Low-Level Expression of CD138 Marks Naturally Arising Anergic B Cells
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Autoreactive B cells are not entirely deleted, but some remain as immunocompetent or anergic B cells. Although the persistence of autoreactive B cells as anergic cells has been shown in transgenic mouse models with the expression of B cell receptor (BCR) reactive to engineered self-antigen, the characterization of naturally occurring anergic B cells is important to identify them and understand their contribution to immune regulation or autoimmune diseases. We report here that a low-level expression of CD138 in the splenic B cells marks naturally arising anergic B cells, not plasma cells. The CD138int B cells consisted of IgMlowIgDhigh follicular (FO) B cells and transitional 3 B cells in homeostatic conditions. The CD138int FO B cells showed an anergic gene expression profile shared with that of monoclonal anergic B cells expressing engineered BCRs and the gene expression profile was different from those of plasma cells, age-associated B cells, or germinal center B cells. The anergic state of the CD138int FO B cells was confirmed by attenuated Ca2+ response and failure to upregulate CD69 upon BCR engagement with anti-IgM, anti-IgD, anti-Igκ, or anti-IgG. The BCR repertoire of the CD138int FO B cells was distinct from that of the CD138− FO B cells and included some class-switched B cells with low-level somatic mutations. These findings demonstrate the presence of polyclonal anergic B cells in the normal mice that are characterized by low-level expression of CD138, IgM downregulation, reduced Ca2+ and CD69 responses upon BCR engagement, and distinct BCR repertoire.
Abstract
Autoreactive B cells are not entirely deleted, but some remain as immunocompetent or anergic B cells. Although the persistence of autoreactive B cells as anergic cells has been shown in transgenic mouse models with the expression of B cell receptor (BCR) reactive to engineered self-antigen, the characterization of naturally occurring anergic B cells is important to identify them and understand their contribution to immune regulation or autoimmune diseases. We report here that a low-level expression of CD138 in the splenic B cells marks naturally arising anergic B cells, not plasma cells. The CD138int B cells consisted of IgMlowIgDhigh follicular (FO) B cells and transitional 3 B cells in homeostatic conditions. The CD138int FO B cells showed an anergic gene expression profile shared with that of monoclonal anergic B cells expressing engineered BCRs and the gene expression profile was different from those of plasma cells, age-associated B cells, or germinal center B cells. The anergic state of the CD138int FO B cells was confirmed by attenuated Ca2+ response and failure to upregulate CD69 upon BCR engagement with anti-IgM, anti-IgD, anti-Igκ, or anti-IgG. The BCR repertoire of the CD138int FO B cells was distinct from that of the CD138− FO B cells and included some class-switched B cells with low-level somatic mutations. These findings demonstrate the presence of polyclonal anergic B cells in the normal mice that are characterized by low-level expression of CD138, IgM downregulation, reduced Ca2+ and CD69 responses upon BCR engagement, and distinct BCR repertoire.
