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1.
Int J Mol Sci ; 19(10)2018 Oct 19.
Article in English | MEDLINE | ID: mdl-30347705

ABSTRACT

Gut commensal microorganisms have been linked with chronic inflammation at the extra-intestinal niche of the body. The object of the study was to investigate on the chronic effects of a gut commensal Escherichia coli on extra-intestinal glands. The presence of autoimmune response was diagnosed by autoantibody levels and histological methods. Repeated injection of E. coli induced mononuclear cell inflammation in the Harderian and submandibular salivary glands of female C57BL/6 mice. Inflammation was reproduced by adoptive transfer of splenocytes to immune-deficient Rag2 knockout mice and CD4⁺ T cells to mature T cell-deficient TCRß-TCRδ knockout mice. MALDI TOF mass spectrometry of the protein to which sera of E. coli-treated mice reacted was determined as the outer membrane protein A (OmpA) of E. coli. Multiple genera of the Enterobacteriaceae possessed OmpA with high amino-acid sequence similarities. Repeated injection of recombinant OmpA reproduced mononuclear cell inflammation of the Harderian and salivary glands in mice and elevation of autoantibodies against Sjögren's-syndrome-related antigens SSA/Ro and SSB/La. The results indicated the possibility of chronic stimuli from commensal bacteria-originated components as a pathogenic factor to elicit extra-intestinal autoimmunity.


Subject(s)
Autoantibodies/immunology , Bacterial Outer Membrane Proteins/immunology , Gastrointestinal Microbiome/immunology , Salivary Glands/immunology , Animals , Female , Mice , Mice, Inbred C57BL , Monocytes/immunology , Salivary Glands/microbiology
2.
Shock ; 45(5): 564-9, 2016 May.
Article in English | MEDLINE | ID: mdl-26682949

ABSTRACT

Sepsis is a serious condition related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of the cytokine storm caused by dysregulation of cytokine production. Morphine influences the severity of infection in vivo and in vitro because it regulates cytokine production. We investigated the immunological function of morphine using a mouse model of septic shock. We treated mice with α-galactosylceramide (2 µg/mouse) to induce lethal endotoxic shock following a challenge with lipopolysaccharide (LPS, 1.5 µg/mouse). This model represents acute lung injury and respiratory failure, and reflects the clinical features of severe septic shock. We evaluated the effect of the timing of morphine (0.8 mg/mouse) administration on the survival rate, cytokine production in vivo, and histological changes of mice with LPS-mediated lethal endotoxic shock. Morphine treatment before LPS challenge suppressed lethal endotoxic shock. In contrast, when we administered after LPS, morphine exacerbated lethal endotoxic shock; hematoxylin and eosin staining revealed a marked increase in the accumulation of infiltrates comprising polymorphonuclear leukocytes and mononuclear cells in the lung; and Elastica van Gieson staining revealed the destruction of alveoli. The plasma levels of tumor necrosis factor-α, interferon-γ, monocyte-chemotactic protein-1, and interleukin-12 in the group treated with morphine after LPS challenge were higher than those treated with morphine before LPS challenge. In conclusion, one of the factors that determine whether morphine exacerbates or inhibits infection is the timing of its administration. Morphine treatment before shock improved the survival rate, and morphine treatment after shock decreased the rate of survival.


Subject(s)
Lipopolysaccharides/toxicity , Morphine/administration & dosage , Morphine/therapeutic use , Shock, Septic/chemically induced , Shock, Septic/drug therapy , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Animals , Disease Models, Animal , Female , Galactosylceramides/pharmacology , Interferon-gamma/metabolism , Interleukin-12/metabolism , Mice , Shock, Septic/metabolism , Time Factors , Tumor Necrosis Factor-alpha/metabolism
3.
Intern Med ; 51(21): 3085-8, 2012.
Article in English | MEDLINE | ID: mdl-23124156

ABSTRACT

We herein report a case of toxic shock syndrome (TSS) associated with the 2009 pandemic H1N1 (pH1N1) influenza virus and a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection in a 16-year-old Vietnamese girl. Staphylococcal enterotoxin B (SEB) was detected in the patient's serum, and the level of anti-SEB antibodies was found to be elevated. A flow cytometric analysis showed evidence of activated SEB-reactive Vß3+ and Vß12+ T cells. These data suggest that the CA-MRSA-induced activation of SEB-reactive T cells may cause TSS in patients with pH1N1 virus infection. Moreover, this is the first report describing immunological confirmation of SEB contributing directly to TSS in a patient fulfilling the diagnostic criteria of TSS.


