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Type III Hereditary Angioedema: First Description of a Mutation in Factor XII Gene and Clinical Features in a Brazilian Family
AB82 Abstracts
308
SUNDAY
Type III Hereditary Angioedema: First Description of a Mutation in Factor XII Gene and Clinical Features in a Brazilian Family A. S. Moreno1, S. O. R. Valle2, A. T. Franca2, S. A. Levy2, D. Ponard3, N. Monnier3, J. Lunardi3, L. Arruda1; 1School of Medicine of Ribeirao Preto, Ribeirao Preto, BRAZIL, 2Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, BRAZIL, 3JosephFourier University of Grenoble, Grenoble, FRANCE. RATIONALE: Hereditary Angioedema (HAE) type III has been described mostly in women, being influenced by exogenous estrogen exposure. Patients with HAE type III present normal levels and function of C1-inhibitor (C1-INH), and normal C4. Our aim was to describe characteristics of patients with HAE type III in a Brazilian family. METHODS: A 26-year-old female patient, with a history of recurrent episodes of angioedema was evaluated. Whole blood and serum were collected for measurements of C1-INH and C4 by nephelometry. Genomic DNA was isolated from whole blood from the patient, her father and a paternal aunt who have experienced recurrent angioedema attacks, and one maternal uncle with no history of angioedema. PCR was performed with 50 ng genomic DNA, and sequencing of exon 9 from the F12 gene was performed. RESULTS: Patient’s symptoms started at age 17, with episodes of edema of extremities, face, tongue, lips, larynx, and genitalia, abdominal pain, ascitis and dyspnea. Episodes occurred once a month with severe intensity, being triggered by stress, sexual intercourse and oral contraceptives. Diagnosis was made at age 26, and symptoms were controlled after withdrawal of oral contraceptives. C4 and C1-INH levels were normal on at least two occasions. Genetic analysis revealed a missense mutation in exon 9 of the F12 gene, previously identified as p.Thr309Lys, on the index case and her paternal relatives, but not on the asymptomatic maternal uncle. CONCLUSIONS: This study demonstrates for the first time in Brazil the presence of a genetic mutation in factor XII as a cause of HAE type III.
309
Parasite-related IgE Antibodies, Including IgE to Galactosealpha-1,3-galactose, in Sera from Virginia and Ecuador H. R. James1, L. A. Kelly1, S. L. Pochan1, S. P. Commins1, L. J. Workman1, L. W. Nganga2, P. J. Cooper3,4, T. A. E. Platts-Mills1; 1University of Virginia, Charlottesville, VA, 2Futures Group International, Nairobi, KENYA, 3Universidad San Francisco de Quito, Cumbay, ECUADOR, 4 Liverpool School of Tropical Medicine, Liverpool, UNITED KINGDOM. RATIONALE: IgE antibodies to galactose-alpha-1,3-galactose (alphagal) have become increasingly prevalent in the southeastern United States. These antibodies have recently been linked to bites from the tick Amblyomma americanum, but the possibility of a role for other parasites remains. METHODS: Assays for IgE were performed on patients with delayed urticaria or anaphylaxis to meat and controls in Virginia (n5125), as well as a cohort from Esmeraldas Province, Ecuador (n5295) where Echinococcus is not endemic. RESULTS: The significant association between IgE antibodies to alphagal and IgE to Echinococcus was strongest in Virginia (r50.74 vs r50.62 for Ecuador, both p<0.001). Further, only 3/37 Echinococcus IgE-positive subjects in Virginia were not positive for IgE to alpha-gal. In Ecuador, 118/ 223 Ascaris-positive sera were negative for IgE to alpha-gal; by contrast, in Virginia 52/79 alpha-gal positive sera were negative for Ascaris and only one sera was Ascaris-positive and alpha-gal negative. Virginia sera with IgE to Echinococcus (class 2 and 3) were absorbed with alpha-gal linked to Sepharose beads, which removed all detectable IgE to Echinococcus. CONCLUSIONS: We think that the limited number of positive assays for Echinococcus and Ascaris in Virginia can be explained by cross-reactivity with alpha-gal, which may also be relevant for Echinococcus in Esmeraldas. By contrast, many sera in Ecuador had high titer IgE to Ascaris with negative responses to alpha-gal. None of these IgE antibodies were significantly associated with asthma in the United States, while IgE to Ascaris was significantly associated with asthma in Ecuador.
