scholarly journals Antibody Is Critical for the Clearance of Murine Norovirus Infection

2008 ◽  
Vol 82 (13) ◽  
pp. 6610-6617 ◽  
Author(s):  
Karen A. Chachu ◽  
David W. Strong ◽  
Anna D. LoBue ◽  
Christiane E. Wobus ◽  
Ralph S. Baric ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Murine Norovirus ◽  
Wild Type ◽  
Human Norovirus ◽  
Mucosal Infection ◽  
Antibody Levels ◽  
Deficient Mice ◽  
Immune Antibody

ABSTRACT Human noroviruses cause more than 90% of epidemic nonbacterial gastroenteritis. However, the role of B cells and antibody in the immune response to noroviruses is unclear. Previous studies have demonstrated that human norovirus specific antibody levels increase upon infection, but they may not be protective against infection. In this report, we used murine norovirus (MNV), an enteric norovirus, as a model to determine the importance of norovirus specific B cells and immune antibody in clearance of norovirus infection. We show here that mice genetically deficient in B cells failed to clear primary MNV infection as effectively as wild-type mice. In addition, adoptively transferred immune splenocytes derived from B-cell-deficient mice or antibody production-deficient mice were unable to efficiently clear persistent MNV infection in RAG1−/− mice. Further, adoptive transfer of either polyclonal anti-MNV serum or neutralizing anti-MNV monoclonal antibodies was sufficient to reduce the level of MNV infection both systemically and in the intestine. Together, these data demonstrate that antibody plays an important role in the clearance of MNV and that immunoglobulin G anti-norovirus antibody can play an important role in clearing mucosal infection.

scholarly journals Cytosolic Phospholipase A2α–deficient Mice Are Resistant to Collagen-induced Arthritis

2003 ◽  
Vol 197 (10) ◽  
pp. 1297-1302 ◽  
Author(s):  
Martin Hegen ◽  
Linhong Sun ◽  
Naonori Uozumi ◽  
Kazuhiko Kume ◽  
Mary E. Goad ◽  
...  
Keyword(s):  
Critical Role ◽  
Wild Type ◽  
Collagen Induced Arthritis ◽  
Cytosolic Phospholipase ◽  
Severity Scores ◽  
In The Wild ◽  
Cytosolic Phospholipase A2α ◽  
Antibody Levels ◽  
Deficient Mice

Pathogenic mechanisms relevant to rheumatoid arthritis occur in the mouse model of collagen-induced arthritis (CIA). Cytosolic phospholipase A2α (cPLA2α) releases arachidonic acid from cell membranes to initiate the production of prostaglandins and leukotrienes. These inflammatory mediators have been implicated in the development of CIA. To test the hypothesis that cPLA2α plays a key role in the development of CIA, we backcrossed cPLA2α-deficient mice on the DBA/1LacJ background that is susceptible to CIA. The disease severity scores and the incidence of disease were markedly reduced in cPLA2α-deficient mice compared with wild-type littermates. At completion of the study, >90% of the wild-type mice had developed disease whereas none of the cPLA2α-deficient mice had more than one digit inflamed. Furthermore, visual disease scores correlated with severity of disease determined histologically. Pannus formation, articular fibrillation, and ankylosis were all dramatically reduced in the cPLA2α-deficient mice. Although the disease scores differed significantly between cPLA2α mutant and wild-type mice, anti-collagen antibody levels were similar in the wild-type mice and mutant littermates. These data demonstrate the critical role of cPLA2α in the pathogenesis of CIA.

scholarly journals Neutralization or Absence of the Interleukin-23 Pathway Does Not Compromise Immunity to Mycobacterial Infection

2006 ◽  
Vol 74 (11) ◽  
pp. 6092-6099 ◽  
Author(s):  
Alissa A. Chackerian ◽  
Shi-Juan Chen ◽  
Scott J. Brodie ◽  
Jeanine D. Mattson ◽  
Terrill K. McClanahan ◽  
...  
Keyword(s):  
Immune Response ◽  
Secondary Infection ◽  
Mycobacterial Infection ◽  
Effective Control ◽  
Bacterial Burden ◽  
Wild Type ◽  
Interleukin 23 ◽  
Deficient Mice ◽  
Stimulation Of

