Immunoregulatory role of B lymphocytes in alloresponse to kidney transplant
Tomasz Baran 1 , Maria Boratyńska 1Abstract
B cells are a group of diverse phenotype and function subsets, which can both stimulate and inhibit the immune response to an allograft. They participate in the rejection process by influencing differentiation, proliferation and effector functions of T lymphocytes. B cells injure the graft via the ADCC (antibody-dependent cellular cytotoxicity) reaction and humoral rejection through plasmocyte production of donor-specific antibodies.A converse, suppressive mode of B cells can attribute to the development of tolerance and protect the graft from rejection. This function is provided by the regulatory B cells, which negatively control the immune response by producing suppressor cytokines (IL-10, IL-35, TGF-β), natural antibodies and through cellular interactions. In effect they inhibit the development of Th1 and Th17 effector cells, and induce differentiation of regulatory T cells.Operational immune tolerance in human kidney transplant recipients was associated with increased number of naïve and transitional B cells of regulatory function, and increased gene expression for differentiation of B cells. However, in chronic alloantibody transplant rejection the distorted distribution and function of regulatory B cells was found, which implies their pivotal role in graft tolerance.Currently, the immunosuppressive regimens unselectively inhibit the activity of T and B cells, by interfering with their effector and immunoregulatory functions. They do not fully control the chronic rejection reaction, which is the major cause of graft loss. Comprehension of the mechanisms of immunologic homeostasis dependent on B cells can help develop immunosuppressive protocols targeted at tolerance.
References
- 1. Agematsu K., Hokibara S., Nagumo H., Komiyama A.: CD27: a memoryB-cell marker. Immunol. Today, 2000; 21: 204-206
Google Scholar - 2. Baba Y., Matsumoto M., Kurosaki T.: Signals controlling the developmentand activity of regulatory B-lineage cells. Int. Immunol.,2015; 27: 487-493
Google Scholar - 3. Banasik M., Boratyńska M., Kościelska-Kasprzak K., MazanowskaO., Bartoszek D., Zabińska M., Myszka M., Nowakowska B., Hałoń A.,Szyber P., Patrzałek D., Klinger M.: Long-term follow-up of non-HLAand anti-HLA antibodies: incidence and importance in renal transplantation.Transplant. Proc., 2013; 45: 1462-1465
Google Scholar - 4. Blair P.A., Norena L.Y., Flores-Borja F., Rawlings D.J., Isenberg D.A.,Ehrenstein M.R., Mauri C.: CD19+CD24hiCD38hi B cells exhibit regulatorycapacity in healthy individuals but are functionally impaired insystemic Lupus Erythematosus patients. Immunity, 2010; 32: 129-140
Google Scholar - 5. Bohana-Kashtan O., Civin C.I.: Fas ligand as a tool for immunosuppressionand generation of immune tolerance. Stem Cells, 2004;22: 908-924
Google Scholar - 6. Brouard S., Le Bars A., Dufay A., Gosselin M., Foucher Y., GuilletM., Cesbron-Gautier A., Thervet E., Legendre C., Dugast E., Pallier A.,Guillot-Gueguen C., Lagoutte L., Evanno G., Giral M., Soulillou J.P.:Identification of a gene expression profile associated with operationaltolerance among a selected group of stable kidney transplantpatients. Transpl. Int., 2011; 24: 536-547
