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Early Life Transepidermal Water Loss (TEWL) Values Can Predate Atopic Dermatitis At Six and Twelve Months in Asymptomatic Infants: Results From the Baseline Study
AB102 Abstracts
370
SUNDAY
Association of Stress, Pruruitis and Illness Severity in Children with Atopic Dermatitis Kimberly Kelsay, MD1, Eleni Weisnicht2,3, Bruce G. Bender, PhD FAAAAI4, Donald Y. M. Leung, MD, PhD, FAAAAI4, Mary D. Klinnert, PhD4,5; 1University of Colorado, School of Medicine, Aurora, 2National Jewish Health, 3Univeristy of Colorado, Boulder, 4National Jewish Health, Denver, CO, 5University of Colorado School of Medicine. RATIONALE: For children with atopic dermatitis (AD), itching is the primary factor affecting quality of life. In adults with AD, psychological stress increases inflammation (including total IgE) and pruritus. These relationships have not been examined in children. We hypothesized that for children with AD, psychological stress would be associated with increased IgE levels and also with AD severity and/or pruritus. METHODS: 69 children with AD, mean age 4.9 (SD53.2) years old, 59% male, 72% Caucasian, were enrolled upon admission to National Jewish Health. Parents completed Child Behavior Checklist, and Affective Disorders scale t-score was used as marker of child stress. Clinicians and parents completed ratings of atopic dermatitis severity and pruritis using the SCORAD and Atopic Dermatitis Quickscore (ADQ), respectively. Total serum IgE levels at admission were obtained from chart review. Total IgE was log transformed and Spearman’s correlations were computed. RESULTS: Children’s psychological stress was correlated with clinician rated pruritis (r50.38, p<0.05) and both parent rated pruritus (r50.28, p<0.001) and severity of AD (r50.34, p<0.05). Stress was also correlated with total IgE (r50.27, p<0.05). In addition, total IgE was correlated with clinician rated severity (r50.22, p<0.001), and both parent rated pruritus (r50.44, p<0.001) and severity (r50.47, p<0.001). CONCLUSIONS: As hypothesized, children with AD with greater psychological stress had higher total IgE, increased pruritis and more severe AD. Reduction of psychological stress may be a key intervention strategy for children with AD. Investigation is needed to test effects of behavioral interventions and their physiological mechanisms.
371
Human Basophils Express Novel TSLPR Variants Including a Putative Secreted Form Martin J. Romeo, PhD1, Rachana Agrawal, PhD1, Anna Pomes, PhD, FAAAAI2, Judith A. Woodfolk, MBChB, PhD, FAAAAI1; 1University of Virginia, Charlottesville, VA, 2Indoor Biotechnologies, Inc., Charlottesville, VA. RATIONALE: Basophils from atopic dermatitis (AD) patients efficiently upregulate thymic stromal lymphopoietin receptor (TSLPR) surface expression upon allergen stimulation, but fail to express interleukin-7 receptor alpha (IL-7Ra). We hypothesized that activated basophils express non-canonical variants of TSLPR that arise from alternative RNA splicing events. METHODS: Sort purified basophils from 2 AD patients and a control were cultured in complete medium containing autologous serum for 4 to 5 hours in the presence or absence of allergen. Total RNA from these cells was reverse transcribed into first-strand cDNA and analyzed by quantitative and qualitative PCR using transcript-specific primer pairs. Molecular modeling of proteins encoded by canonical and non-canonical TSLPR transcripts was performed using Swiss-Prot. RESULTS: Two novel TSLPR transcripts were preferentially induced in activated basophils from AD patients only. Predicted protein products of these transcripts corresponded to a truncated variant lacking an N-terminal extracellular fibronectin III domain, and to a putative secreted form with a unique C-terminus lacking an obvious membrane spanning region. Molecular modeling based on homology to related cytokine receptors predicted overall structural similarity among the extracellular domains of all 3 variants but variable ligand binding potential owing to either alterations in amino acid side chain orientation or to the presence of unique residues in the cytokine binding ‘‘elbow’’ regions of these molecules. CONCLUSIONS: Activated basophils express novel TSLPR splice variants, including a putative secreted form. We propose that production of these variants may contribute to regulation of the TSLP pathway in allergic disease.
