scholarly journals Role of Antibodies in Immunity to Bordetella Infections

2003 ◽  
Vol 71 (4) ◽  
pp. 1719-1724 ◽  
Author(s):  
Girish S. Kirimanjeswara ◽  
Paul B. Mann ◽  
Eric T. Harvill
Keyword(s):  
Mouse Model ◽  
Protective Immunity ◽  
Comparative Approach ◽  
Human Pathogens ◽  
Clinical Observations ◽  
Limited Efficacy ◽  
Antibody Titers ◽  
Rapid Clearance ◽  
Deficient Mice

ABSTRACT The persistence of Bordetella pertussis and B. parapertussis within vaccinated populations and the reemergence of associated disease highlight the need to better understand protective immunity. The present study examined host immunity to bordetellae and addressed potential concerns about the mouse model by using a comparative approach including the closely related mouse pathogen B. bronchiseptica. As previously observed with B. pertussis, all three organisms persisted throughout the respiratory tracts of B-cell-deficient mice, indicating that B cells are required for bacterial clearance. However, adoptively transferred antibodies rapidly cleared B. bronchiseptica but not human pathogens. These results obtained with the mouse model are consistent with human clinical observations, including the lack of correlation between antibody titers and protection, as well as the limited efficacy of intravenous immunoglobulin treatments against human disease. Together, this evidence suggests that the mouse model accurately reflects substantial differences between immunities to these organisms. Although both B. pertussis and B. parapertussis are more closely related to B. bronchiseptica than they are to each other, they share the ability to resist rapid clearance from the lower respiratory tract by adoptively transferred antibodies, an adaptation that correlates with their emergence as human pathogens that circulate within vaccinated populations.

scholarly journals An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3

2019 ◽  
Author(s):  
Jillian M. Richmond ◽  
Dhrumil Patel ◽  
Tomoya Watanabe ◽  
Colton J. Garelli ◽  
Madhuri Garg ◽  
...  
Keyword(s):  
Mouse Model ◽  
Localized Scleroderma ◽  
Lesional Skin ◽  
Chemokine Expression ◽  
Inflammatory Phase ◽  
Deficient Mice ◽  
Over Time ◽  
Cutaneous Fibrosis

AbstractMorphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. We first characterized which cells produce the CXCR3 ligands in the skin using the Reporter of Expression of CXCR3 ligands mouse (REX3). We found that fibroblasts contribute the bulk of CXCL9 and CXCL10, whereas endothelial cells are key dual chemokine producers. Macrophages, which have high MFI of chemokine expression, upregulated CXCL9 production over time, fibroblasts CXCL10 production, and T cells dual chemokine expression. To determine whether bleomycin treatment could directly induce expression of these chemokines, we treated cultured REX3 mouse dermis monolayers in vitro with bleomycin or IFNγ with TNF and found that bleomycin could induce low amounts of CXCL9 directly in fibroblasts, whereas the cytokines were required for optimal CXCL9 and CXCL10 production. To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9, but not CXCL10, to cultured mouse fibroblasts induces collagen 1a1 mRNA expression, indicating the chemokine itself can contribute to fibrosis. Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis.One Sentence SummaryCXCL9 drives acute morphea pathogenesis in mice.

Protective immunity to erythrocytic Plasmodium chabaudi AS infection involves IFNγ-mediated responses and a cellular infiltrate to the liver

Parasitology ◽  
2000 ◽  
Vol 121 (5) ◽  
pp. 473-482 ◽  
Author(s):  
P. BALMER ◽  
J. ALEXANDER ◽  
R. S. PHILLIPS
Keyword(s):  
Mortality Rate ◽  
Adoptive Transfer ◽  
Protective Immunity ◽  
No Reduction ◽  
Cytological Analysis ◽  
Plasmodium Chabaudi ◽  
Cellular Infiltrate ◽  
Specific Igg ◽  
Deficient Mice