Google Scholar - 7. Brouard S., Pallier A., Renaudin K., Foucher Y., Danger R., DevysA., Cesbron A., Guillot-Guegen C., Ashton-Chess J., Le Roux S., HarbJ., Roussey G., Subra J.F., Villemain F., Legendre C. i wsp.: The naturalhistory of clinical operational tolerance after kidney transplantationthrough twenty-seven cases. Am. J. Transplant., 2012; 12: 3296-3307
Google Scholar - 8. Candando K.M., Lykken J.M., Tedder T.F.: B10 cell regulation ofhealth and disease. Immunol. Rev., 2014; 259: 259-272
Google Scholar - 9. Capolunghi F., Cascioli S., Giorda E., Rosado M.M., Plebani A., AuritiC., Seganti G., Zuntini R., Ferrari S., Cagliuso M., Quinti I., CarsettiR.: CpG drives human transitional B cells to terminal differentiationand production of natural antibodies. J. Immunol., 2008; 180: 800-808
Google Scholar - 10. Carsetti R., Rosado M.M., Wardmann H.: Peripheral developmentof B cells in mouse and man. Immunol. Rev., 2004; 197: 179-191
Google Scholar - 11. Chapman J.R.: Clinical renal transplantation: where are we now,what are our key challenges? Transplant. Proc., 2010; 42 (Suppl.9): S3-S6
Google Scholar - 12. Chen X., Jensen P.E.: Cutting edge: primary B lymphocytes preferentiallyexpand allogeneic FoxP3+ CD4 T cells. J. Immunol., 2007;179: 2046-2050
Google Scholar - 13. Cherukuri A., Rothstein D.M., Clark B., Carter C.R., Davison A.,Hernandez-Fuentes M., Hewitt E., Salama A.D., Baker R.J.: Immunologichuman renal allograft injury associates with an altered IL-10/TNF-α expression ratio in regulatory B cells. J. Am. Soc. Nephrol.,2014; 25: 1575-1585
Google Scholar - 14. Chesneau M., Michel L., Dugast E., Chenouard A., Baron D., PallierA., Durand J., Braza F., Guerif P., Laplaud D.A., Soulillou J.P., GiralM., Degauque N., Chiffoleau E., Brouard S:. Tolerant kidney transplantpatients produce B Cells with regulatory properties. J. Am.Soc. Nephrol., 2015; 26: 2588-2598
Google Scholar - 15. Chesneau M., Pallier A., Braza F., Lacombe G., Le Gallou S., BaronD., Giral M., Danger R., Guerif P., Aubert-Wastiaux H., Neel A., MichelL., Laplaud D.A., Degauque N., Soulillou J.P., Tarte K., BrouardS.: Unique B cell differentiation profile in tolerant kidney transplantpatients. Am. J. Transplant., 2014; 14: 144-155
Google Scholar - 16. Chung B.H., Kim K.W., Yu J.H., Kim B.M., Choi B.S., Park C.W.,Kim Y.S., Cho M.L., Yang C.W.: Decrease of immature B cell and interleukin-10during early-post-transplant period in renal transplantrecipients under tacrolimus based immunosuppression. Transpl.Immunol., 2014; 30: 159-167
Google Scholar - 17. Clatworthy M.R., Watson C.J., Plotnek G., Bardsley V., ChaudhryA.N., Bradley J.A., Smith K.G.: B-cell-depleting induction therapyand acute cellular rejection. N. Engl. J. Med., 2009; 360: 2683-2685
Google Scholar - 18. Cobaleda C., Schebesta A., Delogu A., Busslinger M.: Pax5: theguardian of B cell identity and function. Nat. Immunol., 2007; 8:463-470
Google Scholar - 19. Cooper M.D.: Exploring lymphocyte differentiation pathways.Immunol. Rev., 2002; 185: 175-185
Google Scholar - 20. De Bruyne R., Bogaert D., De Ruyck N., Lambrecht B.N., VanWinckel M., Gevaert P., Dullaers M.: Calcineurin inhibitors dampenhumoral immunity by acting directly on naive B cells. Clin. Exp. Immunol.,2015; 180: 542-550
