Review Article | Published:

Effector and regulatory B cells in immune-mediated kidney disease

Nature Reviews Nephrologyvolume 15pages1126 (2019) | Download Citation

Abstract

B cells have a central role in many autoimmune diseases, including in those with renal involvement, as well as in the immunological response to kidney transplantation. The majority of B cell studies have focused on their pathological role as antibody producers. However, these cells have broad functions in immune responses beyond immunoglobulin secretion, including antigen presentation to T cells and cytokine production. Importantly, not all B cell subsets enhance immune responses. Regulatory B (Breg) cells attenuate inflammation and contribute to the maintenance of immune tolerance. Breg cells are numerically deficient and/or dysfunctional in several autoimmune diseases that can affect the kidneys, including systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody-associated vasculitis, as well as in some groups of renal transplant recipients with alloimmune graft damage. B cell-targeting biologics have been trialled with promising results in diverse immune-mediated renal conditions. These therapies can affect both pro-inflammatory B cells and Breg cells, potentially limiting their long-term efficacy. Future strategies might involve the modulation of pro-inflammatory B cells in combination with the stimulation of regulatory subsets. Additionally, the monitoring of individual B cell subsets in patients may lead to the discovery of novel biomarkers that could help to predict disease relapse or progression.

Key points

  • B cells can promote disease through the production of antibodies, the release of pro-inflammatory cytokines and the presentation of antigen to T cells, which leads to T cell activation and polarization

  • Regulatory B (Breg) cell subsets can attenuate disease through the action of the immunomodulatory cytokine IL-10 and various other mechanisms

  • An imbalance in the numbers or function of pro-inflammatory and regulatory B cell subsets is found in various immune-mediated renal diseases and in renal transplant cohorts

  • Quantitative and qualitative assessment of B cell subsets may lead to the identification of biomarkers that could predict disease outcomes or relapse and instruct therapeutic strategies

  • B cell depletion has been successfully used for the treatment of various autoimmune diseases that affect the kidneys; the utility of B cell depletion therapy in kidney transplantation remains uncertain

  • As the available agents that are used for total B cell depletion remove Breg cells as well as pro-inflammatory B cells, a need exists for more targeted approaches using novel agents or combination therapies

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References

  1. 1.

    Guillevin, L. et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N. Engl. J. Med. 371, 1771–1780 (2014).

  2. 2.

    Jones, R. B. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N. Engl. J. Med. 363, 211–220 (2010).

  3. 3.

    Stone, J. H. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N. Engl. J. Med. 363, 221–232 (2010).

  4. 4.

    De Vita, S. et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum. 64, 843–853 (2012).

  5. 5.

    Fornoni, A. et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci. Transl Med. 3, 85ra46 (2011).

  6. 6.

    Liu, L. L. et al. Th17/Treg imbalance in adult patients with minimal change nephrotic syndrome. Clin. Immunol. 139, 314–320 (2011).

  7. 7.

    Sims, G. P. et al. Identification and characterization of circulating human transitional B cells. Blood 105, 4390–4398 (2005).

  8. 8.

    Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272, 54–60 (1996).

  9. 9.

    Mesin, L., Ersching, J. & Victora, G. D. Germinal center B cell dynamics. Immunity 45, 471–482 (2016).

  10. 10.

    Plotkin, S. A. Correlates of protection induced by vaccination. Clin. Vaccine Immunol. 17, 1055–1065 (2010).

  11. 11.

    Epstein, M. M., Di Rosa, F., Jankovic, D., Sher, A. & Matzinger, P. Successful T cell priming in B cell-deficient mice. J. Exp. Med. 182, 915–922 (1995).

  12. 12.

    Phillips, J. A. et al. CD4+ T cell activation and tolerance induction in B cell knockout mice. J. Exp. Med. 183, 1339–1344 (1996).

  13. 13.

    Topham, D. J., Tripp, R. A., Hamilton-Easton, A. M., Sarawar, S. R. & Doherty, P. C. Quantitative analysis of the influenza virus-specific CD4+ T cell memory in the absence of B cells and Ig. J. Immunol. 157, 2947–2952 (1996).

  14. 14.

    Angeli, V. et al. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24, 203–215 (2006).

  15. 15.

    Homann, D. et al. Evidence for an underlying CD4 helper and CD8 T cell defect in B cell-deficient mice: failure to clear persistent virus infection after adoptive immunotherapy with virus-specific memory cells from muMT/muMT mice. J. Virol. 72, 9208–9216 (1998).

  16. 16.

    Bouaziz, J. D. et al. Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice. Proc. Natl Acad. Sci. USA 104, 20878–20883 (2007).

  17. 17.

    Chan, O. T., Hannum, L. G., Haberman, A. M., Madaio, M. P. & Shlomchik, M. J. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J. Exp. Med. 189, 1639–1648 (1999).

  18. 18.

    Chatzidionysiou, K. et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann. Rheum. Dis. 70, 1575–1580 (2011).

  19. 19.

    Tomana, M. et al. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J. Clin. Invest. 104, 73–81 (1999).

  20. 20.

    van der Woude, F. J. et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1, 425–429 (1985).

  21. 21.

    Wilson, C. B. & Dixon, F. J. Anti-glomerular basement membrane antibody-induced glomerulonephritis. Kidney Int. 3, 74–89 (1973).

  22. 22.

    Boh, E. E. Neonatal lupus erythematosus. Clin. Dermatol. 22, 125–128 (2004).

  23. 23.

    Schlieben, D. J., Korbet, S. M., Kimura, R. E., Schwartz, M. M. & Lewis, E. J. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am. J. Kidney Dis. 45, 758–761 (2005).