IFNγ receptor (IFNγR) deficient mice and IL-4 deficient mice were infected with blood-stage Plasmodium chabaudi AS in order to analyse the role of Th1 (IFNγ) and Th2 (IL-4)-associated cytokines in the development of protective immunity to the parasite. A high mortality rate and failure to reduce the primary parasitaemia to subpatent levels was observed in the IFNγR deficient mice. IL-4 deficient mice controlled a primary P. chabaudi AS infection in a similar manner to control mice and no mortality was observed. IFNγR deficient mice had a reduction in parasite-specific IgG and a significantly increased level of total IgE compared to control mice. There was no reduction in the level of parasite-specific IgG in IL-4 deficient mice. Cytological analysis of the cells present in the spleen and liver during the primary parasitaemia revealed a reduction in the numbers of lymphocytes, monocytes and polymorphonuclear (PMN) cells in the liver at the peak of parasitaemia in both IFNγR deficient mice and IL-4 deficient mice compared to control mice. Adoptive transfer studies demonstrated that cells isolated from the liver at day 11 post-infection could confer some protective immunity to P. chabaudi AS infection.

Abstract O.24: Gut Microflora Influences Pathology in the Kawasaki Disease Vasculitis Mouse Model

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Daiko Wakita ◽  
Yosuke Kurashima ◽  
Yoshihiro Takasato ◽  
Youngho Lee ◽  
Kenichi Shimada ◽  
...  
Keyword(s):  
Cell Wall ◽  
Kawasaki Disease ◽  
Mouse Model ◽  
Immune Responses ◽  
Critical Role ◽  
Gut Microflora ◽  
Vascular Abnormalities ◽  
Coronary Arteritis ◽  
Deficient Mice

Background: Kawasaki Disease (KD) is the leading cause of acquired heart disease in the US. We have demonstrated the critical role of innate immune responses via IL-1R/MyD88 signaling in the Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model. The diversity and composition of microflora (both bacterial and fungal) have been associated with the regulation and alterations of immune responses and various pathologies. However, the role of gut microbiota in immunopathology of KD has not been investigated. Objective: To evaluate the role of gut microflora in development of coronary arteritis, and vascular abnormalities in KD mouse model. Methods and Results: We investigated the role of gut microflora in the LCWE-induced KD mouse model, using Specific-Pathogen Free (SPF) and Germ Free (GF) mice (C57BL/6). GF mice showed a significant decrease of KD lesions, including coronary arteritis compared with SPF mice. The development of LCWE-induced AAA, which we recently discovered in this mouse model, was also markedly diminished in GF mice. In addition to GF mice, we also investigated the specific role of commensal fungi, and determined whether altered fungal burden in this KD mouse model contributes to disease severity. To deplete fungi in the gut microflora, we exposed pregnant SPF mice and their offspring to fluconazole (antifungal) in their drinking water for 5 wks and induced KD. The fluconazole treated mice had significantly reduced coronary arteritis, and AAA compared to controls. Since Dectin-1 has emerged as a key receptor that recognizes β-1,3-glucans found in the cell wall of nearly all fungi, we next induced KD in Dectin-1 deficient mice. Dectin-1 deficient mice also had significantly reduced KD lesions such as coronary arteritis compared with WT mice. Conclusions: We demonstrate here that gut microflora play a critical role in the development of KD vasculitis in LCWE-induced mouse model. Our results suggest that fungi in the intestinal microbiota may specifically control the induction and severity of KD vasculitis, which may be mediated by Dectin-1. These findings provide a new perspective on the potential role of the microbiome in KD pathogenesis and may offer new diagnostic and therapeutic strategies for KD patients.

Platelet Btk is Required for Maintaining Lung Vascular Integrity during Murine Pneumococcal Pneumosepsis

2019 ◽  
Vol 119 (06) ◽  
pp. 930-940 ◽  
Author(s):  
Alexander P. N. A. de Porto ◽  
Theodora A. M. Claushuis ◽  
Lieve E. H. van der Donk ◽  
Regina de Beer ◽  
Onno J. de Boer ◽  
...  
Keyword(s):  
Host Defence ◽  
Causative Pathogen ◽  
Human Pathogens ◽  
Vascular Integrity ◽  
Glycoprotein Vi ◽  
P2y12 Receptor Antagonist ◽  
The Common ◽  
Collagen Receptor ◽  
Deficient Mice

