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Article ; Online: At last - linking ORMDL3 polymorphisms, decreased sphingolipid synthesis, and asthma susceptibility.

Wills-Karp, Marsha

2020 Volume 130, Issue 2, Page(s) 604–607

Abstract: Asthma is a common chronic respiratory disease that has a heritable component. Polymorphisms in the endoplasmic reticular protein orosomucoid-like protein 3 (ORMDL3), which regulates sphingolipid homeostasis, have been strongly linked with childhood- ... ...

Abstract	Asthma is a common chronic respiratory disease that has a heritable component. Polymorphisms in the endoplasmic reticular protein orosomucoid-like protein 3 (ORMDL3), which regulates sphingolipid homeostasis, have been strongly linked with childhood-onset asthma. Despite extensive investigation, a link between ORMDL3 asthma-risk genotypes and altered sphingolipid synthesis has been lacking. In this issue of the JCI, Ono et al. establish a clear association between nonallergic childhood asthma, lower whole-blood sphingolipids, and asthma-risk 17q21 genotypes. These results demonstrate that genetic variants in ORMDL3 may confer a risk of developing childhood asthma through dysregulation of sphingolipid synthesis. As such, modulation of sphingolipids may represent a promising avenue of therapeutic development for childhood asthma.
MeSH term(s)	Asthma ; Child ; Genotype ; Humans ; Membrane Proteins/genetics ; Polymorphism, Genetic ; Sphingolipids
Chemical Substances	Membrane Proteins ; ORMDL3 protein, human ; Sphingolipids
Language	English
Publishing date	2020-01-11
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI134333
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Article ; Online: Neutrophil ghosts worsen asthma.

Wills-Karp, Marsha

Science immunology

2018 Volume 3, Issue 26

Abstract: Neutrophil cytoplasts are linked to amplification of T helper 17-mediated inflammation and severe asthma. ...

Abstract	Neutrophil cytoplasts are linked to amplification of T helper 17-mediated inflammation and severe asthma.
MeSH term(s)	Asthma ; Erythrocyte Membrane ; Humans ; Inflammation ; Leukocytosis ; Neutrophils
Language	English
Publishing date	2018-07-28
Publishing country	United States
Document type	Journal Article ; Review ; Comment
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.aau0112
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Article ; Online: Histamine-releasing factor: a promising therapeutic target for food allergy.

Wills-Karp, Marsha

The Journal of clinical investigation

2017 Volume 127, Issue 12, Page(s) 4238–4241

Abstract: The prevalence of food allergies has been increasing at an alarming rate over the last few decades. Despite the dramatic increase in disease prevalence, the development of effective therapies has not kept pace. In this issue of the JCI, Ando et al. ... ...

Abstract	The prevalence of food allergies has been increasing at an alarming rate over the last few decades. Despite the dramatic increase in disease prevalence, the development of effective therapies has not kept pace. In this issue of the JCI, Ando et al. provide a causal link between histamine-releasing factor (HRF) interactions with IgE and food allergy in a murine model. Successful oral immunotherapy of both egg-allergic human patients and food-allergic mice was associated with sustained suppression of HRF-reactive IgE levels. These results support a role for HRF-IgE interactions in the amplification of intestinal inflammation and suggest HRF as a therapeutic target in food allergy.
MeSH term(s)	Animals ; Egg Hypersensitivity ; Food Hypersensitivity ; Histamine ; Histamine Release ; Humans ; Immunoglobulin E ; Mice
Chemical Substances	Immunoglobulin E (37341-29-0) ; Histamine (820484N8I3)
Language	English
Publishing date	2017-11-13
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI98297
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Article ; Online: Editorial: Activation of Innate Immunity by Allergens and Allergenic Sources.

Ferreira, Fatima / Mueller, Geoffrey A / Gilles, Stefanie / Wills-Karp, Marsha

Frontiers in allergy

2021 Volume 2, Page(s) 800929

Language	English
Publishing date	2021-11-12
Publishing country	Switzerland
Document type	Editorial
ISSN	2673-6101
ISSN (online)	2673-6101
DOI	10.3389/falgy.2021.800929
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Article ; Online: IL-4 and IL-13 signaling in allergic airway disease.

