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Genetic Variation of the Histamine Pathway in Subjects with Asthma
AB116 Abstracts
420
SUNDAY
Aspirin Augments IgE-Mediated Histamine Release From Human Peripheral Basophils Via Syk Kinase Activation Hiroaki Matsuo1, Tomoharu Yokooji1, Hironobu Morita1, Mina Ooi1, Kana Urata1, Shunsuke Takahagi2, Kaori Ishii2, Yuhki Yanase2, Takaaki Hiragun2, Shoji Mihara2, Michihiro Hide2; 1Department of Pathophysiology and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan, 2Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. RATIONALE: Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, and food additives (FAs) may exacerbate allergic symptoms in patients with chronic idiopathic urticaria and food-dependent exerciseinduced anaphylaxis (FDEIA). Augmentation of histamine release from human mast cells and basophils by those substances is speculated to be the cause of exacerbated allergic symptoms. We sought to investigate the mechanism of action of aspirin on IgE-mediated histamine release. METHODS: The effects of NSAIDs, FAs or cyclooxygenase (COX) inhibitors on histamine release from human basophils concentrated by gravity separation were evaluated. The phosphorylation of Syk kinase was detected with anti-phospho-Syk antibodies. RESULTS: Benzoate and tartrazine, which have no COX inhibitory activity, augmented histamine release from basophils similar to aspirin. In contrast, ibuprofen, meloxicam, FR122047 and NS-398, which have COX inhibitory activity, did not affect histamine release. These results indicate that the augmentation of histamine release by aspirin is not due to COX inhibition. It was observed that aspirin augmented histamine release from human basophils only when specifically activated by anti-IgE antibodies, but not by A23187 or formyl-methionyl-leucyl-phenylalanine. When the IgE receptor signaling pathway was activated, aspirin increased the phosphorylation of Syk. Moreover, patients with chronic urticaria and FDEIA tended to be more sensitive to aspirin as regards the augmentation of histamine release, compared with healthy controls. CONCLUSIONS: Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA.
421
Withdrawn
J ALLERGY CLIN IMMUNOL FEBRUARY 2013
422
Genetic Variation of the Histamine Pathway in Subjects with Asthma Nikita Raje, MD, MBBS1,2, Carrie A. Vyhlidal, PhD1, Amanda K. Riffel1, Hongying Dai, PhD1, Bridgette L. Jones, MD FAAAAI1; 1 Children’s Mercy Hospital & Clinics, Kansas City, MO, 2University of Missouri- Kansas City. RATIONALE: Histamine is known to be an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed in subjects with asthma relative to those without asthma. Genetic variations in the pathway responsible for histamine production, response, and degradation have been observed to be related to the disease. We aimed to determine if single nucleotide polymorphisms (SNPs) in genes involved in the histamine pathway were associated with diagnosis of asthma and/or mRNA expression of HRH1. METHODS: We enrolled children and adults (n594) with and without asthma who met inclusion/exclusion criteria. HRH1 expression was determined by qRT-PCR on mRNA. Genotyping was performed by real time PCR for known SNPs (n510) in HDC, HRH1, HRH4, HNMT and ABP1. Linear regression analysis, Fisher’s Exact test and Chi square test were used to determine differences in genotype for gene expression and asthma diagnosis with significance determined by p<0.05. RESULTS: No difference was observed for genotype among the 10 SNPs tested between subjects with and without asthma. Subjects who possessed a T allele at ABP1 995 exhibited higher expression of HRH1 (14.1 CT, 15 TT) relative to those homozygous for the major allele (12.7 CC), (p value 0.037). CONCLUSIONS: SNPs tested within genes along the histamine pathway do not appear to be associated with a diagnosis of asthma in our study population. Presence of a T allele at ABP1 995 may result in increased expression of HRH1. Further studies are needed to determine the potential biological and clinical significance of this finding.
423
The Mastocytosis Society Survey On Mast Cell Disorders: Patient Experiences and Perceptions Susan Jennings1, Nancy C. Russell1, Blair Jennings1, Valerie Slee1, Lisa Sterling1, Mariana C. Castells, MD PhD FAAAAI2, Peter Valent3, Cem Akin, MD PhD FAAAAI2; 1The Mastocytosis Society, Hastings, NE, 2 Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 3Medical University of Vienna, Vienna, Austria. RATIONALE: Mast cell diseases include mastocytosis and mast cell activation syndromes, some of which have been shown to involve clonal defects in mast cells that result in abnormal cellular proliferation or activation. Numerous clinical studies of mastocytosis have been published, but no population based comprehensive surveys of patients in the United States (U.S.) have been identified. Few mast cell disease specialty centers exist in the U.S. and awareness of these mast cell disorders is limited among non-specialists. Accordingly, information concerning the experiences of the overall estimated population of these patients has been lacking. In order to identify the experiences and perceptions of patients with mastocytosis, mast cell activation syndrome and related disorders, The Mastocytosis Society, a U.S. based patient advocacy, research and education organization, conducted a survey of its members and other people known or suspected to be part of this patient population. METHODS: A web-based survey was publicized through clinics treating such patients and the Society’s newsletter, Web site and online blogs. Both online and paper copies of the questionnaire were provided, together with required statements of consent. RESULTS: The first results are presented for 420 patients. These results include demographics, diagnoses, symptoms, allergies, triggers of mast cell symptoms, and disease impact. CONCLUSIONS: Patients with mastocytosis and mast cell activation syndromes have provided clinical specialists, collaborators, and other patients with information to enable them to explore and deepen their understanding of the experiences and perceptions of people coping with these disorders.
