scholarly journals Partial Protection against Helicobacter pylori in the Absence of Mast Cells in Mice

2009 ◽  
Vol 77 (12) ◽  
pp. 5543-5550 ◽  
Author(s):  
Hua Ding ◽  
John G. Nedrud ◽  
Barry Wershil ◽  
Raymond W. Redline ◽  
Thomas G. Blanchard ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Mast Cell ◽  
Mast Cells ◽  
Bacterial Load ◽  
Interleukin 17 ◽  
Wild Type ◽  
Spleen Cells ◽  
Tnf Α ◽  
H Pylori ◽  
Deficient Mice

ABSTRACT The goal of this study is to evaluate the contribution of mast cells to Helicobacter pylori immunity in a model of vaccine-induced protection. Mast cell-deficient KitlSl /KitlSl-d and control mice were immunized with H. pylori sonicate plus cholera toxin and challenged with H. pylori, and the bacterial loads, inflammatory infiltrates, and cytokine responses were evaluated and compared at 1, 2, and 4 weeks postchallenge. In vitro stimulation assays were performed using bone marrow-derived mast cells, and recall assays were performed with spleen cells of immunized mast cell-deficient and wild-type mice. Bacterial clearance was observed by 2 weeks postchallenge in mast cell-deficient mice. The bacterial load was reduced by 4.0 log CFU in wild-type mice and by 1.5 log CFU in mast cell-deficient mice. Neutrophil numbers in the gastric mucosa of immune KitlSl /KitlSl-d mice were lower than those for immune wild-type mice (P < 0.05). Levels of gastric interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-α) were also significantly lower in immune KitlSl /KitlSl-d mice than in wild-type mice (P < 0.001). Immunized mast cell-deficient and wild-type mouse spleen cells produced IFN-γ and IL-17 in response to H. pylori antigen stimulation. TNF-α and CXC chemokines were detected in mast cell supernatants after 24 h of stimulation with H. pylori antigen. The results indicate that mast cells are not essential for but do contribute to vaccine-induced immunity and that mast cells contribute to neutrophil recruitment and inflammation in response to H. pylori.

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.

scholarly journals Coinfection with Enterohepatic Helicobacter Species Can Ameliorate or Promote Helicobacter pylori-Induced Gastric Pathology in C57BL/6 Mice

2011 ◽  
Vol 79 (10) ◽  
pp. 3861-3871 ◽  
Author(s):  
Zhongming Ge ◽  
Yan Feng ◽  
Sureshkumar Muthupalani ◽  
Laura Lemke Eurell ◽  
Nancy S. Taylor ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Interleukin 17 ◽  
Mrna Levels ◽  
Cytokine Mrna ◽  
Content Type ◽  
Time Points ◽  
Gastric Pathology ◽  
Tnf Α ◽  
Ifn Γ ◽  
H Pylori

ABSTRACTTo investigate how different enterohepaticHelicobacterspecies (EHS) influenceHelicobacter pylorigastric pathology, C57BL/6 mice were infected withHelicobacter hepaticusorHelicobacter muridarum, followed byH. pyloriinfection 2 weeks later. Compared toH. pylori-infected mice, mice infected withH. muridarumandH. pylori(HmHp mice) developed significantly lower histopathologic activity index (HAI) scores (P< 0.0001) at 6 and 11 months postinoculation (MPI). However, mice infected withH. hepaticusandH. pylori(HhHp mice) developed more severe gastric pathology at 6 MPI (P= 0.01), with a HAI at 11 MPI (P= 0.8) similar to that ofH. pylori-infected mice.H. muridarum-mediated attenuation of gastritis in coinfected mice was associated with significant downregulation of proinflammatory Th1 (interlukin-1beta [Il-1β], gamma interferon [Ifn-γ], and tumor necrosis factor-alpha [Tnf-α]) cytokines at both time points and Th17 (Il-17A) cytokine mRNA levels at 6 MPI in murine stomachs compared to those ofH. pylori-infected mice (P< 0.01). Coinfection withH. hepaticusalso suppressedH. pylori-induced elevation of gastric Th1 cytokinesIfn-γandTnf-α(P< 0.0001) but increased Th17 cytokine mRNA levels (P= 0.028) at 6 MPI. Furthermore, mRNA levels ofIl-17Awere positively correlated with the severity of helicobacter-induced gastric pathology (HhHp>H. pylori>HmHp) (at 6 MPI,r2= 0.92,P< 0.0001; at 11 MPI,r2= 0.82,P< 0.002). Despite disparate effects on gastritis, colonization levels of gastricH. pyloriwere increased in HhHp mice (at 6 MPI) and HmHp mice (at both time points) compared to those in mono-H. pylori-infected mice. These data suggest that despite consistent downregulation of Th1 responses, EHS coinfection either attenuated or promoted the severity ofH. pylori-induced gastric pathology in C57BL/6 mice. This modulation was related to the variable effects of EHS on gastric interleukin 17 (IL-17) responses toH. pyloriinfection.