J ALLERGY CLIN IMMUNOL FEBRUARY 2013
372
Early Life Transepidermal Water Loss (TEWL) Values Can Predate Atopic Dermatitis At Six and Twelve Months in Asymptomatic Infants: Results From the Baseline Study Maeve M. Kelleher1, Audrey Dunn Galvin1, Deirdre Murray1, Alan David Irvine2, Jonathan O. Hourihane1, Baseline Team1; 1University College Cork, Ireland, 2Trinity College Dublin, Dublin, Ireland. RATIONALE: Atopic Dermatitis (AD) is a multifactorial disease. We sought to ascertain whether a non invasive measurement of skin barrier function at birth could predict the development of eczema in asymptomatic infants enrolled in an unselected prospective birth cohort. METHODS: 1903 infants were enrolled on the Cork BASELINE Birth Cohort study from July 2009 to Oct 2011. Infants had TEWL measured at birth, 2 and 6 months. AD was assessed at 6 and 12 months, using the UK Diagnostic Criteria. Severity was assessed by SCORAD method at 6 months and by both SCORAD and Nottingham Severity Score (NSS) at 12 months. Multiple regression analyses were conducted to investigate the relationship between TEWL values and eczema at both time points. Birthweight, parental allergy, sex, the use of emollient, and washing at birth were included in the predictive models. RESULTS: Eczema rate was 19% (292/1537) at 6 months and 16% (212/ 1315). The multiple regression model controlling for sex, use of emollient, washing, and eczema was statistically significant for eczema in asymptomatic 2 month old infants at both 6 months [R2 50.02, F5 3.8, p<0.05] and 12 months [R2 50.04, F5 8.2, p<0.05]. Parental allergy did not contribute to the model. CONCLUSIONS: A signal for impaired skin barrier function is not seen at birth. By 2 months TEWL can be used as a predictor for developing AD in later infancy in asymptomatic infants. An intervention trial in these infants to maintain skin barrier function would be welcome.
373
Leukotriene B4 Driven Neutrophil Recruitment to the Skin Is Essential for Allergic Skin Inflammation Michiko K. Oyoshi, PhD1, Rui He1, Yitang Li1, Subhanjan Mondal1, Juhan Yoon1, Roshi Afshar2, Mei Chen3, David M. Lee, MD, PhD3, Hongbo Luo1, Andrew D. Luster, MD, PhD2, John Cho4, Lloyd Miller4, Allison Larson3, George Murphy5, Raif Geha, MD1; 1Boston Children’s Hospital, Boston, MA, 2Massachusetts General Hospital, Charlestown, MA, 3Brigham and Women’s Hospital, 4University of California Los Angeles, 5Brigham and Women’s Hospital/Harvard Medical School, Boston, MA. RATIONALE: Scratching triggers skin flares in atopic dermatitis (AD) with Th2 cell infiltration in the skin lesions. Leukotriene B4 (LTB4) levels are elevated in AD lesions. We examined the potential role of LTB4 in AD. METHODS: Scratched skin samples were obtained from healthy adults. The skin of BLT1-/- and LTA4H-/- mice and WT controls were tape stripped or epicutaneously (EC) sensitized by application of ovalbumin (OVA) to tape stripped skin. Skin histology was assessed by H&E staining and immunohistochemistry. LTB4 concentrations were determined using solid phase extraction. Cytokine mRNA expression was examined by qPCR. RESULTS: Scratching of healthy human skin, and its surrogate, tape stripping of mouse skin, caused cutaneous neutrophil influx. This influx in mice was largely dependent on the generation of LTB4 by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation, evidenced by increased epidermal and dermal thickness, dermal infiltration by CD4+ T cells and eosinophils, and Th2 cytokine mRNA expression in the skin in response to EC sensitization with OVA was severely impaired in BLT1-/- mice, and required the expression of BLT1 on both T cells and non-T cells. Co-transfer of WT neutrophils, but not neutrophils deficient in BLT1 or the LTB4 synthesizing enzyme LTA4H, restored the ability of WT CD4+ effector T cells to transfer allergic skin inflammation to BLT1-/- recipients. Pharmacologic blockade of LTB4 synthesis inhibited allergic skin inflammation elicited by cutaneous antigen challenge in previously EC-sensitized mice. CONCLUSIONS: The neutrophil-T cell axis reliant on LTB4-BLT1 interaction is required for allergic skin inflammation in mice.
