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Identification of toxemia in patients with Clostridium difficile infection.
Yu H, Chen K, Wu J, Yang Z, Shi L, Barlow LL, Aronoff DM, Garey KW, Savidge TC, von Rosenvinge EC, Kelly CP, Feng H
(2015) PLoS One 10: e0124235
MeSH Terms: Animals, Anti-Bacterial Agents, Antibodies, Bacterial, Antibodies, Neutralizing, Bacterial Proteins, Bacterial Toxins, Biological Assay, Blood Preservation, Cercopithecus aethiops, Clostridium difficile, Diverticulitis, Colonic, Enterocolitis, Pseudomembranous, Enterotoxins, False Negative Reactions, Female, Glycosylation, Humans, Immunocompromised Host, Immunoglobulin G, Multiple Trauma, Protein Processing, Post-Translational, Protein Stability, Risk Factors, Toxemia, Vero Cells, Young Adult, rac1 GTP-Binding Protein
Show Abstract · Added June 2, 2017
Toxemia can develop in Clostridium difficile-infected animals, and correlates with severe and fulminant disease outcomes. Circumstantial evidence suggests that toxemia may occur in patients with C. difficile infection (CDI), but positive diagnosis is extremely rare. We analyzed the potential for C. difficile toxemia in patients, determined its characteristics, and assessed challenges. C. difficile toxins in serum from patients were tested using an ultrasensitive cell-based assay and further confirmed by Rac1 glucosylation assay. The factors that hinder a diagnosis of toxemia were assessed, including investigation of toxin stability, the level of toxins-specific neutralizing antibodies in sera and its effect on diagnosis limits. CDI patients develop detectable toxemia in some cases (2.3%). Toxins were relatively stable in stored sera. Neutralizing anti-toxin antibodies were present during infection and positively correlated with the diagnosis limits. Thus, the masking effect of toxin-specific neutralizing antibodies is the major obstacle in diagnosing C. difficile toxemia using cell-based bioassays.
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27 MeSH Terms
A monoclonal antibody against hinge-cleaved IgG restores effector function to proteolytically-inactivated IgGs in vitro and in vivo.
Brezski RJ, Kinder M, Grugan KD, Soring KL, Carton J, Greenplate AR, Petley T, Capaldi D, Brosnan K, Emmell E, Watson S, Jordan RE
(2014) MAbs 6: 1265-73
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, Antibody-Dependent Cell Cytotoxicity, Bacterial Proteins, Blood Platelets, Cell Line, Cell Line, Tumor, Cysteine Endopeptidases, Dogs, Enzyme-Linked Immunosorbent Assay, Epitopes, Humans, Immunoglobulin Fab Fragments, Immunoglobulin G, Matrix Metalloproteinase 3, Platelet Count, Proteolysis, Rats, Rituximab
Show Abstract · Added April 22, 2016
We report a chimeric monoclonal antibody (mAb) directed to a neo-epitope that is exposed in the IgG lower hinge following proteolytic cleavage. The mAb, designated 2095-2, displays specificity for IdeS-generated F(ab')₂ fragments, but not for full-length IgG or for closely-related F(ab')₂ fragments generated with other proteases. A critical component of the specificity is provided by the C-terminal amino acid of the epitope corresponding to gly-236 in the IgG1 (also IgG4) hinge. By its ability to bind to IdeS-cleaved anti-CD20 mAb, mAb 2095-2 fully restored antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against WIL2-S cells to the otherwise inactive anti-CD20 IgG1 F(ab')₂ fragment. Similarly, 2095-2 reinstated ADCC against MDA-MB-231 cells to an anti-CD142 IgG1 F(ab')₂ fragment. mAb 2095-2 was also capable of eliciting both CDC and ADCC to IgG4 F(ab')₂ fragments, an IgG subclass that has weaker ADCC and CDC when intact relative to intact IgG1. The in vitro cell-based efficacy of 2095-2 was extended to the in vivo setting using platelets as a cell clearance surrogate. In a canine model, the co-administration of 2095-2 together with IdeS-generated, platelet-targeting anti-CD41/61 F(ab')₂ fragment not only restored platelet clearance, but did so at a rate and extent of clearance that exceeded that of intact anti-CD41/61 IgG at comparable concentrations. To further explore this unexpected amplification effect, we conducted a rat study in which 2095-2 was administered at a series of doses in combination with a fixed dose of anti-CD41/61 F(ab')₂ fragments. Again, the combination, at ratios as low as 1:10 (w/w) 2095-2 to F(ab')₂, proved more effective than the anti-CD41/61 IgG1 alone. These findings suggest a novel mechanism for enhancing antibody-mediated cell-killing effector functions with potential applications in pathologic settings such as tumors and acute infections where protease activity is abundant.
