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PAF Induced Vascular Permeability in Autosomal Dominant-Hyper IgE Syndrome (AD-HIES)
AB200 Abstracts
647
Anaphylaxis to Mint in a 5 Year Old Boy: A Case Report Leah K. Middelberg, MD, Joyce C. Rabbat, MD; Loyola University Medical Center. RATIONALE: Mint is derived from the aromatic plant Mentha spicata; together with oregano, rosemary, basil and thyme, it is a member of the Lamiaceaefamily. Allergic contact dermatitis to mint is well described. We report the first case of delayed IgE-mediated anaphylaxis to mint in a pediatric patient. METHODS: A 5 year-old boy with a history of asthma presented with multiple adverse food reactions. His first reaction was at age 4; several hours after swallowing a few pieces of mint gum he awoke with 5 episodes of emesis and an erythematous rash to arms and legs. Several hours after chewing mint gum he vomited multiple times. Several hours after eating a chocolate mint he vomited. In contrast to these delayed reactions, the child had immediate reactions of repeated vomiting 30-45 minutes after using mint toothpaste. Subsequent reactions to mint involved repeated emesis, erythematous rash to arms and legs, and diarrhea. RESULTS: Skin prick testing (SPT) was performed to fresh leaves of mint, oregano, rosemary, basil, and thyme; peppermint gum; aeroallergens; milk; egg; wheat; soy; and peanut. Five controls had SPT to fresh mint leaf for comparison. The patient had a positive SPT to fresh mint leaves and to standardized dust mite mix. No control subjects reacted to fresh mint. Serum specific IgE to mint, sage, basil, oregano and thyme were undetectable. The patient was advised to strictly avoid mint; an allergy action plan and epinephrine autoinjector were provided. CONCLUSIONS: We report the first case of delayed IgE-mediated anaphylaxis to mint in a pediatric patient.
648
MONDAY
Deficiencies in STAT3 Signaling Confers Resistance to Histamine/PAF Induced Vascular Permeability in Autosomal Dominant-Hyper IgE Syndrome (AD-HIES) Michael P. O’Connell, PhD1, Valerie Hox, MD, PhD1, Celeste Nelson, NP1, Thomas DiMaggio, BSN1, Nina Jones, RN, BSN2, Paul Sackstein1, Alexandra F. Freeman, MD3, Ana Olivera, PhD1, Dean D. Metcalfe, MD4, Joshua D. Milner, MD1; 1Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, MD, 2Frederick National Laboratory for Clinical Research, Frederick, MD, 3NIH/NIAID, Laboratory of Clinical Infectious Diseases, Bethesda, MD, 4Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD. RATIONALE: To determine whether a reduction in STAT3 signaling due to small molecule inhibition or in STAT3mutated patient cells provides protection against enhanced vascular permeability, potentially explaining previously observed protection from anaphylaxis in AD-HIES patients and a mouse model. METHODS: Mouse anaphylaxis models were used to determine the effects of Stat3 inhibition. Control human umbilical vascular endothelial cells (HUVECs), mouse lung microvascular endothelial cells (MLMEC), and AD-HIES HUVECs were used to determine the role of STAT3 signaling in regulating vascular permeability in vitro. Confocal microscopy and Western analysis was used to assess the mechanism by which STAT3 contributes to vascular leakage. AD-HIES and control patient histamine skin prick testing (SPT) was performed to compare histamine responses. RESULTS: AD-HIES patients have a decreased response to histamine skin prick testing compared healthy controls. In vivo treatment of healthy mice with STAT3-inhibitor C188-9 prevents IgE, platelet activating factor (PAF), and histamine-induced anaphylaxis. Treatment with histamine or PAF led to an increase in permeability of control HUVECs, mouse lung microvascular endothelial cells (MLMEC), but not AD-HIES patient HUVECs or C188-9 treated control HUVES or MLMEC. AD-HIES HUVECs and C188-9 treated control HUVECs have increased basal levels of VE-Cadherin and beta-catenin, which do not decrease in response to histamine, preventing permeabilization. CONCLUSIONS: Signaling through STAT3 induces vascular endothelial cells permeability and inhibition of STAT3 signaling can prevent vascular permeability and systemic anaphylaxis.