Gour, Naina / Wills-Karp, Marsha

Cytokine

2015 Volume 75, Issue 1, Page(s) 68–78

Abstract: Aberrant production of the prototypical type 2 cytokines, interleukin (IL)-4 and IL-13 has long been associated with the pathogenesis of allergic disorders. Despite tremendous scientific inquiry, the similarities in their structure, and receptor usage ... ...

Abstract	Aberrant production of the prototypical type 2 cytokines, interleukin (IL)-4 and IL-13 has long been associated with the pathogenesis of allergic disorders. Despite tremendous scientific inquiry, the similarities in their structure, and receptor usage have made it difficult to ascertain the distinct role that these two look-alike cytokines play in the onset and perpetuation of allergic inflammation. However, recent discoveries of differences in receptor distribution, utilization/assembly and affinity between IL-4 and IL-13, along with the discovery of unique innate lymphoid 2 cells (ILC2) which preferentially produce IL-13, not IL-4, are beginning to shed light on these mysteries. The purpose of this chapter is to review our current understanding of the distinct roles that IL-4 and IL-13 play in allergic inflammatory states and the utility of their modulation as potential therapeutic strategies for the treatment of allergic disorders.
MeSH term(s)	Animals ; Asthma/immunology ; Clinical Trials as Topic ; Cytokines/immunology ; Disease Models, Animal ; Epithelial Cells/immunology ; Fibrosis/metabolism ; Humans ; Hypersensitivity/immunology ; Immunity, Innate ; Inflammation ; Interleukin-13/immunology ; Interleukin-4/immunology ; Lymphocytes/immunology ; Macrophages/immunology ; Mice ; Protein Binding ; Respiratory System/immunology ; Signal Transduction
Chemical Substances	Cytokines ; IL13 protein, human ; IL4 protein, human ; Interleukin-13 ; Interleukin-4 (207137-56-2)
Language	English
Publishing date	2015-06-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2015.05.014
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Article ; Online: Summary of the Keystone Symposium "Origins of allergic disease: Microbial, epithelial and immune interactions," March 24-27, Tahoe City, California.

DeKruyff, Rosemarie H / Zhang, Wenming / Nadeau, Kari C / Leung, Donald Y M / Wills-Karp, Marsha

The Journal of allergy and clinical immunology

2020 Volume 145, Issue 4, Page(s) 1072–1081.e1

Abstract: The aims of the Keystone Symposium conference, "Origins of allergic disease: Microbial, epithelial and immune interactions" were to present and discuss potential microbial-epithelial-immune interactions underlying the early-life origins of allergic ... ...

Abstract	The aims of the Keystone Symposium conference, "Origins of allergic disease: Microbial, epithelial and immune interactions" were to present and discuss potential microbial-epithelial-immune interactions underlying the early-life origins of allergic disorders, as well as immune mechanisms that might suggest novel disease prevention or intervention strategies. Cross-talk and sharing of ideas among participating experts in basic science and clinical aspects of allergic diseases provided substantial insight into the concept of allergic disorders as a systems disease. The overriding message distilled from the discussions was that damage to epithelial surfaces lies at the origin of the various manifestations of allergic disease. The epithelium of the lungs, gut, and skin, which operates as a critical sensor of environmental stimuli, is besieged by an onslaught of contemporary environmental forces including an altered microbiome, air pollution, food allergens in a changed diet, and chemicals in modern detergents. Collectively, this onslaught leads to alterations of lung, skin, or gut epithelial surfaces, driving a type 2 immune response that underlies most, if not all, of the atopic diseases. Possible remedies for treatment and prevention of allergic diseases were discussed, including a precision medicine approach using biologics, oral desensitization, targeted gut microbiome alterations, and behavior alteration.
MeSH term(s)	Allergens/immunology ; Animals ; Asthma/immunology ; Asthma/metabolism ; Desensitization, Immunologic/methods ; Epithelium/immunology ; Host-Parasite Interactions ; Humans ; Hypersensitivity/immunology ; Hypersensitivity/microbiology ; Microbiota/immunology ; United States
Chemical Substances	Allergens
Language	English
Publishing date	2020-01-08
Publishing country	United States
Document type	Congress ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2019.11.048
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Article ; Online: Allergen-specific pattern recognition receptor pathways.

