August 13, 2014

Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma


Vol. 164, No. 1, 2014
Issue release date: June 2014

Editor's Choice -- Free Access

Int Arch Allergy Immunol 2014;164:46-63 (DOI:10.1159/000362553)

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A New Era of Targeting the Ancient Gatekeepers of the Immune System: Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma

Aryan Z.a · Holgate S.T.c · Radzioch D.e · Rezaei N.a,b,d

aMolecular Immunology Research Center and Department of Immunology, School of Medicine and bResearch Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; cFaculty of Medicine, Clinical and Experimental Sciences, Southampton General Hospital, Southampton, anddDepartment of Infection and Immunity, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK; eDepartment of Medicine and Department of Human Genetics, McGill University, Montreal, Que., Canada

Corresponding Author

Abstract

Toll-like receptors (TLR) belong to a large family of pattern recognition receptors known as the ancient ‘gatekeepers' of the immune system. TLRs are located at the first line of defense against invading pathogens as well as aeroallergens, making them interesting targets to modulate the natural history of respiratory allergy. Agonists of TLRs have been widely employed in therapeutic or prophylactic preparations useful for asthma/allergic rhinitis (AR) patients. MPL® (a TLR4 agonist) and the CpG oligodeoxynucleotide of 1018 ISS, a TLR9 agonist, show strong immunogenicity effects that make them appropriate adjuvants for allergy vaccines. Targeting the TLRs can enhance the efficacy of specific allergen immunotherapy, currently the only available ‘curative' treatment for respiratory allergies. In addition, intranasal administration of AZD8848 (a TLR7 agonist) and VTX-1463 (a TLR8 agonist) as stand-alone therapeutics have revealed efficacy in the relief of the symptoms of AR patients. No anaphylaxis has been so far reported with such compounds targeting TLRs, with the most common adverse effects being transient and local irritation (e.g. redness, swelling and pruritus). Many other compounds that target TLRs have been found to suppress airway inflammation, eosinophilia and airway hyper-responsiveness in various animal models of allergic inflammation. Indeed, in the future a wide variability of TLR agonists and even antagonists that exhibit anti-asthma/AR effects are likely to emerge.

Outline

TLR4/MD2/CD14

TLR7 and TLR8: Sensors of Single-Stranded Viral RNA

TLR9: Sensor of Bacterial DNA

Key Words 

Toll-like receptors
CD14
Hygiene hypothesis
 Innate immunity
Immunotherapy
Adjuvants
 CpG oligodeoxynucleotide
Immunostimulatory  sequence oligonucleotides
Asthma
Allergic rhinitis

August 12, 2014

The presence of H.pylori in cases of chronic idiopathic urticaria

Rashad Feddah

Ibraheem Banihameem

Anwar Farhan

Saeed Al-Ahmari

Fayeh Asiri

Hamad AL Fahaad

Wadha Alfarwan

Correspondence:
Dr. Anwar Farhan, MD
Consultant dermatologist
King Khalid Hospital, Najran, Saudi Arabia
Tel: (Cell phone) +966 553044333
Email: anwarfarhan@yahoo.com

Abstract
Introduction: Urticaria (or hives) are a kind of skin rash notable for dark red, raised, itchy bumps.Chronic urticaria, defined as urticaria that persists for longer than 6 weeks, it is not a single disease but a reaction pattern that represents cutaneous mast cell degranulation, resulting in extravasation of plasma into the dermis and the patients may not improve or may depend on medication for years to relieve symptoms. chronic urticaria is one of the most common problems facing dermatologists and other specialities. It is the problem which bothers both the patient and the dermatologist. Traditionally, the approach in patients with chronic urticaria (when physical etiology has been excluded) has been to order a panel of laboratory tests to discover an occult medical condition responsible for the skin findings. In many patients, an extensive workup does not discover an etiology. Patients in whom no explanation for his urticaria are said to have chronic idiopathic urticaria. Various infectious agents have been reported as causes of urticaria, including Helicobacter pylori (H. pylori), which is a common worldwide bacterial infection. Its role in inducing allergic conditions, such as chronic urticaria, has been suggested in some reports and ignored in others.

Aim : In our research, we want to look for the prevalence of Helicobacter pylori in the serum of patient who presented with chronic urticaria .The patient has endure treatment and is not cured besides partial treatment causes temporary relive of symptoms. So, it is important to make the right decisions regarding the treatment of chronic urticaria by adding triple therapy for those who are H.pylori positive.

Subjects and Methods: This study is a non controlled , consecutive interventional study involving 60 patients during the period from November 2012 to April 2013 with history of urticarial lesions of > 6 weeks, to search for the possible cause of their chronic urticaria.

Results: Among 60 patients suffering from chronic Urticaria only 40 (66.7%) patients were enrolled in the study with chronic idiopathic urticaria.