370
SUNDAY
Association of Stress, Pruruitis and Illness Severity in Children with Atopic Dermatitis Kimberly Kelsay, MD1, Eleni Weisnicht2,3, Bruce G. Bender, PhD FAAAAI4, Donald Y. M. Leung, MD, PhD, FAAAAI4, Mary D. Klinnert, PhD4,5; 1University of Colorado, School of Medicine, Aurora, 2National Jewish Health, 3Univeristy of Colorado, Boulder, 4National Jewish Health, Denver, CO, 5University of Colorado School of Medicine. RATIONALE: For children with atopic dermatitis (AD), itching is the primary factor affecting quality of life. In adults with AD, psychological stress increases inflammation (including total IgE) and pruritus. These relationships have not been examined in children. We hypothesized that for children with AD, psychological stress would be associated with increased IgE levels and also with AD severity and/or pruritus. METHODS: 69 children with AD, mean age 4.9 (SD53.2) years old, 59% male, 72% Caucasian, were enrolled upon admission to National Jewish Health. Parents completed Child Behavior Checklist, and Affective Disorders scale t-score was used as marker of child stress. Clinicians and parents completed ratings of atopic dermatitis severity and pruritis using the SCORAD and Atopic Dermatitis Quickscore (ADQ), respectively. Total serum IgE levels at admission were obtained from chart review. Total IgE was log transformed and Spearman’s correlations were computed. RESULTS: Children’s psychological stress was correlated with clinician rated pruritis (r50.38, p<0.05) and both parent rated pruritus (r50.28, p<0.001) and severity of AD (r50.34, p<0.05). Stress was also correlated with total IgE (r50.27, p<0.05). In addition, total IgE was correlated with clinician rated severity (r50.22, p<0.001), and both parent rated pruritus (r50.44, p<0.001) and severity (r50.47, p<0.001). CONCLUSIONS: As hypothesized, children with AD with greater psychological stress had higher total IgE, increased pruritis and more severe AD. Reduction of psychological stress may be a key intervention strategy for children with AD. Investigation is needed to test effects of behavioral interventions and their physiological mechanisms.
371
Human Basophils Express Novel TSLPR Variants Including a Putative Secreted Form Martin J. Romeo, PhD1, Rachana Agrawal, PhD1, Anna Pomes, PhD, FAAAAI2, Judith A. Woodfolk, MBChB, PhD, FAAAAI1; 1University of Virginia, Charlottesville, VA, 2Indoor Biotechnologies, Inc., Charlottesville, VA. RATIONALE: Basophils from atopic dermatitis (AD) patients efficiently upregulate thymic stromal lymphopoietin receptor (TSLPR) surface expression upon allergen stimulation, but fail to express interleukin-7 receptor alpha (IL-7Ra). We hypothesized that activated basophils express non-canonical variants of TSLPR that arise from alternative RNA splicing events. METHODS: Sort purified basophils from 2 AD patients and a control were cultured in complete medium containing autologous serum for 4 to 5 hours in the presence or absence of allergen. Total RNA from these cells was reverse transcribed into first-strand cDNA and analyzed by quantitative and qualitative PCR using transcript-specific primer pairs. Molecular modeling of proteins encoded by canonical and non-canonical TSLPR transcripts was performed using Swiss-Prot. RESULTS: Two novel TSLPR transcripts were preferentially induced in activated basophils from AD patients only. Predicted protein products of these transcripts corresponded to a truncated variant lacking an N-terminal extracellular fibronectin III domain, and to a putative secreted form with a unique C-terminus lacking an obvious membrane spanning region. Molecular modeling based on homology to related cytokine receptors predicted overall structural similarity among the extracellular domains of all 3 variants but variable ligand binding potential owing to either alterations in amino acid side chain orientation or to the presence of unique residues in the cytokine binding ‘‘elbow’’ regions of these molecules. CONCLUSIONS: Activated basophils express novel TSLPR splice variants, including a putative secreted form. We propose that production of these variants may contribute to regulation of the TSLP pathway in allergic disease.