Subject(s)
Community-Acquired Infections/etiology , Enterotoxins/toxicity , Methicillin-Resistant Staphylococcus aureus , Shock, Septic/etiology , Staphylococcal Infections/etiology , Adolescent , Anti-Bacterial Agents/administration & dosage , Community-Acquired Infections/drug therapy , Community-Acquired Infections/microbiology , Female , Humans , Influenza A Virus, H1N1 Subtype , Influenza, Human/complications , Pneumonia, Staphylococcal/drug therapy , Pneumonia, Staphylococcal/etiology , Pneumonia, Staphylococcal/microbiology , Shock, Septic/drug therapy , Shock, Septic/microbiology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology
4.
Microbiol Immunol ; 56(10): 708-18, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22725643

ABSTRACT

The aim of the present study was to determine the correlations between leukocyte cell-derived chemotaxin 2 (LECT2) and inflammation-related variables in human inflammatory disease. Plasma samples from 23 septic patients who had been admitted to the intensive care unit (ICU) of our institution and 31 volunteers were used. Plasma LECT2 concentrations were examined retrospectively and compared with those of various inflammatory cytokines and routine laboratory data. The LECT2 concentrations of the septic patients at the time of ICU entry (5.3 ± 4.1 ng/mL) were significantly lower than those of the volunteers (19.7 ± 3.4 ng/mL) and these concentrations had significantly increased by the time of ICU discharge. Individual analyses showed that the LECT2 concentrations of all 19 patients had increased by the time of ICU discharge. A combination of LECT2 and C-reactive protein (CRP) concentrations was capable of discriminating the acute and recovery phases of sepsis to a degree similar to those of the combinations of CRP concentration and percentage of neutrophils, CRP concentration and percentage of immature white blood cells, or CRP and interleukin-6 concentrations. Thus, the LECT2 concentration correlates with the severity of systemic inflammation in patients with sepsis. LECT2 may be a reliable diagnostic indicator of human inflammatory diseases.


Subject(s)
Biomarkers/blood , Intercellular Signaling Peptides and Proteins/blood , Plasma/chemistry , Sepsis/pathology , Severity of Illness Index , Adult , Aged , C-Reactive Protein/analysis , Female , Humans , Male , Middle Aged , Time Factors
5.
J Clin Immunol ; 32(5): 1026-37, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22661269

ABSTRACT

BACKGROUND: We previously reported a mouse model of primary biliary cirrhosis (PBC)-like chronic nonsuppurative destructive cholangitis (CNSDC), in which frequent injections of Streptococcus intermedius induced CNSDC and autoantibody production. The present study was performed to verify the model by examining 1) the reappearance of the PBC-like CNSDC after lymphocyte transfer from model to naïve mice, 2) the involvement of autophagy, and 3) the influence of the strain difference. METHODS: Mice were inoculated with S. intermedius weekly for 8 weeks, then sacrificed to obtain samples. Spleen cells obtained from S. intermedius-inoculated mice were transferred to RAG2(-/-) mice. RESULTS: CNSDC and elevated serum level of anti-gp210 titers were observed in S. intermedius-inoculated C57BL/6 mice, similar to the results of our previous report using BALB/c mice. Portal inflammation was induced in the livers of RAG2(-/-) mice by the transfer of spleen cells from S. intermedius-inoculated C57BL/6 mice. Among the inflammatory cells in the RAG2(-/-) mice, CD3-positive cells were predominant. Autophagosome-like structures were detected histologically, in the cytoplasm of infiltrated cells around the bile ducts in the livers of S. intermedius-inoculated both C57BL/6 and BALB/c mice. In S. intermedius-inoculated C3H/HeJ mice, inflammation in the portal area was less extensive than that in the hepatic parenchyma. CONCLUSION: Bacterial component(s) and sequentially upregulated innate and acquired immune responses, accompanied by autophagy, might trigger CNSDC, via autoimmune mechanisms. Throughout the generation of bacteria-triggered PBC-like CNSDC, strain difference may influence the response to S. intermedius-inoculation in the liver.


