scholarly journals Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation

2021 ◽  
Vol 14 (3) ◽  
pp. dmm047589
Author(s):  
Ewelina Dobosz ◽  
Georg Lorenz ◽  
Andrea Ribeiro ◽  
Vivian Würf ◽  
Marta Wadowska ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Immune Responses ◽  
Cell Activation ◽  
Plasma Cells ◽  
Myeloid Cell ◽  
Skin Inflammation ◽  
Adaptive Immune ◽  
Systemic Autoimmunity ◽  
Key Factor ◽  
Old Mice

ABSTRACTMyeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.

Cellular side of acquired immunity (B cells)

2013 ◽  
pp. 371-378
Author(s):  
Thomas Dörner ◽  
Peter E. Lipsky
Keyword(s):  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasma Cells ◽  
Adaptive Immune System ◽  
Adaptive Immune ◽  
B Cell Homeostasis ◽  
Anti Cd20 ◽  
Antigen Presenting

B cells have gained interest in rheumatoid arthritis (RA) beyond being the precursors of antibody-producing plasma cells since they are also a broader component of the adaptive immune system. They are capable of functioning as antigen-presenting cells for T-cell activation and can produce an array of cytokines. Disturbances of peripheral B-cell homeostasis together with the formation of ectopic lymphoid neogenesis within the inflamed synovium appears to be a characteristic of patients with RA. Enhanced generation of memory B cells and autoreactive plasma cells producing IgM-RF and ACPA-IgG antibodies together with formation of immune complexes contribute to the maintenance of RA, whereas treatment with B-cell-directed anti-CD20 and CLTA4-Ig therapy provides clinical benefit.

scholarly journals Membrane-associated and secreted forms of the Rhesus macaque rhadinovirus-encoded CD200 homologue and cellular CD200 demonstrate differential effects on Rhesus Macaque CD200 Receptor signaling and regulation of myeloid cell activation

2020 ◽  
pp. JVI.01654-20
Author(s):  
Ryan D. Estep ◽  
Aparna N. Govindan ◽  
Kristin Fitzpatrick ◽  
Tiffany C. Blair ◽  
S.A. Rahim Rezaee ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rhesus Macaque ◽  
Cell Activation ◽  
Myeloid Cell ◽  
Functional Protein ◽  
Dna Viruses ◽  
Cd200 Receptor ◽  
First Time

The CD200-CD200R pathway is involved in inhibition of immune responses, and the importance of this pathway to infectious disease is highlighted by the fact that viral CD200 (vCD200) molecules have been found to be encoded by several DNA viruses, including the human gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV), and the closely related rhesus macaque rhadinovirus (RRV). KSHV vCD200 is the most extensively studied vCD200 molecule, however, the only herpesvirus vCD200 molecule to be examined in vivo is that encoded by RRV. Our prior studies have demonstrated that RRV vCD200 is a functional CD200 homologue that is capable of affecting immune responses in vivo, and further, that RRV can express a secreted form of vCD200 (vCD200-Sec) during infection. Despite this information, RRV vCD200 has not been examined specifically for effects on RM CD200R signaling, and the functionality of vCD200-Sec has not been examined in any context. Thus, we developed an in vitro model system in which B cells expressing vCD200 were utilized to assess the effects of this molecule on the regulation of myeloid cells expressing RM CD200R, mimicking interactions that are predicted to occur in vivo. Our findings suggest that RRV vCD200 can bind and induce functional signals through RM CD200R, while vCD200-Sec represents a non-functional protein incapable of affecting CD200R signaling. We also provide the first demonstration of the function of RM CD200, which appears to possess more robust signaling capabilities than RRV vCD200, and also show that KSHV vCD200 does not efficiently induce signaling via RM CD200R.IMPORTANCE Viral CD200 homologues are encoded by KSHV and the closely related RRV. Though RRV vCD200 has been examined, questions still exist in regard to the ability of this molecule to induce signaling via rhesus macaque CD200R, as well as the potential function of a secreted form of vCD200. Further, all previous in vitro studies of RRV vCD200 have utilized an Fc fusion protein to examine functionality, which does not replicate the structural properties of the membrane-associated form of vCD200 that is naturally produced during RRV infection. In this study, we demonstrate for the first time that membrane-expressed RRV vCD200 is capable of inducing signal transduction via RM CD200R, while the secreted form of vCD200 appears to be non-functional. Further, we also demonstrate that RM CD200 induces signaling via RM CD200R, and is more robust than RRV vCD200, while KSHV vCD200 does not appear to induce efficient signaling via RM CD200R.