Google Scholar - 21. Dharnidharka V.R., Lamb K.E., Zheng J., Schechtman K.B., Meier-KriescheH.U.: Lack of significant improvements in long-termallograft survival in pediatric solid organ transplantation: a US nationalregistry analysis. Pediatr. Transplant., 2015; 19: 477-483
Google Scholar - 22. DiLillo D.J., Griffiths R., Seshan S.V., Magro C.M., Ruiz P., CoffmanT.M., Tedder T.F.: B lymphocytes differentially influence acute andchronic allograft rejection in mice. J. Immunol., 2011; 186: 2643-2654
Google Scholar - 23. DiLillo D.J., Matsushita T., Tedder T.F.: B10 cells and regulatoryB cells balance immune responses during inflammation, autoimmunity,and cancer. Ann. N. Y. Acad. Sci., 2010; 1183: 38-57
Google Scholar - 24. Ding Q., Yeung M., Camirand G., Zeng Q., Akiba H., Yagita H.,Chalasani G., Sayegh M.H., Najafian N., Rothstein D.M.: RegulatoryB cells are identified by expression of TIM-1 and can be inducedthrough TIM-1 ligation to promote tolerance in mice. J. Clin. Invest.,2011; 121: 3645-3656
Google Scholar - 25. Evans J.G., Chavez-Rueda K.A., Eddaoudi A., Meyer-Bahlburg A.,Rawlings D.J., Ehrenstein M.R., Mauri C.: Novel suppressive functionof transitional 2 B cells in experimental arthritis. J. Immunol.,2007; 178: 7868-7878
Google Scholar - 26. Feliksbrot M.E., Król M.A., Dwilewicz-Trojaczek J.: Limfopoezakomórek B u człowieka. Adv. Clin. Exp. Med., 2005; 14: 1033-1040
Google Scholar - 27. Gray D., Gray M.: What are regulatory B cells? Eur. J. Immunol.,2010; 40: 2677-2679
Google Scholar - 28. Hagn M., Schwesinger E., Ebel V., Sontheimer K., Maier J., BeyerT., Syrovets T., Laumonnier Y., Fabricius D., Simmet T., Jahrsdörfer B.: Human B cells secrete granzyme B when recognizing viral antigens in the context of the acute phase cytokine IL-21. J. Immunol.,2009; 183: 1838-1845
Google Scholar - 60. Newell K.A., Asare A., Kirk A.D., Gisler T.D., Bourcier K., SuthanthiranM., Burlingham W.J., Marks W.H., Sanz I., Lechler R.I., Hernandez-FuentesM.P., Turka L.A., Seyfert-Margolis V.L., ImmuneTolerance Network ST507 Study Group: Identification of a B cellsignature associated with renal transplant tolerance in humans. J.Clin. Invest., 2010; 120: 1836-1847
Google Scholar - 61. Nouël A., Ségalen I., Jamin C., Doucet L., Caillard S., RenaudineauY., Pers J.O., Le Meur Y., Hillion S.: B cells display an abnormaldistribution and an impaired suppressive function in patients withchronic antibody-mediated rejection. Kidney Int. 2014; 85: 590-599
Google Scholar - 62. Nouël A., Simon Q., Jamin C., Pers J.O., Hillion S.: Regulatory Bcells: an exciting target for future therapeutics in transplantation.Front. Immunol., 2014; 5: 11
Google Scholar - 63. Nova-Lamperti E., Fanelli G., Becker P.D., Chana P., ElguetaR., Dodd P.C., Lord GM., Lombardi G., Hernandez-Fuentes M.P.: IL-10-produced by human transitional B-cells down-regulates CD86expression on B-cells leading to inhibition of CD4+T-cell responses.Sci. Rep., 2016; 6: 20044
Google Scholar - 64. Olkhanud P.B., Damdinsuren B., Bodogai M., Gress R.E., Sen R.,Wejksza K., Malchinkhuu E., Wersto R.P., Biragyn A.: Tumor-evokedregulatory B cells promote breast cancer metastasis by convertingresting CD4⁺ T cells to T-regulatory cells. Cancer Res., 2011; 71:3505-3515
Google Scholar - 65. Pallier, A., Hillion S., Danger R., Giral M., Racapé M., Degauque N.,Dugast E., Ashton-Chess J., Pettré S., Lozano J.J., Bataille R., Devys A.,Cesbron-Gautier A., Braudeau C., Larrose C., Soulillou J.P., Brouard S.:Patients with drug-free long-term graft function display increasednumbers of peripheral B cells with a memory and inhibitory phenotype.Kidney Int., 2010; 78: 503-513
