Immune complex binding Streptococcus pyogenes type M12/emm12 in experimental glomerulonephritis

2013 ◽  
Vol 62 (9) ◽  
pp. 1272-1280 ◽  
Author(s):  
Larissa Burova ◽  
Peter Pigarevsky ◽  
Nadezhda Duplik ◽  
Vlada Snegova ◽  
Alexander Suvorov ◽  
...  
Keyword(s):  
Rabbit Model ◽  
Complement C3 ◽  
Poststreptococcal Glomerulonephritis ◽  
Tnf Α ◽  
Rabbit Igg ◽  
Renal Changes ◽  
Group A ◽  
Study Type ◽  
Binding Component

In a rabbit model, we have previously reported evidence for a pathogenic role of streptococcal IgG Fc-binding proteins (IgGFcBP) in poststreptococcal glomerulonephritis (PSGN). These proteins, of the M protein family, were shown to trigger anti-IgG production and enhance renal deposition of IgG and/or immune complexes (ICs), with resulting activation of complement and cytokine cascades. In the present study, type M12/emm12, group A streptococci (GAS) were found often to bind artificial ICs, viz. peroxidase–anti-peroxidase rabbit IgG (PAP) or tetanus toxoid–anti-tetanus human IgG (TAT), rather than monomeric IgG. Animals injected with each of four IC binding clinical isolates (from patients with scarlet fever or PSGN) showed pronounced inflammatory and degenerative glomerular changes, morphologically similar to human PSGN, with membrane thickening and IgG and complement C3 deposition, as well as secretion of IL-6 and TNF-α by mesangial and endothelial cells. In contrast, non-binding strains (two from asymptomatic carriers and one from a PSGN case) failed to trigger any renal changes. Only the IC binding strains induced elevated titres of anti-IgG. Though the streptococcal binding component(s) has not been demonstrated, the selective binding of ICs by type M12/emm12 strains appears important for the well-known, marked nephritogenic potential of this GAS type.

scholarly journals Impact of IgG Fc-fragments on experimental glomerulonephritis induced by Streptococcus pyogenes strain binding various immunoglobulin classes

2020 ◽  
Vol 10 (1) ◽  
pp. 55-63
Author(s):  
L. A. Burova ◽  
P. V. Pigarevsky ◽  
V. A. Snegova ◽  
A. A. Totolian
Keyword(s):  
Immune Complexes ◽  
Binding Proteins ◽  
Rabbit Model ◽  
Renal Tissue ◽  
Proliferative Glomerulonephritis ◽  
Pathological Changes ◽  
Experimental Glomerulonephritis ◽  
Rabbit Igg ◽  
Group A