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20 MeSH Terms
Antibody-functionalized peptidic membranes for neutralization of allogeneic skin antigen-presenting cells.
Wen Y, Liu W, Bagia C, Zhang S, Bai M, Janjic JM, Giannoukakis N, Gawalt ES, Meng WS
(2014) Acta Biomater 10: 4759-4767
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Antigen-Presenting Cells, Cell Membrane, Computer Systems, Emulsions, Female, Graft Rejection, Immobilized Proteins, Immunoglobulin G, Interferon-gamma, Lymph Nodes, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Nanoparticles, Neutralization Tests, Peptides, Skin, Skin Transplantation, Spectroscopy, Near-Infrared, T-Lymphocytes, Transplantation, Homologous
Show Abstract · Added April 2, 2019
We report herein application of an in situ material strategy to attenuate allograft T cell responses in a skin transplant mouse model. Functionalized peptidic membranes were used to impede trafficking of donor antigen-presenting cells (dAPCs) from skin allografts in recipient mice. Membranes formed by self-assembling peptides (SAPs) presenting antibodies were found to remain underneath grafted skins for up to 6 days. At the host-graft interface, dAPCs were targeted by using a monoclonal antibody that binds to a class II major histocompatibility complex (MHC) molecule (I-A(d)) expressed exclusively by donor cells. Using a novel cell labeling near-infrared nanoemulsion, we found more dAPCs remained in allografts treated with membranes loaded with anti-I-A(d) antibodies than without. In vitro, dAPCs released from skin explants were found adsorbed preferentially on anti-I-A(d) antibody-loaded membranes. Recipient T cells from these mice produced lower concentrations of interferon-gamma cultured ex vivo with donor cells. Taken together, the data indicate that the strategy has the potential to alter the natural course of rejection immune mechanisms in allogeneic transplant models.
Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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MeSH Terms
Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1.
de la Croix Ndong J, Makowski AJ, Uppuganti S, Vignaux G, Ono K, Perrien DS, Joubert S, Baglio SR, Granchi D, Stevenson DA, Rios JJ, Nyman JS, Elefteriou F
(2014) Nat Med 20: 904-10
MeSH Terms: Adolescent, Alkaline Phosphatase, Animals, Bone Development, Bone Diseases, Developmental, Bone Morphogenetic Protein 2, Calcification, Physiologic, Cells, Cultured, Child, Child, Preschool, Collagen Type I, Collagen Type II, Diphosphates, Disease Models, Animal, Durapatite, Humans, Immunoglobulin G, Infant, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinases, Neurofibromatosis 1, Neurofibromin 1, Osteoblasts, Osteogenesis, Phosphate Transport Proteins, Phosphoric Diester Hydrolases, Pyrophosphatases, Recombinant Fusion Proteins, Sp7 Transcription Factor, Transcription Factors
Show Abstract · Added July 28, 2014
Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PPi breakdown, further contributing to PPi accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase-α enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PPi homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.
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32 MeSH Terms
IgG4-restricted anti-glomerular basement membrane autoantibodies targeting quaternary epitopes of native α345(IV) collagen.