ABSTRACT Interleukin-23 (IL-23), a member of the IL-12 family, is a heterodimeric cytokine that is composed of the p40 subunit of IL-12 plus a unique p19 subunit. IL-23 is critical for autoimmune inflammation, in part due to its stimulation of the proinflammatory cytokine IL-17A. It is less clear, however, if IL-23 is required during the immune response to pathogens. We examined the role of IL-23 during Mycobacterium bovis BCG infection. We found that IL-23 reduces the bacterial burden and promotes granuloma formation when IL-12 is absent. However, IL-23 does not contribute substantially to host resistance when IL-12 is present, as the ability to control bacterial growth and form granulomata is not affected in IL-23p19-deficient mice and mice treated with a specific anti-IL-23p19 antibody. IL-23p19-deficient mice are also able to mount an effective memory response to secondary infection with BCG. While IL-23p19-deficient mice do not produce IL-17A, this cytokine is not necessary for effective control of infection, and antibody blocking of IL-17A in both wild-type and IL-12-deficient mice also has little effect on the bacterial burden. These data suggest that IL-23 by itself does not play an essential role in the protective immune response to BCG infection; however, the presence of IL-23 can partially compensate for the absence of IL-12. Furthermore, neutralization of IL-23 or IL-17A does not increase susceptibility to mycobacterial BCG infection.

scholarly journals Are B Lymphocytes of Importance in Severe Staphylococcus aureus Infections?

2000 ◽  
Vol 68 (5) ◽  
pp. 2431-2434 ◽  
Author(s):  
Inger Gjertsson ◽  
Olof Hörnquist Hultgren ◽  
Martin Stenson ◽  
Rikard Holmdahl ◽  
Andrzej Tarkowski
Keyword(s):  
Staphylococcus Aureus ◽  
B Cells ◽  
B Cell ◽  
Interleukin 4 ◽  
Wild Type ◽  
Toxic Shock ◽  
Toxic Shock Syndrome Toxin ◽  
Deficient Mice ◽  
Wild Type Control

ABSTRACT To investigate the role of B cells in experimental, superantigen-mediated Staphylococcus aureus arthritis and sepsis, we used gene-targeted B-cell-deficient mice. The mice were inoculated intravenously with a toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus strain. The B-cell-deficient and thus agamma-globulinemic mice showed striking similarities to the wild-type control animals with respect to the development of arthritis, the mortality rate, and the rate of bacterial clearance. Surprisingly, we found that the levels of gamma interferon in serum were significantly lower (P < 0.0001) in B-cell-deficient mice than in the controls, possibly due to impaired superantigen presentation and a diminished expression of costimulatory molecules. In contrast, the levels of interleukin-4 (IL-4), IL-6, and IL-10 in serum were equal in both groups. Our findings demonstrate that neither mature B cells nor their products significantly contribute to the course ofS. aureus-induced septic arthritis.

scholarly journals Critical Role of T Cells in PF4/Heparin Antibody Production

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1554-1554
Author(s):  
Yongwei Zheng ◽  
Mei Yu ◽  
Anand Padmanabhan ◽  
Richard H. Aster ◽  
Renren Wen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Antibody Production ◽  
Cd4 T Cells ◽  
Wild Type ◽  
Specific Antibodies ◽  
Deficient Mice

Abstract Heparin-induced thrombocytopenia (HIT) is an antibody-mediated disorder that can cause arterial or venous thrombosis/thromboembolism, and platelet factor 4 (PF4)/ heparin-reactive antibodies are essential to the pathogenesis of HIT. Our recent studies have demonstrated that marginal zone (MZ) B cells play a major role in production of PF4/heparin-specific antibodies. However, the role of T cells in production of these pathogenic antibodies is not clear. Here we showed that PF4/heparin complex-induced production of PF4/heparin-specific antibodies was markedly impaired in mice, in which CD4 T cells were depleted by administration of GK1.5 anti-CD4 monoclonal antibody. As expected, the CD4 T cell-depleted mice responded normally to T cell-independent antigen TNP-Ficoll but not T cell-dependent antigen NP-CGG, in agreement with the lack of CD4 T cells in these GK1.5-treated mice. Further, following adoptive transfer of a mixture of wild-type splenic B cells and splenocytes from B cell-deficient μMT mice, T and B cell-deficient Rag1 knockout mice responded to PF4/heparin complex challenge to produce PF4/heparin-specific antibodies. In contrast, Rag1-deficient mice that received a mixture of wild-type splenic B cells and splenocytes from Rag1-deficient mice barely produced PF4/heparin-specific antibodies upon PF4/heparin complex challenge. These data suggest that T cells are required for production of PF4/heparin-specific antibodies. Consistent with this concept, mice with B cells lacking CD40 molecule, a B cell costimulatory molecule that helps T cell-dependent B cell responses, displayed a marked reduction of PF4/heparin-specific antibody production following PF4/heparin complex challenge. Also as expected, mice with CD40-deficient B cells were able to respond to T cell-independent antigen TNP-Ficoll but not T cell-dependent antigen NP-CGG, consistent with the lack of T-cell help in these mice. Taken together, these findings demonstrate that T cells play an essential role in production of PF4/heparin-specific antibodies by MZ B cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immunoglobulin Class Switch Recombination Is Impaired in Atm-deficient Mice

