Regulatory B cells

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Regulatory B cells (Bregs) represent a small population of B cells which participates in immunomodulations and in suppression of immune responses. These cells regulate the immune system by different mechanisms. The main mechanism is a production of anti-inflammatory cytokine interleukin 10 (IL-10). The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions and in anti-tumor immunity.

History[edit]

In the 1970s it was noticed that Bregs could suppress immune reaction independently of antibody production.[1] In 1996 Janeway´s group observed an immunomodulation of experimental autoimmune encephalomyelitis (EAE) by B cells.[2] Similar results were shown in a model of chronic colitis one year later.[3] Then a role of Bregs was found in many mouse models of autoimmune diseases as rheumatoid arthritis[4] or systemic lupus erythematosus (SLE).[5]

Development and Breg populations[edit]

Bregs can develop from different subsets of B cells. Whether Breg cells uniquely derive from a specific progenitor or originate within conventional B cell subsets is still an open question.[6] Bregs shared many markers with various B cells subsets due to their origin. Mouse Bregs were mainly CD5 and CD1d positive in model of EAE or after exposition of Leishmania major.[7][8] By contrast mouse Bregs in model of collagen-induced arthritis (CIA) were mainly CD21 and CD23 positive.[9] Breg were found in human, too. Markers of peripheral blood Bregs were molecules CD24 and CD38.[10] However, peripheral blood Bregs were mostly CD24 and CD27 positive after cultivation with anti-CD40 antibody and CpG bacterial DNA.[11] They were also positive for CD25, CD71 and PD-L1 after stimulation by CpG bacterial DNA and through TLR9.[12]

Mechanisms of Breg action[edit]

There are several mechanisms of Breg action. Nevertheless, the most examined mechanism is production of IL-10. IL-10 has strong anti-inflammatory effects.[13][14] and it inhibits or suppresses inflammatory reactions mediated by T cells, especially Th1 type immune reactions. This was shown for example in model EAE,[15] CIA[16] or contact hypersensitivity.[17] Likewise, regulatory B cell subsets have also been demonstrated to inhibit Th1 responses through IL-10 production during chronic infectious diseases such as visceral leishmaniasis.[18] Next suppressive Breg mechanism is production of transforming growth factor (TGF-β), another anti-inflammatory cytokine.[13] Role of Bregs producing TGF-β was found in mouse of models of SLE [5] and diabetes.[19] Another mechanism of Breg acting involves surface molecules, for example FasL[20] or PD-L1,[18][21] which cause death of target cells.

References[edit]