scholarly journals MGL1 Receptor Plays a Key Role in the Control of T. cruzi Infection by Increasing Macrophage Activation through Modulation of ERK1/2, c-Jun, NF-κB and NLRP3 Pathways

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 108
Author(s):  
Tonathiu Rodriguez ◽  
Thalia Pacheco-Fernández ◽  
Alicia Vázquez-Mendoza ◽  
Oscar Nieto-Yañez ◽  
Imelda Juárez-Avelar ◽  
...  
Keyword(s):  
Immune Responses ◽  
Macrophage Activation ◽  
Cell Activation ◽  
Wild Type ◽  
Mhc Ii ◽  
Adaptive Immune ◽  
Splenic Cell ◽  
Tnf Α ◽  
Cruzi Infection

Macrophage galactose-C type lectin (MGL)1 receptor is involved in the recognition of Trypanosoma cruzi (T. cruzi) parasites and is important for the modulation of the innate and adaptive immune responses. However, the mechanism by which MGL1 promotes resistance to T. cruzi remains unclear. Here, we show that MGL1 knockout macrophages (MGL1−/− Mφ) infected in vitro with T. cruzi were heavily parasitized and showed decreased levels of reactive oxygen species (ROS), nitric oxide (NO), IL-12 and TNF-α compared to wild-type macrophages (WT Mφ). MGL1−/− Mφ stimulated in vitro with T. cruzi antigen (TcAg) showed low expression of TLR-2, TLR-4 and MHC-II, which resulted in deficient splenic cell activation compared with similar co-cultured WT Mφ. Importantly, the activation of p-ERK1/2, p-c-Jun and p-NF-κB p65 were significantly reduced in MGL1−/− Mφ exposed to TcAg. Similarly, procaspase 1, caspase 1 and NLRP3 inflammasome also displayed a reduced expression that was associated with low IL-β production. Our data reveal a previously unappreciated role for MGL1 in Mφ activation through the modulation of ERK1/2, c-Jun, NF-κB and NLRP3 signaling pathways, and to the development of protective innate immunity against experimental T. cruzi infection.

CD154:CD40 Co-Stimulatory Blockade: A Novel Approach To Prevent Sensitization to Donor Alloantigens.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1273-1273
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Suzanne T. Ildstad
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
B Cell ◽  
Germinal Center ◽  
Cell Activation ◽  
Cell Tolerance ◽  
B Cell Activation ◽  
B Cell Tolerance ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

