scholarly journals A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X duringAcinetobacter baumanniiInfection

2019 ◽  
Vol 87 (5) ◽  
Author(s):  
Jacob E. Choby ◽  
Andrew J. Monteith ◽  
Lauren E. Himmel ◽  
Paris Margaritis ◽  
Jana K. Shirey-Rice ◽  
...  
Keyword(s):  
Immune Response ◽  
Association Study ◽  
Immune Cell ◽  
Coagulation Factor ◽  
Factor X ◽  
Human Pathogens ◽  
Chemokine Production ◽  
Content Type ◽  
Factor X Deficiency ◽  
Deficient Mice

ABSTRACTCoagulation and inflammation are interconnected, suggesting that coagulation plays a key role in the inflammatory response to pathogens. A phenome-wide association study (PheWAS) was used to identify clinical phenotypes of patients with a polymorphism in coagulation factor X. Patients with this single nucleotide polymorphism (SNP) were more likely to be hospitalized with hemostatic and infection-related disorders, suggesting that factor X contributes to the immune response to infection. To investigate this, we modeled infections by human pathogens in a mouse model of factor X deficiency. Factor X-deficient mice were protected from systemicAcinetobacter baumanniiinfection, suggesting that factor X plays a role in the immune response toA. baumannii. Factor X deficiency was associated with reduced cytokine and chemokine production and alterations in immune cell population during infection: factor X-deficient mice demonstrated increased abundance of neutrophils, macrophages, and effector T cells. Together, these results suggest that factor X activity is associated with an inefficient immune response and contributes to the pathology ofA. baumanniiinfection.

Immunological Studies on the Blood Coagulation Factor X and Its Warfarin-induced Precursor

1974 ◽  
Vol 31 (01) ◽  
pp. 040-051 ◽  
Author(s):  
Gustav Gaudernack ◽  
Åse Gladhaug Berre ◽  
Bjarne Østerud ◽  
Hans Prydz
Keyword(s):  
Coagulation Factor ◽  
Factor X ◽  
Intrinsic Pathway ◽  
Coagulation Activity ◽  
Factor X Deficiency ◽  
Warfarin Treatment ◽  
The Cross ◽  
Monospecific Antisera ◽  
Purified Antigen ◽  
Congenital Factor

SummaryMonospecific antisera against the human coagulation factor X have been raised in rabbits by injections of purified antigen. Such antiserum was used to study the cross-reacting material without factor X activity which is present in the blood of warfarin-treated patients and animals as well as to study the changes in factor X during coagulation. One patient with congenital factor X deficiency was also studied.A complete identity was found between factor X in Macaca mulatta and human blood. During warfarin treatment antigenically cross-reacting material appeared in plasma. This was not adsorbed on BaSO4, and inhibited the coagulation activity of normal factor X.Both this material, normal factor X and the cross-reacting material in plasma from a patient congenitally deficient in factor X gave rise to split products during coagulation by the intrinsic pathway, i. e. all of them served as substrates for the intrinsic activator of factor X.

scholarly journals Tim-3 Induces Th2-Biased Immunity and Alternative Macrophage Activation during Schistosoma japonicum Infection

2015 ◽  
Vol 83 (8) ◽  
pp. 3074-3082 ◽  
Author(s):  
Nan Hou ◽  
Xianyu Piao ◽  
Shuai Liu ◽  
Chuang Wu ◽  
Qijun Chen
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Schistosoma Japonicum ◽  
Immune Cell ◽  
Nk Cell ◽  
Alternative Activation ◽  
Interleukin 12 ◽  
Content Type

T cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected withSchistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response againstS. japonicuminfection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4+and CD8+T cells, NK1.1+cells, and CD11b+cells from the livers ofS. japonicum-infected mice. However, the increased level of Tim-3 was lower in the spleen than in the liver, and no increase in Tim-3 expression was observed on splenic CD8+T cells or CD11b+cells. The schistosome-induced upregulation of Tim-3 on natural killer (NK) cells was accompanied by reduced NK cell numbersin vitroandin vivo. Tim-3 antibody blockade led to upregulation of inducible nitric oxide synthase and interleukin-12 (IL-12) mRNA in CD11b+cells cocultured with soluble egg antigen and downregulation of Arg1 and IL-10, which are markers of M2 macrophages. In summary, we observed schistosome-induced expression of Tim-3 on critical immune cell populations, which may be involved in the Th2-biased immune response and alternative activation of macrophages during infection.

scholarly journals Human Keratinocyte Response to Superantigens

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Patrick M. Schlievert ◽  
Francoise A. Gourronc ◽  
Donald Y. M. Leung ◽  
Aloysius J. Klingelhutz
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pyogenes ◽  
Skin Barrier ◽  
Human Keratinocytes ◽  
Human Diseases ◽  
Human Pathogens ◽  
Chemokine Production ◽  
Content Type ◽  
Human Keratinocyte ◽  
Stimulation Of

ABSTRACT Staphylococcus aureus and Streptococcus pyogenes are significant human pathogens, causing infections at multiple body sites, including across the skin. Both are organisms that cause human diseases and secrete superantigens, including toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxins (SEs), and streptococcal pyrogenic exotoxins (SPEs). On the skin, human keratinocytes represent the first cell type to encounter these superantigens. We employed transcriptome sequencing (RNA-seq) to evaluate the human primary keratinocyte response to both TSST-1 and staphylococcal enterotoxin B (SEB) in triplicate analyses. Both superantigens caused large numbers of genes to be up- and downregulated. The genes that exhibited 2-fold differential gene expression compared to vehicle-treated cells, whether up- or downregulated, totaled 5,773 for TSST-1 and 4,320 for SEB. Of these, 4,482 were significantly upregulated by exposure of keratinocytes to TSST-1, whereas 1,291 were downregulated. For SEB, expression levels of 3,785 genes were upregulated, whereas those of 535 were downregulated. There was the expected high overlap in both upregulation (3,412 genes) and downregulation (400 genes). Significantly upregulated genes included those associated with chemokine production, with the possibility of stimulation of inflammation. We also tested an immortalized human keratinocyte line, from a different donor, for chemokine response to four superantigens. TSST-1 and SEB caused production of interleukin-8 (IL-8), MIP-3α, and IL-33. SPEA and SPEC were evaluated for stimulation of expression of IL-8 as a representative chemokine; both stimulated production of IL-8. IMPORTANCE Staphylococcus aureus and Streptococcus pyogenes are common human pathogens, causing infections that include the skin. Both pathogens produce a family of secreted toxins called superantigens, which have been shown to be important in human diseases. The first cell types encountered by superantigens on skin are keratinocytes. Our studies demonstrated, that the human keratinocyte pathway, among other pathways, responds to superantigens with production of chemokines, setting off inflammation. This inflammatory response may be harmful, facilitating opening of the skin barrier.

scholarly journals The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum

2016 ◽  
Vol 85 (3) ◽  
Author(s):  
Jennifer L. Reedy ◽  
Paige E. Negoro ◽  
Marianela Feliu ◽  
Allison K. Lord ◽  
Nida S. Khan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Wide Spectrum ◽  
Granulomatous Inflammation ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Macrophage Response ◽  
Lectin Receptor ◽  
Exserohilum Rostratum

ABSTRACT Dematiaceous molds are found ubiquitously in the environment and cause a wide spectrum of human disease, including infections associated with high rates of mortality. Despite this, the mechanism of the innate immune response has been less well studied, although it is key in the clearance of fungal pathogens. Here, we focus on Exserohilum rostratum, a dematiaceous mold that caused 753 infections during a multistate outbreak due to injection of contaminated methylprednisolone. We show that macrophages are incapable of phagocytosing Exserohilum. Despite a lack of phagocytosis, macrophage production of tumor necrosis factor alpha is triggered by hyphae but not spores and depends upon Dectin-1, a C-type lectin receptor. Dectin-1 is specifically recruited to the macrophage-hyphal interface but not the macrophage-spore interface due to differences in carbohydrate antigen expression between these two fungal forms. Corticosteroid and antifungal therapy perturb this response, resulting in decreased cytokine production. In vivo soft tissue infection in wild-type mice demonstrated that Exserohilum provokes robust neutrophilic and granulomatous inflammation capable of thwarting fungal growth. However, coadministration of methylprednisolone acetate results in robust hyphal tissue invasion and a significant reduction in immune cell recruitment. Our results suggest that Dectin-1 is crucial for macrophage recognition and the macrophage response to Exserohilum and that corticosteroids potently attenuate the immune response to this pathogen.