Subject(s)
Liver Cirrhosis, Biliary/immunology , Streptococcal Infections/immunology , Streptococcus intermedius , Adoptive Transfer , Animals , Antibodies, Antinuclear/immunology , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Disease Models, Animal , Female , Liver Cirrhosis, Biliary/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Nuclear Pore Complex Proteins/immunology , Spleen/cytology , Streptococcal Infections/pathology
6.
Clin Immunol ; 137(3): 311-21, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20805039

ABSTRACT

To elucidate whether leukocyte cell-derived chemotaxin 2 (LECT2) controls the progression of staphylococcal enterotoxin A (SEA)-induced toxicity, we examined the role of LECT2 in a mouse model. Almost all the C57BL/6J (B6) mice survived for 72 h after the injection of 0.1 µg of SEA and 20 mg of d-galactosamine (d-GalN). However, the same treatment protocol in LECT2(-/-) mice produced a high lethality (~90%), severe hepatic apoptosis, and massive hepatic and pulmonary hemorrhage, similar to the situation observed in B6 mice treated with 1.0 µg SEA/d-GalN. The plasma LECT2 levels in B6 mice treated with 1.0 µg SEA/d-GalN were inversely correlated with the plasma cytokine levels and were associated with prognosis. LECT2 administration increased the survival of B6 mice and down-regulated TNF-α and IL-6. These results suggest the involvement of LECT2 in the regulation of fatal SEA-induced toxicity in d-GalN-sensitized mice.


Subject(s)
Chemical and Drug Induced Liver Injury/pathology , Enterotoxins , Galactosamine/immunology , Intercellular Signaling Peptides and Proteins/immunology , Liver/pathology , Lung/pathology , Shock, Septic/immunology , T-Lymphocytes/immunology , Animals , Apoptosis , Chemical and Drug Induced Liver Injury/immunology , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/immunology , Enterotoxins/immunology , Enterotoxins/toxicity , Female , Flow Cytometry , Hemorrhage/chemically induced , In Situ Nick-End Labeling , Intercellular Signaling Peptides and Proteins/administration & dosage , Intercellular Signaling Peptides and Proteins/pharmacology , Interleukin-6/metabolism , Liver/drug effects , Liver/immunology , Lung/drug effects , Lung/immunology , Mice , Mice, Inbred C57BL , Shock, Septic/chemically induced , Shock, Septic/pathology , T-Lymphocytes/drug effects , Time Factors , Tumor Necrosis Factor-alpha/metabolism
7.
Lab Invest ; 90(12): 1757-69, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20733561

ABSTRACT

The pathogenesis of autoimmune pancreatitis (AIP) remains unknown. Here, we investigated the possible involvement of chronic, persistent exposure to avirulent bacteria in the pathogenesis of AIP. C57BL/6 mice were inoculated with heat-killed Escherichia coli weekly for 8 weeks. At 1 week and up to 12 months after the final inoculation, the mice were killed to obtain samples. At 1 week after the final E. coli inoculation, marked cellular infiltration with fibrosis was observed in the exocrine pancreas. Cellular infiltration in the exocrine pancreas was still observed up to 12 months after the completion of E. coli inoculation. At 10 months after the final inoculation, duct-centric fibrosis became obvious. Inflammation around the ducts in the salivary glands was also observed. Furthermore, sera from heat-killed E. coli-inoculated mice possessed anti-carbonic anhydrase, anti-lactoferrin, and antinuclear antibodies. Exposure to E. coli-triggered AIP-like pancreatitis in C57BL/6 mice. We propose a hypothetical mechanism for AIP pathogenesis. During the initiation phase, silently infiltrating pathogen-associated molecular patterns (PAMP) and/or antigen(s) such as avirulent bacteria might trigger and upregulate the innate immune system. Subsequently, the persistence of such PAMP attacks or stimulation by molecular mimicry upregulates the host immune response to the target antigen. These slowly progressive steps may lead to the establishment of AIP and associated extrapancreatic lesions. Our model might be useful for clarifying the pathogenesis of AIP.


Subject(s)
Autoimmune Diseases/immunology , Disease Models, Animal , Escherichia coli/immunology , Immunity, Innate , Pancreatitis/immunology , Salivary Gland Diseases/immunology , Salivary Glands/pathology , Animals , Antibodies, Antinuclear/immunology , Autoimmune Diseases/microbiology , Autoimmune Diseases/pathology , Female , Inflammation/immunology , Inflammation/pathology , Mice , Mice, Inbred C57BL , Pancreas, Exocrine/immunology , Pancreas, Exocrine/pathology , Pancreatitis/microbiology , Pancreatitis/pathology , Salivary Gland Diseases/microbiology , Salivary Glands/immunology
8.
J Biol Chem ; 285(40): 30427-35, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20663890