Borza DB
(2014) Am J Kidney Dis 64: 156-7
MeSH Terms: Anti-Glomerular Basement Membrane Disease, Autoantibodies, Female, Humans, Immunoglobulin G
Added December 2, 2016
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The role of CXCL10 in the pathogenesis of experimental septic shock.
Herzig DS, Luan L, Bohannon JK, Toliver-Kinsky TE, Guo Y, Sherwood ER
(2014) Crit Care 18: R113
MeSH Terms: Animals, Body Temperature, Chemokine CXCL10, Cytokines, Female, Immunoglobulin G, Killer Cells, Natural, Lymphocyte Activation, Male, Mice, Inbred C57BL, Mice, Knockout, Peritoneal Cavity, Shock, Septic
Show Abstract · Added October 18, 2015
INTRODUCTION - The chemokine CXCL10 is produced during infection and inflammation to activate the chemokine receptor CXCR3, an important regulator of lymphocyte trafficking and activation. The goal of this study was to assess the contributions of CXCL10 to the pathogenesis of experimental septic shock in mice.
METHODS - Septic shock was induced by cecal ligation and puncture (CLP) in mice resuscitated with lactated Ringer's solution and, in some cases, the broad spectrum antibiotic Primaxin. Studies were performed in CXCL10 knockout mice and mice treated with anti-CXCL10 immunoglobulin G (IgG). Endpoints included leukocyte trafficking and activation, core body temperature, plasma cytokine concentrations, bacterial clearance and survival.
RESULTS - CXCL10 was present at high concentrations in plasma and peritoneal cavity during CLP-induced septic shock. Survival was significantly improved in CXCL10 knockout (CXCL10KO) mice and mice treated with anti-CXCL10 IgG compared to controls. CXCL10KO mice and mice treated with anti-CXCL10 IgG showed attenuated hypothermia, lower concentrations of interleukin-6 (IL-6) and macrophage inhibitory protein-2 (MIP-2) in plasma and lessened natural killer (NK) cell activation compared to control mice. Compared to control mice, bacterial burden in blood and lungs was lower in CXCL10-deficient mice but not in mice treated with anti-CXCL10 IgG. Treatment of mice with anti-CXCL10 IgG plus fluids and Primaxin at 2 or 6 hours after CLP significantly improved survival compared to mice treated with non-specific IgG under the same conditions.
CONCLUSIONS - CXCL10 plays a role in the pathogenesis of CLP-induced septic shock and could serve as a therapeutic target during the acute phase of septic shock.
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13 MeSH Terms
Neonatal Fc receptor promotes immune complex-mediated glomerular disease.
Olaru F, Luo W, Suleiman H, St John PL, Ge L, Mezo AR, Shaw AS, Abrahamson DR, Miner JH, Borza DB
(2014) J Am Soc Nephrol 25: 918-25
MeSH Terms: Albuminuria, Animals, Anti-Glomerular Basement Membrane Disease, Antigen-Antibody Complex, Autoantigens, Collagen Type IV, Glomerulonephritis, HEK293 Cells, Histocompatibility Antigens Class I, Humans, Immunoglobulin G, Male, Mice, Mice, Inbred C57BL, Receptors, Fc
Show Abstract · Added December 2, 2016
The neonatal Fc receptor (FcRn) is a major regulator of IgG and albumin homeostasis systemically and in the kidneys. We investigated the role of FcRn in the development of immune complex-mediated glomerular disease in mice. C57Bl/6 mice immunized with the noncollagenous domain of the α3 chain of type IV collagen (α3NC1) developed albuminuria associated with granular capillary loop deposition of exogenous antigen, mouse IgG, C3 and C5b-9, and podocyte injury. High-resolution imaging showed abundant IgG deposition in the expanded glomerular basement membrane, especially in regions corresponding to subepithelial electron dense deposits. FcRn-null and -humanized mice immunized with α3NC1 developed no albuminuria and had lower levels of serum IgG anti-α3NC1 antibodies and reduced glomerular deposition of IgG, antigen, and complement. Our results show that FcRn promotes the formation of subepithelial immune complexes and subsequent glomerular pathology leading to proteinuria, potentially by maintaining higher serum levels of pathogenic IgG antibodies. Therefore, reducing pathogenic IgG levels by pharmacologic inhibition of FcRn may provide a novel approach for the treatment of immune complex-mediated glomerular diseases. As proof of concept, we showed that a peptide inhibiting the interaction between human FcRn and human IgG accelerated the degradation of human IgG anti-α3NC1 autoantibodies injected into FCRN-humanized mice as effectively as genetic ablation of FcRn, thus preventing the glomerular deposition of immune complexes containing human IgG.