J ALLERGY CLIN IMMUNOL FEBRUARY 2013
372
Early Life Transepidermal Water Loss (TEWL) Values Can Predate Atopic Dermatitis At Six and Twelve Months in Asymptomatic Infants: Results From the Baseline Study Maeve M. Kelleher1, Audrey Dunn Galvin1, Deirdre Murray1, Alan David Irvine2, Jonathan O. Hourihane1, Baseline Team1; 1University College Cork, Ireland, 2Trinity College Dublin, Dublin, Ireland. RATIONALE: Atopic Dermatitis (AD) is a multifactorial disease. We sought to ascertain whether a non invasive measurement of skin barrier function at birth could predict the development of eczema in asymptomatic infants enrolled in an unselected prospective birth cohort. METHODS: 1903 infants were enrolled on the Cork BASELINE Birth Cohort study from July 2009 to Oct 2011. Infants had TEWL measured at birth, 2 and 6 months. AD was assessed at 6 and 12 months, using the UK Diagnostic Criteria. Severity was assessed by SCORAD method at 6 months and by both SCORAD and Nottingham Severity Score (NSS) at 12 months. Multiple regression analyses were conducted to investigate the relationship between TEWL values and eczema at both time points. Birthweight, parental allergy, sex, the use of emollient, and washing at birth were included in the predictive models. RESULTS: Eczema rate was 19% (292/1537) at 6 months and 16% (212/ 1315). The multiple regression model controlling for sex, use of emollient, washing, and eczema was statistically significant for eczema in asymptomatic 2 month old infants at both 6 months [R2 50.02, F5 3.8, p<0.05] and 12 months [R2 50.04, F5 8.2, p<0.05]. Parental allergy did not contribute to the model. CONCLUSIONS: A signal for impaired skin barrier function is not seen at birth. By 2 months TEWL can be used as a predictor for developing AD in later infancy in asymptomatic infants. An intervention trial in these infants to maintain skin barrier function would be welcome.
373
Leukotriene B4 Driven Neutrophil Recruitment to the Skin Is Essential for Allergic Skin Inflammation Michiko K. Oyoshi, PhD1, Rui He1, Yitang Li1, Subhanjan Mondal1, Juhan Yoon1, Roshi Afshar2, Mei Chen3, David M. Lee, MD, PhD3, Hongbo Luo1, Andrew D. Luster, MD, PhD2, John Cho4, Lloyd Miller4, Allison Larson3, George Murphy5, Raif Geha, MD1; 1Boston Children’s Hospital, Boston, MA, 2Massachusetts General Hospital, Charlestown, MA, 3Brigham and Women’s Hospital, 4University of California Los Angeles, 5Brigham and Women’s Hospital/Harvard Medical School, Boston, MA. RATIONALE: Scratching triggers skin flares in atopic dermatitis (AD) with Th2 cell infiltration in the skin lesions. Leukotriene B4 (LTB4) levels are elevated in AD lesions. We examined the potential role of LTB4 in AD. METHODS: Scratched skin samples were obtained from healthy adults. The skin of BLT1-/- and LTA4H-/- mice and WT controls were tape stripped or epicutaneously (EC) sensitized by application of ovalbumin (OVA) to tape stripped skin. Skin histology was assessed by H&E staining and immunohistochemistry. LTB4 concentrations were determined using solid phase extraction. Cytokine mRNA expression was examined by qPCR. RESULTS: Scratching of healthy human skin, and its surrogate, tape stripping of mouse skin, caused cutaneous neutrophil influx. This influx in mice was largely dependent on the generation of LTB4 by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation, evidenced by increased epidermal and dermal thickness, dermal infiltration by CD4+ T cells and eosinophils, and Th2 cytokine mRNA expression in the skin in response to EC sensitization with OVA was severely impaired in BLT1-/- mice, and required the expression of BLT1 on both T cells and non-T cells. Co-transfer of WT neutrophils, but not neutrophils deficient in BLT1 or the LTB4 synthesizing enzyme LTA4H, restored the ability of WT CD4+ effector T cells to transfer allergic skin inflammation to BLT1-/- recipients. Pharmacologic blockade of LTB4 synthesis inhibited allergic skin inflammation elicited by cutaneous antigen challenge in previously EC-sensitized mice. CONCLUSIONS: The neutrophil-T cell axis reliant on LTB4-BLT1 interaction is required for allergic skin inflammation in mice.