The pathogenesis of poststreptococcal glomerulonephritis (PSGN), a major complication of acute infections caused by group A streptococci (GAS) remains unclear. Several theories, based on the role of certain streptococcal virulence factors, as well as immunological mimicry between GAS and renal tissue, have been proposed. Earlier, we reported that many virulent clinical GAS isolates showing confirmed nephritogenic activity were capable of nonimmune Fc binding of monomeric or aggregated IgG. Moreover, a rabbit model of PSGN allowed to obtain findings regarding a crucial role of streptococcal IgG Fc binding proteins belonging to the M family surface proteins, in the onset of PSGN. Rabbits injected with inactivated IgGFcBP-positive streptococci, acquired changes in the renal tissue with deposited IgG and complement C3, as well as signs of immune inflammation characteristic for human PSGN. Also, it was shown that the induction of experimental glomerulonephritis could be inhibited after normal IgG or its purified Fc fragments were inoculated at early stages of the process. The data obtained in rabbits injected with group A streptococcal type M60 also showed pathogenic functions of the IgA Fc-binding proteins of GAS. The aim of the study was to examine inhibiting activity of the purified rabbit IgG Fc fragments on the manifestations of glomerulonephritis induced by S. pyogenes strains capable of binding diverse forms of immunoglobulins such native IgG, immune complexes, and IgA.Materials and methods. GAS strains of emml, emml2 and emm60 genotypes were used to induce PSGN or IgA-nephropa-thy in rabbits. Fc fragments derived from rabbit IgG were obtained by enzymatic digestion and purified by affinity chromatography on a protein G-sepharose FF column. Immunomorphological changes of renal tissue were estimated by morphometric analysis.Results. In the present study, using the rabbit model, we revealed pathological changes of different intensity and localization in the renal tissue. For streptococci of the emm1 and emm12 genotypes, PSGN was characterized by deposition of IgG or IgG-anti-IgG immune complexes within the basal glomerular membrane. Morphological changes were evaluated as a membranous-proliferative glomerulonephritis. Meanwhile, IgA-glomerulonephritis is characterized by deposition of IgA in mesangial cells of glomeruli, leading to the mesangial-proliferative glomerulonephritis or IgA-nephropathy. Intravenously administered purified Fc fragments derived from normal rabbit IgG varied in effects on pathological processes: (i) IgG Fc fragments of fully inhibited development of the PSGN induced by IgG Fc binding strain of emml genotype, (ii) IgG Fc fragments of partially reverted changes caused by the emm12 genotype strain, which was binding only to immune complexes, and (iii) had no effects on pathological changes caused by the emm60 genotype GAS strain, which was binding only IgA.Conclusion. The data obtained point and emergence of differences in mechanisms of renal lesions development at glomerulonephritis, depending on the emm genotype of GAS strain. In addition, it also confirmed GAS-derived involvement for various IgFc-receptor proteins in the pathology. Further studies on potential prophylactic or curative effects of IgG Fc fragments in PSGN should therefore be of interest. The findings might suggest a new therapeutic approach for non-suppurative poststreptococcal diseases.

Complement activating ABO IgM/IgG act synergistically to cause erythrophagocytosis: implications among minor ABO incompatible platelet transfusions

2020 ◽  
Author(s):  
Priyanka Pandey ◽  
Waseem Q. Anani ◽  
Tina Pugh ◽  
Jerome L. Gottschall ◽  
Gregory A Denomme
Keyword(s):  
Complement Activation ◽  
Complement C3 ◽  
Transfusion Reaction ◽  
Single Donor ◽  
Healthy Donors ◽  
Hemolytic Transfusion Reaction ◽  
Group A ◽  
Donor Sample ◽  
Donor Plasma

Abstract Background Typically minor ABO incompatible platelet products are transfused without any incident, yet serious hemolytic transfusion reactions occur. To mitigate these events, ABO ‘low titer’ products are used for minor ABO incompatible transfusions. We sought to understand the role of IgG and complement activation by anti-A on extravascular hemolysis. Samples evaluated: i) Group O plasma from a blood donor whose apheresis platelet product resulted in an extravascular transfusion reaction, ii) Group O plasma from 12 healthy donors with matching titers that activated complement (N = 6) or not (N = 6), and iii) Group O sera from 10 patients with anti-A hemolysin activity. Monocytes from healthy donors were co-incubated with anti-A-sensitized fluorescently-labeled Group A1+ RBCs with and without fresh Group A serum, as a source of complement C3, and phagocytosis was analyzed by flow cytometry. The plasma and sera had variable direct agglutinating (IgM) and indirect (IgG) titers. Results None of 12 selected samples showed monocyte-dependent erythrophagocytosis with or without complement activation. The donor sample causing a hemolytic transfusion reaction and 2 of the 10 patient sera with hemolysin activity showed significant erythrophagocytosis (>10%) only when complement C3 was activated. The single donor plasma and two sera demonstrating significant erythrophagocytosis had high IgM (≥128) and IgG titers (>1024). The donor plasma anti-A was IgG1, while the patient sera were an IgG3 and an IgG1 plus IgG2. Conclusion High anti-A IgM/IgG titers act synergistically to cause significant monocyte erythrophagocytosis by activating complement C3, thus engaging both Fcγ- and CR1-receptors.