Abstract Introduction: Recipient sensitization is one of the most critical problems facing clinical transplantation. Allosensitized recipients often rapidly reject vascularized solid organ grafts as a result of preformed anti-donor antibody. Similarly, bone marrow transplantation for sickle cell disease and thalassemia is limited by sensitization from transfusion. A method to prevent sensitization would have a significant impact on transplant outcomes. Until recently, T cells were believed to be the primary effector cell in the induction of adaptive immune responses. We recently found that humoral immunity provides a dominant barrier in allosensitization to MHC antigens. B cell activation occurs through T-cell-dependent responses via signaling from the co-stimulatory molecule CD154 (on T cells) to its ligand CD40 (on B cells). Here, we examined whether blocking the costimulatory interaction between T and B cells during exposure to alloantigen would prevent allosensitization. Materials and Methods: Mice deficient for CD154 molecule (CD154−/ −, H-2b), α β-TCR+ T cells (TCRβ −/ −, H-2b); or wild type B6 (H-2b) mice received allogeneic BALB/c (H-2d) skin grafts (SG) on day 0. Some B6 mice were also treated with anti-CD154 (day0 and day+3) and/or anti-α β-TCR mAb (day-3) peritransplant. Antibodies were detected by flow cytometry cross-match (FCM) assay and reported as mean fluorescence intensity (MFI). Results: CD154−/ − mice rejected primary BALB/c SG with a time course similar to normal B6 controls (12.4 ± 2.1 vs. 12.7 ± 2.4 days). TCRβ −/ − mice accepted SG permanently (>120 days). Notably, anti-donor antibody was not generated in either the CD154−/ − or TCRβ −/ − mice (MFI: 4.1 ± 0.1 and 4.2 ± 0.4) after SG compared with Ab in naïve serum (3.0±0.2). Sensitized B6 mice had significantly higher antibody titers (106.8 ± 35.1) 4 weeks after SG rejection. A second SG transplanted 5 to 7 weeks after the first graft was rejected at an accelerated rate (9.0 ± 0.8 days, P < 0.05) in the CD154−/ − mice, but no anti-donor MHC antibody was produced. Second grafts placed on TCRβ −/ − mice were accepted, as were the primary SG. In normal B6 recipients pretreated with anti-CD154 or anti-α β-TCR alone, SG survival was not significantly prolonged. The Ab titers were only slightly higher in mice treated with anti-CD154 (5.9±3.4; P>0.05) than in naïve mice, and significantly higher in mice treated with mAb anti-α β-TCR (45.1±25.6; P=0.03). The combined treatment with both mAbs resulted in complete abrogation of Ab production (4.2±0.9) and 70% of skin grafts survived >100 days. Germinal center formation, reflective of B cell activation, was completely disrupted in mice treated with anti-CD154 alone or combined with anti-α β-TCR. Conclusion: These results suggest that the CD40/CD154 co-stimulatory pathway is critically important in B cell activation to generate alloantibody. Notably, blocking molecular interactions between CD40/CD154 abrogated the generation of antibody and blocked germinal center formation, inducing B cell tolerance. The additional removal of recipient T cells in the context of co-stimulatory blockade resulted in the induction of T as well as B cell tolerance. These findings are the first demonstration that sensitization can be prevented through blockade of co-stimulatory interactions in the generation of adaptive immune responses and could have a significant impact on management of sensitized recipients in the clinic.

scholarly journals NK-DC Crosstalk in Immunity to Microbial Infection

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Rony Thomas ◽  
Xi Yang
Keyword(s):  
Immune Responses ◽  
Cell Activation ◽  
Nk Cell ◽  
Adaptive Immune Response ◽  
Microbial Infection ◽  
Adaptive Immune ◽  
Microbial Infections ◽  
Cellular Components ◽  
Secondary Lymphoid Organs ◽  
Dc Maturation

The interaction between natural killer (NK) cell and dendritic cell (DC), two important cellular components of innate immunity, started to be elucidated in the last years. The crosstalk between NK cells and DC, which leads to NK cell activation, DC maturation, or apoptosis, involves cell-cell contacts and soluble factors. This interaction either in the periphery or in the secondary lymphoid organs acts as a key player linking innate and adaptive immune responses to microbial stimuli. This review focuses on the mechanisms of NK-DC interaction and their relevance in antimicrobial responses. We specifically aim to emphasize the ability of various microbial infections to differently influence NK-DC crosstalk thereby contributing to distinct adaptive immune response.

scholarly journals In Vitro Platform Establishes Antigen-Specific CD8+ T Cell Cytotoxicity to Encapsulated Cells via Indirect Antigen Recognition

2019 ◽  
Author(s):  
Ying Li ◽  
Anthony W. Frei ◽  
Ethan Y. Yang ◽  
Irayme Labrada-Miravet ◽  
Chuqiao Sun ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Recognition ◽  
Adaptive Immune Responses ◽  
Activated T Cells ◽  
Encapsulated Cells ◽  
Adaptive Immune