참고문헌 (60)
- Lee S, "Homeostasis and regulation of autoreactive B cells", Cell Mol Immunol, 17, pp.561~569 (2020)
- Wardemann H, "Predominant autoantibody production by early human B cell precursors", Science, 301, pp.1374~1377 (2003)
- Liu Z, "BAFF and selection of autoreactive B cells", Trends Immunol, 32, pp.388~394 (2011)
- Shlomchik MJ, "Sites and stages of autoreactive B cell activation and regulation", Immunity, 28, pp.18~28 (2008)
- Gaudin E, "Positive selection of B cells expressing low densities of self-reactive BCRs", J Exp Med, 199, pp.843~853 (2004)
- Nemazee D, "Mechanisms of central tolerance for B cells", Nat Rev Immunol, 17, pp.281~294 (2017)
- Meffre E, "B-cell tolerance checkpoints in health and autoimmunity", Curr Opin Immunol, 20, pp.632~638 (2008)
- Grimaldi CM, "B cell selection and susceptibility to autoimmunity", J Immunol, 174, pp.1775~1781 (2005)
- Pelanda R, "Central B-cell tolerance : where selection begins", Cold Spring Harb Perspect Biol, 4, pp.a007146~ (2012)
- Schmidt KN, "Follicular exclusion and rapid elimination of hen egg lysozyme autoantigenbinding B cells are dependent on competitor B cells, but not on T cells", J Immunol, 162, pp.284~291 (1999)
- Turner M, "Syk tyrosine kinase is required for the positive selection of immature B cells into the recirculating B cell pool", J Exp Med, 186, pp.2013~2021 (1997)
- Tan C, "Self-reactivity on a spectrum : a sliding scale of peripheral B cell tolerance", Immunol Rev, 292, pp.37~60 (2019)
- Zikherman J, "Endogenous antigen tunes the responsiveness of naive B cells but not T cells", Nature, 489, pp.160~164 (2012)
- Goodnow CC, "Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice", Nature, 334, pp.676~682 (1988)
- Gauld SB, "Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling", Nat Immunol, 6, pp.1160~1167 (2005)
- Sabouri Z, "IgD attenuates the IgM-induced anergy response in transitional and mature B cells", Nat Commun, 7, pp.13381~ (2016)
- Merrell KT, "Identification of anergic B cells within a wild-type repertoire", Immunity, 25, pp.953~962 (2006)
- Duty JA, "Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors", J Exp Med, 206, pp.139~151 (2009)
- Chernova I, "Lasting antibody responses are mediated by a combination of newly formed and established bone marrow plasma cells drawn from clonally distinct precursors", J Immunol, 193, pp.4971~4979 (2014)
- Wilmore JR, "Protocol for improved resolution of plasma cell subpopulations by flow cytometry", Eur J Immunol, 47, pp.1386~1388 (2017)
- Boldison J, "Phenotypically distinct anti-insulin B cells repopulate pancreatic islets after anti-CD20 treatment in NOD mice", Diabetologia, 62, pp.2052~2065 (2019)
- Lee JG, "Reversible expression of CD138 on mature follicular B cells is downregulated by IL-4", Immunol Lett, 156, pp.38~45 (2013)
- Mason DY, "Development and follicular localization of tolerant B lymphocytes in lysozyme", anti-lysozyme IgM, Int Immunol, pp.1992, 4[DOI]
- Subramanian A, "Gene set enrichment analysis : a knowledge-based approach for interpreting genome-wide expression profiles", Proc Natl Acad Sci U S A, 102, pp.15545~15550 (2005)
- Briney BS, "High-throughput antibody sequencing reveals genetic evidence of global regulation of the naïve and memory repertoires that extends across individuals", Genes Immun, 13, pp.469~473 (2012)
- Chaudhary N, "Analyzing immunoglobulin repertoires", Front Immunol, 9, pp.462~ (2018)
- DeWolf S, "Quantifying size and diversity of the human T cell alloresponse", JCI Insight, 3, pp.e121256~ (2018)
- Venturi V, "Method for assessing the similarity between subsets of the T cell receptor repertoire", J Immunol Methods, 329, pp.67~80 (2008)
- Fossati V, "Progenitor cell origin plays a role in fate choices of mature B cells", J Immunol, 184, pp.1251~1260 (2010)
- Glynne R, "B-lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays", Immunol Rev, 176, pp.216~246 (2000)
- Klonowski KD, "Atypical VH-D-JH rearrangements in newborn autoimmune MRL mice", J Immunol, 162, pp.1566~1572 (1999)