AbstractPlatelet Bruton's tyrosine kinase (Btk) is an essential signalling protein for the collagen receptor glycoprotein VI (GPVI) and podoplanin receptor C-type-lectin-like receptor-2, which are platelet receptors implicated in the maintenance of vascular integrity during inflammation. Moreover, platelets, platelet GPVI and Btk are important for host defence during murine bacterial pneumosepsis. The aim of this study was to determine the role of platelet Btk in vascular integrity and host defence during murine pneumosepsis caused by the common human pathogens Streptococcus pneumoniae and Klebsiella pneumoniae. Using the Cre-loxP system, male platelet-specific Btk-deficient mice (PF4creBtkfl/Y) were created. Similar to platelets from total Btk-deficient mice, platelets from PF4creBtkfl/Y mice showed abrogated aggregation and P-selectin expression when stimulated with the GPVI ligand cross-linked collagen-related peptide. Upon infection with S. pneumoniae, PF4creBtkfl/Y mice showed increased lung bleeding, but unimpaired anti-bacterial defence. During pneumosepsis evoked by K. pneumoniae, platelet Btk deficiency was not associated with lung bleeding and did not impact on host defence, even when platelet function was further compromised by blocking secondary platelet activation by the P2Y12 receptor antagonist clopidogrel. Together, these data indicate that, while platelet Btk is not important for anti-bacterial defence in pneumosepsis, its role in maintaining vascular integrity in the lung depends on the causative pathogen.

scholarly journals Role of Erythroferrone in the Pathophysiology of Common Anemias

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 213-213 ◽  
Author(s):  
Leon Kautz ◽  
Grace Jung ◽  
Elizabeta Nemeth ◽  
Tomas Ganz
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Iron Overload ◽  
Wild Type ◽  
Hepcidin Expression ◽  
Iron Restriction ◽  
Equity Ownership ◽  
Deficient Mice ◽  
Anemia Of Inflammation

Abstract Introduction: We recently described the erythroid hormone erythroferrone (ERFE) as a critical regulator of hepcidin production during increased erythropoietic activity. Both anemia of inflammation (AI) and beta-thalassemia are associated with elevated levels of erythropoietin, the signal directing ERFE expression, suggesting that ERFE may play a role in the pathogenesis of these disorders. Indeed, Erfe mRNA expression was highly increased in the bone marrow and the spleen of a mouse model of β-thalassemia Hbbth3/+ (Th3/+). We therefore investigated the role of erythroferrone in hepcidin regulation in anemia of inflammation and β-thalassemia. We report that ERFE contributes to the recovery from anemia of inflammation and may be a hepcidin-suppressive factor responsible for iron accumulation in thalassemia. Methods: We explored the role of ERFE in anemia of inflammation using the heat-killed Brucellaabortus (BA) mouse model of AI. Hepcidin regulation and recovery from anemia was compared between wild-type and Erfe-deficient mice. To determine whether ERFE is the hepcidin-suppressive factor in thalassemia, we generated Erfe-/-/Th3/+ double mutant mice and compared them to their littermate WT, Erfe-/- and Th3/+ mice. Mice were compared at 3, 6 and 12 weeks of age. Results: Compared to wild-type mice, Erfe-deficient mice did not appropriately decrease hepcidin production during recovery from AI and exhibited greater severity of anemia (figure). These data suggest that compensatory hepcidin suppression during the recovery phase of AI is mediated by ERFE. However, in mice this defect was partly compensated by prolonged stimulation of erythropoiesis and higher reticulocytosis resulting in Erfe-deficient mice reaching wild-type hemoglobin levels by day 28 (figure). Figure 1 Figure 1. At the other end of the spectrum, we showed that thalassemic mice exhibited greatly increased expression of Erfe mRNA in the bone marrow and the spleen. Ablation of Erfe in Th3/+ mice restored normal hepcidin levels and significantly reduced serum iron concentration and hepatic iron overload at 6 weeks of age. Comparison of Erfe-/- / Th3/+ and Th3/+ mice at 3, 6 and 12 weeks of age did not show any difference in the severity of the anemia in absence of ERFE suggesting that ERFE regulates hepcidin expression but its absence did not cause iron restriction and did not ameliorate ineffective erythropoiesis. Conclusion: ERFE is a critical regulator of hepcidin expression during recovery from AI and ERFE agonists may alleviate iron restriction in AI. ERFE may also be the factor responsible for hepcidin suppression and secondary iron overload in β-thalassemia. Disclosures Ganz: Intrinsic LifeSciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Keryx Pharma: Consultancy; Merganser Biotech: Consultancy, Equity Ownership.

