scholarly journals Induction of Protective Immunity by a Single Low Dose of a Master Cell Bank cGMP-rBCG-P Vaccine Against the Human Metapneumovirus in Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Jorge A. Soto ◽  
Nicolás M. S. Gálvez ◽  
Gaspar A. Pacheco ◽  
Gisela Canedo-Marroquín ◽  
Susan M. Bueno ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Plasma Cells ◽  
The Elderly ◽  
Human Metapneumovirus ◽  
Cell Bank ◽  
Marginal Zone B Cells ◽  
Hmpv Infection

Human metapneumovirus (hMPV) is an emergent virus, which mainly infects the upper and lower respiratory tract epithelium. This pathogen is responsible for a significant portion of hospitalizations due to bronchitis and pneumonia in infants and the elderly worldwide. hMPV infection induces a pro-inflammatory immune response upon infection of the host, which is not adequate for the clearance of this pathogen. The lack of knowledge regarding the different molecular mechanisms of infection of this virus has delayed the licensing of effective treatments or vaccines. As part of this work, we evaluated whether a single and low dose of a recombinant Mycobacterium bovis Bacillus Calmette-Guérin (BCG) expressing the phosphoprotein of hMPV (rBCG-P) can induce a protective immune response in mice. Immunization with the rBCG-P significantly decreased neutrophil counts and viral loads in the lungs of infected mice at different time points. This immune response was also associated with a modulated infiltration of innate cells into the lungs, such as interstitial macrophages (IM) and alveolar macrophages (AM), activated CD4+ and CD8+ T cells, and changes in the population of differentiated subsets of B cells, such as marginal zone B cells and plasma cells. The humoral immune response induced by the rBCG-P led to an early and robust IgA response and a late and constant IgG response. Finally, we determined that the transfer of cells or sera from immunized and infected mice to naïve mice promoted an efficient viral clearance. Therefore, a single and low dose of rBCG-P can protect mice from the disease caused by hMPV, and this vaccine could be a promising candidate for future clinical trials.

scholarly journals Hematological disorder associated Cxcr4-gain-of-function mutation leads to uncontrolled extrafollicular immune response

Blood ◽  
2021 ◽  
Author(s):  
Nagham Alouche ◽  
Amélie Bonaud ◽  
Vincent Rondeau ◽  
Rim Hussein-Agha ◽  
Julie Nguyen ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Fine Tuning ◽  
Transient Wave ◽  
Gain Of Function ◽  
Hematological Disorders ◽  
Cxcr4 Signaling ◽  
Whim Syndrome

The extrafollicular immune response is essential to generate a rapid but transient wave of protective antibodies upon infection. Despite its importance, the molecular mechanisms controlling this first response are poorly understood. Here, we demonstrate that enhanced Cxcr4 signaling due to defective receptor desensitization leads to exacerbated extrafollicular B cell response. Using a mouse model bearing a gain of function mutation of Cxcr4 described in two human hematological disorders, WHIM syndrome and Waldenström's Macroglobulinemia, we demonstrated that mutant B cells exhibited enhanced mTOR signaling, cycled more and differentiated more potently into plasma cells than wild-type B cells upon TLR stimulation. Moreover, Cxcr4 gain-of-function promoted enhanced homing and persistence of immature plasma cells in the bone marrow, a phenomenon recapitulated in WHIM syndrome patient samples. This translated in increased and more sustained production of antibodies upon T-independent immunization in Cxcr4 mutant mice. Thus, our results establish that fine-tuning of Cxcr4 signaling is essential to limit the strength and length of the extrafollicular immune response.

scholarly journals Morphologic and Functional Effects of Gamma Secretase Inhibition on Splenic Marginal Zone B Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Maria Cristina de Vera Mudry ◽  
Franziska Regenass-Lechner ◽  
Laurence Ozmen ◽  
Bernd Altmann ◽  
Matthias Festag ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Nuclear Translocation ◽  
Recovery Period ◽  
Functional Characterization ◽  
Notch Receptor ◽  
Marginal Zone B Cells ◽  
Cell Fate Decisions

