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Purinergic signaling in B cells

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Adenosine and adenosine triphosphate are involved in purinergic signaling which plays an important role in control of the immune system. Much data have been obtained regarding impact of purinergic signaling on dendritic cells, macrophages, monocytes and T lymphocytes, however less attention has been paid to purinergic regulation of B cells. This review summarizes present knowledge on ATP- and Ado-dependent signaling in B lymphocytes. Human B cells have been shown to express A1-AR, A2A-AR, A2B-AR and A3-AR and each subtype of P2 receptors. Surface of B cells exhibits two antagonistic ectoenzymatic pathways, one relies on constitutive secretion and resynthesis of ATP, while the second one depends on degradation of adenosine nucleotides to nucleosides and their subsequent degradation. Inactivated B cells remain under the suppressive impact of autocrine and paracrine Ado, whereas activated B lymphocytes increase ATP release and production. ATP protects B cells from Ado-induced suppression and exerts pro-inflammatory effect on the target tissues, and it is also involved in the IgM release. On the other hand, Ado synthesis is necessary for optimal development, implantation and maintenance of the plasmocyte population in bone marrow in the course of the primary immune response. Moreover, Ado plays an important role in immunoglobulin class switching, which is a key mechanism of humoral immune response. Disruption of purinergic signaling leads to severe disorders. Impairment of Ado metabolism is one of the factors responsible for common variable immunodeficiency. There are several lines of evidence that dysfunction of the immune system observed during diabetes may in part depend on disrupted ATP and Ado metabolism in the B cells.
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  • Department of Molecular Medicine, Medical University of Gdansk, Gdańsk, Poland
  • Department of Molecular Medicine, Medical University of Gdansk, Gdańsk, Poland
  • Department of Molecular Medicine, Medical University of Gdansk, Gdańsk, Poland
  • Burnstock G (2004) Introduction: P2 receptors. Curr Top Med Chem 4: 793-803.
  • Burnstock G (2007) Purine and pyrimidine receptors. Cell Mol Life Sci 64: 1471-1483. doi: 10.1007/s00018-007-6497-0.
  • Burnstock G, Boeynaems JM (2014) Purinergic signalling and immune cells. Purinergic Signal 10: 529-564. doi: 10.1007/s11302-014-9427-2.
  • Cass CE, Young JD, Baldwin SA, Cabrita MA, Graham KA, Griffiths M, Jennings LL, Mackey JR, Ng AM, Ritzel MW, Vickers MF, Yao SY (2002) Nucleoside transporters of mammalian cells. In Membrane Transporters as Drug Targets. Gordon L. Amidon, Wolfgang Sadée eds, pp 313-352. Springer.
  • Cekic C, Linden J (2016) Purinergic regulation of the immune system. Nat Rev Immunol 16: 177-192. doi: 10.1038/nri.2016.4.
  • Chaplin DD (2010) Overview of the immune response. J Allergy Clin Immunol 125: S3-S23. doi: 10.1016/j.jaci.2009.12.980.
  • Cherukuri A, Cheng PC, Pierce SK (2001) The role of the CD19/CD21 complex in B cell processing and presentation of complement-tagged antigens. J Immunol 167: 163-172. doi: org/10.4049/jimmunol.167.1.163.
  • Chung JB, Sater RA, Fields ML, Erikson J, Monroe JG (2002) CD23 defines two distinct subsets of immature B cells which differ in their responses to T cell help signals. Int Immunol 14: 157-166. doi: 10.1093/intimm/14.2.157.
  • Conter LJ, Song E, Shlomchik MJ, Tomayko MM (2014) CD73 expression is dynamically regulated in the germinal center and bone marrow plasma cells are diminished in its absence. PloS ONE 9: e92009. doi: 10.1371/journal.pone.0092009.
  • Crotty S (2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol 29: 621-663. doi: 10.1146/annurev-immunol-031210-101400.
  • Deng J, Galipeau J (2012) Reprogramming of B cells into regulatory cells with engineered fusokines. Infect Disord Drug Targets 12: 248-254doi: 10.2174/187152612800564392.
  • Di Virgilio F, Vuerich M (2015) Purinergic signaling in the immune system. Auton Neurosci 191: 117-123. doi: 10.1016/j.autneu.2015.04.011.
