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Article ; Online: Identification of a heterozygous pathogenic variant in IRAK4 in an adult patient with pneumococcal sepsis, monoclonal gammopathy of uncertain significance, and idiopathic systemic capillary leak syndrome.

Galant-Swafford, Jessica / Druey, Kirk M / Verma, Divya / Alam, Rafeul

The journal of allergy and clinical immunology. Global

2023 Volume 2, Issue 3

Language	English
Publishing date	2023-05-18
Publishing country	United States
Document type	Journal Article
ISSN	2772-8293
ISSN (online)	2772-8293
DOI	10.1016/j.jacig.2023.100116
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Article ; Online: Autologous hematopoietic stem cell transplantation in Clarkson disease.

Druey, Kirk M / Eisch, A Robin / Cunningham-Rundles, Charlotte

The journal of allergy and clinical immunology. In practice

2022 Volume 11, Issue 1, Page(s) 347–349

MeSH term(s)	Humans ; Capillary Leak Syndrome ; Hematopoietic Stem Cell Transplantation ; Transplantation, Autologous
Language	English
Publishing date	2022-10-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2843237-X
ISSN	2213-2201 ; 2213-2198
ISSN (online)	2213-2201
ISSN	2213-2198
DOI	10.1016/j.jaip.2022.10.023
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Zs.A 7086: Show issues

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Article ; Online: RGS4 controls airway hyperresponsiveness through GAP-independent mechanisms.

Joshi, Ilin V / Chan, Eunice C / Lack, Justin B / Liu, Chengyu / Druey, Kirk M

The Journal of biological chemistry

2024 Volume 300, Issue 4, Page(s) 107127

Abstract: Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not exclusively, through their GTPase-activating protein activity. Asthma is a highly prevalent ... ...

Abstract	Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not exclusively, through their GTPase-activating protein activity. Asthma is a highly prevalent condition characterized by airway hyper-responsiveness (AHR) to environmental stimuli resulting in part from amplified GPCR-mediated airway smooth muscle contraction. Rgs2 or Rgs5 gene deletion in mice enhances AHR and airway smooth muscle contraction, whereas RGS4 KO mice unexpectedly have decreased AHR because of increased production of the bronchodilator prostaglandin E2 (PGE2) by lung epithelial cells. Here, we found that knockin mice harboring Rgs4 alleles encoding a point mutation (N128A) that sharply curtails RGS4 GTPase-activating protein activity had increased AHR, reduced airway PGE2 levels, and augmented GPCR-induced bronchoconstriction compared with either RGS4 KO mice or WT controls. RGS4 interacted with the p85α subunit of PI3K and inhibited PI3K-dependent PGE2 secretion elicited by transforming growth factor beta in airway epithelial cells. Together, these findings suggest that RGS4 affects asthma severity in part by regulating the airway inflammatory milieu in a G protein-independent manner.
MeSH term(s)	Animals ; RGS Proteins/metabolism ; RGS Proteins/genetics ; Mice ; Dinoprostone/metabolism ; Asthma/metabolism ; Asthma/genetics ; Asthma/pathology ; Mice, Knockout ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphatidylinositol 3-Kinases/genetics ; GTPase-Activating Proteins/genetics ; GTPase-Activating Proteins/metabolism ; Humans ; Respiratory Hypersensitivity/metabolism ; Respiratory Hypersensitivity/genetics ; Respiratory Hypersensitivity/pathology ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Bronchoconstriction
Chemical Substances	RGS Proteins ; RGS4 protein (175335-35-0) ; Dinoprostone (K7Q1JQR04M) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; GTPase-Activating Proteins
Language	English
Publishing date	2024-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.107127
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Uc I Zs.108: Show issues

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Article ; Online: Emerging Roles of Regulators of G Protein Signaling (RGS) Proteins in the Immune System.

Druey, Kirk M

Advances in immunology

2017 Volume 136, Page(s) 315–351

Abstract: The regulators of G protein signaling (RGS) proteins are a large, evolutionarily conserved group of intracellular proteins expressed in every cell type and tissue throughout the body including the immune system. Through their signature GTPase-activating ... ...

Abstract	The regulators of G protein signaling (RGS) proteins are a large, evolutionarily conserved group of intracellular proteins expressed in every cell type and tissue throughout the body including the immune system. Through their signature GTPase-activating protein (GAP) activity on heterotrimeric G proteins and interactions with signaling complexes and membrane constituents (e.g., lipids), RGS proteins determine the intensity and duration of G protein-coupled receptor-induced responses. They may also have a function in generating intracellular signaling gradients necessary for the directional migration of leukocytes to inflamed tissues containing local accumulations of chemoattractants. Although physiological functions of most RGS proteins in leukocytes and lymphoid organs are largely unknown, it appears thus far that deficiency of individual RGS proteins in mice does not affect homeostatic immune responses in the absence of immunogenic challenge and/or microbial infection. Although aberrant expression of some RGS proteins has been linked to dysregulated immunity and/or neoplasia in humans, there are no human diseases attributed to specific RGS dysfunction. Here, we highlight mostly published work describing expression and functions of the core group of RGS proteins that were among the first discovered, in both innate and adaptive immune processes, with particular emphasis on cell trafficking.
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ZDB-ID	80226-8
ISSN	1557-8445 ; 0065-2776
ISSN (online)	1557-8445
ISSN	0065-2776
DOI	10.1016/bs.ai.2017.05.001
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Ud II Zs.191: Show issues