Theγ-secretase complex is a promising target in Alzheimer’s disease because of its role in the amyloidogenic processing ofβ-amyloid precursor protein. This enzyme also catalyzes the cleavage of Notch receptor, resulting in the nuclear translocation of intracellular Notch where it modulates gene transcription. Notch signaling is essential in cell fate decisions during embryogenesis, neuronal differentiation, hematopoiesis, and development of T and B cells, including splenic marginal zone (MZ) B cells. This B cell compartment participates in the early phases of the immune response to blood-borne bacteria and viruses. Chronic treatment with the oralγ-secretase inhibitor RO4929097 resulted in dose-dependent decreased cellularity (atrophy) of the MZ of rats and mice. Significant decreases in relative MZ B-cell numbers of RO4929097-treated animals were confirmed by flow cytometry. Numbers of MZ B cells reverted to normal after a sufficient RO4929097-free recovery period. Functional characterization of the immune response in relation to RO4929097-related MZ B cell decrease was assessed in mice vaccinated with inactivated vesicular stomatitis virus (VSV). Compared with the immunosuppressant cyclosporin A, RO4929097 caused only mild and reversible delayed early neutralizing IgM and IgG responses to VSV. Thus, the functional consequence of MZ B cell decrease on host defense is comparatively mild.

scholarly journals Cell-Mediated Responses to Human Metapneumovirus Infection

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 542
Author(s):  
Marlies Ballegeer ◽  
Xavier Saelens
Keyword(s):  
Immune Response ◽  
Rna Virus ◽  
Cell Types ◽  
Host Immune Response ◽  
Human Metapneumovirus ◽  
Comprehensive Overview ◽  
Hmpv Infection ◽  
Life Threatening ◽  
Tract Infections ◽  
Almost All

Viruses are the most common cause of acute respiratory tract infections (ARTI). Human metapneumovirus (hMPV) frequently causes viral pneumonia which can become life-threatening if the virus spreads to the lungs. Even though hMPV was only isolated in 2001, this negative-stranded RNA virus has probably been circulating in the human population for many decades. Interestingly, almost all adults have serologic evidence of hMPV infection. A well-established host immune response is evoked when hMPV infection occurs. However, the virus has evolved to circumvent and even exploit the host immune response. Further, infection with hMPV induces a weak memory response, and re-infections during life are common. In this review, we provide a comprehensive overview of the different cell types involved in the immune response in order to better understand the immunopathology induced by hMPV. Such knowledge may contribute to the development of vaccines and therapeutics directed against hMPV.

scholarly journals Ubiquitination of IgG1 cytoplasmic tail modulates B-cell signalling and activation

2020 ◽  
Vol 32 (6) ◽  
pp. 385-395
Author(s):  
Tadahiro Kodama ◽  
Mika Hasegawa ◽  
Yui Sakamoto ◽  
Kei Haniuda ◽  
Daisuke Kitamura
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Cell Signalling ◽  
Cytoplasmic Tail ◽  
Cell Receptor ◽  
Germinal Centre ◽  
Antigen Stimulation