25 patients (62.5%) of chronic idiopathic urticaria were infected with H.pylori and 15 patients (37.5%) had negative serology for H.pylori. 80% of patients with positive H.pylori had G.I.T symptoms ,18 patients (72%) were achieved eradication with the first line therapy while 5 patients (20%) required the second line therapy for eradication. In 2 patients (8%) H.pyloripersisted despite two courses of eradication therapy. Response to eradication therapy was evident in 19 patients (76%) in whom H.pylori was eradicated while 4 patients (16%) showed no response despite eradication of H.pylori. Two patients (8%) with persistent H.pylori infection showed no improvement in the urticarial symptoms at the end of study period.

Conclusion: The results of our study strongly suggest that H.pylori should be specifically tested in all patients of CIU, to identify subset of patients who are infected and who could benefit from eradication therapy. H.pylori should be included in the diagnostic work up of all patients with CIU.

Key words : H.pylori, chronic idiopathic urticaria , chronic urticaria

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Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis

Published Date December 2013 Volume 2014:8 Pages 1—12

DOI http://dx.doi.org/10.2147/BTT.S35475

Received 16 September 2013, Accepted 11 October 2013, Published 9 December 2013

Filipe Seguro Paula,1 José Delgado Alves1,2

1Immunomediated Systemic Diseases Unit, Department of Medicine 4, Fernando Fonseca Hospital, Amadora, 2Center for the Study of Chronic Diseases, Department of Pharmacology, Faculty of Medical Sciences, Lisbon, Portugal

Abstract: The way rheumatoid arthritis is treated has changed dramatically with the introduction of anti-tumor necrosis factor (anti-TNF) biologics. Nevertheless, many patients still have less than adequate control of their disease activity even with these therapeutic regimens, and current knowledge fails to explain all the data already gathered. There is now a wide range of drugs from different classes of biologic disease-modifying anti-rheumatic drugs available (and soon this number will increase significantly), that provides the opportunity to address each patient as a particular case and thereby optimize medical intervention. Currently available biologics for the treatment of rheumatoid arthritis apart from anti-TNF-based therapies are reviewed, along with an analysis of the new insights they provide into the pathogenesis of the disease and a discussion of future prospects in the area.

Keywords: rheumatoid arthritis, non-anti-tumor necrosis factor, treatment, pathogenesis

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August 11, 2014

Capsaicin-sensitive cough receptors in lower airway are responsible for cough hypersensitivity in patients with upper airway cough syndrome

Med Sci Monit. 2013 Dec 3;19:1095-101. doi: 10.12659/MSM.889118.

Yu L1, Xu X, Wang L, Yang Z, Lü H, Qiu Z.

Abstract

BACKGROUND:

Cough hypersensitivity may be related to the pathogenesis of upper airway cough syndrome (UACS). The purpose of the study was to investigate the role of capsaicin-sensitive cough receptors on the laryngopharynx and lower airway in the cough hypersensitivity of patients with UACS.

MATERIAL AND METHODS:

59 patients with UACS, 33 patients with rhinitis/sinusitis without cough, and 39 healthy volunteers were recruited for the study. Cough threshold C5, defined as the lowest concentration of capsaicin required for the induction of ≥ 5 coughs upon exposure to capsaicin, were determined at baseline and after laryngopharngeal anesthesia with lidocaine in all the subjects. After induced sputum cytology, the concentrations of histamine, prostaglandin E2 (PGE2), and calcitonin-gene-related peptide (CGPR) in the induced sputum were measured by ELISA. In 15 patients with UACS, sputum cytology and measurement of the above mediators were repeated after successful therapy.

RESULTS:

C5 response to capsaicin was significantly lower in the UACS group than in the rhinitis/sinusitis group and healthy control groups [3.9 (0.98, 7.8) µmol/L vs. 7.8 (3.9, 93.75) µmol/L vs. 31.2 (15.6, 62.5) µmol/L, H=40.12, P=0.000]. Laryngopharngeal anesthesia with lidocaine dramatically increased C5 to capsaicin in the subjects of all 3 groups by a similar degree, but the increase in the UACS group was still the lowest, with an increased level of histamine, PGE2, and CGRP in the induced sputum. When cough resolved with the treatment of cetirizine alone or in combination with erythromycin, the levels of CGRP and histamine in the induced sputum decreased significantly in 15 patients with UACS, with no obvious change in cell differential or concentration of PGE2 in the induced sputum.

CONCLUSIONS:

Laryngeal TRPV1 plays an important role in cough sensitivity, but sensitization of capsaicin-sensitive cough receptors in the lower airway may be more responsible for the cough hypersensitivity in patients with UACS.

Free PMC Article

Natural killer cells from patients with chronic rhinosinusitis have impaired effector functions

PLoS One. 2013 Oct 18;8(10):e77177. doi: 10.1371/journal.pone.0077177. eCollection 2013.

Kim JH1, Kim GE, Cho GS, Kwon HJ, Joo CH, Kim HS, Jang YJ.