AbstractCell replacement therapy has the potential to cure diseases caused by the absence or malfunction of specialized cells. A substantial impediment to the success of any non-autologous cellular transplant is the need for systemic immunosuppressive drugs to prevent host-mediated rejection of the foreign cells. Cellular encapsulation, i.e., the entrapment of cells within stable polymeric hydrogels, has been clinically explored to prevent host immune recognition and attack, but the efficacy of these encapsulated grafts is poor. While several studies have explored improvements in innate immune acceptance of these encapsulated cells, little attention has been paid to the roles of adaptive immune responses, specifically graft-targeting T cell activation, in graft destabilization. Herein, we established an efficient, single-antigen in vitro platform capable of delineating direct and indirect host T cell recognition to microencapsulated cellular grafts and evaluating their consequential impacts. Using alginate as the model hydrogel, encapsulated membrane-bound ovalbumin (mOVA) stimulator cells were incubated with antigen-specific OTI lymphocytes and subsequent OVA-specific CD8+ T cell activation and effector function were quantified. We established that alginate microencapsulation abrogates direct T cell activation by interrupting donor-host interaction; however, indirect T cell activation mediated by host antigen presenting cells (APCs) primed with shed donor antigens still occurs. These activated T cells imparted cytotoxicity on the encapsulated cells, likely via diffusion of cytotoxic solutes. Overall, this platform delivers unique mechanistic insight into the impacts of hydrogel encapsulation on host adaptive immune responses, as well as a tool for the efficient immune screening on new encapsulation methods and/or synergistic immunomodulatory agents.

scholarly journals Immune asynchrony in COVID-19 pathogenesis and potential immunotherapies

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Ting Zhou ◽  
Tina Tianjiao Su ◽  
Tenny Mudianto ◽  
Jun Wang
Keyword(s):  
Immune Responses ◽  
Cell Activation ◽  
Myeloid Cell ◽  
Blood Analysis ◽  
Health Crisis ◽  
Antiviral Immune Response ◽  
Innate And Adaptive Immunity ◽  
Immune Sensing ◽  
Spatiotemporal Control ◽  
Peripheral Blood Analysis

The outbreak of coronavirus disease 2019 (COVID-19) is an unprecedented global health crisis. Tissue and peripheral blood analysis indicate profound, aberrant myeloid cell activation, cytokine storm, and lymphopenia, with unknown immunopathological mechanisms. Spatiotemporal control of the quality and quantity of the antiviral immune responses involves synchronized cellular and molecular cascades and cross-talk between innate and adaptive immunity. Dysregulated responses in immunity, such as at the stages of immune sensing, alarming, polarization, and resolution, may contribute to disease pathology. Herein, we approach SARS-CoV-2 through an immunomodulatory lens, discussing possible mechanisms of the asynchronized antiviral immune response and proposing potential therapeutic strategies to correct the dysregulation.

scholarly journals Regulation of B1 cell migration by signals through Toll-like receptors

2006 ◽  
Vol 203 (11) ◽  
pp. 2541-2550 ◽  
Author(s):  
Seon-ah Ha ◽  
Masayuki Tsuji ◽  
Keiichiro Suzuki ◽  
Bob Meek ◽  
Nobutaka Yasuda ◽  
...  
Keyword(s):  
Cell Migration ◽  
Immune Responses ◽  
High Velocity ◽  
Chemokine Receptors ◽  
Plasma Cells ◽  
Toll Like Receptors ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
B1 Cells ◽  
Molecular Signals

Peritoneal B1 cells are known to generate large amounts of antibodies outside their residential site. These antibodies play an important role in the early defense against bacteria and viruses, before the establishment of adaptive immune responses. Although many stimuli, including antigen, lipopolysaccharide, or cytokines, have been shown to activate B1 cells and induce their differentiation into plasma cells, the molecular signals required for their egress from the peritoneal cavity are not understood. We demonstrate here that direct signals through Toll-like receptors (TLRs) induce specific, rapid, and transient down-regulation of integrins and CD9 on B1 cells, which is required for detachment from local matrix and a high velocity movement of cells in response to chemokines. Thus, we revealed an unexpected role for TLRs in governing the interplay between integrins, tetraspanins, and chemokine receptors required for B1 cell egress and, as such, in facilitating appropriate transition from innate to adaptive immune responses.

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