scholarly journals Allele Substitution of the Streptokinase Gene Reduces the Nephritogenic Capacity of Group A Streptococcal Strain NZ131

2000 ◽  
Vol 68 (3) ◽  
pp. 1019-1025 ◽  
Author(s):  
Annika Nordstrand ◽  
W. Michael McShan ◽  
Joseph J. Ferretti ◽  
Stig E. Holm ◽  
Mari Norgren
Keyword(s):  
Allelic Variant ◽  
Wild Type ◽  
Poststreptococcal Glomerulonephritis ◽  
Acute Poststreptococcal Glomerulonephritis ◽  
Site Specific Integration ◽  
Allele Substitution ◽  
Group A ◽  
Type Strains ◽  
Streptococcal Strain

ABSTRACT To investigate the role of allelic variants of streptokinase in the pathogenesis of acute poststreptococcal glomerulonephritis (APSGN), site-specific integration plasmids were constructed, which contained either the non-nephritis-associated streptokinase gene (skc5) from the group C streptococcal strainStreptococcus equisimilis H46A or the nephritis-associated streptokinase gene (ska1) from the group A streptococcal nephritogenic strain NZ131. The plasmids were introduced by electroporation and homologous recombination into the chromosome of an isogenic derivative of strain NZ131, in which the streptokinase gene had been deleted and which had thereby lost its nephritogenic capacity in a mouse model of APSGN. The introduction of a non-nephritis-associated allelic variant of streptokinase did not rescue the nephritogenic capacity of the strain. The mutant and the wild-type strains produced equivalent amounts of streptokinase. Complementation of the ska deletion derivative with the original ska allele reconstituted the nephritogenicity of wild-type NZ131. The findings support the hypothesis that the role of streptokinase in the pathogenesis of APSGN is related to the allelic variant of the protein.

scholarly journals The role of cytomegalovirus infection in ischemic heart failure progression

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
E Grakova ◽  
S.N Shilov ◽  
E.N Berezikova ◽  
K.V Kopeva ◽  
A.A Popova ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ischemic Heart ◽  
Interleukin 1Β ◽  
Ischemic Heart Failure ◽  
Tnf Α ◽  
Heart Failure Progression ◽  
Group A ◽  
Group B

Abstract Objective To study an association between cytomegalovirus infection (CMV) and molecular biomarkers (NT-proBNP, tumor necrosis factor (TNF-α), Interleukin-1β) and evaluate prognostic role of CMV infection in ischemic heart failure (HF) progression during the 12-month follow-up period. Methods A total of 104 patients (61.5% men, median age of 59 [53; 62.5] years) with stable coronary artery disease and baseline left ventricular ejection fraction (LVEF) of 43% [36; 57]% were enrolled in the study. At baseline evaluation HF patients were of New York Heart Association (NYHA) class I (7.7%), class II (61.0%), and class III (31.3%). Sixty five percent of patients had prior myocardial infarction and 70.2% received prior myocardial revascularization (coronary artery bypass graft/stent). Cytomegalovirus DNA concentrations in EDTA whole-blood samples were measured using a polymerase chain reaction baseline and at 12 months of follow-up period. Serum levels of NT-proBNP, Interleukin-1β, TNF-α were measured baseline using an enzyme immunoassay. Two-dimensional transthoracic echocardiography was performed at baseline and at the 12 months. Results At baseline, all patients were divided into 2 groups: group A comprised CMV seropositive patients (n=52); group B comprised CMV seronegative patients (n=52). Plasma concentration of cytomegalovirus DNA was 1709.4 [615; 3176] copies/mL. The values of cytomegalovirus DNA significantly correlated with NT-proBNP (r=0.781), TNF-α (r=0.799) and Interleukin-1β (r=0.756). Levels of NT-proBNP were higher (p=0.0001) in group A by 36.6% than in group 2 (559 [364; 756] vs. 354.5 [279; 545.5] pg/mL, respectively). Levels of TNF-α were also higher (p<0,001) by 35.3% (8.5 [6.5; 10.9] vs. 5.5 [4.1; 7.3] ng/mL, respectively) and levels of Interleukin-1β (p<0,001) by 17.6% (19.3 [15.8; 23.75] vs. 15.9 [13.15; 18.7] ng/mL, respectively) in group A than in group B. During the 12-month follow-up period in group A the rate of HF progression was 51.6% cases, and in group B 26.9% (p=0.009). Based on ROC-analysis, baseline plasma concentration of cytomegalovirus DNA ≥2020 copies/mL (AUC=0.798; specificity 67%, sensitivity 82%; p<0.001) were identified as a cut-off values predicting development of HF progression during the 12-month follow-up period. 12-month levels of cytomegalovirus DNA did not differ (p=0,678) in comparison to baseline ones and were 1737.9 [321; 3384] copies /mL. In group A LVEF significantly increased by 18.8% from 50.5 [36.5; 56.0] to 41.0 [35.0; 50.0]%, end-systolic dimension significantly increased by 7.3%, end-diastolic dimension by 9.6% (p<0,0001), while in group B these parameters did not change. Conclusion Our data suggest that values of cytomegalovirus DNA are associated with NT-proBNP, TNF-α, Interleukin-1β levels, and may be considered as non-invasive biomarker for prediction of ischemic heart failure progression during the 12-month follow-up period. FUNDunding Acknowledgement Type of funding sources: None.