J ALLERGY CLIN IMMUNOL FEBRUARY 2015
649
Loss of IL-4Ra-Mediated PI3K Signaling Accelerates the Onset and Progression of IgE/Mast Cell-Mediated Reactions David Xiao Yang Wu, PhD, Lisa Waggoner, Yi-Ting Tsai, Yui-Hsi Wang, PhD, Simon P. Hogan, PhD; Cincinnati Children’s Hospital Medical Center, Cincinnati, OH. RATIONALE: Clinical and experimental evidence indicates that interleukin 4 (IL-4) receptor (IL-4R) chain motif polymorphisms that negatively regulate the IL-4/IL-13 signal are sufficient to induce a gainof-function, promote an exaggerated allergic inflammatory response and increase susceptibility to allergic phenotypes. We hypothesized that the IL4RaY500F mutation would enhance the susceptibility of mice to foodinduced anaphylaxis. METHODS: We examined signs of anaphylaxis (hypothermia, hematocrit concentration), evidence of mast cell activation (intestinal mast cell and mast cell protease-1 (mcpt-1) levels) in passive systemic and oralantigen-induced anaphylaxis and histamine-induced hypothermia models in WT and IL4RaY500F mice. In vitro studies were used to determine the interaction of histamine and phosphatidylinositol 3-kinase (PI3K) activity on endothelial barrier function in a human vascular endothelial cell line. RESULTS: In the present study, we show that ablation of IL-4Ra–induced PI3K signaling by germline point mutation within the IL-4Ra motif (IL4RaY500F mice) did not alter susceptibility to IgE-mediated, foodinduced anaphylaxis. Moreover, diarrhea occurrence, antigen-specific IgE and intestinal mastocytosis were comparable between WT and IL4RaY500F mice. However, mice unable to stimulate IL-4Ra–mediated PI3K signaling had accelerated disease progression. Moreover, the IL4RaY500F mice demonstrated a more rapid decrease in body temperature than the WT mice. Notably, the accelerated anaphylactic response was associated with more rapid histamine-induced hypovolemia. Mechanistic in vitro and in vivo analyses revealed that endothelial PI3K signaling negatively regulates histamine-induced response. CONCLUSIONS: These results define an unanticipated role for IL-4Ra– mediated PI3K signaling in negative regulation of IgE-mediated anaphylactic reactions.
647
Anaphylaxis to Mint in a 5 Year Old Boy: A Case Report Leah K. Middelberg, MD, Joyce C. Rabbat, MD; Loyola University Medical Center. RATIONALE: Mint is derived from the aromatic plant Mentha spicata; together with oregano, rosemary, basil and thyme, it is a member of the Lamiaceaefamily. Allergic contact dermatitis to mint is well described. We report the first case of delayed IgE-mediated anaphylaxis to mint in a pediatric patient. METHODS: A 5 year-old boy with a history of asthma presented with multiple adverse food reactions. His first reaction was at age 4; several hours after swallowing a few pieces of mint gum he awoke with 5 episodes of emesis and an erythematous rash to arms and legs. Several hours after chewing mint gum he vomited multiple times. Several hours after eating a chocolate mint he vomited. In contrast to these delayed reactions, the child had immediate reactions of repeated vomiting 30-45 minutes after using mint toothpaste. Subsequent reactions to mint involved repeated emesis, erythematous rash to arms and legs, and diarrhea. RESULTS: Skin prick testing (SPT) was performed to fresh leaves of mint, oregano, rosemary, basil, and thyme; peppermint gum; aeroallergens; milk; egg; wheat; soy; and peanut. Five controls had SPT to fresh mint leaf for comparison. The patient had a positive SPT to fresh mint leaves and to standardized dust mite mix. No control subjects reacted to fresh mint. Serum specific IgE to mint, sage, basil, oregano and thyme were undetectable. The patient was advised to strictly avoid mint; an allergy action plan and epinephrine autoinjector were provided. CONCLUSIONS: We report the first case of delayed IgE-mediated anaphylaxis to mint in a pediatric patient.