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Article ; Online: Aspergillus fumigatus

Druey, Kirk M / McCullough, Morgan / Krishnan, Ramaswamy

Journal of fungi (Basel, Switzerland)

2020 Volume 6, Issue 2

Abstract: We review three recent findings that have fundamentally altered our understanding of causative mechanisms underlying fungal-related asthma. These mechanisms may be partially independent of host inflammatory processes but are strongly dependent upon the ... ...

Abstract	We review three recent findings that have fundamentally altered our understanding of causative mechanisms underlying fungal-related asthma. These mechanisms may be partially independent of host inflammatory processes but are strongly dependent upon the actions of Alp1 on lung structural cells. They entail (i) bronchial epithelial sensing of Alp1; (ii) Alp1-induced airway smooth muscle (ASM) contraction; (iii) Alp1-induced airflow obstruction. Collectively, these mechanisms point to Alp1 as a new target for intervention in fungal asthma.
Language	English
Publishing date	2020-06-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2784229-0
ISSN	2309-608X ; 2309-608X
ISSN (online)	2309-608X
ISSN	2309-608X
DOI	10.3390/jof6020088
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Article ; Online: RGS proteins, GRKs, and beta-arrestins modulate G protein-mediated signaling pathways in asthma.

Fuentes, Nathalie / McCullough, Morgan / Panettieri, Reynold A / Druey, Kirk M

Pharmacology & therapeutics

2021 Volume 223, Page(s) 107818

Abstract: Asthma is a highly prevalent disorder characterized by chronic lung inflammation and reversible airways obstruction. Pathophysiological features of asthma include episodic and reversible airway narrowing due to increased bronchial smooth muscle ... ...

Abstract	Asthma is a highly prevalent disorder characterized by chronic lung inflammation and reversible airways obstruction. Pathophysiological features of asthma include episodic and reversible airway narrowing due to increased bronchial smooth muscle shortening in response to external and host-derived mediators, excessive mucus secretion into the airway lumen, and airway remodeling. The aberrant airway smooth muscle (ASM) phenotype observed in asthma manifests as increased sensitivity to contractile mediators (EC
MeSH term(s)	Asthma/metabolism ; G-Protein-Coupled Receptor Kinases/physiology ; GTP-Binding Proteins/physiology ; Humans ; RGS Proteins/physiology ; Receptors, G-Protein-Coupled/physiology ; Signal Transduction/physiology ; beta-Arrestins/physiology
Chemical Substances	RGS Proteins ; Receptors, G-Protein-Coupled ; beta-Arrestins ; G-Protein-Coupled Receptor Kinases (EC 2.7.11.16) ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2021-02-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2021.107818
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Zs.A 1183: Show issues

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Article ; Online: Management of Acute Episodes of Clarkson Disease (Monoclonal Gammopathy-Associated Systemic Capillary Leak Syndrome) With Intravenous Immunoglobulins.

Pecker, Mark S / Hammudi, Mustafa / Melchio, Remo / Eisch, A Robin / Verlicchi, Franco / Druey, Kirk M

Annals of internal medicine. Clinical cases

2022 Volume 1, Issue 6

Abstract: Monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS, Clarkson disease) is a rare disorder defined by transient but recurrent bouts of hypotensive shock and anasarca resulting from plasma extravasation. Although ... ...

Abstract	Monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS, Clarkson disease) is a rare disorder defined by transient but recurrent bouts of hypotensive shock and anasarca resulting from plasma extravasation. Although prophylactic treatment with high-dose intravenous immunoglobulins (IVIG, 1-2 g/kg/mo) prevents most disease flares, its utility for acute episodes of ISCLS is unclear. Here, we report the results of a retrospective study of subjects with acute ISCLS treated at or near the onset of symptoms with IVIG. We found that administration of IVIG with minimal additional intravenous fluids was safe and associated with rapid clinical improvement. IVIG given close to the onset of ISCLS-related symptoms is associated with a favorable outcome.
Language	English
Publishing date	2022-08-02
Publishing country	United States
Document type	Journal Article
ISSN	2767-7664
ISSN (online)	2767-7664
DOI	10.7326/aimcc.2022.0496
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Article ; Online: Severe capillary leak syndrome with cardiac arrest triggered by influenza virus infection.

