Regulatory B cells

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

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

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

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 SLE [5] or 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

  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. 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. 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. 1 2 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. doi:10.1172/JCI36030.
  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 (Baltimore, Md. : 1950) 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 (Baltimore, Md. : 1950) 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. 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. 1 2 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. 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. 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. 1 2 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 (Baltimore, Md. : 1950). 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 (Baltimore, Md. : 1950) 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. 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.
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