Acquired Factor X Deficiency in a Negro Boy

PEDIATRICS ◽  
1969 ◽  
Vol 44 (6) ◽  
pp. 1007-1009
Author(s):  
William L. Bayer ◽  
Dario Curiel C. ◽  
Isabel L. F. Szeto ◽  
Jessica H. Lewis
Keyword(s):  
Coagulation Factor ◽  
Hemorrhagic Disease ◽  
Vitamin K1 ◽  
Factor X ◽  
Factor X Deficiency

A Negro boy suffering from severe hemorrhagic disease associated with a single acquired defect in coagulation factor X is presented. No cause for this deficiency could be found. Vitamin K1 had no effect. He improved spontaneously and is completely healthy 6 months later.

Blood Coagulation Factor X Deficiency Causes Partial Embryonic Lethality and Fatal Neonatal Bleeding in Mice

2000 ◽  
Vol 83 (02) ◽  
pp. 185-190 ◽  
Author(s):  
Mieke Dewerchin ◽  
Zhong Liang ◽  
Lieve Moons ◽  
Peter Carmeliet ◽  
Francis Castellino ◽  
...  
Keyword(s):  
Blood Coagulation ◽  
Coagulation Factor ◽  
Massive Bleeding ◽  
Embryonic Lethality ◽  
Genotype Distribution ◽  
Bleeding Disorders ◽  
Factor X ◽  
Factor X Deficiency ◽  
Effective Models ◽  
The Brain

SummaryMice with a total deficiency in blood coagulation Factor X (FX) were generated by targeted replacement of an 18-kb fragment of the FX gene, comprising all exons encoding the mature FX protein, with a neor cassette. The genotype distribution among the offspring from heterozygous breeding pairs suggested that FX deficiency resulted in partial embryonic lethality, with approximately one-third of the FX −/− embryos dying around embryonic day (E) 11.5-12.5. Two of 44 non-resorbed FX −/− embryos analyzed at these stages showed signs of massive bleeding, one of which into the brain ventricles, but no histological defects in the vasculature of these embryos or their yolk sac were observed. The remainder of the FX −/− embryos appeared normal and survived to term, but the majority of neonates (90%) died within 5 days, most frequently from intraabdominal bleeding. The remaining FX −/− animals succumbed between postnatal day (P)5 and P20 with intraabdominal, subcutaneous, or intracranial bleeding or a combination thereof. The lethal phenotype of the FX −/− mice illustrates the importance of FX function in embryonic and postnatal survival and demonstrates that these mice serve as effective models of the bleeding disorders observed in severe FX deficiency in humans.

scholarly journals Selenium Status Alters the Immune Response and Expulsion of Adult Heligmosomoides bakeri Worms in Mice

2013 ◽  
Vol 81 (7) ◽  
pp. 2546-2553 ◽  
Author(s):  
Allen D. Smith ◽  
Lumei Cheung ◽  
Ethiopia Beshah ◽  
Terez Shea-Donohue ◽  
Joseph F. Urban
Keyword(s):  
Immune Response ◽  
Small Intestine ◽  
Metabolic Activity ◽  
Surrounding Tissue ◽  
Th2 Response ◽  
Content Type ◽  
Adequate Diet ◽  
Th2 Immune Response ◽  
Heligmosomoides Bakeri ◽  
Deficient Mice