Ebdrup, Lotte / Druey, Kirk M / Druey, Kirk / Mogensen, Trine Hyrup

BMJ case reports

2018 Volume 2018

Abstract: Systemic capillary leak syndrome (SCLS), also known as Clarkson syndrome, is a rare disease with potential fatal outcome. The clinical picture involves leakage of fluid and protein from the bloodstream into peripheral tissues, resulting in ... ...

Abstract	Systemic capillary leak syndrome (SCLS), also known as Clarkson syndrome, is a rare disease with potential fatal outcome. The clinical picture involves leakage of fluid and protein from the bloodstream into peripheral tissues, resulting in hypoalbuminaemia, elevated haematocrit, oedema and hypotension. The spectrum of the symptoms ranges from discrete swelling/oedema of extremities to fulminant cardiogenic shock. We present a case with a 52-year-old man diagnosed with SCLS after being resuscitated from cardiac arrest, which was complicated by compartment syndrome. The severe episode of capillary leak was potentially triggered by influenza virus infection. With the benefit of hindsight, he presented with symptoms of SCLS 2 years prior the major acute episode. Here we describe this case and review some aspects of the literature on SCLS, with particular focus on the pathogenesis, treatment/prophylaxis and long-term physical and psychological complications.
MeSH term(s)	Capillary Leak Syndrome/complications ; Capillary Leak Syndrome/diagnosis ; Capillary Leak Syndrome/diagnostic imaging ; Capillary Leak Syndrome/drug therapy ; Coronary Angiography ; Diagnosis, Differential ; Heart Arrest/complications ; Heart Arrest/diagnosis ; Heart Arrest/diagnostic imaging ; Heart Arrest/drug therapy ; Humans ; Immunoglobulins, Intravenous/administration & dosage ; Immunoglobulins, Intravenous/therapeutic use ; Influenza, Human/complications ; Influenza, Human/diagnosis ; Influenza, Human/diagnostic imaging ; Influenza, Human/drug therapy ; Male ; Middle Aged
Chemical Substances	Immunoglobulins, Intravenous
Language	English
Publishing date	2018-08-29
Publishing country	England
Document type	Case Reports ; Journal Article
ISSN	1757-790X
ISSN (online)	1757-790X
DOI	10.1136/bcr-2018-226108
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Article ; Online: Modeling asthma: Pitfalls, promises, and the road ahead.

Rosenberg, Helene F / Druey, Kirk M

Journal of leukocyte biology

2018 Volume 104, Issue 1, Page(s) 41–48

Abstract: Asthma is a chronic, heterogeneous, and recurring inflammatory disease of the lower airways, with exacerbations that feature airway inflammation and bronchial hyperresponsiveness. Asthma has been modeled extensively via disease induction in both wild- ... ...

Abstract	Asthma is a chronic, heterogeneous, and recurring inflammatory disease of the lower airways, with exacerbations that feature airway inflammation and bronchial hyperresponsiveness. Asthma has been modeled extensively via disease induction in both wild-type and genetically manipulated laboratory mice (Mus musculus). Antigen sensitization and challenge strategies have reproduced numerous important features of airway inflammation characteristic of human asthma, notably the critical roles of type 2 T helper cell cytokines. Recent models of disease induction have advanced to include physiologic aeroallergens with prolonged respiratory challenge without systemic sensitization; others incorporate tobacco, respiratory viruses, or bacteria as exacerbants. Nonetheless, differences in lung size, structure, and physiologic responses limit the degree to which airway dynamics measured in mice can be compared to human subjects. Other rodent allergic airways models, including those featuring the guinea pig (Cavia porcellus) might be considered for lung function studies. Finally, domestic cats (Feline catus) and horses (Equus caballus) develop spontaneous obstructive airway disorders with clinical and pathologic features that parallel human asthma. Information on pathogenesis and treatment of these disorders is an important resource.
MeSH term(s)	Animals ; Asthma ; Disease Models, Animal ; Humans
Language	English
Publishing date	2018-02-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1002/JLB.3MR1117-436R
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Zs.A 603: Show issues

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Article ; Online: Intrinsic endothelial hyper-responsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease.

Ablooglu, Ararat J / Chen, Wei-Sheng / Xie, Zhihui / Desai, Abhishek / Paul, Subrata / Lack, Justin B / Scott, Linda A / Eisch, A Robin / Dudek, Arkadiusz Z / Parikh, Samir M / Druey, Kirk M

The Journal of clinical investigation

2024

Abstract: Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to ... ...

Abstract	Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. Specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here we characterize an autonomous vascular endothelial defect in ISCLS that is recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs are functionally hyper-responsive to permeability-inducing factors like VEGF and histamine in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N(γ)-nitro-L-arginine methyl ester (L-NAME) ameliorates vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyper-activation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.
Language	English
Publishing date	2024-03-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI169137
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