Google Scholar - 66. Qian L., Qian C., Chen Y., Bai Y., Bao Y., Lu L., Cao X.: Regulatorydendritic cells program B cells to differentiate into CD19hiFcgIIbhiregulatory B cells through IFN-β and CD40L. Blood, 2012; 120: 581-591
Google Scholar - 67. Ray A., Wang L., Dittel B.N.: IL-10-independent regulatory B-cellsubsets and mechanisms of action. Int. Immunol., 2015; 27: 531-536
Google Scholar - 68. Rosser E.C., Mauri C.: Regulatory B cells: origin, phenotype, andfunction. Immunity, 2015; 42: 607-612
Google Scholar - 69. Sagoo P., Perucha E., Sawitzki B., Tomiuk S., Stephens D.A., MiqueuP., Chapman S., Craciun L., Sergeant R., Brouard S., Rovis F.,Jimenez E., Ballow A., Giral M., Rebollo-Mesa I. i wsp.: Developmentof a cross-platform biomarker signature to detect renal transplanttolerance in humans. J. Clin. Invest., 2010; 120: 1848-1861
Google Scholar - 70. Shabir S., Girdlestone J., Briggs D., Kaul B., Smith H., Daga S.,Chand S., Jham S., Navarrete C., Harper L., Ball S., Borrows R.: TransitionalB lymphocytes are associated with protection from kidneyallograft rejection: a prospective study. Am. J. Transplant., 2015;15: 1384-1391
Google Scholar - 71. Shen P., Roch T., Lampropoulou V., O’Connor R.A., Stervbo U.,Hilgenberg E., Ries S., Dang V.D., Jaimes Y., Daridon C., Li R., JouneauL., Boudinot P., Wilantri S., Sakwa I. i wsp.: IL-35-producing B cellsare critical regulators of immunity during autoimmune and infectiousdiseases. Nature, 2014; 507: 366-370
Google Scholar - 72. Silva H.M., Takenaka M.C., Moraes-Vieira P.M., Monteiro S.M.,Hernandez M.O., Chaara W., Six A., Agena F., Sesterheim P., Barbé–Tuana F.M., Saitovitch D., Lemos F., Kalil J., Coelho V.: Preservingthe B-cell compartment favors operational tolerance in human renaltransplantation. Mol. Med., 2012; 18: 733-743
Google Scholar - 73. Sims G.P., Ettinger R., Shirota Y., Yarboro C.H., Illei G.G., LipskyP.E.: Identification and characterization of circulating human transitionalB cells. Blood, 2005; 105: 4390-4398
Google Scholar - 74. Svachova V., Sekerkova A., Hruba P., Tycova I., Rodova M., CecrdlovaE., Slatinska J., Honsova E., Striz I., Viklicky O.: Dynamicchanges of B-cell compartments in kidney transplantation: lack oftransitional B cells is associated with allograft rejection. Transpl.Int., 2016; 29: 540-548
Google Scholar - 75. Tedder T.F.: B10 cells: a functionally defined regulatory B cellsubset. J. Immunol., 2015; 194: 1395-1401
Google Scholar - 76. Todeschini M., Cortinovis M., Perico N., Poli F., Innocente A.,Cavinato R.A., Gotti E., Ruggenenti P., Gaspari F., Noris M., RemuzziG., Casiraghi F.: In kidney transplant patients, alemtuzumab but notbasiliximab/low-dose rabbit anti-thymocyte globulin induces B celldepletion and regeneration, which associates with a high incidenceof de novo donor-specific anti-HLA antibody development. J. Immunol.,2013; 191: 2818-2828
Google Scholar - 77. van de Berg P.J., Hoevenaars E.C., Yong S.L., van Donselaar-vander Pant K.A., van Tellingen A., Florquin S., van Lier R.A., BemelmanF.J., ten Berge I.J.: Circulating lymphocyte subsets in different clinicalsituations after renal transplantation. Immunology, 2012; 136: 198-207