J ALLERGY CLIN IMMUNOL FEBRUARY 2012
310
Analysis Of 4,610 Patients With Elevated Serum Immunoglubulin E R. Rokutanda, K. Yamaguchi, H. Shimizu, Y. Suyama, Y. Ohara, A. Takeda, M. Kishimoto, M. Okada; St.Luke’s International Hospital, Tokyo, Japan, Tokyo, JAPAN. RATIONALE: This study was designed to describe the demographic characteristics of patients with elevated total immunoglobulin E (IgE). METHODS: During the period 2003 to 2011, we identified 4610 patients whose total IgE levels exceeded the upper limit of normal at least once. Medical records were retrospectively reviewed to check their age, sex, maximum total IgE values, maximum eosinophil counts, specific diagnoses, i.e. food allergy, bronchial asthma, allergic rhinitis, anaphylaxis, atopic dermatitis, urticaria and non-allergic disease. RESULTS: In 4610 patients, total of 8610 diagnoses were identified. Most of the patients (96.6%) had at least one allergic diseases, and allergic rhinitis was the most common diagnosis (2438 out of 4610 patients, 52.9%) followed by bronchial asthma (45.0%) and atopic dermatitis (32.8%). The IgE level was significantly higher in men than women (p<0.001), and also higher in allergic diseases than non-allergic diseases (p<0.001). Among allergic diseases, only atopic dermatitis showed especially higher IgE than the others (p<0.001). In 97 patients who showed very high IgE, greater than 10,000 IU/mL, atopic dermatitis was the most common diagnosis (85.7%). Eosinophil counts significantly correlated with IgE in all allergic diseases (p<0.001), while they didn’t show any correlation in non-allergic disease. CONCLUSIONS: Allergic diseases were overrepresented in populations with elevated serum total IgE. Allergic diseases, especially atopic dermatitis, tended to have higher value than non-allergic disease.
311
Relationship Of Toll-like Receptors 2 And 4 Gene Polymorphisms With Elevated Production Of Specific Immunoglobulin E I. P. Kaidashev1, O. V. Izmaylova1, N. L. Kutsenko1, O. A. Shlykova1, L. E. Vesnina1, L. M. DuBuske2; 1Ukrainian Medical Stomatological Academy, Poltava, UKRAINE, 2Immunology Research Institute of New England, Gardner, MA. RATIONALE: Polymorphisms of genes encoding TLR2 (NP_003255.2) and TLR4 (NP_612564.1) increase production of IgE. METHODS: Three single nucleotide polymorphisms of TLR2 (rs5743708) and TLR4 (rs4986790, rs4986791) were genotyped in the control group which of 95 volunteers and 38 patients allergic diseases: 19 asthmatics, 13 atopic dermatitics and 6 allergic rhinitics. Selection required presence of high concentrations of allergen-specific IgE (> 3.5 kU / l) to at least one inhalant or food allergen. Allergen-specific IgE were determined by ELISA ("Rolycheck", Germany). Isolation of genomic DNA from blood used "rapid DNA-blood" (NPF "Lytech", Moscow). Genotyping of specific regions of the genome was performed by polymerase chain reaction. RESULTS: Analysis of the frequency of polymorphic variants of the gene TLR4 (rs4986790, rs4986791) and TLR2 (rs5743708) showed the presence of significant correlation between the presence of a polymorphic allele of the gene and increased production of TLR2-specific IgE (p 5 0.028). Allergic patients with elevated levels of specific IgE had significantly more common genotypes carrying the polymorphic allele G (AG and GG) of the gene TLR4 (rs4986790), than the control group (p 5 0.013). The second single-nucleotide polymorphisms TLR4 (rs4986791) showed a possible link between the presence of at least one polymorphic allele T (genotype CT and TT) with elevated levels of specific IgE (p 5 0.07). CONCLUSIONS: A relationship of polymorphisms of TLR2 (rs5743708) and TLR4 (rs4986790) with a high level of production of specific IgE was seen in patients with allergic diseases, suggesting singlenucleotide substitution as an additional predictor of individual propensity for these diseases.