ABSTRACT

In mice implanted with an osmotic pump filled with the superantigen (SAG) staphylococcal enterotoxin A (SEA), the Vß3(+)CD4(+) T cells exhibited a high level of expansion whereas the Vß11(+)CD4(+) T cells exhibited a mild level of expansion. In contrast, in mice implanted with an osmotic pump filled with SE-like type P (SElP, 78.1% homologous with SEA), the Vß11(+)CD4(+) T cells exhibited a high level of expansion while the Vß3(+)CD4(+) T cells exhibited a low level of expansion, suggesting that the level of the SAG-induced response is determined by the affinities between the TCR Vß molecules and SAG. Analyses using several hybrids of SEA and SElP showed that residue 206 of SEA determines the response levels of Vß3(+)CD4(+) and Vß11(+)CD4(+) T cells both in vitro and in vivo. Analyses using the above-mentioned hybrids showed that the binding affinities between SEA and the Vß3/Vß11 ß chains and between SEA-MHC class II-molecule complex and Vß3(+)/Vß11(+) CD4(+) T cells determines the response levels of the SAG-reactive T cells both in vitro and in vivo.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Enterotoxins/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Superantigens/immunology , Animals , Enterotoxins/genetics , Mice , Receptors, Antigen, T-Cell, alpha-beta/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Superantigens/genetics
9.
Lab Invest ; 90(4): 577-88, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20142809

ABSTRACT

Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). We earlier reported that the bacterial lipoteichoic acid was detected at the sites of inflammation around damaged bile ducts in the livers of PBC, and PBC patients' sera showed high titers against streptococcal histone-like protein. Here, we investigated whether chronic bacterial exposure could trigger PBC-like epithelial cell damage in normal mouse. BALB/c mice were repeatedly inoculated with various bacteria for 8 weeks. At 1 week (Group 1) and 3, 4, or 20 months (long term; Group 2) after the final inoculation, mice were killed to obtain samples. In the livers of the Streptococcus intermedius (S.i.)-inoculated mice in Group 1, cellular infiltration was predominantly observed around the bile ducts over the hepatic parenchyma. In the S.i.-inoculated mice in Group 2, portal but not parenchymal inflammation was observed in the livers, and periductal cellular infiltrates were detected in the salivary glands. Both S.i.-inoculated Groups 1 and 2 BALB/c mice sera had antibodies against HuCCT1 biliary epithelial cells, anti-nuclear antibodies, and anti-gp210 antibodies, but not anti-mitochondrial antibodies. Immunoreactivity to histone-like DNA-binding protein of S.i. (S.i.-HLP) was detectable around the sites of chronic nonsuppurative destructive cholangitis in the portal area in the livers of both S.i.-inoculated Groups 1 and 2 BALB/c mice. Furthermore, anti-S.i.-HLP antibody bound to synthetic gp210 peptide, as well. Bacteria triggered PBC-like cholangitis, multifocal epithelial inflammation, and autoantibody production. Bacteria are likely involved in the pathogenesis of PBC and of associated multifocal epithelial inflammation.


Subject(s)
Antibodies, Antinuclear/physiology , Liver Cirrhosis, Biliary/immunology , Liver Cirrhosis, Biliary/microbiology , Streptococcus intermedius/immunology , Animals , Disease Models, Animal , Epithelial Cells/immunology , Immunity, Innate/immunology , Inflammation/microbiology , Inflammation/physiopathology , Liver Cirrhosis, Biliary/physiopathology , Mice , Mice, Inbred BALB C , Nuclear Pore Complex Proteins/immunology , Streptococcus intermedius/pathogenicity
10.
Microbiol Immunol ; 54(1): 38-45, 2010.
Article in English | MEDLINE | ID: mdl-20055941

ABSTRACT

The aim of this study was to determine the percentage of CD45RO(+) T cells in umbilical cord blood from neonates born at less than 37 weeks of gestation. Fifty-nine patients were enrolled in this study, including 49 with preterm and 10 with term deliveries. Preterm deliveries were divided into two categories; spontaneous (Group A, n= 31) and indicated (Group B, n= 18). Perinatal infection was categorized as C-CAM, H-CAM and neonatal infection. The percentage of CD45RO(+) T cells in the umbilical cord was assessed using flow cytometry. IL-6 was measured using ELISA. In Group A, the percentage of CD45RO(+) T cells and concentrations of IL-6 in patients with perinatal infection (n= 18) were significantly higher than in those without perinatal infection (n= 13). A significant correlation between percentage of CD45RO(+) T cells and IL-6 concentrations was observed in the cord blood (r= 0.62, P= 0.001). In Group B, pink-tinged amniotic fluid was observed in seven cases. In these cases, an increase in the percentage of CD45RO(+) T cells (>10%) was noted. In the cases without perinatal infection, which included all those delivered at term (n= 32), no correlation was observed between the percentage of CD45RO(+) T cells and gestational age at delivery (r=-0.139, P= 0.448). We concluded that a high percentage of CD45RO(+) cord blood T cells is observed not only in perinatal infection, but also in the presence of abnormal perinatal events such as maternal bleeding in preterm gestation.


