroundAtopic dermatitis and psoriasis are the two most common chronic inflammatory skin diseases. There is an unmet medical need to overcome limitations for transcutaneous drug development posed by the skin barrier.ObjectiveWe aimed to identify a novel transdermal delivery peptide and to develop a transcutaneously applicable immunomodulatory protein for treating atopic dermatitis and psoriasis.MethodsWe identified and generated reporter proteins conjugated to AP, a novel transdermal delivery peptide of human origin, and analyzed the intracellular delivery efficiency of these proteins in mouse and human skin cells and tissues using multi-photon confocal microscopy. We also generated a recombinant therapeutic protein, AP-rPTP, consisting of the phosphatase domain of T cell protein tyrosine phosphatase (TC-PTP) conjugated to AP. The immunomodulatory function of AP-rPTP was confirmed in splenocytes upon cytokine stimulation and TcR stimulation. Finally, we confirmed the in vivo efficacy of AP-rPTP transdermal delivery in OXA-induced contact hypersensitivity, OVA-induced atopic dermatitis-like, and imiquimod-induced psoriasis-like skin inflammation models.ResultsAP-conjugated reporter proteins exhibited significant intracellular transduction efficacy in keratinocytes, fibroblasts, and immune cells. In addition, transcutaneous administration of AP-dTomato resulted in showed significant localization into the dermis and epidermis in both mouse and human skin. AP-rPTP inhibited pSTAT1, pSTAT3, and pSTAT6 in splenocytes and also regulated T cell activation and proliferation. Transcutaneous administration of AP-rPTP via the paper-patch technique significantly ameliorated skin tissue thickening, inflammation, and cytokine expression in both atopic dermatitis-like and psoriasis-like dermatitis models.ConclusionWe identified a 9-amino acid-long novel transdermal delivery peptide, AP, and demonstrated its feasibility for transcutaneous biologic drug development. Moreover, AP-rPTP is a novel immunomodulatory drug candidate for human dermatitis.

Teaser

A novel therapeutic version of protein tyrosine phosphatase with a biochemical enhancer penetrated the skin tissue barrier and ameliorated the inflammatory response in AD-like and psoriasis- like skin diseases.


http://ift.tt/2poyl0d

IgE Sensitization in Relation to Preschool Eczema and Filaggrin Mutation

Publication date: Available online 26 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Emma Kristin Johansson, Anna Bergström, Inger Kull, Tomas Lind, Cilla Söderhäll, Marianne van Hage, Magnus Wickman, Natalia Ballardini, Carl-Fredrik Wahlgren
BackgroundEczema (atopic dermatitis) is associated with an increased risk of having IgE antibodies. IgE sensitization may occur through an impaired skin barrier. Filaggrin (FLG) mutation is associated with eczema, and possibly also with IgE sensitization.ObjectiveTo explore the longitudinal relation between preschool eczema and/or FLG mutation and IgE sensitization in childhood.MethodsA total of 3201 children from the BAMSE birth cohort recruited from the general population were included. Regular parental questionnaires identified children with eczema. Blood samples were collected at 4, 8, and 16 years for analysis of specific IgE. FLG mutation analysis was performed on 1890 of the children.ResultsPreschool eczema was associated with IgE sensitization to both food and aeroallergens up to age 16 (overall adjOR 2.30; 95%CI: 2.00-2.66). This association was even stronger among children with persistent preschool eczema. FLG mutation was associated with IgE sensitization to peanut at age 4 years (adjOR 1.88; 95% CI: 1.03-3.44), but not to other allergens up to age 16 years. FLG mutation and preschool eczema were not effect modifiers for the association between IgE sensitization and preschool eczema or FLG mutation, respectively. Sensitized children with preschool eczema were characterized by polysensitization, but no other specific IgE sensitization patterns were found.ConclusionsPreschool eczema is associated with IgE sensitization, to both food and aeroallergens, up to 16 years of age. FLG mutation is associated with IgE sensitization to peanut, but not to other allergens. Sensitized children with preceding preschool eczema are more often polysensitized.

Teaser

Preschool eczema is associated with IgE sensitization to food and aeroallergens. FLG mutation is associated with IgE sensitization to peanut, but not other allergens. Preschool eczema is associated with polysensitization among sensitized children.


http://ift.tt/2qhuiQy

Measuring Long-term Disease Control in Atopic Dermatitis: a Validation Study of Well Controlled Weeks

Publication date: Available online 26 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Sinéad M. Langan, Beth Stuart, Lucy Bradshaw, Jochen Schmitt, Hywel C. Williams, Kim S. Thomas
BackgroundBecause atopic dermatitis (AD) is a relapsing, remitting disease, assessing long-term control is important. Well controlled weeks (WCWs) have been used to assess asthma long-term control, but never validated for AD.ObjectivesTo assess feasibility, validity and interpretability of WCWs in AD patients.MethodsThree studies of patients with moderate-to-severe AD including 4-6 months of daily/weekly symptom and treatment use data were evaluated (Study A: n=336; Study B: n=60; Study C: n=224). WCWs were defined by worsening symptoms and increased medication use. Feasibility, construct validity and interpretability of WCWs were determined by assessing missing data, association with validated AD outcomes, and floor/ceiling effects. Analysis used linear and logistic regression.ResultsWCWs were feasible to collect - 95.2% (study A) and 94.7% (study B) contributed data for at least half of the weekly data-points, and 93.2% and 88.7% contributed to all data-points up to 4 months. WCWs were significantly associated with validated AD severity instruments including patient-reported (POEM) and objective signs (EASI, TIS and SASSAD). The odds of experiencing a WCW if AD severity was clear/mild was 5.8 (95% confidence interval (CI) 3.5 to 9.7), 1.9 (95%CI 0.8 to 4.4) and 8.1 (95%CI 4.5 to 14.6) in Studies A, B and C, respectively. WCWs were associated with ceiling effects- 31.6% (study A) and 37.5% (study B) of participants had no WCWs for >90% of the time.ConclusionsWCWs are valid and feasible for measuring long-term control in AD trials. However, ceiling effects and burden of data collection may limit use.