Abstract

Natural killer (NK) cells are multicompetent lymphocytes of the innate immune system that play a central role in host defense and immune regulation. Although increasing evidence suggests that innate immunity plays a key role in the pathogenesis of chronic rhinosinusitis (CRS), the role of NK cells in CRS has been poorly studied. This study aimed to characterize the peripheral blood NK cells from patients with CRS, and to compare the functions of these cells with those from non-CRS controls. The correlation between NK cell functional activity and prognosis was also assessed. Eighteen CRS patients and 19 healthy non-CRS controls were included. The patients with CRS were classified into two subgroups, namely a treatment-responsive group and recalcitrant group. NK cell degranulation was determined by measuring the cell surface expression of CD107a against 721.221 and K562 cells. Intracytoplasmic cytokine production was determined by flow cytometry. Compared to the controls, the NK cells of CRS group had an impaired ability to degranulate and to produce cytokines such as IFN-γ and TNF-α. The recalcitrant subgroup showed the most severe defects in NK cell effector functions. Moreover, the decreased NK cell functions in patients with CRS were associated with poor prognostic factors such as concomitant asthma and peripheral blood eosinophilia. NK cells, which were originally named for their ability to mediate spontaneous cytotoxicity towards diseased cells including infected cells, may play an important role in regulating the inflammatory process in CRS pathogenesis.

Free PMC Article

Vitamin A supplementation and risk of atopy: long-term follow-up of a randomized trial of vitamin A supplementation at six and nine months of age

Research article

Nicholas Kiraly¹²^*, Aliu Balde¹, Ida Marie Lisse¹, Helle Brander Eriksen¹³, Peter Aaby¹³and Christine Stabell Benn¹³

*Corresponding author: Nicholas Kiraly nicholas.kiraly@mcri.edu.au

Author Affiliations

¹Bandim Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau

²Gastro and Food Allergy, Murdoch Childrens Research Institute, Royal Children’s Hospital, Flemington Rd, Parkville VIC 3052, Australia

³Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, 5 Artillerivej, Copenhagen S DK-2300, Denmark

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BMC Pediatrics 2013, 13:190 doi:10.1186/1471-2431-13-190

The electronic version of this article is the complete one and can be found online at:http://www.biomedcentral.com/1471-2431/13/190

Received:	21 July 2013
Accepted:	15 November 2013
Published:	19 November 2013

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The World Health Organization recommends high-dose vitamin A supplementation (VAS) for children above six months of age in low-income countries. VAS has been associated with up-regulation of the Th2 response. We aimed to determine if VAS is associated with atopy in childhood.

Methods

Infants in Guinea-Bissau were randomly allocated VAS or placebo, either at six and nine months of age, or only at nine months of age. At six months of age, children were furthermore randomized to measles vaccine or inactivated polio vaccine. At nine months of age all children received measles vaccine. Children were revisited seven years later and skin prick testing was performed. Atopy was defined as a skin prick reaction ≥3 mm.

Results

40 of 263 children (15%) were atopic. Overall VAS had no significant effect on the risk of atopy (Prevalence Ratio 1.23; 95% CI 0.69-2.18). The Prevalence Ratio was 1.60 (0.66-3.90) for males and 1.00 (0.46-2.15) for females.

Conclusions

There was no significant effect of VAS in infancy on atopy later in childhood. The role of infant VAS in the development of atopy is still unclear.

Keywords:

Atopy; Immunization; Measles vaccine; Vitamin A supplementation

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Melatonin and atopy: role in atopic dermatitis and asthma

Int J Mol Sci. 2014 Aug 4;15(8):13482-93. doi: 10.3390/ijms150813482.

Marseglia L, D'Angelo G, Manti S, Salpietro C, Arrigo T, Barberi I, Reiter RJ, Gitto E.

Abstract

Melatonin may have important immunostimulatory actions in allergic diseases, in addition to its well-known antioxidant and cytoprotective effects in several inflammatory conditions. The activation of the immune system leads to free radical production associated with decreased melatonin levels and depressed antioxidant enzyme activities in several inflammatory diseases. Many skin disorders, including atopic dermatitis, are accompanied by infiltration and activation of mast cells, which release vasoactive and proinflammatory mediators. Experimental data suggest that melatonin inhibits development of atopic eczema and reduces serum total IgE and IL-4. Allergic asthma is a condition characterized by bronchial hyperresponsiveness and the presence of IgE antibodies in response to inhaled allergens; often there is also enhanced total serum IgE levels. Melatonin regulates smooth muscle tone and influences the immune response. Melatonin may, however, act as a pro-inflammatory agent in asthma leading to bronchial constriction. The safety of melatonin as a sleep-inducing agent has been confirmed in asthmatic subjects, but its routine use is not recommended in bronchial asthma. This review summarizes what is known about the role of melatonin as an immunomodulatory agent in asthma and atopic eczema.

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Helicobacter pylori immunization and atopic dermatitis in South Italian children

United European Gastroenterol J. Aug 2014; 2(4): 263–267.

doi: 10.1177/2050640614544314

PMCID: PMC4114125

Marcella Pedullà,1 Vincenzo Fierro,1 Ester Del Tufo,1 Rossella Alfano, corresponding author

2 Maria Triassi,2 and Laura Perrone1

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