Copyright © 2014 by the American Society of Nephrology.
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15 MeSH Terms
Present and past Helicobacter pylori infection in Mexican school children.
Mendoza E, Camorlinga-Ponce M, Perez-Perez G, Mera R, Vilchis J, Moran S, Rivera O, Coria R, Torres J, Correa P, Duque X
(2014) Helicobacter 19: 55-64
MeSH Terms: Adolescent, Antibodies, Bacterial, Antigens, Bacterial, Bacterial Proteins, Breath Tests, Child, Cross-Sectional Studies, Enzyme-Linked Immunosorbent Assay, Female, Helicobacter Infections, Helicobacter pylori, Humans, Immunoglobulin G, Male, Mexico, Prevalence, Schools, Students, Urease
Show Abstract · Added March 7, 2014
BACKGROUND - In developing countries, more than 50% of children have serological evidence of Helicobacter pylori infection. However, serological tests for H. pylori did not differentiate between active and past infection. The objectives of this study were to estimate the frequency of active and past H. pylori infection utilizing functional urea breath test (UBT) and serological tests and evaluate factors associated with the infection.
METHODS - A total of 675 school children, 6-13 years of age, participated. UBT was performed to detect active H. pylori infection. Blood samples were obtained to determine iron status and Immunoglobulin G (IgG) responses to the H. pylori whole-cell and to Cag A antigens by antigen-specific enzyme-linked immunosorbent assays. Weight, height, and sociodemographic characteristics were recorded.
RESULTS - A total of 37.9% (95% Confidence Intervals (CI): 34.2-41.6) of school children had active or past H. pylori infection; of them, 73.8% (CI95% 68.4-79.2) were carrying CagA-positive strain, 26.5% (CI95% 23.2-29.8) had active infection, and 11.4% (95%CI: 9.0-13.8) had evidence of past H. pylori infection. School children with iron deficiency and low height for age had higher risk of H. pylori infection: [OR to active or past infection was 2.30 (CI 95% 1.01-5.23) and to active infection it was 2.64 (CI 95% 1.09-6.44)] compared to school children with normal iron status and height for age or with normal iron status but low height for age or with iron deficiency and normal height for age.
CONCLUSIONS - The estimated prevalence of infection depends of the test utilized. Frequency of H. pylori infection and carrying CagA-positive strains was high in this population. Malnutrition was associated with active H. pylori infection.
© 2013 John Wiley & Sons Ltd.
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19 MeSH Terms
Reduced T cell-dependent humoral immune response in microsomal prostaglandin E synthase-1 null mice is mediated by nonhematopoietic cells.