Wills-Karp, Marsha

Current opinion in immunology

2010 Volume 22, Issue 6, Page(s) 777–782

Abstract: Allergic diseases continue to plague modernized societies, underscoring the need to identify the molecular basis for the propensity of a small number of environmental proteins to provoke maladaptive, allergic responses. Recent data suggest that the ... ...

Abstract	Allergic diseases continue to plague modernized societies, underscoring the need to identify the molecular basis for the propensity of a small number of environmental proteins to provoke maladaptive, allergic responses. Recent data suggest that the ability of allergenic proteins to drive allergic responses in susceptible hosts is driven by their unique innate immune activating capabilities. Although the identification of allergen-specific pattern recognition receptors is in its infancy, studies to date have shown that allergens drive Th2-biased immune responses via directly engaging C-type lectin receptors (dectin-2, DC-SIGN, and mannose receptor) on dendritic cells and/or mimicking toll-like receptor 4 signaling complex molecules expressed on airway structural cells. Elucidation of the specific innate immune pathways activated by allergens holds great promise in defining new therapeutic targets for the treatment of allergic diseases.
MeSH term(s)	Allergens/immunology ; Humans ; Lectins, C-Type/immunology
Chemical Substances	Allergens ; Lectins, C-Type
Language	English
Publishing date	2010-11-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2010.10.011
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Zs.A 2773: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: New twist on an ancient innate immune pathway.

Lajoie, Stephane / Wills-Karp, Marsha

Immunity

2013 Volume 39, Issue 6, Page(s) 1000–1002

Abstract: Activation of the complement system has long been known to be regulated by a series of steps involving fluid-phase convertases. In this issue of Immunity, Liszewski et al. (2013) report the discovery of an intracellular cathepsin-L-dependent C3 ... ...

Abstract	Activation of the complement system has long been known to be regulated by a series of steps involving fluid-phase convertases. In this issue of Immunity, Liszewski et al. (2013) report the discovery of an intracellular cathepsin-L-dependent C3 activation pathway.
MeSH term(s)	B-Lymphocyte Subsets/cytology ; CD4-Positive T-Lymphocytes/immunology ; Cathepsin L/metabolism ; Cell Differentiation ; Complement Activation/physiology ; Complement C3/metabolism ; Homeostasis/physiology ; Humans
Chemical Substances	Complement C3 ; CTSL protein, human (EC 3.4.22.15) ; Cathepsin L (EC 3.4.22.15)
Language	English
Publishing date	2013-12-11
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2013.11.015
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Zs.A 4227: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 69: Show issues

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Article: New perspectives on the regulation of type II inflammation in asthma.

Becerra-Díaz, Mireya / Wills-Karp, Marsha / Heller, Nicola M

F1000Research

2017 Volume 6, Page(s) 1014

Abstract: Asthma is a chronic inflammatory disease of the lungs which has been thought to arise as a result of inappropriately directed T helper type-2 (Th2) immune responses of the lungs to otherwise innocuous inhaled antigens. Current asthma therapeutics are ... ...

Abstract	Asthma is a chronic inflammatory disease of the lungs which has been thought to arise as a result of inappropriately directed T helper type-2 (Th2) immune responses of the lungs to otherwise innocuous inhaled antigens. Current asthma therapeutics are directed towards the amelioration of downstream consequences of type-2 immune responses (i.e. β-agonists) or broad-spectrum immunosuppression (i.e. corticosteroids). However, few approaches to date have been focused on the primary prevention of immune deviation. Advances in molecular phenotyping reveal heterogeneity within the asthmatic population with multiple endotypes whose varying expression depends on the interplay between numerous environmental factors and the inheritance of a broad range of susceptibility genes. The most common endotype is one described as "type-2-high" (i.e. high levels of interleukin [IL]-13, eosinophilia, and periostin). The identification of multiple endotypes has provided a potential explanation for the observations that therapies directed at typical Th2 cytokines (IL-4, IL-5, and IL-13) and their receptors have often fallen short when they were tested in a diverse group of asthmatic patients without first stratifying based on disease endotype or severity. However, despite the incorporation of endotype-dependent stratification schemes into clinical trial designs, variation in drug responses are still apparent, suggesting that additional genetic/environmental factors may be contributing to the diversity in drug efficacy. Herein, we will review recent advances in our understanding of the complex pathways involved in the initiation and regulation of type-2-mediated immune responses and their modulation by host factors (genetics, metabolic status, and the microbiome). Particular consideration will be given to how this knowledge could pave the way for further refinement of disease endotypes and/or the development of novel therapeutic strategies for the treatment of asthma
Language	English
Publishing date	2017
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2699932-8
ISSN	2046-1402
ISSN	2046-1402
DOI	10.12688/f1000research.11198.1
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Article ; Online: Predictors and reproducibility of urinary organophosphate ester metabolite concentrations during pregnancy and associations with birth outcomes in an urban population.

