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Abnormalities In B Cell Homeostasis And Tolerance In Common Variable Immunodeficiency (CVID)
AB146 Abstracts
551
SUNDAY
T-cell Receptor Excision Circles of Newborns Are Associated with Gestational Age: Data from Wisconsin Newborn Screening for Severe Combined Immunodeficiency M. Baker1, A. Atkins1, W. Grossman2, C. Seroogy1, M. Lindstrom1, C. Brokopp1, J. Routes2; 1University of Wisconsin School of Medicine and Public Health, Madison, WI, 2Medical College of Wisconsin, Milwaukee, WI. RATIONALE: To determine whether the copy number of T-cell Receptor Excision Circles (TRECs) differs between full-term and preterm newborns (gestation age < 37 weeks), and, if so, to develop an appropriate action plan to deal with preterm newborns who have low TRECs reported in newborn screening (NBS) for severe combined immunodeficiency (SCID). METHODS: Wisconsin NBS Program quantitates TRECs on dried blood NBS specimens to screen for SCID. From January 1 to June 30, 2008, the TREC assay was performed on 2510 preterm newborns (gestational age, _ 72 hours after birth. The re23-36 weeks) whose samples were collected < sults of the TREC assay from 5,020 full term newborns were included as controls. The relationship between TRECs and gestation age in weeks was estimated using separate univariate linear regression with an added blocking factor to adjust for the effect of plates. TRECs were transformed to the log scale before analysis to satisfy modeling assumptions. RESULTS: The estimated increase in TRECs for every additional week of gestation is 9.76%. The 95% confidence interval is 9.21% to 10.31% _ 0.0001). (p < CONCLUSIONS: TRECs of newborns increase at a steady rate of 9.8% per week as gestational age increases. The steady increase in TRECs in preterm newborns likely reflects the longitudinal maturation of the immune system. In the newborn screening for SCID program, preterm newborns with low TRECs should be monitored by repeating the TREC assay in one or two week intervals until they reach an adjusted gestation age of _ 37 weeks. >
552
Abnormalities In B Cell Homeostasis And Tolerance In Common Variable Immunodeficiency (CVID) G. Dhillon, C. Z. Marcus, J. Hossler, A. Palanichamy, J. H. Anolik; University of Rochester, Rochester, NY. RATIONALE: CVID is a heterogeneous group of antibody deficiency disorders in which failed B cell differentiation with impaired secretion of immunoglobulins is likely key to pathogenesis. Our objective was to further refine disturbances in B cell homeostasis in CVID using state-ofthe-art multi-chromatic flow cytometry. METHODS: 11-color flow cytometry was used to analyze multiple markers, including core markers (CD19, IgD, CD27, CD24, CD38) and additional markers to subset memory B cells (CD21, CXCR3, CD95) and transitional B cells (mitotracker extrusion, CD10, IgM, CD23) in the peripheral blood of healthy controls (HC, n513) and CVID patients (n513). The effect of CVID on censoring of autoreative B cells was examined using the 9G4 idiotype. RESULTS: CVID patients were characterized by a significant reduction in CD271IgD- switched memory (3.964.1 vs. 17.364.3, p50.002) and lesser reduction in CD271IgD1 unswitched memory B cells (3.162 vs. 10.768.3, p50.14). Circulating plasmablasts were also reduced in CVID (p50.01). In contrast, CD27-IgD- memory B cells were not altered (p50.5), suggesting a distinct developmental origin likely outside the germinal center. The majority of CVID patients had a striking absence of CXCR31 memory B cells, a putative marker of activated effector cells. Autoreactive B cells (9G41) were notably expanded in CVID (p50.05), suggesting an alteration in B cell censoring. Early transitional (T1,T2) B cells were not expanded, but a subset had a late transitional T3 expansion. CONCLUSIONS: CVID is associated with major disturbances in B cell homeostasis, with previously unrecognized defects in effector memory and late transitional B cells, as well as autoreactive B cell censoring.