Google Scholar - 78. van de Veen W., Stanic B., Yaman G., Wawrzyniak M., Söllner S., AkdisD.G., Rückert B., Akdis C.A., Akdis M.: IgG4 production is confined tohuman IL-10-producing regulatory B cells that suppress antigen-specificimmune responses. J. Allergy Clin. Immunol., 2013; 131: 1204-1212
Google Scholar - 79. Viklicky O., Krystufkova E., Brabcova I., Sekerkova A., Wohlfahrt P.,Hribova P., Wohlfahrtova M., Sawitzki B., Slatinska J., Striz I., Volk H.D.,Reinke P.: B-cell-related biomarkers of tolerance are up-regulated in rejection-freekidney transplant recipients. Transplantation, 2013; 95: 148-154
Google Scholar - 80. Walsh L., Dinavahi R.: Current unmet needs in renal transplantation:a review of challenges and therapeutics. Front. Biosci., 2016; 8: 1-14
Google Scholar - 81. Wang R.X., Yu C.R., Dambuza I.M., Mahdi R.M., Dolinska M.B.,Sergeev Y.V., Wingfield P.T., Kim S.H., Egwuagu C.E.: Interleukin-35induces regulatory B cells that suppress autoimmune disease. Nat.Med., 2014; 20: 633-641
Google Scholar - 82. Wolf S.D., Dittel B.N., Hardardottir F., Janeway C.A.Jr.: Experimentalautoimmune encephalomyelitis induction in genetically Bcell-deficient mice. J. Exp. Med., 1996; 184: 2271-2278
Google Scholar - 83. Wootla B., Nicoletti A., Patey N., Dimitrov J.D., Legendre C., ChristopheO.D., Friboulet A., Kaveri S.V., Lacroix-Desmazes S., ThaunatO.: Hydrolysis of coagulation factors by circulating IgG is associatedwith a reduced risk for chronic allograft nephropathy in renal transplantedpatients. J. Immunol., 2008; 180: 8455-8460
Google Scholar - 84. Yan Y., van der Putten K., Bowen D.G., Painter D.M., Kohar J.,Sharland A.F., McCaughan G.W., Bishop G.A.: Postoperative administrationof donor B cells induces rat kidney allograft acceptance: lackof association with Th2 cytokine expression in long-term acceptedgrafts. Transplantation, 2002; 73: 1123-1130
Google Scholar - 85. Yanaba K., Bouaziz J.D., Matsushita T., Magro C.M., St Clair E.W.,Tedder T.F.: B-lymphocyte contributions to human autoimmune disease.Immunol. Rev., 2008; 223: 284-299
Google Scholar - 86. Yanaba K., Hamaguchi Y., Venturi G.M., Steeber D.A., St ClairE.W., Tedder T.F.: B cell depletion delays collagen-induced arthritisin mice: arthritis induction requires synergy between humoral andcell-mediated immunity. J. Immunol., 2007; 179: 1369-1380
Google Scholar - 87. Yang M., Deng J., Liu Y., Ko K.H., Wang X., Jiao Z., Wang S., Hua Z.,Sun L., Srivastava G., Lau C.S., Cao X., Lu L.: IL-10-producing regulatoryB10 cells ameliorate collagen-induced arthritis via suppressingTh17 cell generation. Am. J. Pathol., 2012; 180: 2375-2385
Google Scholar - 88. Zand M.S., Vo T., Huggins J., Felgar R., Liesveld J., Pellegrin T.,Bozorgzadeh A., Sanz I., Briggs B.J.: Polyclonal rabbit antithymocyteglobulin triggers B-cell and plasma cell apoptosis by multiple pathways.Transplantation, 2005; 79: 1507-1515
Google Scholar - 89. Zarkhin V., Lovelace P.A., Li L., Hsieh S.C., Sarwal M.M.: Phenotypicevaluation of B-cell subsets after rituximab for treatment ofacute renal allograft rejection in pediatric recipients. Transplantation,2011; 91: 1010-1018
Google Scholar - 90. Zhang Y., Gallastegui N., Rosenblatt J.D.: Regulatory B cells inanti-tumor immunity. Int. Immunol., 2015; 27: 521-530
Google Scholar