  • Dubyak GR (2009) Both sides now: multiple interactions of ATP with pannexin-1 hemichannels. Focus on 'A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP'. Am J Physiol Cell Physiol 296: C235-C241. doi: 10.1152/ajpcell.00639.2008.
  • Dubyak GR (2012) P2X7 receptor regulation of no-classical secretion from immune effector cells. Cell Microbiol 14: 1697-1706. doi: 10.1111/cmi.12001.
  • Figueiró F, Muller L, Funk S, Jackson EK, Battastini AM, Whiteside TL (2016) Phenotypic and functional characteristics of CD39high human regulatory B cells (Breg). Oncoimmunology 5: e1082703-e1082703-10doi: 10.1080/2162402X.2015.1082703.
  • Floudas A, Amu S, Fallon PG (2016) New insights into IL-10 dependent and IL-10 independent mechanisms of regulatory B cell immune suppression. J Clin Immunol 36: 25-33. doi: 10.1007/s10875-016-0263-8.
  • Frémeaux-Bacchi V, Fischer E, Lecoanet-Henchoz S, Mani JC, Bonnefoy JY, Kazatchkine MD (1998) Soluble CD21 (sCD21) forms biologically active complexes with CD23: sCD21 is present in normal plasma as a complex with trimeric CD23 and inhibits soluble CD23-induced IgE synthesis by B cells. Int Immunol 10: 1459-1466.
  • Gessi S, Varani K, Merighi S, Cattabriga E, Avitabile A, Gavioli R, Fortini C, Leung E, Mac Lennan S, Borea PA (2004) Expression of A3 adenosine receptors in human lymphocytes: up-regulation in T cell activation. Mol Pharmacol 65: 711-719. doi: 10.1124/mol.65.3.711.
  • Gu B, Bendall LJ, Wiley JS (1998) Adenosine triphosphate-induced shedding of CD23 and L-selectin (CD62L) from lymphocytes is mediated by the same receptor but different metalloproteases. Blood 92: 946-951.
  • Henttinen T, Jalkanen S, Yegutkin GG (2003) Adherent leukocytes prevent adenosine formation and impair endothelial barrier function by Ecto-5'-nucleotidase/CD73-dependent mechanism. J Biol Chem 278: 24888-24895. doi: 10.1074/jbc.M300779200.
  • Herlands RA, Christensen SR, Sweet RA, Hershberg U, Shlomchik MJ (2008) T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells. Immunity 29: 249-260. doi: 10.1016/j.immuni.2008.06.009.
  • Herrera C, Casado V, Ciruela F, Schofield P, Mallol J, Lluis C, Franco R (2001) Adenosine A2B receptors behave as an alternative anchoring protein for cell surface adenosine deaminase in lymphocytes and cultured cells. Mol Pharmacol 59: 127-134. doi: 10.1124/mol.59.1.127.
  • Jacob F, Novo CP, Bachert C, Van Crombruggen K (2013) Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal 9: 285-306doi: 10.1007/s11302-013-9357-4.
  • Kaku H, Cheng KF, Al-Abed Y, Rothstein TL (2014) A novel mechanism of B-cell mediated immune suppression through CD73-expression and adenosine production. J Immunol 193: 5904-5913. doi: 10.4049/jimmunol.1400336.
  • Kocbuch K, Sakowicz-Burkiewicz M, Grden M, Szutowicz A, Pawelczyk T (2009) Effect of insulin and glucose on adenosine metabolizing enzymes in human B lymphocytes. Acta Biochim Pol 56: 439-446.
  • Koshiba M, Rosin DL, Hayashi N, Linden J, Sitkovsky MV (1999) Patterns of A2A extracellular adenosine receptor expression in different functional subsets of human peripheral T cells. Flow cytometry studies with anti-A2A receptor monoclonal antibodies. Mol Pharmacol 55: 614-624.
  • Lee DH, Park KS, Kong ID, Kim JW, Han BG (2006) Expression of P2 receptors in human B cells and Epstein-Barr virus-transformed lymphoblastoid cell lines. BMC Immunol 7: 22-32. doi: 10.1186/1471-2172-7-22.
  • Melchers F (2015) Checkpoints that control B cell development. J Clin Invest 125: 2203-2210. doi: 10.1172/JCI78083.