308
SUNDAY
Type III Hereditary Angioedema: First Description of a Mutation in Factor XII Gene and Clinical Features in a Brazilian Family A. S. Moreno1, S. O. R. Valle2, A. T. Franca2, S. A. Levy2, D. Ponard3, N. Monnier3, J. Lunardi3, L. Arruda1; 1School of Medicine of Ribeirao Preto, Ribeirao Preto, BRAZIL, 2Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, BRAZIL, 3JosephFourier University of Grenoble, Grenoble, FRANCE. RATIONALE: Hereditary Angioedema (HAE) type III has been described mostly in women, being influenced by exogenous estrogen exposure. Patients with HAE type III present normal levels and function of C1-inhibitor (C1-INH), and normal C4. Our aim was to describe characteristics of patients with HAE type III in a Brazilian family. METHODS: A 26-year-old female patient, with a history of recurrent episodes of angioedema was evaluated. Whole blood and serum were collected for measurements of C1-INH and C4 by nephelometry. Genomic DNA was isolated from whole blood from the patient, her father and a paternal aunt who have experienced recurrent angioedema attacks, and one maternal uncle with no history of angioedema. PCR was performed with 50 ng genomic DNA, and sequencing of exon 9 from the F12 gene was performed. RESULTS: Patient’s symptoms started at age 17, with episodes of edema of extremities, face, tongue, lips, larynx, and genitalia, abdominal pain, ascitis and dyspnea. Episodes occurred once a month with severe intensity, being triggered by stress, sexual intercourse and oral contraceptives. Diagnosis was made at age 26, and symptoms were controlled after withdrawal of oral contraceptives. C4 and C1-INH levels were normal on at least two occasions. Genetic analysis revealed a missense mutation in exon 9 of the F12 gene, previously identified as p.Thr309Lys, on the index case and her paternal relatives, but not on the asymptomatic maternal uncle. CONCLUSIONS: This study demonstrates for the first time in Brazil the presence of a genetic mutation in factor XII as a cause of HAE type III.
309
Parasite-related IgE Antibodies, Including IgE to Galactosealpha-1,3-galactose, in Sera from Virginia and Ecuador H. R. James1, L. A. Kelly1, S. L. Pochan1, S. P. Commins1, L. J. Workman1, L. W. Nganga2, P. J. Cooper3,4, T. A. E. Platts-Mills1; 1University of Virginia, Charlottesville, VA, 2Futures Group International, Nairobi, KENYA, 3Universidad San Francisco de Quito, Cumbay, ECUADOR, 4 Liverpool School of Tropical Medicine, Liverpool, UNITED KINGDOM. RATIONALE: IgE antibodies to galactose-alpha-1,3-galactose (alphagal) have become increasingly prevalent in the southeastern United States. These antibodies have recently been linked to bites from the tick Amblyomma americanum, but the possibility of a role for other parasites remains. METHODS: Assays for IgE were performed on patients with delayed urticaria or anaphylaxis to meat and controls in Virginia (n5125), as well as a cohort from Esmeraldas Province, Ecuador (n5295) where Echinococcus is not endemic. RESULTS: The significant association between IgE antibodies to alphagal and IgE to Echinococcus was strongest in Virginia (r50.74 vs r50.62 for Ecuador, both p<0.001). Further, only 3/37 Echinococcus IgE-positive subjects in Virginia were not positive for IgE to alpha-gal. In Ecuador, 118/ 223 Ascaris-positive sera were negative for IgE to alpha-gal; by contrast, in Virginia 52/79 alpha-gal positive sera were negative for Ascaris and only one sera was Ascaris-positive and alpha-gal negative. Virginia sera with IgE to Echinococcus (class 2 and 3) were absorbed with alpha-gal linked to Sepharose beads, which removed all detectable IgE to Echinococcus. CONCLUSIONS: We think that the limited number of positive assays for Echinococcus and Ascaris in Virginia can be explained by cross-reactivity with alpha-gal, which may also be relevant for Echinococcus in Esmeraldas. By contrast, many sera in Ecuador had high titer IgE to Ascaris with negative responses to alpha-gal. None of these IgE antibodies were significantly associated with asthma in the United States, while IgE to Ascaris was significantly associated with asthma in Ecuador.