Kuiper, Jordan R / Stapleton, Heather M / Wills-Karp, Marsha / Wang, Xiaobin / Burd, Irina / Buckley, Jessie P

Environmental health : a global access science source

2020 Volume 19, Issue 1, Page(s) 55

Abstract: Background: Organophosphate esters (OPEs) are synthetic chemicals used as flame retardants and plasticizers in a variety of goods. Despite ubiquitous human exposures and laboratory evidence that prenatal OPE exposures may disrupt offspring metabolism, ... ...

Abstract	Background: Organophosphate esters (OPEs) are synthetic chemicals used as flame retardants and plasticizers in a variety of goods. Despite ubiquitous human exposures and laboratory evidence that prenatal OPE exposures may disrupt offspring metabolism, perinatal studies of OPE health effects are limited. The objectives of this study were to: 1) Determine predictors and reproducibility of urinary OPE biomarker concentrations during pregnancy, and 2) Estimate the relation of prenatal OPE exposures with birth outcomes and cord blood adipokine and insulin concentrations. Methods: We analyzed five OPE metabolites in urine samples collected at up to three visits during pregnancy from 90 women enrolled in the ORigins of Child Health And Resilience in Development (ORCHARD) pregnancy cohort in Baltimore, MD from 2017 to 2019. To quantify the variability of metabolite concentrations during pregnancy, we calculated intraclass correlation coefficients (ICCs) for each metabolite using mixed effects regression models. Using self-reported questionnaire data collected during gestation, we assessed possible sociodemographic and environmental/behavioral predictors of each OPE metabolite using generalized estimating equations to account for repeated exposure measures. We ascertained birth outcomes of 76 offspring from medical records, including weight-for-gestational age, length, ponderal index, and gestational age. In a subset of 37 infants, we measured cord blood concentrations of leptin, adiponectin, and insulin. To account for repeated exposure measures, we used linear structural equation models to assess the relations of standard deviation (SD) increases in prenatal OPE metabolite factor scores with continuous birth outcomes and cord blood biomarker concentrations. Results: ICCs ranged from 0.09 for isopropylphenyl-phenyl phosphate (ip-PPP) to 0.59 for bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We observed little consistency in environmental or behavioral predictors of OPE exposures, although concentrations were generally lower for samples collected in the afternoon compared to morning and winter compared to other seasons. In adjusted analyses, a SD increase in BDCIPP concentration was associated with a 0.06 g/cm Conclusions: These findings suggest some OPEs may be metabolic disruptors warranting investigation in larger studies.
MeSH term(s)	Adolescent ; Adult ; Baltimore ; Biomarkers/blood ; Environmental Pollutants/urine ; Esters/urine ; Female ; Fetal Blood/chemistry ; Flame Retardants/metabolism ; Humans ; Infant, Newborn ; Male ; Maternal Exposure ; Middle Aged ; Organophosphates/urine ; Plasticizers/metabolism ; Pregnancy/urine ; Reproducibility of Results ; Urban Population/statistics & numerical data ; Young Adult
Chemical Substances	Biomarkers ; Environmental Pollutants ; Esters ; Flame Retardants ; Organophosphates ; Plasticizers
Language	English
Publishing date	2020-05-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2092232-2
ISSN	1476-069X ; 1476-069X
ISSN (online)	1476-069X
ISSN	1476-069X
DOI	10.1186/s12940-020-00610-0
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