scholarly journals SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

2017 ◽  
Vol 42 (4) ◽  
pp. 1358-1365 ◽  
Author(s):  
Piyush Sharma ◽  
Vishal Khairnar ◽  
Ivana Vrhovac Madunić ◽  
Yogesh Singh ◽  
Aleksandra Pandyra ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Glucose Uptake ◽  
Bacterial Load ◽  
Bacterial Clearance ◽  
Wild Type ◽  
Hepatic Expression ◽  
Cell Functions ◽  
Tnf Α ◽  
Listeria Infection ◽  
Deficient Mice

Background: Cellular glucose uptake may involve either non-concentrative glucose carriers of the GLUT family or Na+-coupled glucose-carrier SGLT1, which accumulates glucose against glucose gradients and may thus accomplish cellular glucose uptake even at dramatically decreased extracellular glucose concentrations. SGLT1 is not only expressed in epithelia but as well in tumour cells and immune cells. Immune cell functions strongly depend on their metabolism, therefore we hypothesized that deficiency of SGLT1 modulates the defence against bacterial infection. To test this hypothesis, we infected wild type mice and gene targeted mice lacking functional SGLT1 with Listeria monocytogenes. Methods: SGLT1 deficient mice and wild type littermates were infected with 1x104 CFU Listeria monocytogenes intravenously. Bacterial titers were determined by colony forming assay, SGLT1, TNF-α, IL-6 and IL-12a transcript levels were determined by qRT-PCR, as well as SGLT1 protein abundance and localization by immunohistochemistry. Results: Genetic knockout of SGLT1 (Slc5a1–/– mice) significantly compromised bacterial clearance following Listeria monocytogenes infection with significantly enhanced bacterial load in liver, spleen, kidney and lung, and significantly augmented hepatic expression of TNF-α and IL-12a. While all wild type mice survived, all SGLT1 deficient mice died from the infection. Conclusions: SGLT1 is required for bacterial clearance and host survival following murine Listeria infection.

scholarly journals Contribution of Secretory Antibodies to Intestinal Mucosal Immunity against Helicobacter pylori

2013 ◽  
Vol 81 (10) ◽  
pp. 3880-3893 ◽  
Author(s):  
Rebecca J. Gorrell ◽  
Odilia L. C. Wijburg ◽  
John S. Pedersen ◽  
Anna K. Walduck ◽  
Terry Kwok ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Antibody Response ◽  
Bacterial Load ◽  
Secretory Iga ◽  
Mouse Strains ◽  
Wild Type ◽  
Content Type ◽  
Immunoglobulin Receptor ◽  
H Pylori ◽  
Secretory Antibodies

ABSTRACTThe natural immune response toHelicobacter pylorineither clears infection nor prevents reinfection. However, the ability of secretory antibodies to influence the course ofH. pyloriinfection has not been determined. We compared the natural progression ofH. pyloriinfection in wild-type C57BL/6 mice with that in mice lacking the polymeric immunoglobulin receptor (pIgR) that is essential for the secretion of polymeric antibody across mucosal surfaces.H. pyloriSS1-infected wild-type and pIgR knockout (KO) mice were sampled longitudinally for gastrointestinal bacterial load, antibody response, and histological changes. The gastric bacterial loads of wild-type and pIgR KO mice remained constant and comparable at up to 3 months postinfection (mpi) despite SS1-reactive secretory IgA in the intestinal contents of wild-type mice at that time. Conversely, abundant duodenal colonization of pIgR KO animals contrasted with the near-total eradication ofH. pylorifrom the intestine of wild-type animals by 3 mpi.H. pyloriwas cultured only from the duodenum of those animals in which colonization in the distal gastric antrum was of sufficient density for immunohistological detection. By 6 mpi, the gastric load ofH. pyloriin wild-type mice was significantly lower than in pIgR KO animals. While there was no corresponding difference between the two mouse strains in gastric pathology results at 6 mpi, reductions in gastric bacterial load correlated with increased gastric inflammation together with an intestinal secretory antibody response in wild-type mice. Together, these results suggest that naturally produced secretory antibodies can modulate the progress ofH. pyloriinfection, particularly in the duodenum.