Subject(s)
Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Female , Gestational Age , Humans , Infant, Newborn , Interleukin-6/metabolism , Leukocyte Common Antigens/immunology , Pregnancy , Premature Birth/immunology
11.
Microbiol Immunol ; 53(9): 524-30, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19703246

ABSTRACT

A new epidemic, NTED, has recently occurred in Japan. The cause of NTED is a bacterial superantigen, TSST-1. The aim of the present study was to analyze the change in Vbeta2(+) T cells reactive to TSST-1 in NTED in order to establish T-cell-targeted diagnostic criteria for NTED. Blood samples from 75 patients with clinically diagnosed NTED were collected from 13 neonatal intensive care units throughout Japan. We investigated the percentages of Vbeta2(+), Vbeta3(+) and Vbeta12(+) T cells and their CD45RO expressions in the samples using flow cytometry. In 18 of the 75 patients, we conducted multiple examinations of the T cells and monitored serial changes. The Vbeta2(+) T-cell population rapidly changed over three phases of the disease. Whereas the percentage of Vbeta2(+) T cells was widely distributed over the entire control range, CD45RO expression on Vbeta2(+) T cells in CD4(+) in all 75 patients was consistently higher than the control range. Patients cannot necessarily be diagnosed as having NTED based on expansion of Vbeta2(+) T cells alone in the early acute phase. Instead, CD45RO expression on specific Vbeta2(+) cells is a potential diagnostic marker for a rapid diagnosis of NTED. We present three diagnostic categories of NTED. Fifty patients (66.7%) were included in the category 'definitive NTED'. It is important to demonstrate an increase of Vbeta2(+) T cells in the following phase in cases of 'probable NTED' or 'possible NTED'.


Subject(s)
Bacterial Infections/immunology , Communicable Diseases/immunology , Infant, Newborn, Diseases/immunology , Superantigens/immunology , T-Lymphocytes/immunology , Bacterial Infections/microbiology , Communicable Diseases/microbiology , Female , Humans , Infant, Newborn , Infant, Newborn, Diseases/microbiology , Leukocyte Common Antigens/genetics , Leukocyte Common Antigens/immunology , Male
12.
Microbiol Immunol ; 52(11): 513-21, 2008 Nov.
Article in English | MEDLINE | ID: mdl-19090830

ABSTRACT

Two methods of TSS diagnosis were evaluated: comparison of symptoms with clinical criteria and monitoring for evidence of selective activation of Vbeta2(+) T cells by the causative toxin, TSS toxin-1 (TSST-1). Ten patients with acute and systemic febrile infections caused by Staphylococcus aureus were monitored for increase in TSST-1-reactive Vbeta2(+) T cells during their clinical courses. Nine of the ten patients were diagnosed with TSS based on evidence of selective activation of Vbeta2(+) T cells by TSST-1; however, clinical symptoms met the clinical criteria for TSS in only six of these nine patients. In the remaining patient, clinical symptoms met the clinical criteria, but selective activation of Vbeta2(+) T cells was not observed. Time taken to reach the diagnosis of TSS could be significantly shortened by utilizing the findings from tracing Vbeta2(+) T cells. In vitro studies showed that TSST-1- reactive T cells from TSS patients were anergic in the early phase of their illness. Examining selective activation of Vbeta2(+) T cells could be a useful tool to supplement clinical criteria for early diagnosis of TSS.