Kojima F, Frolov A, Matnani R, Woodward JG, Crofford LJ
(2013) J Immunol 191: 4979-88
MeSH Terms: Animals, Arthritis, Experimental, Bone Marrow Transplantation, Cells, Cultured, Collagen, Female, Immunity, Humoral, Immunoglobulin G, Immunoglobulin M, Interferon-gamma, Interleukin-17, Interleukin-2, Interleukin-4, Intramolecular Oxidoreductases, Male, Mice, Mice, Inbred DBA, Mice, Knockout, Prostaglandin-E Synthases, T-Lymphocytes
Show Abstract · Added January 21, 2015
Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that specifically catalyzes the conversion of PGH2 to PGE2. We showed that mPGES-1 null mice had a significantly reduced incidence and severity of collagen-induced arthritis compared with wild-type (WT) mice associated with a marked reduction in Abs to type II collagen. In this study, we further elucidated the role of mPGES-1 in the humoral immune response. Basal levels of serum IgM and IgG were significantly reduced in mPGES-1 null mice. Compared with WT mice, mPGES-1 null mice exhibited a significant reduction of hapten-specific serum Abs in response to immunization with the T cell-dependent (TD) Ag DNP-keyhole limpet hemocyanin. Immunization with the T cell-independent type 1 Ag trinitrophenyl-LPS or the T cell-independent type 2 Ag DNP-Ficoll revealed minimal differences between strains. Germinal center formation in the spleen of mPGES-1 null and WT mice were similar after immunization with DNP-keyhole limpet hemocyanin. To determine whether the effect of mPGES-1 and PGE2 was localized to hematopoietic or nonhematopoietic cells, we generated bone marrow chimeras. We demonstrated that mPGES-1 deficiency in nonhematopoietic cells was the critical factor for reduced TD Ab production. We conclude that mPGES-1 and PGE2-dependent phenotypic changes of nonhematopoietic/mesenchymal stromal cells play a key role in TD humoral immune responses in vivo. These findings may have relevance to the pathogenesis of rheumatoid arthritis and other autoimmune inflammatory diseases associated with autoantibody formation.
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20 MeSH Terms
Brown Recluse spider bite mediated hemolysis: clinical features, a possible role for complement inhibitor therapy, and reduced RBC surface glycophorin A as a potential biomarker of venom exposure.
Gehrie EA, Nian H, Young PP
(2013) PLoS One 8: e76558
MeSH Terms: Adolescent, Adult, Antibodies, Monoclonal, Humanized, Biomarkers, Brown Recluse Spider, CD55 Antigens, CD59 Antigens, Child, Complement System Proteins, Environmental Exposure, Erythrocytes, Female, Gene Expression Regulation, Glycophorin, Hemolysis, Humans, Immunoglobulin G, Male, Retrospective Studies, Spider Bites, Spider Venoms
Show Abstract · Added March 7, 2014
BACKGROUND - The venom of Loxosceles reclusa (Brown Recluse spider) can cause a severe, life-threatening hemolysis in humans for which no therapy is currently available in the USA beyond supportive measures. Because this hemolysis is uncommon, relatively little is known about its clinical manifestation, diagnosis, or management. Here, we aimed to clarify the clinical details of envenomation, to determine the efficacy of the complement inhibitor eculizumab to prevent the hemolysis in vitro, and to investigate markers of exposure to Brown Recluse venom.
STUDY DESIGN AND METHODS - We performed a 10-year chart review of cases of Brown Recluse spider bite-mediated hemolysis at our institution. We also designed an in vitro assay to test the efficacy of eculizumab to inhibit hemolysis of venom exposed red blood cells. Finally, we compared levels of CD55, CD59 and glycophorin A on venom exposed versus venom-naïve cells.
RESULTS - Most victims of severe Brown Recluse spider mediated hemolysis at our institution are children and follow an unpredictable clinical course. Brown Recluse spider bite mediated hemolysis is reduced by 79.2% (SD=18.8%) by eculizumab in vitro. Erythrocyte glycophorin A, but not CD55 or CD59, is reduced after red blood cells are incubated with venom in vitro.
CONCLUSION - Taken together, our laboratory data and clinical observations indicate that L. reclusa venom exposure results in non-specific antibody and complement fixation on red blood cells, resulting in complement mediated hemolysis that is curtailed by the complement inhibitor eculizumab in vitro. Glycophorin A measurement by flow cytometry may help to identify victims of L. reclusa envenomation.
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21 MeSH Terms