Article

Cannabinoid receptor 2 positions and retains marginal zone B cells with the splenic marginal zone

Howard Hughes Medical Institute, Department of Microbiology and Immunology, and Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/2011; 208(10):1941-8. DOI: 10.1084/jem.20111083
Source: PubMed

ABSTRACT

Specialized B cells residing in the splenic marginal zone (MZ) continuously survey the blood for antigens and are important for immunity to systemic infections. However, the cues that uniquely attract cells to the MZ have not been defined. Previous work demonstrated that mice deficient in cannabinoid receptor 2 (CB2) have decreased numbers of MZ B cells but it has been unclear whether CB2 regulates MZ B cell development or positioning. We show that MZ B cells are highly responsive to the CB2 ligand 2-arachidonylglycerol (2-AG) and that CB2 antagonism rapidly displaces small numbers of MZ B cells to the blood. Antagonism for longer durations depletes MZ B cells from the spleen. In mice deficient in sphingosine-1-phosphate receptor function, CB2 antagonism causes MZ B cell displacement into follicles. Moreover, CB2 overexpression is sufficient to position B cells to the splenic MZ. These findings establish a role for CB2 in guiding B cells to the MZ and in preventing their loss to the blood. As a consequence of their MZ B cell deficiency, CB2-deficient mice have reduced numbers of CD1d-high B cells. We show that CB2 deficiency results in diminished humoral responses to a CD1d-restricted systemic antigen.

Download full-text

Full-text

Available from: Yelena Bronevetsky, Apr 16, 2015
  • Source
    • "It is therefore of interest to investigate possible adverse effects on blood cells in patients treated with rimonabant. The endocannabinoid system is regulating various aspects of lymphocyte proliferation, maturation and immune response (Klein, 2005; Muppidi et al., 2011; Pandey et al., 2009; Pereira et al., 2009; Sido, Nagarkatti & Nagarkatti, 2014). Targeting the endocannabinoid system may therefore be a possible new treatment option in various lymphoproliferative disorders. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cannabinoid receptor type 1 (CB1) antagonist rimonabant has been used as treatment for obesity. In addition, anti-proliferative effects on mitogen-activated leukocytes have been demonstrated in vitro. We have previously shown that rimonabant (SR141716A) induces cell death in ex vivo isolated malignant lymphomas with high expression of CB1 receptors. Since CB1 targeting may be part of a future lymphoma therapy, it was of interest to investigate possible effects on peripheral blood mononuclear cells (PBMC) in patients treated with rimonabant. We therefore evaluated leukocyte subsets by 6 color flow cytometry in eight patients before and at treatment with rimonabant for 4 weeks. Whole-transcript gene expression profiling in PBMC before and at 4 weeks of rimonabant treatment was done using Affymetrix Human Gene 1.0 ST Arrays. Our data show no significant changes of monocytes, B cells, total T cells or T cell subsets in PBMC during treatment with rimonabant. There was a small but significant increase in CD3-, CD16+ and/or CD56+ cells after rimonabant therapy. Gene expression analysis detected significant changes in expression of genes associated with innate immunity, cell death and metabolism. The present study shows that normal monocytes and leukocyte subsets in blood remain rather constant during rimonabant treatment. This is in contrast to the induction of cell death previously observed in CB1 expressing lymphoma cells in response to treatment with rimonabant in vitro. These differential effects observed on normal and malignant lymphoid cells warrant investigation of CB1 targeting as a potential lymphoma treatment.
    Full-text · Article · Jun 2015 · PeerJ
  • Source
    • "As a result of this computational analysis, an association has now been made in the CL between “mature B cell” and “professional antigen presenting cell” by declaring both cell types are capable of the GO process “antigen processing and presentation of peptide or polysaccharide antigen via MHC class II” (GO:0002504). Other interesting GO associations that we found through term enrichment and that are supported by evidence in the literature include the findings that B-2 B cells are in resting state compared to B-1 B cells [22] by “negative regulation of lymphocyte activation” (GO:0051250), and that marginal zone B cells are capable of “antigen processing and presentation, endogenous lipid antigen via MHC class Ib” (GO:0048006) [23]. Thus one benefit of this approach is the review of the completeness of CL representations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: New technologies are focusing on characterizing cell types to better understand their heterogeneity. With large volumes of cellular data being generated, innovative methods are needed to structure the resulting data analyses. Here, we describe an 'Ontologically BAsed Molecular Signature' (OBAMS) method that identifies novel cellular biomarkers and infers biological functions as characteristics of particular cell types. This method finds molecular signatures for immune cell types based on mapping biological samples to the Cell Ontology (CL) and navigating the space of all possible pairwise comparisons between cell types to find genes whose expression is core to a particular cell type's identity. We illustrate this ontological approach by evaluating expression data available from the Immunological Genome project (IGP) to identify unique biomarkers of mature B cell subtypes. We find that using OBAMS, candidate biomarkers can be identified at every strata of cellular identity from broad classifications to very granular. Furthermore, we show that Gene Ontology can be used to cluster cell types by shared biological processes in order to find candidate genes responsible for somatic hypermutation in germinal center B cells. Moreover, through in silico experiments based on this approach, we have identified genes sets that represent genes overexpressed in germinal center B cells and identify genes uniquely expressed in these B cells compared to other B cell types. This work demonstrates the utility of incorporating structured ontological knowledge into biological data analysis -- providing a new method for defining novel biomarkers and providing an opportunity for new biological insights.
    Full-text · Article · Aug 2013 · BMC Bioinformatics
  • Source
    • "Mice deficient in CB2 have a significant reduction in marginal zone B cells that was attributed to a reduction in the homing and retention of these B cells within the marginal zone of the spleen [7]–[9]. In addition, CB2-deficient mice were shown to have impaired T-independent humoral immune responses [8], [9]. However, whether CB2 also regulates T-dependent humoral responses is not well understood. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cannabinoid receptor 2 (CB2) has been reported to modulate B cell functions including migration, proliferation and isotype class switching. Since these processes are required for the generation of the germinal center (GC) and antigen-specific plasma and memory cells following immunization with a T-dependent antigen, CB2 has the capacity to alter the quality and magnitude of T-dependent immune responses. To address this question, we immunized WT and CB2(-/-) mice with the T-dependent antigen 4-hydroxy-3-nitrophenylacetyl (NP)-chicken-gamma-globulin (CGG) and measured GC B cell formation and the generation of antigen-specific B cells and serum immunoglobulin (Ig). While there was a significant reduction in the number of splenic GC B cells in CB2(-/-) mice early in the response there was no detectable difference in the number of NP-specific IgM and IgG1 plasma cells. There was also no difference in NP-specific IgM and class switched IgG1 in the serum. In addition, we found no defect in the homing of plasma cells to the bone marrow (BM) and affinity maturation, although memory B cell cells in the spleen were reduced in CB2(-/-) mice. CB2-deficient mice also generated similar levels of antigen-specific IgM and IgG in the serum as WT following immunization with sheep red blood cells (sRBC). This study demonstrates that although CB2 plays a role in promoting GC and memory B cell formation/maintenance in the spleen, it is dispensable on all immune cell types required for the generation of antigen-specific IgM and IgG in T-dependent immune responses.
    Full-text · Article · Jun 2013 · PLoS ONE
Show more