Subject(s)
Shock, Septic/diagnosis , Staphylococcal Infections/diagnosis , T-Lymphocyte Subsets/metabolism , Adult , Bacterial Toxins/immunology , Enterotoxins/immunology , Female , Flow Cytometry , Humans , Lymphocyte Activation/immunology , Male , Methicillin-Resistant Staphylococcus aureus/immunology , Middle Aged , Shock, Septic/immunology , Shock, Septic/microbiology , Staphylococcal Infections/immunology , Staphylococcal Infections/microbiology , Superantigens/immunology , T-Lymphocyte Subsets/immunology
13.
Infect Immun ; 76(11): 4999-5005, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18710864

ABSTRACT

In addition to two known staphylococcal enterotoxin-like genes (selj and selr), two novel genes coding for two superantigens, staphylococcal enterotoxins S and T (SES and SET), were identified in plasmid pF5, which is harbored by food poisoning-related Staphylococcus aureus strain Fukuoka 5. This strain was implicated in a food poisoning incident in Fukuoka City, Japan, in 1997. Recombinant SES (rSES) specifically stimulated human T cells in a T-cell receptor Vbeta9- and Vbeta16-specific manner in the presence of major histocompatibility complex (MHC) class II(+) antigen-presenting cells (APC). rSET also stimulated T cells in the presence of MHC class II(+) APC, although its Vbeta skewing was not found in reactive T cells. Subsequently, we examined the emetic activity of SES and SET. We also studied SElR to determine emetic activity in primates. This toxin was identified in previous studies but was not examined in terms of possession of emetic activity for primates. rSES induced emetic reactions in two of four monkeys at a dose of 100 microg/kg within 5 h of intragastric administration. In one monkey, rSET induced a delayed reaction (24 h postadministration) at a dose of 100 microg/kg, and in the other one, the reaction occurred 5 days postadministration. rSElR induced a reaction in two of six animals within 5 h at 100 microg/kg. On this basis, we speculate that the causative toxins of vomiting in the Fukuoka case are SES and SER. Additionally, SES, SER, and SET also induced emesis in house musk shrews as in the monkeys.


Subject(s)
Enterotoxins/genetics , Staphylococcal Food Poisoning/immunology , Staphylococcus aureus/genetics , Staphylococcus aureus/immunology , Superantigens/genetics , Animals , Base Sequence , Histocompatibility Antigens Class II , Humans , Lymphocyte Activation/immunology , Macaca fascicularis , Molecular Sequence Data , Phylogeny , Reverse Transcriptase Polymerase Chain Reaction , Shrews , Staphylococcal Food Poisoning/microbiology , T-Lymphocytes/immunology , T-Lymphocytes/microbiology
14.
Clin Immunol ; 127(2): 245-51, 2008 May.
Article in English | MEDLINE | ID: mdl-18337173

ABSTRACT

Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). It was reported that anti-histone autoantibody was detected in PBC, suggesting that bacterial histone-like DNA-binding protein (HLP) may be involved in the pathogenesis of PBC. To identify bacterial species in PBC to confirm this possibility, serum reactivity to bacterial cells was studied by ELISA. The IgM class Streptococcus intermedius titers were significantly higher in PBC than chronic hepatitis due to hepatitis C virus (CH-C) and healthy subjects. Among the streptococci, S. intermedius was selected for further study. The antigenic peptide of S. intermedius of HLP was synthesized to examine the serum reactivity to Si-HLP. IgM class anti-Si-HLP peptide titers were significantly higher in PBC. Immunoreactivity to anti-Si-HLP was detected in the cytoplasm of biliary epithelial cells and inflammatory cells in the portal area in PBC patients' livers. Streptococci, especially S. intermedius, might play a key role in the pathogenesis of PBC, possibly involving HLP.


Subject(s)
DNA-Binding Proteins/immunology , Liver Cirrhosis, Biliary/immunology , Liver Cirrhosis, Biliary/microbiology , Streptococcal Infections/immunology , Streptococcus intermedius/immunology , Adult , Aged , Antibodies, Bacterial/blood , Biopsy , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Liver Cirrhosis, Biliary/blood , Liver Cirrhosis, Biliary/pathology , Male , Middle Aged , Streptococcal Infections/blood , Streptococcal Infections/microbiology , Streptococcal Infections/pathology
15.
J Mol Biol ; 373(5): 1089-97, 2007 Nov 09.
Article in English | MEDLINE | ID: mdl-17900619

ABSTRACT

Bacterial superantigens are protein toxins with an ability to cause serious diseases in humans by activating a large number of T cells. Streptococcus dysgalactiae-derived mitogen (SDM) is a novel superantigen that is distinct from other known superantigens based on phylogenetic analysis. The X-ray structure of SDM has been determined at 1.95 A resolution. SDM shares the same characteristic fold with other superantigens, but it shows a major structural difference due to the lack of the alpha5 helix between the beta10 and beta11 strands. A bound zinc ion was identified in the structure at the C-terminal domain of the molecule. SDM appears to bind to the major histocompatibility complex class II beta-chain through the zinc-binding site, as described by mutagenesis data and structural comparisons. T-cell binding instead shows a significant difference compared to other superantigens. The mutation of Asn11 (a conserved residue that is known to be significant for T-cell-receptor binding in other superantigens) and Lys15 to Ala did not cause any decrease in the mitogenic activity of SDM. This observation and the lack of the alpha5 helix suggest alterations in T-cell-receptor binding.