Abstract Upon antigen stimulation, IgG+ B cells rapidly proliferate and differentiate into plasma cells, which has been attributed to the characteristics of membrane-bound IgG (mIgG), but the underlying molecular mechanisms remain elusive. We have found that a part of mouse mIgG1 is ubiquitinated through the two responsible lysine residues (K378 and K386) in its cytoplasmic tail and this ubiquitination is augmented upon antigen stimulation. The ubiquitination of mIgG1 involves its immunoglobulin tail tyrosine (ITT) motif, Syk/Src-family kinases and Cbl proteins. Analysis of a ubiquitination-defective mutant of mIgG1 revealed that ubiquitination of mIgG1 facilitates its ligand-induced endocytosis and intracellular trafficking from early endosome to late endosome, and also prohibits the recycling pathway, thus attenuating the surface expression level of mIgG1. Accordingly, ligation-induced activation of B-cell receptor (BCR) signalling molecules is attenuated by the mIgG1 ubiquitination, except MAP kinase p38 whose activation is up-regulated due to the ubiquitination-mediated prohibition of mIgG1 recycling. Adaptive transfer experiments demonstrated that ubiquitination of mIgG1 facilitates expansion of germinal centre B cells. These results indicate that mIgG1-mediated signalling and cell activation is regulated by ubiquitination of mIgG1, and such regulation may play a role in expansion of germinal centre B cells.

scholarly journals Human Metapneumovirus Establishes Persistent Infection in Lung Microvascular Endothelial Cells and Primes a Th2-Skewed Immune Response

2020 ◽  
Vol 8 (6) ◽  
pp. 824
Author(s):  
Antonella Bugatti ◽  
Stefania Marsico ◽  
Manuela Fogli ◽  
Sara Roversi ◽  
Serena Messali ◽  
...  
Keyword(s):  
Immune Response ◽  
Endothelial Cells ◽  
Human Metapneumovirus ◽  
Size Exclusion ◽  
Microvascular Endothelial Cells ◽  
Cytopathic Effects ◽  
Viral Particles ◽  
Hmpv Infection ◽  
Microvascular Endothelial ◽  
Tract Infections

Human Metapneumovirus (HMPV) is a major cause of lower respiratory tract infections. HMPV infection has been hypothesized to alter dendritic cell (DC) immune response; however, many questions regarding HMPV pathogenesis within the infected lung remain unanswered. Here, we show that HMPV productively infects human lung microvascular endothelial cells (L-HMVECs). The release of infectious virus occurs for up to more than 30 days of culture without producing overt cytopathic effects and medium derived from persistently HMPV-infected L-HMVECs (secretome) induced monocyte-derived DCs to prime naïve CD4 T-cells toward a Th2 phenotype. Moreover, we demonstrated that infected secretomes trigger DCs to up-regulate OX40L expression and OX40L neutralization abolished the pro-Th2 effect that is induced by HMPV-secretome. We clarified secretome from HMPV by size exclusion and ultracentrifugation with the aim to characterize the role of viral particles in the observed pro-Th2 effect. In both cases, the percentage of IL-4-producing cells and expression of OX40L returned at basal levels. Finally, we showed that HMPV, per se, could reproduce the ability of secretome to prime pro-Th2 DCs. These results suggest that HMPV, persistently released by L-HMVECs, might take part in the development of a skewed, pro-Th2 lung microenvironment.

Protein Signature of LMP1 Signaling in PTLDs Identifies and Mimics Inter/Perifollicular CD30+ EBV− B Blasts.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3251-3251
Author(s):  
Rita Shaknovich ◽  
Katia Basso ◽  
Govind Bhagat ◽  
Bachir Alobeid ◽  
Giorgio Cattoretti
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Subset ◽  
Cellular Transformation ◽  
Cell Types ◽  
Marginal Zone B Cells ◽  
Latently Infected ◽  
Protein Signature