scholarly journals Peptidoglycan Deacetylation in Helicobacter pylori Contributes to Bacterial Survival by Mitigating Host Immune Responses

2010 ◽  
Vol 78 (11) ◽  
pp. 4660-4666 ◽  
Author(s):  
Ge Wang ◽  
Susan E. Maier ◽  
Leja F. Lo ◽  
George Maier ◽  
Shruti Dosi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Helicobacter Pylori ◽  
Immune Responses ◽  
Bacterial Load ◽  
Host Cells ◽  
Infection Model ◽  
Wild Type ◽  
Mouse Infection Model ◽  
Mouse Infection ◽  
H Pylori

ABSTRACT An oxidative stress-induced enzyme, peptidoglycan deacetylase (PgdA), in the human gastric pathogen Helicobacter pylori was previously identified and characterized. In this study, we constructed H. pylori pgdA mutants in two mouse-adapted strains, X47 and B128, to investigate the role of PgdA in vivo (to determine the mutants’ abilities to colonize mice and to induce an immune response). H. pylori pgdA mutant cells showed increased sensitivity to lysozyme compared to the sensitivities of the parent strains. We demonstrated that the expression of PgdA was significantly induced (3.5-fold) when H. pylori cells were in contact with macrophages, similar to the effect observed with oxidative stress as the environmental inducer. Using a mouse infection model, we first examined the mouse colonization ability of an H. pylori pgdA mutant in X47, a strain deficient in the major pathway (cag pathogenicity island [PAI] encoded) for delivery of peptidoglycan into host cells. No animal colonization difference between the wild type and the mutant was observed 3 weeks after inoculation. However, the pgdA mutant showed a significantly attenuated ability to colonize mouse stomachs (9-fold-lower bacterial load) at 9 weeks postinoculation. With the cag PAI-positive strain B128, a significant colonization difference between the wild type and the pgdA mutant was observed at 3 weeks postinoculation (1.32 × 104 versus 1.85 × 103 CFU/gram of stomach). To monitor the immune responses elicited by H. pylori in the mouse infection model, we determined the concentrations of cytokines present in mouse sera. In the mice infected with the pgdA mutant strain, we observed a highly significant increase in the level of MIP-2. In addition, significant increases in interleukin-10 and tumor necrosis factor alpha in the pgdA mutant-infected mice compared to the levels in the wild-type H. pylori-infected mice were also observed. These results indicated that H. pylori peptidoglycan deacetylation is an important mechanism for mitigating host immune detection; this likely contributes to pathogen persistence.

scholarly journals Leukocyte common antigen (CD45) is required for immunoglobulin E-mediated degranulation of mast cells.

1994 ◽  
Vol 180 (2) ◽  
pp. 471-476 ◽  
Author(s):  
S A Berger ◽  
T W Mak ◽  
C J Paige
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Immunoglobulin E ◽  
Tyrosine Phosphatase ◽  
Cross Linking ◽  
Ionophore A23187 ◽  
Wild Type ◽  
Ige Receptor ◽  
High Affinity ◽  
Deficient Mice