Subject(s)
Mitogens/chemistry , Receptors, Antigen, T-Cell/metabolism , Streptococcus/chemistry , Zinc/metabolism , Binding Sites , Crystallography, X-Ray , Mutation , Protein Binding , Protein Conformation , Protein Structure, Secondary , Superantigens/chemistry
16.
Infect Immun ; 75(4): 1721-9, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17283088

ABSTRACT

We identified seven novel variants of streptococcal pyrogenic exotoxin G (SPEGG), a superantigen, in Streptococcus dysgalactiae subsp. dysgalactiae or equisimilis isolates from clinical cases of infection in humans and animals. Phylogenetic analysis of the SPEGG variants indicated two clades in the dendrogram: one composed of variants derived from the bacteria isolated from the humans and the other composed of variants from the bacteria isolated from the animals. Bovine peripheral blood mononuclear cells (PBMCs) were stimulated effectively by recombinant SPEGGs (rSPEGGs) expressed in Escherichia coli, while human PBMCs were not stimulated well by any of the rSPEGGs tested. SPEGGs selectively stimulated bovine T cells bearing Vbeta1,10 and Vbeta4. Bovine serum showed reactivity to the rSPEGG proteins. These results indicated that SPEGGs have properties as superantigens, and it is likely that SPEGGs play a pathogenic role in animals.


Subject(s)
Bacterial Proteins/genetics , Bacterial Proteins/immunology , Exotoxins/genetics , Exotoxins/immunology , Streptococcus/immunology , Superantigens/genetics , Superantigens/immunology , Amino Acid Sequence , Animals , Antibodies, Bacterial/blood , Bacterial Proteins/chemistry , Cattle , Cattle Diseases/microbiology , Cloning, Molecular , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , Escherichia coli/genetics , Exotoxins/chemistry , Gene Expression , Humans , Leukocytes, Mononuclear/immunology , Lymphocyte Activation , Lymphocyte Subsets/immunology , Molecular Sequence Data , Phylogeny , Sequence Analysis, DNA , Sequence Homology, Amino Acid , Streptococcal Infections/microbiology , Streptococcal Infections/veterinary , Streptococcus/genetics , Streptococcus/isolation & purification , Superantigens/chemistry , T-Lymphocytes/immunology
17.
Pediatr Infect Dis J ; 25(10): 950-2, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17006297

ABSTRACT

Most newborn patients with a neonatal type of toxic shock syndrome (TSS), called neonatal TSS-like exanthematous disease (NTED), exhibit mild clinical symptoms. We present the case of a patient with NTED who exhibited exceptionally severe clinical symptoms and an adult-type T cell response to the causative toxin TSS toxin-1.


Subject(s)
Bacterial Toxins/immunology , Enterotoxins/immunology , Shock, Septic/immunology , Staphylococcal Infections/immunology , Superantigens/immunology , T-Lymphocytes/immunology , Female , Flow Cytometry , Humans , Infant, Newborn , Shock, Septic/microbiology , Staphylococcal Infections/microbiology , Staphylococcus aureus/isolation & purification , T-Lymphocyte Subsets/immunology
18.
Autoimmunity ; 39(2): 129-35, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16698669

ABSTRACT

AIM: Intrahepatic bile ducts are the targets for inflammation in primary biliary cirrhosis (PBC), but their pathogenesis is not known. Gram-positive bacterial DNA was detected recently in gallbladder bile of PBC patients. In the present study, we assessed the possible pathological role of lipoteichoic acid (LTA), the gram-positive bacterial cell wall component, in PBC. METHODS: Liver samples, obtained from 20 patients with PBC (stage 1-2 with CNSDC: stage 3-4 with loss of bile ducts = 10:10) and from 13 patients with chronic hepatitis due to hepatitis C virus (CH-C) with lymphocytic cholangitis, were subjected to immunohistochemical staining with polyclonal rabbit anti-LTA as the primary antibody. Serum reactivities to LTA were studied by ELISA. After 1 microg of purified LTA was placed in a 96-well microplate as an antigen, an antibody capture assay was carried out using serum samples from PBC (n = 20), CH-C (n = 13) and healthy subjects (n = 11). RESULTS: LTA was localized around the sites of chronic non-suppurative destructive cholangitis (CNSDC) in the portal area in stage 1-2 PBC but was not detected in the portal area in CH-C. In stage 3-4 PBC, LTA was localized around sites of ductular proliferation at the periphery of portal tracts. IgM class anti-LTA serum titers were significantly higher in PBC than in CH-C. IgA class anti-LTA serum titers were significantly higher in PBC than in healthy subjects. CONCLUSIONS: In the PBC livers, the profile of immunoreactivity to LTA changed markedly as the disease progressed. Sera from PBC showed higher levels of anti-LTA titers than CH-C (IgM) or from healthy subjects (IgA). The LTA-mediated immune system might affect the initiation and/or progression of PBC.