Abstract EBV-associated B-cell Post-Transpant Lymphoproliferative Disorders (PTLDs) represent a diverse group of lesions morphologically, in clinical presentation and behaviour, ranging from early reversible lesions to monomorphic aggressive lymphomas. Polymorphic cases, which represent the focus of our analysis, contain a mixture of cells in various EBV latency stages, defined by EBNA1, EBNA2 and LMP1 immunostaining. LMP1 is a key viral protein for cellular transformation and, analogously to CD40, engages TNF Receptor Associated Proteins and activates NF-kB and NF-kB-responsive genes. We analyzed the protein signature of LMP1 in PTLDs and non-PTLD tonsils by double staining for LMP1, CD30, CD20, Pax5 and signaling molecules. A remarkably conserved set of proteins, associated with LMP1/CD40 signaling and NF-kB activation is expressed both in the EBV-infected lymphoid population in polymorphic PTLDs and in a normal B-cell subset(s) in reactive tonsils. These proteins include highly expressed CD30, JunB, nuclear cRel, TRAF-1, Bcl-XL, MUM1, CCL22 and downregulated BCL6 and CD10. We observed that EBV infection, possibly through LMP1 and LMP2A signaling, results in varioius degrees of differentiation within the neoplastic clone. EBER+ terminally differentiated mucosa-associated IRTA-1+ marginal zone B-cells and CD138+ plasma cells were identified in most cases, including control post-transplant tonsils with no overt disease. We document for the first time in situ, in-vivo evidence of EBV latently infected post-Germinal Center B cells of marginal and plasma cell types in PTLDs. Polymorphic PTLD cases represent EBV-induced expansion of B cells, mimicking CD40L-like activated Peri/Interfollicular CD30+ normal B-cells.

Comparable Long-Term Persistence of Anti-FVIII Antibodies in Hemophilic E17 Mice on Different Genetic Backgrounds Despite Significant Differences in the Amplitude of the Immune Responses.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1027-1027
Author(s):  
Natalie Bauer ◽  
Christina Hausl ◽  
Rafi U. Ahmad ◽  
Bernhard Baumgartner ◽  
Hans Peter Schwarz ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Genetic Background ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Mouse Strains ◽  
Igg Antibodies ◽  
Specific Memory

Abstract About 30% of patients with severe hemophilia A develop neutralizing antibodies against FVIII (FVIII inhibitors) following replacement therapy. The type of FVIII gene mutation as well as other predisposing genetic factors contribute to the inhibitor phenotype. Based on these findings, we asked if the genetic background modulates the long-term persistence of anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells in the E17 murine hemophilia model. Furthermore, we asked if the recently described inhibition of memory-B-cell re-stimulation by high doses of FVIII is influenced by the genetic background of the murine model. E17 mice on two different genetic backgrounds (C57Bl/6J and Balb/c) were treated with four doses of 200 ng human FVIII at weekly intervals. Anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells were followed up to 12 months after the last dose of FVIII. Antibody titers and subclasses of antibodies (IgM, IgG1, IgG2a, IgG2b, IgG3) were measured by ELISA. Antibody secreting plasma cells in spleen and bone marrow were detected by ELISPOT as described (Hausl et al., Thromb Haemost 2002). The re-stimulation of FVIII-specific memory B cells was studied as described recently (Hausl et al., Blood 2005). Anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells were first detectable in E17 Balb/c mice. IgM antibodies in the circulation and IgM secreting plasma cells in the spleen were observed after the first dose of FVIII, IgG antibodies and IgG secreting plasma cells after the second dose. No anti-FVIII antibodies after the first dose of FVIII were observed in E17 C57BL/6J mice but both IgM and IgG antibodies as well as IgM and IgG producing plasma cells were detectable after the second dose of FVIII. The antibody response involved all IgG subclasses in both mouse strains. However, IgG1 was dominant in E17 Balb/c mice whereas IgG2a was dominant in E17 C57BL/6J mice. When the in vitro restimulation of FVIII-specific memory B cells was examined, similar patterns were observed for both mouse strains. Low concentrations of FVIII between 10 and 100 ng/ml FVIII restimulated memory B cells and induced their differentiation into antibody secreting plasma cells whereas high concentrations of FVIII between 1,000 and 20,000 ng/ml FVIII inhibited memory-B-cell-restimulation. These results indicate that the dose-dependent effect of FVIII on the restimulation of FVIII-specific memory B cells does not depend on the genetic background. The major difference between both hemophilic mouse strains was the amplitude of the anti-FVIII immune response. Peak titers of anti-FVIII antibodies and peak concentrations of anti-FVIII antibody secreting plasma cells in spleen and bone marrow were significantly higher in E17 C57BL/6J mice than in E17 Balb/c mice. Whether or not higher ELISA titers correlate with higher Bethesda titers of neutralizing antibodies is currently being investigated. Despite the substantial differences in the amplitude of the immune response, anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells persisted for the whole observation period of 12 months after the last dose of FVIII in both mouse strains. We conclude that the amplitude of the anti-FVIII immune response in hemophilic mice is significantly different between E17 C57BL/6J and E17 Balb/c mice. However, the persistence of the immune response is comparable.