2004 ◽  
Vol 200 (9) ◽  
pp. 1111-1121 ◽  
Author(s):  
Joanne M. Lumsden ◽  
Thomas McCarty ◽  
Lisa K. Petiniot ◽  
Rhuna Shen ◽  
Carrolee Barlow ◽  
...  
Keyword(s):  
B Cells ◽  
Dna Recombination ◽  
Class Switch Recombination ◽  
Intrinsic Defect ◽  
Wild Type ◽  
Immunoglobulin Class ◽  
Class Switch ◽  
Deficient Mice

Immunoglobulin class switch recombination (Ig CSR) involves DNA double strand breaks (DSBs) at recombining switch regions and repair of these breaks by nonhomologous end-joining. Because the protein kinase ataxia telengiectasia (AT) mutated (ATM) plays a critical role in DSB repair and AT patients show abnormalities of Ig isotype expression, we assessed the role of ATM in CSR by examining ATM-deficient mice. In response to T cell–dependent antigen (Ag), Atm−/− mice secreted substantially less Ag-specific IgA, IgG1, IgG2b, and IgG3, and less total IgE than Atm+/+ controls. To determine whether Atm−/− B cells have an intrinsic defect in their ability to undergo CSR, we analyzed in vitro responses of purified B cells. Atm−/− cells secreted substantially less IgA, IgG1, IgG2a, IgG3, and IgE than wild-type (WT) controls in response to stimulation with lipopolysaccharide, CD40 ligand, or anti-IgD plus appropriate cytokines. Molecular analysis of in vitro responses indicated that WT and Atm−/− B cells produced equivalent amounts of germline IgG1 and IgE transcripts, whereas Atm−/− B cells produced markedly reduced productive IgG1 and IgE transcripts. The reduction in isotype switching by Atm−/− B cells occurs at the level of genomic DNA recombination as measured by digestion–circularization PCR. Analysis of sequences at CSR sites indicated that there is greater microhomology at the μ–γ1 switch junctions in ATM B cells than in wild-type B cells, suggesting that ATM function affects the need or preference for sequence homology in the CSR process. These findings suggest a role of ATM in DNA DSB recognition and/or repair during CSR.

scholarly journals Collagen-induced Arthritis Is Reduced in 5-Lipoxygenase-activating Protein-deficient Mice

1997 ◽  
Vol 185 (6) ◽  
pp. 1123-1130 ◽  
Author(s):  
Richard J. Griffiths ◽  
MaryAlice Smith ◽  
Marsha L. Roach ◽  
Jeffrey L. Stock ◽  
Ethan J. Stam ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Es Cells ◽  
Embryonic Stem ◽  
Human Rheumatoid Arthritis ◽  
Wild Type ◽  
Collagen Induced Arthritis ◽  
Chronic Inflammatory Response ◽  
Antibody Levels ◽  
Deficient Mice

Collagen-induced arthritis in the DBA/1 mouse is an experimental model of human rheumatoid arthritis. To examine the role of leukotrienes in the pathogenesis of this disease, we have developed embryonic stem (ES) cells from this mouse strain. Here, we report that DBA/1 mice made deficient in 5-lipoxygenase-activating protein (FLAP) by gene targeting in ES cells develop and grow normally. Zymosan-stimulated leukotriene production in the peritoneal cavity of these mice is undetectable, whereas they produce substantial amounts of prostaglandins. The inflammatory response to zymosan is reduced in FLAP-deficient mice. The severity of collagen-induced arthritis in the FLAP-deficient mice was substantially reduced when compared with wild-type or heterozygous animals. This was not due to an immunosuppressive effect, because anti-collagen antibody levels were similar in wild-type and FLAP-deficient mice. These data demonstrate that leukotrienes play an essential role in both the acute and chronic inflammatory response in mice.