Subject(s)
Lipopolysaccharides/immunology , Liver Cirrhosis, Biliary/etiology , Teichoic Acids/immunology , Adult , Aged , Antibodies, Bacterial/blood , Bile Ducts, Intrahepatic/drug effects , Bile Ducts, Intrahepatic/metabolism , Bile Ducts, Intrahepatic/microbiology , Bile Ducts, Intrahepatic/pathology , Female , Gram-Positive Bacteria/immunology , Gram-Positive Bacteria/pathogenicity , Hepatitis C, Chronic/etiology , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/microbiology , Hepatitis C, Chronic/pathology , Humans , Lipopolysaccharides/metabolism , Liver Cirrhosis, Biliary/immunology , Liver Cirrhosis, Biliary/microbiology , Liver Cirrhosis, Biliary/pathology , Middle Aged , Teichoic Acids/metabolism
19.
Article in English | MEDLINE | ID: mdl-16511312

ABSTRACT

Superantigens are bacterial or viral toxins with potent immunostimulatory properties. Streptococcus dysgalactiae-derived mitogen, a 25 kDa protein, is a recently discovered superantigen isolated from S. dysgalactiae culture supernatant. Sequence considerations suggest that it belongs to a new superantigen family distinct from other superantigens. The protein was expressed in Escherichia coli cells and purified to homogeneity. Crystals were grown at pH 4.2-4.4 in the presence of 18-20%(w/v) PEG 3350 and 0.4 M lithium nitrate. A complete data set to 2.4 A resolution was collected from a single crystal at liquid-nitrogen temperatures using synchrotron radiation. The crystals belong to space group P3/P3(1)/P3(2), with unit-cell parameters a = b = 52.7, c = 62.4 A, gamma = 120 degrees and one molecule in the crystallographic asymmetric unit.


Subject(s)
Mitogens/chemistry , Streptococcus/chemistry , Superantigens/chemistry , Crystallization/methods , Crystallography, X-Ray , Escherichia coli/metabolism , Mitogens/biosynthesis , Mitogens/isolation & purification , Superantigens/biosynthesis , Superantigens/isolation & purification
20.
Infect Immun ; 73(9): 5540-6, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16113270

ABSTRACT

We investigated the biological properties of a novel staphylococcal enterotoxin (SE)-like toxin type P (SElP). SElP induced a substantial proliferative response and the production of cytokines interleukin-2, gamma interferon, tumor necrosis factor alpha, and interleukin-4 from human T cells when administered at a concentration of 0.4 pM (0.01 ng/ml) or more. The expression of major histocompatibility complex class II molecules on accessory cells was required for T-cell stimulation by SElP. SElP selectively stimulated a vast number of human T cells bearing receptors Vbeta 5.1, 6, 8, 16, 18, and 21.3. These results indicated that SElP acts as a superantigen. SElP proved to be emetic in the house musk shrew emetic assay, although at a relatively high dose (50 to 150 mug/animal). A quantitative assay of SElP production with 30 Staphylococcus aureus strains harboring selp showed that 60% of these strains produced significant amounts of SElP in vitro. All 10 strains carrying seb and selp produced SEB but not SElP, suggesting the inactivation of the selp locus in S. aureus strains with a particular se gene constitution.


Subject(s)
Enterotoxins/chemistry , Staphylococcus aureus/pathogenicity , Superantigens/genetics , Animals , Enterotoxins/administration & dosage , Enterotoxins/genetics , Enterotoxins/immunology , Humans , Lymphocytes/immunology , Staphylococcus aureus/genetics , Staphylococcus aureus/immunology , Staphylococcus aureus/isolation & purification , Superantigens/administration & dosage , Superantigens/chemistry , Superantigens/immunology
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