  • Molina-Arcas M, Bellosillo B, Casado FJ, Montserrat E, Gil J, Colomer D, Pastor-Anglada M (2003) Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia. Blood 101: 2328-2334. doi: 10.1182/blood-2002-07-2236.
  • Molina-Arcas M, Casado FJ, Pastor-Anglada M (2009) Nucleoside transporter proteins. Curr Vasc Pharmacol 7: 426-434.
  • Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM (2015) The generation of antibody-secreting plasma cells. Nat Rev Immunol 15: 160-171. doi: 10.1038/nri3795.
  • Palanichamy A, Barnard J, Zheng B, Owen T, Quach T, Wei C, Looney JR, Sanz J, Anolik JH (2009) Novel human transitional B cell populations revealed by B cell depletion therapy. J Immunol 182: 5982-5993. doi: 10.4049/jimmunol.0801859.
  • Panés J, Perry M, Granger DN (1999) Leukocyte-endothelial cell adhesion: avenues for therapeutic intervention. Br J Pharmacol 126: 537-550. doi: 10.1038/sj.bjp.0702328.
  • Pillai S, Cariappa A, Moran T (2005) Marginal zone B cells. Annu Rev Immunol 23: 161-196. doi: 10.1146/annurev.immunol.23.021704.115728.
  • Podgorska M, Kocbuch K, Pawelczyk T (2005) Recent advances in studies on biochemical and structural properties of equilibrative nucleoside transporters. Acta Biochim Pol 52: 749-758.
  • Rayah A, Kanellopoulos JM, Di Virgilio F (2012) P2 receptors and immunity. Microbes Infect 14: 1254-1262. doi: 10.1016/j.micinf.2012.07.006.
  • Rosser EC, Oleinika K, Tonon S, Doyle R, Bosma A, Carter NA, Harris KA, Jones SA, Klein N, Mauri C (2014) Regulatory B cells are induced by gut microbiota-driven interleukin-1beta and interleukin-6 production. Nat Med 20: 1334-1339. doi: 10.1038/nm.3680.
  • Sakowicz M, Szutowicz A, Pawelczyk T (2005) Differential effect of insulin and elevated glucose level on adenosine transport in rat B lymphocytes. Int Immunol 17: 145-154. doi: 10.1093/intimm/dxh195.
  • Sakowicz-Burkiewicz M, Kocbuch K, Grden M, Szutowicz A, Pawelczyk T (2006) Diabetes-induced decrease of adenosine kinase expression impairs the proliferation potential of diabetic rat T lymphocytes. Immunology 118: 402-412.
  • Sakowicz-Burkiewicz M, Kocbuch K, Grden M, Szutowicz A, Pawelczyk T (2009) Protein kinase C mediated high glucose effect on adenosine receptors expression in rat B lymphocytes. J Physiol Pharmacol 60: 145-153.
  • Sakowicz-Burkiewicz M, Kocbuch K, Grden M, Szutowicz A, Pawelczyk T (2010) Adenosine 5'-triphosphate is the predominant source of peripheral adenosine in human B lymphoblasts. J Physiol Pharmacol 61: 491-499.
  • Sakowicz-Burkiewicz M, Pawelczyk T (2011) Recent advances in understanding the relationship between adenosine metabolism and the function of T and B lymphocytes in diabetes. J Physiol Pharmacol 62: 505-512.
  • Sakowicz-Burkiewicz M, Kocbuch K, Grden M, Maciejewska I, Szutowicz A, Pawelczyk T (2012) Impact of adenosine receptors on immunoglobin production by human peripheral blood B lymphocytes. J Physiol Pharmacol 63: 661-668.
  • Sakowicz-Burkiewicz M, Grden M, Maciejewska I, Szutowicz A, Pawelczyk T (2013a) High glucose impairs ATP formationon the surface of human peripheral blood B lymphocytes. Int J Biochem Cell Biol 45: 1246-1254. doi: 10.1016/j.biocel.2013.03.008.
  • Sakowicz-Burkiewicz M, Kocbuch K, Grden M, Maciejewska I, Szutowicz A, Pawelczyk T (2013b) High glucose concentration impairs ATP outflow and immunoglobulin production by human peripheral B lymphocytes: involvement of P2X7 receptor. Immunobiology 218: 591-601. doi: 10.1016/j.imbio.2012.07.010.