scholarly journals Cyclophosphamide immunosuppressed Xid mice model clarify the protective role of B cells in experimental encephalitozoonosis

2018 ◽  
Author(s):  
Carla Renata Serantoni Moysés ◽  
Lidiana Flora Vidôto da Costa ◽  
Elizabeth Cristina Perez ◽  
José Guilherme Xavier ◽  
Diva Denelle Spadacci-Morena ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
B Cells ◽  
T Lymphocytes ◽  
Proinflammatory Cytokines ◽  
The Other ◽  
Natural Resistance ◽  
Encephalitozoon Cuniculi ◽  
Deficient Mice

AbstractEncephalitozoon cuniculiis an intracellular pathogen that stablishes a balanced relationship with immunocompetent individuals, which is dependent of T lymphocytes activity. We previously showed X-linked immunodeficiency (XID – B cell deficient) mice are more susceptible to encephalitozoonosis and B-1 cells presence influences in the immune response. Because XID mice are deficient both in B-1 and B-2 cells, here we investigate the role of these cells againstE. cuniculiinfection using cyclophosphamide (Cy) immunosuppressed murine model to exacerbate the infection. XID mice presented lethargy and severe symptoms, associated with encephalitozoonosis and there was an increase in the peritoneal populations of CD8+and CD4+T lymphocytes and macrophages and also in the proinflammatory cytokines IFN-γ, TNF-α and IL-6. In BALB/c mice, no clinical signs were observed and there was an increase of T lymphocytes and macrophages in the spleen, showing an effective immune response. B-2 cells transfer to XID mice resulted in reduction of symptoms and lesion area with increase of B-2 and CD4+T populations in the spleen. B-1 cells transfer increased the peritoneal populations of B-2 cells and macrophages and also reduced the symptoms. Therefore, the immunodeficiency of B cells associated to Cy immunosuppression condition leads to disseminated and severe encephalitozoonosis in XID mice with absence of splenic immune response and ineffective local immune response, evidencing the B-1 and B-2 cells role against microsporidiosis.Author summaryThe adaptive immune response plays a key role againstEncephalitozoon cuniculi, an opportunistic fungus for T cells immunodeficient patients. The role of B cells and antibody play in natural resistance toEncephalitozoon cuniculiremains unresolved. Previously, we demonstrated that B-1 deficient mice (XID), an important component of innate immunity, were more susceptible to encephalitozoonosis, despite the increase in the number of CD4+and CD8+T lymphocytes. In order to better understand the role of B-1 and B-2 cells and the relationship with the other cells of the immune response in encephalitozoonosis, we infected withE. cuniculiin cyclophosphamide immunosuppressed mice. Here we demonstrate that infected XID mice showed reduction of T cells and macrophages and increase of proinflammatory cytokines associated with disseminated and severe encephalitozoonosis with presence of abdominal effusion and lesions in multiple organs. This pattern of infection observed in mice with genetic deficiency in T cells, so we suggest that the absence of B-1 cells affects the cytotoxic capacity of these lymphocytes. When we transfer B-2 cells to XID mice, the lesion areas caused by the fungus, the populations of T lymphocytes in the peritoneum and the proinflammatory cytokines decrease, indicating a better resolution of the infection. We speculate that B-1 and B-2 cells participate in the immune response againstE. cuniculi, interacting with the other components effective in immunity. The results shown here indicate that B-1 cells as a constituent of the innate response to microsporidia.

scholarly journals Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Adria Carbo ◽  
Danyvid Olivares-Villagómez ◽  
Raquel Hontecillas ◽  
Josep Bassaganya-Riera ◽  
Rupesh Chaturvedi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Wild Type ◽  
Content Type ◽  
Interleukin 21 ◽  
H Pylori ◽  
Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

Selected Contribution: Differential role of nitric oxide synthase isoforms in fever of different etiologies: studies using Nosgene-deficient mice