- Wijdenes J, "CD138", J Biol Regul Homeost Agents, 16, pp.152~155 (2002)
- Moreaux J, "APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop", Eur J Haematol, 83, pp.119~129 (2009)
- Culton DA, "Early preplasma cells define a tolerance checkpoint for autoreactive B cells", J Immunol, 176, pp.790~802 (2006)
- Huizar J, "Nur77 is upregulated in B-1a cells by chronic selfantigen stimulation and limits generation of natural IgM plasma cells", Immunohorizons, 1, pp.188~197 (2017)
- Hayakawa K, "NLR Nod1 signaling promotes survival of BCR-engaged mature B cells through up-regulated Nod1 as a positive outcome", J Exp Med, 214, pp.3067~3083 (2017)
- Hobeika E, "Control of B cell responsiveness by isotype and structural elements of the antigen receptor", Trends Immunol, 37, pp.310~320 (2016)
- Übelhart R, "Responsiveness of B cells is regulated by the hinge region of IgD", Nat Immunol, 16, pp.534~543 (2015)
- Noviski M, "Control of autoreactive B cells by IgM and IgD B cell receptors : maintaining a fine balance", Curr Opin Immunol, 55, pp.67~74 (2018)
- Noviski M, "IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate", eLife, 7, pp.e35074~ (2018)
- Cancro MP, "Signalling crosstalk in B cells : managing worth and need", Nat Rev Immunol, 9, pp.657~661 (2009)
- Monroe JG, "ITAM-mediated tonic signalling through pre-BCR and BCR complexes", Nat Rev Immunol, 6, pp.283~294 (2006)
- Okkenhaug K, "Signaling by the phosphoinositide 3-kinase family in immune cells", Annu Rev Immunol, 31, pp.675~704 (2013)
- Srinivasan L, "PI3 kinase signals BCR-dependent mature B cell survival", Cell, 139, pp.573~586 (2009)
- Batten M, "BAFF mediates survival of peripheral immature B lymphocytes", J Exp Med, 192, pp.1453~1466 (2000)
- Tan C, "NR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting", Nat Immunol, 21, pp.1267~1279 (2020)
- Kim EE, "PCP4 regulates Purkinje cell excitability and cardiac rhythmicity", J Clin Invest, 124, pp.5027~5036 (2014)
- Steach HR, "Cross-reactivity with self-antigen tunes the functional potential of naive B cells specific for foreign antigens", J Immunol, 204, pp.498~509 (2020)
- Melamed D, "Developmental regulation of B lymphocyte immune tolerance compartmentalizes clonal selection from receptor selection", Cell, 92, pp.173~182 (1998)
- Mandik-Nayak L, "Regulation of anti-double-stranded DNA B cells in nonautoimmune mice : localization to the T-B interface of the splenic follicle", J Exp Med, 186, pp.1257~1267 (1997)
- Cyster JG, "Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45", Nature, 381, pp.325~328 (1996)
- Basten A, "B-cell tolerance : mechanisms and implications", Curr Opin Immunol, 22, pp.566~574 (2010)
- Dang VD, "CD39 and CD326 are bona fide markers of murine and human plasma cells and identify a bone marrow specific plasma cell subpopulation in lupus", Front Immunol, 13, pp.873217~ (2022)
- Panda S, "Natural antibodies bridge innate and adaptive immunity", J Immunol, 194, pp.13~20 (2015)
- Panda S, "Natural IgG antibodies provide innate protection against ficolinopsonized bacteria", EMBO J, 32, pp.2905~2919 (2013)
- Aung KM, "Naturally occurring IgG antibodies provide innate protection against vibrio cholerae bacteremia by recognition of the outer membrane protein U", J Innate Immun, 8, pp.269~283 (2016)
- Chappert P, "Induction of T cell anergy : integration of environmental cues and infectious tolerance", Curr Opin Immunol, 22, pp.552~559 (2010)
- Kassambara A, "GenomicScape : an easy-to-use web tool for gene expression data analysis. Application to investigate the molecular events in the differentiation of B cells into plasma cells", PLOS Comput Biol, 11, pp.e1004077~ (2015)
- Masle-Farquhar E, "Uncontrolled CD21low age-associated and B1 B cell accumulation caused by failure of an EGR2", 3 tolerance checkpoint, 2022, pp.38, 110259~
- Srivastava B, "Characterization of marginal zone B cell precursors", J Exp Med, 202, pp.1225~1234 (2005)