scholarly journals The Role of IL-6, TNF-α, and VDR in Inhibiting the Growth of Salmonella Typhi: in vivo Study

2020 ◽  
Vol 14 (1) ◽  
pp. 65-71
Author(s):  
Ami Febriza ◽  
Rosdiana Natzir ◽  
Mochammad Hatta ◽  
Suryani As'ad ◽  
. Budu ◽  
...  
Keyword(s):  
Immune Cells ◽  
Peritoneal Fluid ◽  
Innate Immune ◽  
Colony Count ◽  
P Value ◽  
Bacterial Colony ◽  
Tnf Α ◽  
Group A ◽  
Group B

Background and aim: The prevalence of typhoid fever is reportedly high, especially in Asia. When a pathogen enters the human body, there are markers in the form of molecules that will be known by the innate immune system. Specific molecular markers of gram negative bacteria, which are Lipopolysaccharides (LPS) and Toll-Like receptors-4 will interact with LPS. The binding between LPS and TLR-4 will give rise to activation signals that will activate innate immune cells. Immune cells will release a number of proinflammatory cytokines, such as TNF-α, IL-1, and IL-6. While Vitamin D Receptors (VDR) are expressed in large amounts in tumor tissue and infected cells. This study aimed to prove the role of IL-6, TNF-α, and VDR in inhibiting bacterial growth in mice that have been induced by S.Typhi. Methods: This research was a real experimental pre-post test design to investigate the level of IL-6, TNF-α and VDR in suppressing the growth of bacteria in the peritoneal fluid of S. Typhi, male, mice BALB/c. Mice were divided into three groups comprised of 10 mice each. All mice in groups A and B were intraperitoneally inoculated with S. Typhi strain Thy1 in study day 0. Group A was treated with antibiotic Levofloxacine, on study day 4th. Another study group, group B, was used as a placebo and received aquades on study day 4th. While group C as a control was not inoculated with S. Typhi. Blood samples from three groups for the calculation of serum Il-6, TNF-α, and VDR were collected. This examination was taken four times; at baseline, 4th day, 10th day, and 30th day. For the calculation of bacterial colony, peritoneal fluid retrieval was collected three times, which is on 4th day, 10th day, and 30th day. Results: A repeated measure ANOVA in group A (antibiotic) and group B (placebo) group showed that mean IL-6, TNF-α, and VDR level differed statistically significant between times (p-value 0.000). There was a strong negative correlation between bacterial colony count and VDR level, which was statistically significant in both groups (group A; r = -0.875, p-value = 0.000 vs group B; r = -0.470, p-value = 0.002). IL-6 and TNF-α didn't give significant statistical correlation with bacterial colony count. Conclusion: VDR, IL-6, and TNF-α play an important role in killing bacteria. From the results of this study, IL-6 level is related to the number of bacterial colonies, the lower the IL-6 level, the less the number of bacterial colonies. Similarly, TNF-α levels have a positive correlation with the number of bacterial colonies. While VDR levels are also related to the number of bacterial colonies, the higher the VDR level, the lower the number of bacterial colonies.