scholarly journals Involvement of Dendritic Cells and Th17 Cells in Induced Tertiary Lymphoid Structures in a Chronic Beryllium Disease Mouse Model

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Alex KleinJan ◽  
Menno van Nimwegen ◽  
Karolina Leman ◽  
Ke-xin Wen ◽  
Louis Boon ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mouse Model ◽  
Inflammatory Disorder ◽  
Chronic Beryllium Disease ◽  
Th17 Lymphocytes ◽  
Beryllium Disease ◽  
Deficient Mice

Rationale. Sarcoidosis is a systemic inflammatory disorder characterized by the presence of granulomas in various organs, most commonly in the lungs. Although the ethology is unknown, sarcoidosis is thought to be mediated by T helper (Th)1 and Th17 lymphocytes. Chronic airway exposure to beryllium metal leads to chronic beryllium disease (CBD), which shares similarities with pulmonary sarcoidosis. Objective. To study airway pathophysiology and the role of dendritic cells (DCs) and IL-17 receptor (IL-17R) signals in a mouse model for CBD. Methods. Here, we present a CBD mouse model in which mice were exposed to beryllium during three weeks. We also exposed IL-17R-deficient mice and mice in which DCs were depleted. Results. Eight weeks after the initial beryllium exposure, an inflammatory response was detected in the lungs. Mice displayed inflammation of the lower airways that included focal dense infiltrates, granuloma-like foci, and tertiary lymphoid structure (TLS) containing T cells, B cells, and germinal centers. Alveolar cell analysis showed significantly increased numbers of CD4+ T cells expressing IFNγ, IL-17, or both cytokines. The pathogenic role of IL-17R signals was demonstrated in IL-17R-deficient mice, which had strongly reduced lung inflammation and TLS development following beryllium exposure. In CBD mice, pulmonary DC subsets including CD103+ conventional DCs (cDCs), CD11b+ cDCs, and monocyte-derived DCs (moDCs) were also prominently increased. We used diphtheria toxin receptor-mediated targeted cell ablation to conditionally deplete DCs and found that DCs are essential for the maintenance of TLS in CBD. Furthermore, the presence of antinuclear autoantibodies in the serum of CBD mice showed that CBD had characteristics of autoimmune disease. Conclusions. We generated a translational model of sarcoidosis driven by beryllium and show that DCs and IL-17R signals play a pathophysiological role in CBD development as well as in established CBD in vivo.

scholarly journals Anamnestic Protective Immunity to Bacillus anthracis Is Antibody Mediated but Independent of Complement and Fc Receptors

2008 ◽  
Vol 76 (5) ◽  
pp. 2177-2182 ◽  
Author(s):  
Eric T. Harvill ◽  
Manuel Osorio ◽  
Crystal L. Loving ◽  
Gloria M. Lee ◽  
Vanessa K. Kelly ◽  
...  
Keyword(s):  
T Cell ◽  
Bacillus Anthracis ◽  
Adoptive Transfer ◽  
Protective Immunity ◽  
Fc Receptors ◽  
Immunodeficient Mice ◽  
Antibody Titers ◽  
Immunocompetent Mice ◽  
Induced Immunity ◽  
Deficient Mice

ABSTRACT The threat of bioterrorist use of Bacillus anthracis has focused urgent attention on the efficacy and mechanisms of protective immunity induced by available vaccines. However, the mechanisms of infection-induced immunity have been less well studied and defined. We used a combination of complement depletion along with immunodeficient mice and adoptive transfer approaches to determine the mechanisms of infection-induced protective immunity to B. anthracis. B- or T-cell-deficient mice lacked the complete anamnestic protection observed in immunocompetent mice. In addition, T-cell-deficient mice generated poor antibody titers but were protected by the adoptive transfer of serum from B. anthracis-challenged mice. Adoptively transferred sera were protective in mice lacking complement, Fc receptors, or both, suggesting that they operate independent of these effectors. Together, these results indicate that antibody-mediated neutralization provides significant protection in B. anthracis infection-induced immunity.

scholarly journals Transcriptome signature of miRNA-26b KO mouse model suggests novel targets