420
SUNDAY
Aspirin Augments IgE-Mediated Histamine Release From Human Peripheral Basophils Via Syk Kinase Activation Hiroaki Matsuo1, Tomoharu Yokooji1, Hironobu Morita1, Mina Ooi1, Kana Urata1, Shunsuke Takahagi2, Kaori Ishii2, Yuhki Yanase2, Takaaki Hiragun2, Shoji Mihara2, Michihiro Hide2; 1Department of Pathophysiology and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan, 2Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. RATIONALE: Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, and food additives (FAs) may exacerbate allergic symptoms in patients with chronic idiopathic urticaria and food-dependent exerciseinduced anaphylaxis (FDEIA). Augmentation of histamine release from human mast cells and basophils by those substances is speculated to be the cause of exacerbated allergic symptoms. We sought to investigate the mechanism of action of aspirin on IgE-mediated histamine release. METHODS: The effects of NSAIDs, FAs or cyclooxygenase (COX) inhibitors on histamine release from human basophils concentrated by gravity separation were evaluated. The phosphorylation of Syk kinase was detected with anti-phospho-Syk antibodies. RESULTS: Benzoate and tartrazine, which have no COX inhibitory activity, augmented histamine release from basophils similar to aspirin. In contrast, ibuprofen, meloxicam, FR122047 and NS-398, which have COX inhibitory activity, did not affect histamine release. These results indicate that the augmentation of histamine release by aspirin is not due to COX inhibition. It was observed that aspirin augmented histamine release from human basophils only when specifically activated by anti-IgE antibodies, but not by A23187 or formyl-methionyl-leucyl-phenylalanine. When the IgE receptor signaling pathway was activated, aspirin increased the phosphorylation of Syk. Moreover, patients with chronic urticaria and FDEIA tended to be more sensitive to aspirin as regards the augmentation of histamine release, compared with healthy controls. CONCLUSIONS: Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA.
421
Withdrawn
J ALLERGY CLIN IMMUNOL FEBRUARY 2013
422
Genetic Variation of the Histamine Pathway in Subjects with Asthma Nikita Raje, MD, MBBS1,2, Carrie A. Vyhlidal, PhD1, Amanda K. Riffel1, Hongying Dai, PhD1, Bridgette L. Jones, MD FAAAAI1; 1 Children’s Mercy Hospital & Clinics, Kansas City, MO, 2University of Missouri- Kansas City. RATIONALE: Histamine is known to be an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed in subjects with asthma relative to those without asthma. Genetic variations in the pathway responsible for histamine production, response, and degradation have been observed to be related to the disease. We aimed to determine if single nucleotide polymorphisms (SNPs) in genes involved in the histamine pathway were associated with diagnosis of asthma and/or mRNA expression of HRH1. METHODS: We enrolled children and adults (n594) with and without asthma who met inclusion/exclusion criteria. HRH1 expression was determined by qRT-PCR on mRNA. Genotyping was performed by real time PCR for known SNPs (n510) in HDC, HRH1, HRH4, HNMT and ABP1. Linear regression analysis, Fisher’s Exact test and Chi square test were used to determine differences in genotype for gene expression and asthma diagnosis with significance determined by p<0.05. RESULTS: No difference was observed for genotype among the 10 SNPs tested between subjects with and without asthma. Subjects who possessed a T allele at ABP1 995 exhibited higher expression of HRH1 (14.1 CT, 15 TT) relative to those homozygous for the major allele (12.7 CC), (p value 0.037). CONCLUSIONS: SNPs tested within genes along the histamine pathway do not appear to be associated with a diagnosis of asthma in our study population. Presence of a T allele at ABP1 995 may result in increased expression of HRH1. Further studies are needed to determine the potential biological and clinical significance of this finding.
423
The Mastocytosis Society Survey On Mast Cell Disorders: Patient Experiences and Perceptions Susan Jennings1, Nancy C. Russell1, Blair Jennings1, Valerie Slee1, Lisa Sterling1, Mariana C. Castells, MD PhD FAAAAI2, Peter Valent3, Cem Akin, MD PhD FAAAAI2; 1The Mastocytosis Society, Hastings, NE, 2 Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 3Medical University of Vienna, Vienna, Austria. RATIONALE: Mast cell diseases include mastocytosis and mast cell activation syndromes, some of which have been shown to involve clonal defects in mast cells that result in abnormal cellular proliferation or activation. Numerous clinical studies of mastocytosis have been published, but no population based comprehensive surveys of patients in the United States (U.S.) have been identified. Few mast cell disease specialty centers exist in the U.S. and awareness of these mast cell disorders is limited among non-specialists. Accordingly, information concerning the experiences of the overall estimated population of these patients has been lacking. In order to identify the experiences and perceptions of patients with mastocytosis, mast cell activation syndrome and related disorders, The Mastocytosis Society, a U.S. based patient advocacy, research and education organization, conducted a survey of its members and other people known or suspected to be part of this patient population. METHODS: A web-based survey was publicized through clinics treating such patients and the Society’s newsletter, Web site and online blogs. Both online and paper copies of the questionnaire were provided, together with required statements of consent. RESULTS: The first results are presented for 420 patients. These results include demographics, diagnoses, symptoms, allergies, triggers of mast cell symptoms, and disease impact. CONCLUSIONS: Patients with mastocytosis and mast cell activation syndromes have provided clinical specialists, collaborators, and other patients with information to enable them to explore and deepen their understanding of the experiences and perceptions of people coping with these disorders.