J ALLERGY CLIN IMMUNOL FEBRUARY 2011
553
Bisphenol-A Exposure and Asthma In An Inner-City Birth Cohort K. M. Donohue1, R. L. Miller2, M. S. Perzanowski2, A. C. Just2, L. A. Hoepner2, S. Arunajadai3, F. P. Perera2, R. M. Whyatt2; 1Columbia Presbyterian Medical Center, New York, NY, 2Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 3Department of Biostatistics, Mailman School of Public Health, New York, NY. RATIONALE: Bisphenol-A (BPA) is an endocrine disruptor widely used in food containers. Prenatal exposure to BPA has been associated with airway inflammation in a mouse model. We hypothesized that exposure to BPA would be associated with increased odds of asthma during childhood. METHODS: The Columbia Center for Children’s Environmental Health recruited 322 pregnant women for a prospective birth cohort study. Spot urine samples were collected and total urinary BPA level was analyzed via mass spectrometry. Board-certified allergists conducted standardized exams and pulmonary function tests to determine current asthma status using pre-specified criteria. At the time of the exam, children were age 5 to 12 years. Logistic regression was used for analyses. Models controlled for gender, race/ethnicity, maternal asthma, exposure to pre- and post-natal environmental tobacco smoke, and urinary specific gravity. RESULTS: Urinary BPA levels at ages three and five years were associated with increased odds of asthma (n5280, OR 1.49, 95%CI (1.10 to 2.03), p 5 0.009; n5322, OR 1.31, 95%CI (0.99 to 1.74), p 5 0.05, respectively). CONCLUSIONS: Exposure to BPA during childhood is associated with increased risk of asthma in a prospective, population-based birth cohort.
554
Circulating Eosinophil/Basophil (Eo/B) Progenitors at One Year of Age Positively Correlate with Atopic Eczema and Indoor Chemical Exposure in the LINA Study K. Weisse1,2, I. Lehmann1, G. Herberth1, T. Kohajda3, S. R€oder4, M. Borte5, D. Heroux2, J. Denburg2; 1Helmholtz Centre for Environmental Research - UFZ, Department Environmental Immunology, Leipzig, GERMANY, 2McMaster University, Division of Clinical Immunology and Allergy, Hamilton, ON, CANADA, 3Helmholtz Centre for Environmental Research - UFZ, Department Metabolomics, Leipzig, GERMANY, 4 Helmholtz Centre for Environmental Research - UFZ, Core Facility Studies, Leipzig, GERMANY, 5Children’s Hospital, Municipal Hospital ‘‘St. Georg’’, Leipzig, GERMANY. RATIONALE: Hematopioetic progenitor cells are known to contribute to allergic inflammation. The aim of the present study was to investigate whether environmental factors influence the recruitment of Eo/B progenitors in peripheral blood of one year old children. METHODS: Within the LINA cohort study (Lifestyle and environmental factors and their Influence on Newborns Allergy risk) 622 mother-childpairs were recruited during 2006 and 2008 in Leipzig, Germany. Standardized questionnaires were recorded during 34th week of pregnancy. Chemical exposure was assessed annually through VOC measurements in the home. In a subcohort of 60 children, frozen PBMCs were used for methylcellulose assays to assess Eo/B differentiation by colony formation (CFU) in the presence of IL-3, IL-5 or GM-CSF. RESULTS: Children with atopic skin manifestations (atopic dermatitis or cradle cap) within the first year of life had higher numbers of circulating IL3-, IL-5- or GM-CSF-stimulated Eo/B CFU (p<0.005). In children with cradle cap a positive correlation was found between Eo/B CFU and exposure to VOC (benzene, toluene, total concentration of aromatics, total VOC concentration) during pregnancy or at one year of age (p<0.005). CONCLUSIONS: This is the first demonstration that environmental exposures may contribute to the recruitment and differentiation of Eo/B progenitors which, in turn, could play a role in the development of atopic skin manifestations during the first year of life.