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Emiel P. C. van der Vorst ◽  
Mario A. A. Pepe ◽  
Linsey J. F. Peters ◽  
Markus Haberbosch ◽  
Yvonne Jansen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Blood Parameters ◽  
Exact Role ◽  
Neurological Processes ◽  
The Stability ◽  
Deficient Mice

Abstract Background MicroRNAs (miRNAs) are short (20–24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. One of the miRNAs that has been shown to play a role in various pathologies like cancer, neurological disorders and cardiovascular diseases is miRNA-26b. However, these studies only demonstrated rather ambiguous associations without revealing a causal relationship. Therefore, the aim of this study is to establish and validate a mouse model which enables the elucidation of the exact role of miRNA-26b in various pathologies. Results A miRNA-26b-deficient mouse model was established using homologous recombination and validated using PCR. miRNA-26b-deficient mice did not show any physiological abnormalities and no effects on systemic lipid levels, blood parameters or tissue leukocytes. Using next generation sequencing, the gene expression patterns in miRNA-26b-deficient mice were analyzed and compared to wild type controls. This supported the already suggested role of miRNA-26b in cancer and neurological processes, but also revealed novel associations of miRNA-26b with thermogenesis and allergic reactions. In addition, detailed analysis identified several genes that seem to be highly regulated by miRNA-26b, which are linked to the same pathological conditions, further confirming the role of miRNA-26b in these pathologies and providing a strong validation of our mouse model. Conclusions miRNA-26b plays an important role in various pathologies, although causal relationships still have to be established. The described mouse model of miRNA-26b deficiency is a crucial first step towards the identification of the exact role of miRNA-26b in various diseases that could identify miRNA-26b as a promising novel diagnostic or even therapeutic target in a broad range of pathologies.

Abstract 426: Abdominal Aorta Dilatation and Aneurysm in Kawasaki Disease Vasculitis Mouse Model: Role of IL-1 Signaling

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Daiko Wakita ◽  
Yosuke Kurashima ◽  
Youngho Lee ◽  
Kenichi Shimada ◽  
Shuang Chen ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Mouse Model ◽  
Abdominal Aorta ◽  
Active Form ◽  
Aortic Dilatation ◽  
Caspase 1 ◽  
Abdominal Aortic ◽  
Aorta Dilatation ◽  
Deficient Mice

Background: Kawasaki disease (KD) is the most common cause of acquired cardiac disease among US children. KD causes coronary artery aneurysms in up to 25% of untreated patients, and less frequently aneurysms in other systemic arteries including the abdominal aorta. Objective: To evaluate the development of abdominal aorta dilatation and aneurysm in KD mouse model and investigate the role of IL-1 signaling. Methods and Results: We investigated the incidence and progression of abdominal aorta aneurysm (AAA) and dilatation in the Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model at 1, 2, 5 wks. Over 80% of the mice developed significant dilation of abdominal aorta at 1 wk with progressively greater dilatation at 5 wks, with greater severity in males. KD mice showed fusiform and saccular AAA, which were always below the renal artery. Immunohistochemistry showed significant intimal proliferation, massive myofibroblastic proliferation that breaks the elastin layer, infiltration of large numbers of neutrophils and macrophages into the media and adventitia. IL-1R- or IL-1beta-deficient mice were completely protected from the KD associated abdominal aorta dilatation and AAA. Active form Caspase-1 was detected at infiltrated macrophages and the Caspase-1-deficient mice showed significant reduction of AAA formation. Blockade of IL-1/IL-1R signaling with IL-1R antagonist (Anakinra), or neutralizing antibody against IL-1α or IL-1β significantly prevented the AAA in the KD mice. Conclusions: We report a new model of AAA and aortic dilatation in the LCWE-induced KD mouse model. These studies suggest that in children with KD the incidence of abdominal aortic dilatation and AAA maybe higher than currently appreciated, thus requiring prospective studies to determine the frequency of these vascular complications. Our findings also demonstrate that IL-1 plays an important role in development of LCWE-induced abdominal aortic lesions and blockade of IL-1 signaling may be a promising therapeutic target not only for KD vasculitis and coronary arteritis, but also for abdominal aorta dilatation and AAA associated with the disease.

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