2003 ◽  
Vol 94 (6) ◽  
pp. 2534-2544 ◽  
Author(s):  
Wieslaw Kozak ◽  
Anna Kozak
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Corn Oil ◽  
Normal Male ◽  
Wild Type ◽  
Oxide Synthase ◽  
And Control ◽  
Nos Isoforms ◽  
Deficient Mice

Male C57BL/6J mice deficient in nitric oxide synthase (NOS) genes (knockout) and control (wild-type) mice were implanted intra-abdominally with battery-operated miniature biotelemeters (model VMFH MiniMitter, Sunriver, OR) to monitor changes in body temperature. Intravenous injection of lipopolysaccharide (LPS; 50 μg/kg) was used to trigger fever in response to systemic inflammation in mice. To induce a febrile response to localized inflammation, the mice were injected subcutaneously with pure turpentine oil (30 μl/animal) into the left hindlimb. Oral administration (gavage) of N G-monomethyl-l-arginine (l-NMMA) for 3 days (80 mg · kg−1 · day−1in corn oil) before injection of pyrogens was used to inhibit all three NOSs ( N G-monomethyl-d-arginine acetate salt and corn oil were used as control). In normal male C57BL/6J mice, l-NMMA inhibited the LPS-induced fever by ∼60%, whereas it augmented fever by ∼65% in mice injected with turpentine. Challenging the respective NOS knockout mice with LPS and with l-NMMA revealed that inducible NOS and neuronal NOS isoforms are responsible for the induction of fever to LPS, whereas endothelial NOS (eNOS) is not involved. In contrast, none of the NOS isoforms appeared to trigger fever to turpentine. Inhibition of eNOS, however, exacerbates fever in mice treated with l-NMMA and turpentine, indicating that eNOS participates in the antipyretic mechanism. These data support the hypothesis that nitric oxide is a regulator of fever. Its action differs, however, depending on the pyrogen used and the NOS isoform.

scholarly journals Leukocyte-type 12-lipoxygenase-deficient mice show impaired ischemic preconditioning-induced cardioprotection

2001 ◽  
Vol 280 (5) ◽  
pp. H1963-H1969 ◽  
Author(s):  
Scott A. Gabel ◽  
Robert E. London ◽  
Colin D. Funk ◽  
Charles Steenbergen ◽  
Elizabeth Murphy
Keyword(s):  
Left Ventricular ◽  
Rate Pressure Product ◽  
Wild Type ◽  
Initial Value ◽  
Triphenyltetrazolium Chloride ◽  
Developed Pressure ◽  
12 Lipoxygenase ◽  
Postischemic Recovery ◽  
Deficient Mice

To investigate the role of 12-lipoxygenase in preconditioning, we examined whether hearts lacking the “leukocyte-type” 12-lipoxygenase (12-LOKO) would be protected by preconditioning. In hearts from wild-type (WT) and 12-LOKO mice, left ventricular developed pressure (LVDP) and 31P NMR were monitored during treatment (±preconditioning) and during global ischemia and reperfusion. Postischemic function (rate-pressure product, percentage of initial value) measured after 20 min of ischemia and 40 min of reperfusion was significantly improved by preconditioning in WT hearts (78 ± 12% in preconditioned vs. 44 ± 7% in nonpreconditioned hearts) but not in 12-LOKO hearts (47 ± 7% in preconditioned vs. 33 ± 10% in nonpreconditioned hearts). Postischemic recovery of phosphocreatine was significantly better in WT preconditioned hearts than in 12-LOKO preconditioned hearts. Preconditioning significantly reduced the fall in intracellular pH during sustained ischemia in both WT and 12-LOKO hearts, suggesting that attenuation of the fall in pH during ischemia can be dissociated from preconditioning-induced protection. Necrosis was assessed after 25 min of ischemia and 2 h of reperfusion using 2,3,5-triphenyltetrazolium chloride. In WT hearts, preconditioning significantly reduced the area of necrosis (26 ± 4%) compared with nonpreconditioned hearts (62 ± 10%) but not in 12-LOKO hearts (85 ± 3% in preconditioned vs. 63 ± 11% in nonpreconditioned hearts). Preconditioning resulted in a significant increase in 12( S)-hydroxyeicosatetraenoic acid in WT but not in 12-LOKO hearts. These data demonstrate that 12-lipoxygenase is important in preconditioning.

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