551
SUNDAY
T-cell Receptor Excision Circles of Newborns Are Associated with Gestational Age: Data from Wisconsin Newborn Screening for Severe Combined Immunodeficiency M. Baker1, A. Atkins1, W. Grossman2, C. Seroogy1, M. Lindstrom1, C. Brokopp1, J. Routes2; 1University of Wisconsin School of Medicine and Public Health, Madison, WI, 2Medical College of Wisconsin, Milwaukee, WI. RATIONALE: To determine whether the copy number of T-cell Receptor Excision Circles (TRECs) differs between full-term and preterm newborns (gestation age < 37 weeks), and, if so, to develop an appropriate action plan to deal with preterm newborns who have low TRECs reported in newborn screening (NBS) for severe combined immunodeficiency (SCID). METHODS: Wisconsin NBS Program quantitates TRECs on dried blood NBS specimens to screen for SCID. From January 1 to June 30, 2008, the TREC assay was performed on 2510 preterm newborns (gestational age, _ 72 hours after birth. The re23-36 weeks) whose samples were collected < sults of the TREC assay from 5,020 full term newborns were included as controls. The relationship between TRECs and gestation age in weeks was estimated using separate univariate linear regression with an added blocking factor to adjust for the effect of plates. TRECs were transformed to the log scale before analysis to satisfy modeling assumptions. RESULTS: The estimated increase in TRECs for every additional week of gestation is 9.76%. The 95% confidence interval is 9.21% to 10.31% _ 0.0001). (p < CONCLUSIONS: TRECs of newborns increase at a steady rate of 9.8% per week as gestational age increases. The steady increase in TRECs in preterm newborns likely reflects the longitudinal maturation of the immune system. In the newborn screening for SCID program, preterm newborns with low TRECs should be monitored by repeating the TREC assay in one or two week intervals until they reach an adjusted gestation age of _ 37 weeks. >
552
Abnormalities In B Cell Homeostasis And Tolerance In Common Variable Immunodeficiency (CVID) G. Dhillon, C. Z. Marcus, J. Hossler, A. Palanichamy, J. H. Anolik; University of Rochester, Rochester, NY. RATIONALE: CVID is a heterogeneous group of antibody deficiency disorders in which failed B cell differentiation with impaired secretion of immunoglobulins is likely key to pathogenesis. Our objective was to further refine disturbances in B cell homeostasis in CVID using state-ofthe-art multi-chromatic flow cytometry. METHODS: 11-color flow cytometry was used to analyze multiple markers, including core markers (CD19, IgD, CD27, CD24, CD38) and additional markers to subset memory B cells (CD21, CXCR3, CD95) and transitional B cells (mitotracker extrusion, CD10, IgM, CD23) in the peripheral blood of healthy controls (HC, n513) and CVID patients (n513). The effect of CVID on censoring of autoreative B cells was examined using the 9G4 idiotype. RESULTS: CVID patients were characterized by a significant reduction in CD271IgD- switched memory (3.964.1 vs. 17.364.3, p50.002) and lesser reduction in CD271IgD1 unswitched memory B cells (3.162 vs. 10.768.3, p50.14). Circulating plasmablasts were also reduced in CVID (p50.01). In contrast, CD27-IgD- memory B cells were not altered (p50.5), suggesting a distinct developmental origin likely outside the germinal center. The majority of CVID patients had a striking absence of CXCR31 memory B cells, a putative marker of activated effector cells. Autoreactive B cells (9G41) were notably expanded in CVID (p50.05), suggesting an alteration in B cell censoring. Early transitional (T1,T2) B cells were not expanded, but a subset had a late transitional T3 expansion. CONCLUSIONS: CVID is associated with major disturbances in B cell homeostasis, with previously unrecognized defects in effector memory and late transitional B cells, as well as autoreactive B cell censoring.