We demonstrate using primary mast cell cultures derived from wild-type and CD45-deficient mice that mast cell triggering through the high-affinity immunoglobulin E (IgE) receptor requires the cell surface tyrosine phosphatase CD45. Unlike wild-type cells, cross-linking of surface-bound IgE in mast cells deficient in CD45 does not induce degranulation. Degranulation in these mutant cells does occur after treatment with the calcium ionophore A23187 indicating that the degranulation machinery is intact in these cells. We also demonstrate that the tyrosine phosphatase inhibitors orthoVanadate and perVanadate inhibit degranulation in wild-type mast cells, as does cross-linking of CD45 by anti-CD45 antibodies. Finally, we show that CD45-deficient mice are resistant to IgE-dependent systemic anaphylaxis. These results show that, like the T cell receptor and the antigen receptor on B cells, there is an absolute requirement for CD45 in signaling via the high affinity IgE receptor, expanding the number of receptors for which CD45 is an essential component.

scholarly journals Mast Cell Deficiency Protects Mice from Surgery-Induced Neuroinflammation

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Xiang Zhang ◽  
Hongquan Dong ◽  
Fei Wang ◽  
Jun Zhang
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Neuronal Apoptosis ◽  
Microglial Activation ◽  
Tibial Fracture ◽  
Wild Type ◽  
The Brain ◽  
Fracture Surgery ◽  
Deficient Mice

Neuroinflammation plays a key role in the occurrence and development of neurodegenerative diseases. Microglia, the resident immune cells in the brain, have been recognized to contribute to neuroinflammation. Previous studies have shown that activated mast cells may be involved in surgery-induced neuroinflammation and neuronal apoptosis by using pharmacological methods. This study is aimed at ascertaining the exactly role of mast cells on neuroinflammation with the mast cell-deficient mice. Adult male C57BL6/J wild-type (WT) and mast cell-deficient (C57BL6/J KitWsh/Wsh (Wsh)) mice underwent tibial fracture surgery. Blood-brain barrier (BBB) breakdown, microglial activation, and neuroinflammatory levels were examined at 1 day after surgery. Surgery-induced BBB breakdown, microglial activation, and neuroinflammatory levels were significantly, pharmacologically reduced using a mast cell stabilizer, cromolyn sodium in WT mice (P<0.05). These results were reproduced with mast cell deficiency. WT mice administered intraventricularly with cromolyn exhibited reduced BBB breakdown, microglial activation, and neuroinflammatory levels versus vehicle (P<0.05). But there was no effect of cromolyn versus vehicle in Wsh mice, clarifying the specificity of cromolyn on brain mast cells. These findings demonstrated that activated mast cells promote surgery-induced BBB breakdown and neuroinflammation in mice, and open up a new therapeutic target for neuroinflammation-related diseases.

scholarly journals Correlation between mast cell density and histological parameters in Helicobacter pylori-associated gastritis

2011 ◽  
Vol 5 (1) ◽  
pp. 163-167 ◽  
Author(s):  
Mana Taweevisit ◽  
Naruemon Klaikaew
Keyword(s):  
Helicobacter Pylori ◽  
Mast Cell ◽  
Mast Cells ◽  
Cell Density ◽  
B Cell Lymphoma ◽  
Inflammatory Cells ◽  
Chronic Inflammatory Cell ◽  
Mast Cell Density ◽  
Sydney System ◽  
H Pylori

Abstract Background: Helicobacter pylori (H. pylori) are a major cause of chronic gastritis and peptic ulcer. This organism plays a role in gastric carcinoma and B-cell lymphoma. However, the exact pathogenesis of gastric inflammation is still unclear. Mast cells, the important inflammatory cells for allergic process, may participate in the pathogenesis of gastritis related to H. pylori infection. Objective: Analyze the relationship between mast cell density, H. pylori intensity, histological alterations, and their severity of biopsy proven gastritis. Methods: One hundred eleven biopsied specimens were collected from Thai patients who were diagnosed H. pylori-associated gastritis of the antrum at King Chulalongkorn Memorial Hospital between 2002 and 2005. All biopsied specimens were examined according to the Updated Sydney System. Mast cell density was evaluated by 0.1% toluidine-stained sections. Results: The higher mast cell density was correlated with increased neutrophilic infiltration (r = 0.220, p = 0.020), chronic inflammatory cell infiltration (r = 0.381, p <0.001), and lymphoid aggregation (r = 0.271, p = 0.004). No relationship was found between mast cell density and intensity of H. pylori, glandular atrophy, or intestinal metaplasia. Conclusion: Mast cells might take part in the pathogenesis of H. pylori gastritis.