  • Saze Z, Schuler PJ, Hong CS, Cheng D, Jackson EK, Whiteside TL (2013) Adenosine production by human B cells and B cell-mediated suppression of activated T cells. Blood 122: 9–18. doi: 10.1182/blood-2013-02-482406.
  • Schena F, Volpi S, Faliti CE, Penco F, Santi S, Proietti M, Schenk U, Damonte G, Salis A, Bellotti M, Fais F, Tenca C, Gattorno M, Eibel H, Rizzi M, Warnatz K, Idzko M, Ayata CK, Rakhmanov M, Galli T, Martini A, Canossa M, Grassi F, Traggiai E (2013) Dependence of immunoglobulin class switch recombination in B cells on vesicular release of ATP and CD73 ectonucleotidase activity. Cell Rep 3: 1824-1831. doi: 10.1016/j.celrep.2013.05.022.
  • Sengstake S, Boneberg EM, Illges H (2006) CD21 and CD62L shedding are both inducible via P2X7Rs. Int Immunol 18: 1171-1178. doi: 10.1093/intimm/dxl051.
  • Sluyter R, Barden JA, Wiley JS (2001) Detection of P2X purinergic receptors on human B lymphocytes. Cell Tissue Res 304: 231-236.
  • Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76: 301-314. doi: 10.1016/0092-8674(94)90337-9.
  • Tobón GJ, Izquierdo JH, Cañas CA (2013) B Lymphocytes: development, tolerance, and their role in autoimmunity - focus on systemic Lupus erythematosus. Autoimmune Diseases 2013: 827254. doi: 10.1155/2013/827254.
  • Venturi GM, Tu L, Kadono T, Khan AI, Fujimoto Y, Oshel P, Bock CB, Miller AS, Albrecht RM, Kubes P, Steeber DA, Tedder TF (2003) Leukocyte migration is regulated by L-selectinendoproteolyticrelease. Immunity 19: 713-724. doi: 10.1016/S1074-7613(03)00295-4.
  • Victora GD, Nussenzweig MC (2012) Germinal Centers. Annu Rev Immunol 30: 429-457. doi: 10.1146/annurev-immunol-020711-075032.
  • Wang L, Jacobsen SE, Bengtsson A, Erlinge D (2004) P2 receptor mRNA expression profiles in human lymphocytes, monocytes and CD34+stem and progenitor cells. BMC Immunology 5: 16-21. doi: 10.1186/1471-2172-5-16.
  • Wang Y, Han X (2014) B Cells with regulatory function in human diseases. Autoimmune Dis Ther Approaches 1: 107-120.
  • Warrier AC, Rao NY, Kulpati DS, Mishra TK, Kabi BC (1995) Evaluation of adenosine deaminase activity and lipid peroxidation levels in diabetes mellitus. Indian J Clin Biochem 10: 9-13. doi: 10.1007/BF02873661
  • Wu G, Marliss EB (1991) Deficiency of purine nucleoside phosphorylase activity in thymocytes from the immunodeficient diabetic BB rat. Clin Exp Immunol 86: 260-265. doi: 10.1111/j.1365-2249.1991.tb05807.x.
  • Yegutkin GG, Henttinen T, Samburski SS, Spychala J, Jalkanen S (2002) The evidence for two opposite, ATP-generating and ATP-consuming, extracellular pathways on endothelial and lymphoid cells. Biochem J 367: 121-128. doi: 10.1042/BJ20020439.
  • Yegutkin GG, Mikhailov A, Samburski SS, Jalkanen S (2006) The detection of micromolar pericellular ATP pool on lymphocyte surface by using lymphoid ecto-adenylate kinase as intrinsic ATP sensor. Mol Biol Cell 17: 3378-3385. doi: 10.1091/mbc.E05-10-0993.
  • Yegutkin GG, Auvinen K, Karikoski M, Rantakari P, Gerke H, Elima K, Maksimow M, Quintero IB, Vihko P, Salmi M, Jalkanen S (2014) Consequences of the lack of CD73 and prostatic acid phosphatase in the lymphoid organs. Mediators Inflamm 2014: 485743. doi: 10.1155/2014/485743.
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