J ALLERGY CLIN IMMUNOL FEBRUARY 2011
553
Bisphenol-A Exposure and Asthma In An Inner-City Birth Cohort K. M. Donohue1, R. L. Miller2, M. S. Perzanowski2, A. C. Just2, L. A. Hoepner2, S. Arunajadai3, F. P. Perera2, R. M. Whyatt2; 1Columbia Presbyterian Medical Center, New York, NY, 2Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, 3Department of Biostatistics, Mailman School of Public Health, New York, NY. RATIONALE: Bisphenol-A (BPA) is an endocrine disruptor widely used in food containers. Prenatal exposure to BPA has been associated with airway inflammation in a mouse model. We hypothesized that exposure to BPA would be associated with increased odds of asthma during childhood. METHODS: The Columbia Center for Children’s Environmental Health recruited 322 pregnant women for a prospective birth cohort study. Spot urine samples were collected and total urinary BPA level was analyzed via mass spectrometry. Board-certified allergists conducted standardized exams and pulmonary function tests to determine current asthma status using pre-specified criteria. At the time of the exam, children were age 5 to 12 years. Logistic regression was used for analyses. Models controlled for gender, race/ethnicity, maternal asthma, exposure to pre- and post-natal environmental tobacco smoke, and urinary specific gravity. RESULTS: Urinary BPA levels at ages three and five years were associated with increased odds of asthma (n5280, OR 1.49, 95%CI (1.10 to 2.03), p 5 0.009; n5322, OR 1.31, 95%CI (0.99 to 1.74), p 5 0.05, respectively). CONCLUSIONS: Exposure to BPA during childhood is associated with increased risk of asthma in a prospective, population-based birth cohort.
554
Circulating Eosinophil/Basophil (Eo/B) Progenitors at One Year of Age Positively Correlate with Atopic Eczema and Indoor Chemical Exposure in the LINA Study K. Weisse1,2, I. Lehmann1, G. Herberth1, T. Kohajda3, S. R€oder4, M. Borte5, D. Heroux2, J. Denburg2; 1Helmholtz Centre for Environmental Research - UFZ, Department Environmental Immunology, Leipzig, GERMANY, 2McMaster University, Division of Clinical Immunology and Allergy, Hamilton, ON, CANADA, 3Helmholtz Centre for Environmental Research - UFZ, Department Metabolomics, Leipzig, GERMANY, 4 Helmholtz Centre for Environmental Research - UFZ, Core Facility Studies, Leipzig, GERMANY, 5Children’s Hospital, Municipal Hospital ‘‘St. Georg’’, Leipzig, GERMANY. RATIONALE: Hematopioetic progenitor cells are known to contribute to allergic inflammation. The aim of the present study was to investigate whether environmental factors influence the recruitment of Eo/B progenitors in peripheral blood of one year old children. METHODS: Within the LINA cohort study (Lifestyle and environmental factors and their Influence on Newborns Allergy risk) 622 mother-childpairs were recruited during 2006 and 2008 in Leipzig, Germany. Standardized questionnaires were recorded during 34th week of pregnancy. Chemical exposure was assessed annually through VOC measurements in the home. In a subcohort of 60 children, frozen PBMCs were used for methylcellulose assays to assess Eo/B differentiation by colony formation (CFU) in the presence of IL-3, IL-5 or GM-CSF. RESULTS: Children with atopic skin manifestations (atopic dermatitis or cradle cap) within the first year of life had higher numbers of circulating IL3-, IL-5- or GM-CSF-stimulated Eo/B CFU (p<0.005). In children with cradle cap a positive correlation was found between Eo/B CFU and exposure to VOC (benzene, toluene, total concentration of aromatics, total VOC concentration) during pregnancy or at one year of age (p<0.005). CONCLUSIONS: This is the first demonstration that environmental exposures may contribute to the recruitment and differentiation of Eo/B progenitors which, in turn, could play a role in the development of atopic skin manifestations during the first year of life.