  1. ^ KATZ, S. I.; PARKER, DARIEN; TURK, J. L. (11 October 1974). "B-cell suppression of delayed hypersensitivity reactions". Nature. 251 (5475): 550–551. doi:10.1038/251550a0. PMID 4547522. 
  2. ^ Wolf, SD; Dittel, BN; Hardardottir, F; Janeway CA, Jr (Dec 1, 1996). "Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice". The Journal of Experimental Medicine. 184 (6): 2271–8. doi:10.1084/jem.184.6.2271. PMC 2196394Freely accessible. PMID 8976182. 
  3. ^ Mizoguchi, A; Mizoguchi, E; Smith, RN; Preffer, FI; Bhan, AK (Nov 17, 1997). "Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice". The Journal of Experimental Medicine. 186 (10): 1749–56. doi:10.1084/jem.186.10.1749. PMC 2199135Freely accessible. PMID 9362534. 
  4. ^ Korganow, AS; Ji, H; Mangialaio, S; Duchatelle, V; Pelanda, R; Martin, T; Degott, C; Kikutani, H; Rajewsky, K; Pasquali, JL; Benoist, C; Mathis, D (Apr 1999). "From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins". Immunity. 10 (4): 451–61. doi:10.1016/s1074-7613(00)80045-x. PMID 10229188. 
  5. ^ a b Douglas, RS; Woo, EY; Capocasale, RJ; Tarshis, AD; Nowell, PC; Moore, JS (Aug 1, 1997). "Altered response to and production of TGF-beta by B cells from autoimmune NZB mice". Cellular immunology. 179 (2): 126–37. doi:10.1006/cimm.1997.1149. PMID 9268496. 
  6. ^ Vitale, G; Mion, F; Pucillo, C (Nov–Dec 2010). "Regulatory B cells: evidence, developmental origin and population diversity". Molecular immunology. 48 (1–3): 1–8. doi:10.1016/j.molimm.2010.09.010. PMID 20950861. 
  7. ^ Matsushita, Takashi; Yanaba, Koichi; Bouaziz, Jean-David; Fujimoto, Manabu; Tedder, Thomas F. (18 September 2008). "Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression". Journal of Clinical Investigation. 118: 3420–30. doi:10.1172/JCI36030. PMC 2542851Freely accessible. PMID 18802481. 
  8. ^ Ronet, C; Hauyon-La Torre, Y; Revaz-Breton, M; Mastelic, B; Tacchini-Cottier, F; Louis, J; Launois, P (Jan 15, 2010). "Regulatory B cells shape the development of Th2 immune responses in BALB/c mice infected with Leishmania major through IL-10 production". Journal of Immunology. 184 (2): 886–94. doi:10.4049/jimmunol.0901114. PMID 19966209. 
  9. ^ Evans, JG; Chavez-Rueda, KA; Eddaoudi, A; Meyer-Bahlburg, A; Rawlings, DJ; Ehrenstein, MR; Mauri, C (Jun 15, 2007). "Novel suppressive function of transitional 2 B cells in experimental arthritis". Journal of Immunology. 178 (12): 7868–78. PMID 17548625. 
  10. ^ Blair, Paul A.; Noreña, Lina Yassin; Flores-Borja, Fabian; Rawlings, David J.; Isenberg, David A.; Ehrenstein, Michael R.; Mauri, Claudia (2010). "CD19+CD24hiCD38hi B Cells Exhibit Regulatory Capacity in Healthy Individuals but Are Functionally Impaired in Systemic Lupus Erythematosus Patients". Immunity. 32 (1): 129–140. doi:10.1016/j.immuni.2009.11.009. PMID 20079667. 
  11. ^ Iwata, Y; Matsushita, T; Horikawa, M; Dilillo, DJ; Yanaba, K; Venturi, GM; Szabolcs, PM; Bernstein, SH; Magro, CM; Williams, AD; Hall, RP; St Clair, EW; Tedder, TF (Jan 13, 2011). "Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells". Blood. 117 (2): 530–41. doi:10.1182/blood-2010-07-294249. PMC 3031478Freely accessible. PMID 20962324. 
  12. ^ van de Veen, W; Stanic, B; Yaman, G; Wawrzyniak, M; Söllner, S; Akdis, DG; Rückert, B; Akdis, CA; Akdis, M (Apr 2013). "IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses". The Journal of Allergy and Clinical Immunology. 131 (4): 1204–12. doi:10.1016/j.jaci.2013.01.014. PMID 23453135. 
  13. ^ a b Berthelot, Jean-Marie; Jamin, Christophe; Amrouche, Kahina; Le Goff, Benoit; Maugars, Yves; Youinou, Pierre (2013). "Regulatory B cells play a key role in immune system balance". Joint Bone Spine. 80 (1): 18–22. doi:10.1016/j.jbspin.2012.04.010. PMID 22858147. 
  14. ^ Asseman, C; Mauze, S; Leach, MW; Coffman, RL; Powrie, F (Oct 4, 1999). "An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation". The Journal of Experimental Medicine. 190 (7): 995–1004. doi:10.1084/jem.190.7.995. PMC 2195650Freely accessible. PMID 10510089. 
  15. ^ Fillatreau, Simon; Sweenie, Claire H.; McGeachy, Mandy J.; Gray, David; Anderton, Stephen M. (3 September 2002). "B cells regulate autoimmunity by provision of IL-10". Nature Immunology. 3 (10): 944–950. doi:10.1038/ni833. PMID 12244307. 
  16. ^ Mauri, C; Gray, D; Mushtaq, N; Londei, M (Feb 17, 2003). "Prevention of arthritis by interleukin 10-producing B cells". The Journal of Experimental Medicine. 197 (4): 489–501. doi:10.1084/jem.20021293. PMC 2193864Freely accessible. PMID 12591906. 
  17. ^ Yanaba, K; Bouaziz, JD; Haas, KM; Poe, JC; Fujimoto, M; Tedder, TF (May 2008). "A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses". Immunity. 28 (5): 639–50. doi:10.1016/j.immuni.2008.03.017. PMID 18482568. 
  18. ^ a b Schaut, RG; Lamb, IM; Toepp, AJ; Scott, B; Mendes-Aguiar, CO; Coutinho, JF; Jeronimo, SM; Wilson, ME; Harty, JT; Waldschmidt, TJ; Petersen, CA (13 April 2016). "Regulatory IgDhi B Cells Suppress T Cell Function via IL-10 and PD-L1 during Progressive Visceral Leishmaniasis". Journal of Immunology. 196: 4100–9. doi:10.4049/jimmunol.1502678. PMID 27076677. 
  19. ^ Tian, J; Zekzer, D; Hanssen, L; Lu, Y; Olcott, A; Kaufman, DL (Jul 15, 2001). "Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice". Journal of Immunology. 167 (2): 1081–9. doi:10.4049/jimmunol.167.2.1081. PMID 11441119. 
  20. ^ Lundy, SK; Boros, DL (Feb 2002). "Fas ligand-expressing B-1a lymphocytes mediate CD4(+)-T-cell apoptosis during schistosomal infection: induction by interleukin 4 (IL-4) and IL-10". Infection and Immunity. 70 (2): 812–9. doi:10.1128/iai.70.2.812-819.2002. PMC 127725Freely accessible. PMID 11796615. 
  21. ^ Carter, Laura L.; Leach, Michael W.; Azoitei, Mihai L.; Cui, Junqing; Pelker, Jeffrey W.; Jussif, Jason; Benoit, Steve; Ireland, Gretchen; Luxenberg, Deborah; Askew, G. Roger; Milarski, Kim L.; Groves, Christopher; Brown, Tom; Carito, Brenda A.; Percival, Karen; Carreno, Beatriz M.; Collins, Mary; Marusic, Suzana (2007). "PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis". Journal of Neuroimmunology. 182 (1–2): 124–134. doi:10.1016/j.jneuroim.2006.10.006. PMID 17182110.