Teaser

WCWs were feasible to collect and demonstrated construct validity (closely related to other measurements of AD severity); however, ceiling effects may be problematic in patients with moderate to severe disease.


http://ift.tt/2poxsEA

BTK inhibition: Clinical Relevance Beyond B Cells

Publication date: Available online 26 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Balaji Banoth, Suzanne L. Cassel




http://ift.tt/2qhzu6J

Oral Corticosteroid Exposure and Adverse Effects in Asthma

Publication date: Available online 27 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Patrick W. Sullivan, Vahram H. Ghushchyan, Gary Globe, Michael Schatz
BackgroundSignificant adverse effects (AEs) have been associated with continuous exposure to oral corticosteroids (OCS). The potential association with intermittent exposure is unknown.ObjectiveAssess the association between OCS and AEs based on the number of OCS prescriptions.MethodsThis was a retrospective cohort study of asthma patients ≥ 18 years in the 2000-2014 MarketScan® dataset. Propensity Score Matching was used at baseline (12 months prior to index date: first OCS use). Logistic regression was used to examine the association between OCS and new-incident AEs (either combined or individual) controlling for covariates. Follow-up continued for 24 months minimum and 10 years maximum after index.ResultsThere were 72,063 and 156,373 individuals in the OCS and no OCS cohorts, respectively. Individuals taking ≥ 4 OCS (1-3) prescriptions within the year had 1.29 (1.04) times the odds of experiencing a new AE within the year. Each year of exposure to ≥ 4 OCS prescriptions (current and past) resulted in 1.20 times the odds of developing an AE in the current year. Exposure to ≥ four prescriptions was associated with significantly greater odds of AEs for: osteoporosis, hypertension, obesity, type 2 diabetes, gastrointestinal ulcers/bleeds, fractures and cataracts (odds 1.21 – 1.44 depending on the AE).ConclusionWhile previous research has documented the deleterious effect of continuous OCS exposure in severe asthma, our results suggest that each OCS prescription may result in a cumulative burden on current and future health, regardless of dose and duration. OCS sparing strategies are extremely important to improving patient outcomes.

Teaser

While previous research has documented the adverse effects (AEs) of continuous oral corticosteroid (OCS) exposure in asthma, our results suggest that intermittent OCS use consistent with "burst" therapy may also result in adverse effects.


http://ift.tt/2qhEF6J

Fusion Proteins of Flagellin and the Major Birch Pollen Allergen Bet v 1 show Enhanced Immunogenicity, Reduced Allergenicity and Intrinsic Adjuvanticity

Publication date: Available online 26 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Claudia Kitzmüller, Julia Kalser, Sonja Mutschlechner, Michael Hauser, Gerhard J. Zlabinger, Fatima Ferreira, Barbara Bohle
BackgroundRecombinant fusion proteins of flagellin and antigens have been demonstrated to induce strong innate and adaptive immune responses. Such fusion proteins may enhance the efficacy of allergen-specific immunotherapy (AIT).ObjectiveTo characterize different fusion proteins of flagellin and the major birch pollen allergen Bet v 1 for suitability as allergy vaccines.MethodsA truncated version of flagellin (NtCFlg) was genetically fused to the N- or C-terminus of Bet v 1. TLR5-binding was assessed with HEK293 cells expressing TLR5. Up-regulation of CD40, CD80, CD83, and CD86 on monocyte-derived dendritic cells (mdDC) from allergic patients was analyzed by flow cytometry. The T cell-stimulatory capacity of the fusion proteins was assessed with naïve and Bet v 1-specific T cells. IgE-binding was tested in inhibition ELISA and basophil activation tests (BAT). Mice were immunized with the fusion proteins in the absence and presence of aluminium hydroxide (alum). Cellular and antibody responses were monitored. Murine antibodies were tested for blocking capacity in BAT.ResultsBoth fusion proteins matured mdDC via TLR5. Compared to Bet v 1 the fusion proteins showed stronger T cell-stimulatory and reduced IgE-binding capacity and induced murine Bet v 1-specific antibodies in the absence of alum. However, only antibodies induced by immunization with NtCFlg fused to the C-terminus of Bet v 1 inhibited the binding of patients´ IgE antibodies to Bet v 1.ConclusionBet v 1-flagellin fusion proteins show enhanced immunogenicity, reduced allergenicity and intrinsic adjuvanticity and thus, represent promising vaccines for birch pollen AIT. However, the sequential order of allergen and adjuvant within a fusion protein determines its immunological characteristics.

Teaser

Bet v 1-flagellin fusion proteins display several advantages over wild-type Bet v 1, namely reduced allergenicity, immunomodulatory capacity, enhanced immunogenicity and intrinsic adjuvanticity.


http://ift.tt/2poqyzg