Complement receptor 2/CD21− human naive B cells contain mostly autoreactive unresponsive clones
Tóm tắt
Complement receptor 2–negative (CR2/CD21−) B cells have been found enriched in patients with autoimmune diseases and in common variable immunodeficiency (CVID) patients who are prone to autoimmunity. However, the physiology of CD21−/lo B cells remains poorly characterized. We found that some rheumatoid arthritis (RA) patients also display an increased frequency of CD21−/lo B cells in their blood. A majority of CD21−/lo B cells from RA and CVID patients expressed germline autoreactive antibodies, which recognized nuclear and cytoplasmic structures. In addition, these B cells were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. Moreover, gene array analyses of CD21−/lo B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Thus, CD21−/lo B cells contain mostly autoreactive unresponsive clones, which express a specific set of molecules that may represent new biomarkers to identify anergic B cells in humans.
Từ khóa
Tài liệu tham khảo
Nemazee, 1995, Does immunological tolerance explain the waste in the B-lymphocyte immune system? experiment and theory., Ann N Y Acad Sci, 764, 397, 10.1111/j.1749-6632.1995.tb55854.x
Radic, 1995, Origins of anti-DNA antibodies and their implications for B-cell tolerance., Ann N Y Acad Sci, 764, 384, 10.1111/j.1749-6632.1995.tb55853.x
Goodnow, 2005, Cellular and genetic mechanisms of self tolerance and autoimmunity., Nature, 435, 590, 10.1038/nature03724
Goodnow, 1988, Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice., Nature, 334, 676, 10.1038/334676a0
Erikson, 1991, Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice., Nature, 349, 331, 10.1038/349331a0
Tsao, 1993, B cells are anergic in transgenic mice that express IgM anti-DNA antibodies., Eur J Immunol, 23, 2332, 10.1002/eji.1830230942
Cambier, 2007, B-cell anergy: from transgenic models to naturally occurring anergic B cells?, Nat Rev Immunol, 7, 633, 10.1038/nri2133
Fulcher, 1994, Reduced life span of anergic self-reactive B cells in a double-transgenic model., J Exp Med, 179, 125, 10.1084/jem.179.1.125
Cyster, 1994, Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire [see comments]., Nature, 371, 389, 10.1038/371389a0
Nemazee, 1989, Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes., Nature, 337, 562, 10.1038/337562a0
Hartley, 1991, Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens., Nature, 353, 765, 10.1038/353765a0
Halverson, 2004, Receptor editing is the main mechanism of B cell tolerance toward membrane antigens., Nat Immunol, 5, 645, 10.1038/ni1076
Healy, 1997, Different nuclear signals are activated by the B cell receptor during positive versus negative signaling., Immunity, 6, 419, 10.1016/S1074-7613(00)80285-X
Gauld, 2005, Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling., Nat Immunol, 6, 1160, 10.1038/ni1256
Merrell, 2006, Identification of anergic B cells within a wild-type repertoire., Immunity, 25, 953, 10.1016/j.immuni.2006.10.017
Duty, 2009, Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors., J Exp Med, 206, 139, 10.1084/jem.20080611
Wehr, 2004, A new CD21low B cell population in the peripheral blood of patients with SLE., Clin Immunol, 113, 161, 10.1016/j.clim.2004.05.010
Wei, 2007, A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus., J Immunol, 178, 6624, 10.4049/jimmunol.178.10.6624
Culton, 2007, Similar CD19 dysregulation in two autoantibody-associated autoimmune diseases suggests a shared mechanism of B-cell tolerance loss., J Clin Immunol, 27, 53, 10.1007/s10875-006-9051-1
Nicholas, 2008, A novel subset of memory B cells is enriched in autoreactivity and correlates with adverse outcomes in SLE., Clin Immunol, 126, 189, 10.1016/j.clim.2007.10.004