scholarly journals Purification and partial characterization of the nephritis strain-associated protein from Streptococcus pyogenes, group A.

1986 ◽  
Vol 163 (3) ◽  
pp. 697-712 ◽  
Author(s):  
K H Johnston ◽  
J B Zabriskie
Keyword(s):  
Biochemical Analysis ◽  
Poststreptococcal Glomerulonephritis ◽  
Isolation And Purification ◽  
Amino Terminal ◽  
Acute Poststreptococcal Glomerulonephritis ◽  
Group A ◽  
Terminal Amino

We report the isolation and purification of the nephritis strain-associated protein (NSAP) first described by Villareal et al. (8). Amino acid analysis, and determination of the first 21 amino-terminal amino acids indicated that this 46 kD protein is a streptokinase. Biochemical analysis confirmed that NSAP could act as a plasminogen activator; immunological investigations indicated that NSAP is antigenically different from streptokinase from group C streptococcus, and possibly represents a unique streptokinase. It is this uniqueness that may contribute to the role of NSAP in the pathogenesis of acute poststreptococcal glomerulonephritis.

scholarly journals THE EXPERIMENTAL INDUCTION OF GLOMERULONEPHRITIS LIKE THAT IN MAN BY INFECTION WITH GROUP A STREPTOCOCCI

1968 ◽  
Vol 127 (1) ◽  
pp. 1-24 ◽  
Author(s):  
Carl G. Becker ◽  
George E. Murphy
Keyword(s):  
Acute Glomerulonephritis ◽  
Group A Streptococci ◽  
Poststreptococcal Glomerulonephritis ◽  
Anatomical Changes ◽  
Naturally Occurring ◽  
Experimental Induction ◽  
Renal Changes ◽  
Group A ◽  
Experimentally Induced

106 rabbits received one or more courses of inoculations, spaced 1–4 months apart, with Group A streptococci, usually of strains isolated from patients with acute glomerulonephritis. 8 days to a few weeks after onset of a given infection with streptococci known to have been nephritogenic for man, marked proteinuria, often with hematuria and occasionally with azotemia, was detected in 22 of the animals. 15 of these were sacrificed a few days to a few weeks thereafter, and 10 showed renal changes like those of acute or recurrent acute glomerulonephritis in man. Such changes occurred in three other rabbits whose urine was not examined that died or were sacrificed 1–3 wk after onset of infection with streptococci of a serotype known to include a strain nephritogenic for man. The remaining seven animals in which marked proteinuria had occurred died or were sacrificed many months later, in some cases after additional infections. Two of these had become azotemic and two convulsed and died after giving birth; in these animals, there were renal changes like those that occur in man in chronic latent glomerulonephritis, toxemia of pregnancy super-imposed on chronic latent glomerulonephritis, or chronic active glomerulonephritis. Anatomical changes in the kidneys in the experimentally induced and in naturally occurring glomerulonephritis, from acute to chronic stages, are compared and illustrated. The pathogenesis of poststreptococcal glomerulonephritis is discussed.

Role of cytokines in caerulein-induced acute pancreatilis of IL-1, IL-6 and TNF-α knockoul mice

2001 ◽  
Vol 120 (5) ◽  
pp. A541-A541
Author(s):  
K KITAMURA ◽  
J NIIKAWA ◽  
T IMAMURA ◽  
A TAKAHASHI ◽  
A IKEGAMI ◽  
...  
Keyword(s):  
Tnf Α
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