648
MONDAY
Deficiencies in STAT3 Signaling Confers Resistance to Histamine/PAF Induced Vascular Permeability in Autosomal Dominant-Hyper IgE Syndrome (AD-HIES) Michael P. O’Connell, PhD1, Valerie Hox, MD, PhD1, Celeste Nelson, NP1, Thomas DiMaggio, BSN1, Nina Jones, RN, BSN2, Paul Sackstein1, Alexandra F. Freeman, MD3, Ana Olivera, PhD1, Dean D. Metcalfe, MD4, Joshua D. Milner, MD1; 1Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, MD, 2Frederick National Laboratory for Clinical Research, Frederick, MD, 3NIH/NIAID, Laboratory of Clinical Infectious Diseases, Bethesda, MD, 4Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD. RATIONALE: To determine whether a reduction in STAT3 signaling due to small molecule inhibition or in STAT3mutated patient cells provides protection against enhanced vascular permeability, potentially explaining previously observed protection from anaphylaxis in AD-HIES patients and a mouse model. METHODS: Mouse anaphylaxis models were used to determine the effects of Stat3 inhibition. Control human umbilical vascular endothelial cells (HUVECs), mouse lung microvascular endothelial cells (MLMEC), and AD-HIES HUVECs were used to determine the role of STAT3 signaling in regulating vascular permeability in vitro. Confocal microscopy and Western analysis was used to assess the mechanism by which STAT3 contributes to vascular leakage. AD-HIES and control patient histamine skin prick testing (SPT) was performed to compare histamine responses. RESULTS: AD-HIES patients have a decreased response to histamine skin prick testing compared healthy controls. In vivo treatment of healthy mice with STAT3-inhibitor C188-9 prevents IgE, platelet activating factor (PAF), and histamine-induced anaphylaxis. Treatment with histamine or PAF led to an increase in permeability of control HUVECs, mouse lung microvascular endothelial cells (MLMEC), but not AD-HIES patient HUVECs or C188-9 treated control HUVES or MLMEC. AD-HIES HUVECs and C188-9 treated control HUVECs have increased basal levels of VE-Cadherin and beta-catenin, which do not decrease in response to histamine, preventing permeabilization. CONCLUSIONS: Signaling through STAT3 induces vascular endothelial cells permeability and inhibition of STAT3 signaling can prevent vascular permeability and systemic anaphylaxis.
J ALLERGY CLIN IMMUNOL FEBRUARY 2015
649
Loss of IL-4Ra-Mediated PI3K Signaling Accelerates the Onset and Progression of IgE/Mast Cell-Mediated Reactions David Xiao Yang Wu, PhD, Lisa Waggoner, Yi-Ting Tsai, Yui-Hsi Wang, PhD, Simon P. Hogan, PhD; Cincinnati Children’s Hospital Medical Center, Cincinnati, OH. RATIONALE: Clinical and experimental evidence indicates that interleukin 4 (IL-4) receptor (IL-4R) chain motif polymorphisms that negatively regulate the IL-4/IL-13 signal are sufficient to induce a gainof-function, promote an exaggerated allergic inflammatory response and increase susceptibility to allergic phenotypes. We hypothesized that the IL4RaY500F mutation would enhance the susceptibility of mice to foodinduced anaphylaxis. METHODS: We examined signs of anaphylaxis (hypothermia, hematocrit concentration), evidence of mast cell activation (intestinal mast cell and mast cell protease-1 (mcpt-1) levels) in passive systemic and oralantigen-induced anaphylaxis and histamine-induced hypothermia models in WT and IL4RaY500F mice. In vitro studies were used to determine the interaction of histamine and phosphatidylinositol 3-kinase (PI3K) activity on endothelial barrier function in a human vascular endothelial cell line. RESULTS: In the present study, we show that ablation of IL-4Ra–induced PI3K signaling by germline point mutation within the IL-4Ra motif (IL4RaY500F mice) did not alter susceptibility to IgE-mediated, foodinduced anaphylaxis. Moreover, diarrhea occurrence, antigen-specific IgE and intestinal mastocytosis were comparable between WT and IL4RaY500F mice. However, mice unable to stimulate IL-4Ra–mediated PI3K signaling had accelerated disease progression. Moreover, the IL4RaY500F mice demonstrated a more rapid decrease in body temperature than the WT mice. Notably, the accelerated anaphylactic response was associated with more rapid histamine-induced hypovolemia. Mechanistic in vitro and in vivo analyses revealed that endothelial PI3K signaling negatively regulates histamine-induced response. CONCLUSIONS: These results define an unanticipated role for IL-4Ra– mediated PI3K signaling in negative regulation of IgE-mediated anaphylactic reactions.