J ALLERGY CLIN IMMUNOL FEBRUARY 2012
310
Analysis Of 4,610 Patients With Elevated Serum Immunoglubulin E R. Rokutanda, K. Yamaguchi, H. Shimizu, Y. Suyama, Y. Ohara, A. Takeda, M. Kishimoto, M. Okada; St.Luke’s International Hospital, Tokyo, Japan, Tokyo, JAPAN. RATIONALE: This study was designed to describe the demographic characteristics of patients with elevated total immunoglobulin E (IgE). METHODS: During the period 2003 to 2011, we identified 4610 patients whose total IgE levels exceeded the upper limit of normal at least once. Medical records were retrospectively reviewed to check their age, sex, maximum total IgE values, maximum eosinophil counts, specific diagnoses, i.e. food allergy, bronchial asthma, allergic rhinitis, anaphylaxis, atopic dermatitis, urticaria and non-allergic disease. RESULTS: In 4610 patients, total of 8610 diagnoses were identified. Most of the patients (96.6%) had at least one allergic diseases, and allergic rhinitis was the most common diagnosis (2438 out of 4610 patients, 52.9%) followed by bronchial asthma (45.0%) and atopic dermatitis (32.8%). The IgE level was significantly higher in men than women (p<0.001), and also higher in allergic diseases than non-allergic diseases (p<0.001). Among allergic diseases, only atopic dermatitis showed especially higher IgE than the others (p<0.001). In 97 patients who showed very high IgE, greater than 10,000 IU/mL, atopic dermatitis was the most common diagnosis (85.7%). Eosinophil counts significantly correlated with IgE in all allergic diseases (p<0.001), while they didn’t show any correlation in non-allergic disease. CONCLUSIONS: Allergic diseases were overrepresented in populations with elevated serum total IgE. Allergic diseases, especially atopic dermatitis, tended to have higher value than non-allergic disease.
311
Relationship Of Toll-like Receptors 2 And 4 Gene Polymorphisms With Elevated Production Of Specific Immunoglobulin E I. P. Kaidashev1, O. V. Izmaylova1, N. L. Kutsenko1, O. A. Shlykova1, L. E. Vesnina1, L. M. DuBuske2; 1Ukrainian Medical Stomatological Academy, Poltava, UKRAINE, 2Immunology Research Institute of New England, Gardner, MA. RATIONALE: Polymorphisms of genes encoding TLR2 (NP_003255.2) and TLR4 (NP_612564.1) increase production of IgE. METHODS: Three single nucleotide polymorphisms of TLR2 (rs5743708) and TLR4 (rs4986790, rs4986791) were genotyped in the control group which of 95 volunteers and 38 patients allergic diseases: 19 asthmatics, 13 atopic dermatitics and 6 allergic rhinitics. Selection required presence of high concentrations of allergen-specific IgE (> 3.5 kU / l) to at least one inhalant or food allergen. Allergen-specific IgE were determined by ELISA ("Rolycheck", Germany). Isolation of genomic DNA from blood used "rapid DNA-blood" (NPF "Lytech", Moscow). Genotyping of specific regions of the genome was performed by polymerase chain reaction. RESULTS: Analysis of the frequency of polymorphic variants of the gene TLR4 (rs4986790, rs4986791) and TLR2 (rs5743708) showed the presence of significant correlation between the presence of a polymorphic allele of the gene and increased production of TLR2-specific IgE (p 5 0.028). Allergic patients with elevated levels of specific IgE had significantly more common genotypes carrying the polymorphic allele G (AG and GG) of the gene TLR4 (rs4986790), than the control group (p 5 0.013). The second single-nucleotide polymorphisms TLR4 (rs4986791) showed a possible link between the presence of at least one polymorphic allele T (genotype CT and TT) with elevated levels of specific IgE (p 5 0.07). CONCLUSIONS: A relationship of polymorphisms of TLR2 (rs5743708) and TLR4 (rs4986790) with a high level of production of specific IgE was seen in patients with allergic diseases, suggesting singlenucleotide substitution as an additional predictor of individual propensity for these diseases.