Warnatz, 2002, Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease., Blood, 99, 1544, 10.1182/blood.V99.5.1544
Warnatz, 2002, Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia., Immunobiology, 206, 502, 10.1078/0171-2985-00198
Rakhmanov, 2009, Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells., Proc Natl Acad Sci U S A, 106, 13451, 10.1073/pnas.0901984106
Wardemann, 2003, Predominant autoantibody production by early human B cell precursors., Science, 301, 1374, 10.1126/science.1086907
National Center for Biotechnology Information Gene Expression Omnibus (GEO). Accessed G5E, 13917 http://www.ncbi.nlm.nih.gov/geo
Cunningham-Rundles, 1999, Common variable immunodeficiency: clinical and immunological features of 248 patients., Clin Immunol, 92, 34, 10.1006/clim.1999.4725
Piqueras, 2003, Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects., J Clin Immunol, 23, 385, 10.1023/A:1025373601374
Wehr, 2008, The EUROclass trial: defining subgroups in common variable immunodeficiency., Blood, 111, 77, 10.1182/blood-2007-06-091744
Moir, 2008, Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals., J Exp Med, 205, 1797, 10.1084/jem.20072683
Ehrhardt, 2005, Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells., J Exp Med, 202, 783, 10.1084/jem.20050879
Ehrhardt, 2008, Discriminating gene expression profiles of memory B cell subpopulations., J Exp Med, 205, 1807, 10.1084/jem.20072682
Radic, 1993, Residues that mediate DNA binding of autoimmune antibodies., J Immunol, 150, 4966, 10.4049/jimmunol.150.11.4966
Isnardi, 2008, IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans., Immunity, 29, 746, 10.1016/j.immuni.2008.09.015
Goodnow, 1991, Breakdown of self-tolerance in anergic B lymphocytes., Nature, 352, 532, 10.1038/352532a0
Hartley, 1993, Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death., Cell, 72, 325, 10.1016/0092-8674(93)90111-3
Cooke, 1994, Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells., J Exp Med, 179, 425, 10.1084/jem.179.2.425
Nguyen, 1997, Characterization of anti-single-stranded DNA B cells in a non-autoimmune background., J Immunol, 159, 2633, 10.4049/jimmunol.159.6.2633
Mandik-Nayak, 1997, 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, 1257, 10.1084/jem.186.8.1257
Cappione, 2005, Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus., J Clin Invest, 115, 3205, 10.1172/JCI24179
Pugh-Bernard, 2001, Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance., J Clin Invest, 108, 1061, 10.1172/JCI200112462
Charles, 2008, Clonal expansion of immunoglobulin M+CD27+ B cells in HCV-associated mixed cryoglobulinemia., Blood, 111, 1344, 10.1182/blood-2007-07-101717
Lyubchenko, 2007, Cutting edge: complement (C3d)-linked antigens break B cell anergy., J Immunol, 179, 2695, 10.4049/jimmunol.179.5.2695
Glynne, 2000, B-lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays., Immunol Rev, 176, 216, 10.1034/j.1600-065X.2000.00614.x
Fujimoto, 1999, Modulation of B lymphocyte antigen receptor signal transduction by a CD19/CD22 regulatory loop., Immunity, 11, 191, 10.1016/S1074-7613(00)80094-1
Pan, 1999, CD72-deficient mice reveal nonredundant roles of CD72 in B cell development and activation., Immunity, 11, 495, 10.1016/S1074-7613(00)80124-7
Nimmerjahn, 2008, Fcgamma receptors as regulators of immune responses., Nat Rev Immunol, 8, 34, 10.1038/nri2206
Allen, 2004, Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5., Nat Immunol, 5, 943, 10.1038/ni1100
Förster, 2008, CCR7 and its ligands: balancing immunity and tolerance., Nat Rev Immunol, 8, 362, 10.1038/nri2297
Cyster, 1995, Antigen-induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate., Immunity, 3, 691, 10.1016/1074-7613(95)90059-4