ABSTRACTHeligmosomoides bakeriis a nematode with parasitic development exclusively in the small intestine of infected mice that induces a potent STAT6-dependent Th2 immune response. We previously demonstrated that host protective expulsion of adultH. bakeriworms from a challenge infection was delayed in selenium (Se)-deficient mice. In order to explore mechanisms associated with the delayed expulsion, 3-week-old female BALB/c mice were placed on a torula yeast-based diet with or without 0.2 ppm Se, and after 5 weeks, they were inoculated withH. bakeriinfective third-stage larvae (L3s). Two weeks after inoculation, the mice were treated with an anthelmintic and then rested, reinoculated with L3s, and evaluated at various times after reinoculation. Analysis of gene expression in parasite-induced cysts and surrounding tissue isolated from the intestine of infected mice showed that the local-tissue Th2 response was decreased in Se-deficient mice compared to that in Se-adequate mice. In addition, adult worms recovered from Se-deficient mice had higher ATP levels than worms from Se-adequate mice, indicating greater metabolic activity in the face of a suboptimal Se-dependent local immune response. Notably, the process of worm expulsion was restored within 2 to 4 days after feeding a Se-adequate diet to Se-deficient mice. Expulsion was associated with an increased local expression of Th2-associated genes in the small intestine, intestinal glutathione peroxidase activity, secreted Relm-β protein, anti-H. bakeriIgG1 production, and reduced worm fecundity and ATP-dependent metabolic activity.

A Rare Case of Congenital Factor X Mild Deficiency Presenting as Life-Threatening Hemorrhagic Shock in a Neonate

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S151-S151
Author(s):  
Rachelle Mendoza ◽  
Tahmineh Haidary ◽  
Steven Kang
Keyword(s):  
Bleeding Event ◽  
Coagulation Factor ◽  
Hemodynamic Instability ◽  
Fresh Frozen Plasma ◽  
Bleeding Disorder ◽  
Activity Level ◽  
Factor X ◽  
Factor X Deficiency ◽  
Life Threatening ◽  
Congenital Factor

Abstract Introduction Congenital factor X deficiency is one of rarest bleeding disorders, occurring in 1 out of 1 million births. Its rarity limits its consideration in newborns presenting with hemodynamic instability. It is autosomal recessive and seen frequently in the consanguineous population. Patients with factor X deficiency are classified into three groups, based on factor X activity level: severe (<1%), moderate (1%-4%), and mild (6%-10%). Severe deficiency presents with bleeding diathesis early in life. Methods A 3-day-old male newborn, delivered at term via spontaneous vaginal delivery, presented in a well-baby clinic for a routine bilirubin check. Family history was negative for bleeding disorder or consanguinity. Nurse noted persistent blood oozing at heel stick site and oral, nasal, and umbilical stump bleeding. The patient immediately developed respiratory distress and shock. Sepsis, vitamin K deficiency, and congenital metabolic syndrome were considered. Liver function, WBC count, and other chemistry were normal, and cultures were negative. Hemoglobin was low and platelet count was elevated. PT (30.3 seconds) and aPTT (53.3 seconds) were both prolonged. Mixing patient’s sample with normal plasma corrected PT (13.1 seconds) and aPTT (25.7 seconds), indicating a factor deficiency. Results Coagulation factor assays revealed normal levels of factors VII, VIII, IX, and II. Factor X activity (12.9%) was low. The patient’s condition improved after multiple pRBC and plasma transfusions. He was placed on a daily 25-mL/kg dose of fresh-frozen plasma, which maintained his PT at 17.6 to 19.1 seconds and aPTT at 34.1 to 48.0 seconds. Factor X level increased to 20% after plasma transfusion. Conclusion Congenital bleeding disorder should be considered for neonates presenting with bleeding and shock. Factor X deficiency is suspected when both PT and aPTT are prolonged and corrected with mixing studies. Although factor levels of 10% to 40% are considered adequate for hemostasis, our patient with 12% factor X activity presented with a life-threatening bleeding event.

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