Both Host-Type and Donor-Type Mast Cells Protect Against Acute Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3248-3248
Author(s):  
Raita Araki ◽  
Hideaki Maeba ◽  
Rie Kuroda ◽  
Shintaro Mase ◽  
Toshihiro Fujiki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Mast Cell ◽  
Mast Cells ◽  
Acute Gvhd ◽  
Dependent Manner ◽  
Spleen Cells ◽  
Graft Versus Host ◽  
Donor Type ◽  
Deficient Mice

Abstract Originally mast cells have been known as effector cells in the IgE-mediated allergic responses. In addition, recent studies demonstrated that mast cells exerted pro-inflammatory or anti-inflammatory effects in complicated immune response depending on the situation. In allogeneic hematopoietic stem cell transplantation (HSCT), exact role of mast cells in graft-versus-host disease (GVHD) remains unclear. First we investigated whether host mast cells protect acute GVHD or not in a murine HSCT model using mast cell deficient mice. When lethally irradiated wild type (WT) B6 or mast cell deficient mice were transplanted with bone marrow cells and spleen cells from WT Balb/c mice, mast cell deficient B6 host mice showed significantly lower survival rate than WT B6 mice (p<0.01) due to acute GVHD. Moreover when irradiated mast cell deficient host mice (B6 derived) were given BM cells and splenocytes from mast cell deficient Balb/c mice, these mice died much faster compared to the mice receiving WT BM plus splenocytes (p<0.01) as shown below. Next, we demonstrated that bone marrow derived cultured mast cells (BMCMCs) inhibited mixed lymphocyte reaction (MLR) in a dose-dependent manner, when added to the coculture (Stimulator: dendritic cells (DCs) from B6, Responder: spleen cells of Balb/c, BMCMCs from B6). In addition when mast cells generated from the same strain of responder cells (Stimulator: DCs from B6, Responder: spleen cells from Balb/c, BMCMCs from Balb/c) were added to the MLR mixture, MLR was also suppressed even in this condition. Taken together, we have clearly demonstrated that both host-type and donor-type mast cells suppressed alloreaction in vivo and in vitro. However when we used anti-CD3 and anti-CD28 monoclonal antibodies to stimulate T-cells instead of DCs, BMCMCs could not suppress the lymphoproliferation any more. It suggested that mast cells could suppress MLR via the regulation of DCs directly, not T-cells. Next we have shown that BMCMCs dominantly regulated the alloreaction in a cell contact-dependent manner by using transwell system, though mast cells contain many kinds of substances to regulate immune reactions such as IL-10. DCs highly expressed costimulatory molecules such as CD80, CD86, CD40, I-A, however expression level of these molecules was not changed during coculture of BMCMCs and DCs. Finally, we compared the MLR suppression rate between naïve and activated BMCMCs using IgE and specific antigens, however no difference was observed between them. In conclusion, both host and donor-type mast cells have a protective role against acute GVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Vaccine-Induced Protection against Helicobacter pylori in Mice Lacking Both Antibodies and Interleukin-4

2003 ◽  
Vol 71 (6) ◽  
pp. 3628-3633 ◽  
Author(s):  
Christine A. Garhart ◽  
John G. Nedrud ◽  
Frederick P. Heinzel ◽  
Norma E. Sigmund ◽  
Steven J. Czinn
Keyword(s):  
Helicobacter Pylori ◽  
B Cell ◽  
Knockout Mice ◽  
Cellular Responses ◽  
Interleukin 4 ◽  
Wild Type ◽  
Double Knockout ◽  
Th2 Response ◽  
H Pylori ◽  
Deficient Mice

ABSTRACT To test the hypothesis that a Th2 response to Helicobacter pylori is necessary for protection and to address the possibility that humoral and Th2 cellular responses may compensate for each other, we generated mice deficient in both interleukin-4 (IL-4) and antibodies. The immunized double-knockout mice were protected from H. pylori challenge, as were the parental strains and wild-type C57BL/6 mice. Neutralization of IL-4 in B-cell-deficient mice did not prevent protection. Immunized IL-5-deficient mice were also protected. Thus, IL-4 and IL-5 are not essential for protection.

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