scholarly journals Identification of Functional Human Splenic Memory B Cells by Expression of CD148 and CD27

1998 ◽  
Vol 188 (9) ◽  
pp. 1691-1703 ◽  
Author(s):  
Stuart G. Tangye ◽  
Yong-Jun Liu ◽  
Gregorio Aversa ◽  
Joseph H. Phillips ◽  
Jan E. de Vries
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
Marginal Zone ◽  
Plasma Cells ◽  
Memory B Cells ◽  
White Pulp ◽  
Human Spleen ◽  
Marginal Zone B Cells ◽  
Surface Phenotype ◽  
V Region

Memory B cells isolated from human tonsils are characterized by an activated cell surface phenotype, localization to mucosal epithelium, expression of somatically mutated immunoglobulin (Ig) variable (V) region genes, and a preferential differentiation into plasma cells in vitro. In spleens of both humans and rodents, a subset of memory B cells is believed to reside in the marginal zone of the white pulp. Similar to tonsil-derived memory B cells, splenic marginal zone B cells can be distinguished from naive follicular B cells by a distinct cell surface phenotype and by the presence of somatic mutations in their Ig V region genes. Although differences exist between human naive and memory B cells, no cell surface molecules have been identified that positively identify all memory B cells. In this study, we have examined the expression of the receptor-type protein tyrosine phosphatase CD148 on human B cells. CD148+ B cells present in human spleen exhibited characteristics typical of memory B cells. These included an activated phenotype, localization to the marginal zone, the expression of somatically mutated Ig V region genes, and the preferential differentiation into plasma cells. In contrast, CD148− B cells appeared to be naive B cells due to localization to the mantle zone, the expression of surface antigens typical of unstimulated B cells, and the expression of unmutated Ig V region genes. Interestingly, CD148+ B cells also coexpressed CD27, whereas CD148− B cells were CD27−. These results identify CD148 and CD27 as markers which positively identify memory B cells present in human spleen. Thus, assessing expression of these molecules may be a convenient way to monitor the development of memory B cell responses in immunocompromised individuals or in vaccine trials.

scholarly journals New Approaches for Immunization and Therapy against Human Metapneumovirus

2015 ◽  
Vol 22 (8) ◽  
pp. 858-866 ◽  
Author(s):  
Sherry C. Wen ◽  
John V. Williams
Keyword(s):  
Animal Models ◽  
Clinical Signs ◽  
Respiratory Illness ◽  
The Elderly ◽  
Human Metapneumovirus ◽  
Research Groups ◽  
Vaccine Candidates ◽  
Hmpv Infection ◽  
Current Therapies ◽  
Upper Respiratory

ABSTRACTHuman metapneumovirus (HMPV) is a paramyxovirus discovered in 2001 in the Netherlands. Studies have identified HMPV as an important causative agent of acute respiratory disease in infants, the elderly, and immunocompromised individuals. Clinical signs of infection range from mild upper respiratory illness to more serious lower respiratory illness, including bronchiolitis and pneumonia. There are currently no licensed therapeutics or vaccines against HMPV. However, several research groups have tested vaccine candidates and monoclonal antibodies in various animal models. Several of these approaches have shown promise in animal models. This minireview summarizes the current therapies used to treat HMPV infection as well as different approaches for immunization.

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