Regulatory B cell

Regulatory B cells (Bregs or Breg cell) 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 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 action

Structure of interleukin 10 (IL-10). Key player in Breg biology.

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] It inhibits (or suppresses) inflammatory reactions mediated by T cells, especially Th1 type immune reactions. This was shown for example in model of 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.

Activation

Resting B lymphocytes do not produce cytokines. After lipopolysaccharide (LPS) stimulation are produced TNFα, IL-1β, IL-10 and IL-6. This indicates that Breg must be stimulated to produce suppressive cytokines. There are two types of signals to activate Breg, namely signals generated by external pathogens and endogenous signals produced by the action of body cells. Structures characteristic of pathogenic microorganisms recognize the TLR receptors that trigger a signal cascade at the end of which is the production of effector cytokines. The main endogenous signal is the stimulation of the surface molecule CD40.[22]

Models of action

Autoimmune diseases

In autoimmune diseases, many models of Breg involvement are described in the suppression or alleviation of autoimmune pathology. The most well-known mechanism of action of Bregs is the production of anti-inflammatory cytokines, most IL-10. This mechanism was described in the EAE model,[15] but also in lupus erythematosus.[23] Another cytokine produced with an anti-inflammatory effect is TGF-β, which has a role in the suppression of T lymphocytes, for example in diabetes.[19] Not just cytokines can cause an anti-inflammatory state. There is also the second option to do it. There are also surface molecules (which may be FasL), which after binding to the target cell receptor, causes apoptosis. An increase in expression of this molecule has been described in the collagen-induced arthritis model.[24]

Tumors

In order to suppress immune responses, it is possible that cancerous proliferation uses Breg for its leakage from the immune system. Leukemia B cells spontaneously produce large amounts of IL-10.[25] Similarly, secretion of TNF-α B cells promotes the development of skin carcinoma.[26] However, the positive effect of Breg on the treatment of cancer is also described. In patients with metastatic cancer, those with a higher number of CD20 positive B lymphocytes in the lymph nodes are more likely to survive.[27]

Transplantation

The immunosuppressive properties of Breg play an essential role in allotransplants. It is necessary to cushion the immune response against the transplant and Breg can do it.[28] For other types of transplants, B cells can participate both in tolerance and more often in transplant rejection, depending on the origin of Breg subpopulations.

References

  1. ↑ Katz SI, Parker D, Turk JL (October 1974). "B-cell suppression of delayed hypersensitivity reactions". Nature. 251 (5475): 550–1. doi:10.1038/251550a0. PMID 4547522. S2CID 4145793.
  2. ↑ Wolf SD, Dittel BN, Hardardottir F, Janeway CA (December 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 2196394. PMID 8976182.
  3. ↑ Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK (November 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 2199135. 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 (April 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 (August 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 T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF (October 2008). "Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression". The Journal of Clinical Investigation. 118 (10): 3420–30. doi:10.1172/JCI36030. PMC 2542851. PMID 18802481.
  8. ↑ Ronet C, Hauyon-La Torre Y, Revaz-Breton M, Mastelic B, Tacchini-Cottier F, Louis J, Launois P (January 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 (June 2007). "Novel suppressive function of transitional 2 B cells in experimental arthritis". Journal of Immunology. 178 (12): 7868–78. doi:10.4049/jimmunol.178.12.7868. PMID 17548625.
  10. ↑ Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, Mauri C (January 2010). "CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients". Immunity. 32 (1): 129–40. 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 (January 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 3031478. PMID 20962324.
  12. ↑ van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Söllner S, Akdis DG, Rückert B, Akdis CA, Akdis M (April 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 JM, Jamin C, Amrouche K, Le Goff B, Maugars Y, Youinou P (January 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 (October 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 2195650. PMID 10510089.
  15. 1 2 Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM (October 2002). "B cells regulate autoimmunity by provision of IL-10". Nature Immunology. 3 (10): 944–50. doi:10.1038/ni833. PMID 12244307. S2CID 8359750.
  16. ↑ Mauri C, Gray D, Mushtaq N, Londei M (February 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 2193864. 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 (May 2016). "Regulatory IgDhi B Cells Suppress T Cell Function via IL-10 and PD-L1 during Progressive Visceral Leishmaniasis". Journal of Immunology. 196 (10): 4100–9. doi:10.4049/jimmunol.1502678. PMC 4868652. PMID 27076677.
  19. 1 2 Tian J, Zekzer D, Hanssen L, Lu Y, Olcott A, Kaufman DL (July 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 (February 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 127725. PMID 11796615.
  21. ↑ Carter LL, Leach MW, Azoitei ML, Cui J, Pelker JW, Jussif J, Benoit S, Ireland G, Luxenberg D, Askew GR, Milarski KL, Groves C, Brown T, Carito BA, Percival K, Carreno BM, Collins M, Marusic S (January 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): 124–34. doi:10.1016/j.jneuroim.2006.10.006. PMID 17182110. S2CID 479907.
  22. ↑ Rosser EC, Mauri C (April 2015). "Regulatory B cells: origin, phenotype, and function". Immunity. 42 (4): 607–12. doi:10.1016/j.immuni.2015.04.005. PMID 25902480.
  23. ↑ Blair PA, Chavez-Rueda KA, Evans JG, Shlomchik MJ, Eddaoudi A, Isenberg DA, Ehrenstein MR, Mauri C (March 2009). "Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice". Journal of Immunology. 182 (6): 3492–3502. doi:10.4049/jimmunol.0803052. PMC 4082659. PMID 19265127.
  24. ↑ Lundy SK, Fox DA (2009). "Reduced Fas ligand-expressing splenic CD5+ B lymphocytes in severe collagen-induced arthritis". Arthritis Research & Therapy. 11 (4): R128. doi:10.1186/ar2795. PMC 2745812. PMID 19706160.
  25. ↑ Wang X, Yuling H, Yanping J, Xinti T, Yaofang Y, Feng Y, Ruijin X, Li W, Lang C, Jingyi L, Zhiqing T, Jingping O, Bing X, Li Q, Chang AE, Sun Z, Youxin J, Jinquan T (September 2007). "CCL19 and CXCL13 synergistically regulate interaction between B cell acute lymphocytic leukemia CD23+CD5+ B Cells and CD8+ T cells". Journal of Immunology. 179 (5): 2880–8. doi:10.4049/jimmunol.179.5.2880. PMID 17709502.
  26. ↑ Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H, Nedospasov S, Mauri C, Coussens LM, Balkwill FR (June 2011). "B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis". Proceedings of the National Academy of Sciences of the United States of America. 108 (26): 10662–7. doi:10.1073/pnas.1100994108. PMC 3127875. PMID 21670304.
  27. ↑ Pretscher D, Distel LV, Grabenbauer GG, Wittlinger M, Buettner M, Niedobitek G (August 2009). "Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+ B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma". BMC Cancer. 9 (1): 292. doi:10.1186/1471-2407-9-292. PMC 2739224. PMID 19698134.
  28. ↑ Silva HM, Takenaka MC, Moraes-Vieira PM, Monteiro SM, Hernandez MO, Chaara W, Six A, Agena F, Sesterheim P, Barbé-Tuana FM, Saitovitch D, Lemos F, Kalil J, Coelho V (July 2012). "Preserving the B-cell compartment favors operational tolerance in human renal transplantation" (PDF). Molecular Medicine. 18 (5): 733–43. doi:10.2119/molmed.2011.00281. PMC 3409285. PMID 22252714.
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