  24. 24.

    Colvin, R. B. & Smith, R. N. Antibody-mediated organ-allograft rejection. Nat. Rev. Immunol. 5, 807–817 (2005).

  25. 25.

    Loupy, A., Hill, G. S. & Jordan, S. C. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat. Rev. Nephrol. 8, 348–357 (2012).

  26. 26.

    Smith, R. N. & Colvin, R. B. Chronic alloantibody mediated rejection. Semin. Immunol. 24, 115–121 (2012).

  27. 27.

    Porcheray, F. et al. Chronic humoral rejection of human kidney allografts associates with broad autoantibody responses. Transplantation 89, 1239–1246 (2010).

  28. 28.

    Kissmeye, F., Olsen, S., Petersen, V. P. & Fjeldborg, O. Hyperacute rejection of kidney allografts associated with pre-existing humoral antibodies against donor cells. Lancet 2, 662–665 (1966).

  29. 29.

    Lefaucheur, C. et al. IgG donor-specific anti-human HLA antibody subclasses and kidney allograft antibody-mediated injury. J. Am. Soc. Nephrol. 27, 293–304 (2016).

  30. 30.

    Vidarsson, G., Dekkers, G. & Rispens, T. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 5, 520 (2014).

  31. 31.

    Wunderlich, C., Oliviera, I., Figueiredo, C. P., Rech, J. & Schett, G. Effects of DMARDs on citrullinated peptide autoantibody levels in RA patients-A longitudinal analysis. Semin. Arthritis Rheum. 46, 709–714 (2017).

  32. 32.

    Huang, H., Benoist, C. & Mathis, D. Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc. Natl Acad. Sci. USA 107, 4658–4663 (2010).

  33. 33.

    Rodriguez-Pinto, D. B cells as antigen presenting cells. Cell. Immunol. 238, 67–75 (2005).

  34. 34.

    Liossis, S. N. & Sfikakis, P. P. Rituximab-induced B cell depletion in autoimmune diseases: potential effects on T cells. Clin. Immunol. 127, 280–285 (2008).

  35. 35.

    Noorchashm, H. et al. B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J. Immunol. 177, 7715–7722 (2006).

  36. 36.

    Zeng, Q. et al. B cells mediate chronic allograft rejection independently of antibody production. J. Clin. Invest. 124, 1052–1056 (2014).

  37. 37.

    Shiu, K. Y. et al. Graft dysfunction in chronic antibody-mediated rejection correlates with B cell-dependent indirect antidonor alloresponses and autocrine regulation of interferon-γ production by Th1 cells. Kidney Int. 91, 477–492 (2017).

  38. 38.

    Yan, J. & Mamula, M. J. B and T cell tolerance and autoimmunity in autoantibody transgenic mice. Int. Immunol. 14, 963–971 (2002).

  39. 39.

    Shen, P. & Fillatreau, S. Antibody-independent functions of B cells: a focus on cytokines. Nat. Rev. Immunol. 15, 441–451 (2015).

  40. 40.

    Harris, D. P. et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat. Immunol. 1, 475–482 (2000). This study is the first to demonstrate that B cells are potent producers of cytokines, which are able to influence T cell responses.

  41. 41.

    Wojciechowski, W. et al. Cytokine-producing effector B cells regulate type 2 immunity to H. polygyrus. Immunity 30, 421–433 (2009).

  42. 42.

    Barr, T. A. et al. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J. Exp. Med. 209, 1001–1010 (2012).

  43. 43.

    Li, R. et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl Med. 7, 310ra166 (2015).

  44. 44.

    Sieber, J. et al. Active systemic lupus erythematosus is associated with a reduced cytokine production by B cells in response to TLR9 stimulation. Arthritis Res. Ther. 16, 477 (2014).

  45. 45.

    Noronha, I. L., Kruger, C., Andrassy, K., Ritz, E. & Waldherr, R. In situ production of TNF-α, IL-1β and IL-2R in ANCA-positive glomerulonephritis. Kidney Int. 43, 682–692 (1993).

  46. 46.

    Haas, C., Ryffel, B. & LeHir, M. IFN-γ is essential for the development of autoimmune glomerulonephritis in MRL/lpr mice. J. Immunol. 158, 5484–5491 (1997).

  47. 47.

    Kerjaschki, D. et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J. Am. Soc. Nephrol. 15, 603–612 (2004).

  48. 48.

    Sarwal, M. et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N. Engl. J. Med. 349, 125–138 (2003).

  49. 49.

    Tsai, E. W. et al. CD20+ lymphocytes in renal allografts are associated with poor graft survival in pediatric patients. Transplantation 82, 1769–1773 (2006).

  50. 50.

    Heller, F. et al. The contribution of B cells to renal interstitial inflammation. Am. J. Pathol. 170, 457–468 (2007).

  51. 51.

    Hruskova, Z. et al. Repeat protocol renal biopsy in ANCA-associated renal vasculitis. Nephrol. Dial. Transplant. 29, 1728–1732 (2014).

  52. 52.

    Mauri, C. & Bosma, A. Immune regulatory function of B cells. Annu. Rev. Immunol. 30, 221–241 (2012).

  53. 53.

    Menon, M., Blair, P. A., Isenberg, D. A. & Mauri, C. A. Regulatory feedback between plasmacytoid dendritic cells and regulatory B cells is aberrant in systemic lupus erythematosus. Immunity 44, 683–697 (2016).

  54. 54.

    Rosser, E. C. et al. Regulatory B cells are induced by gut microbiota-driven interleukin-1β and interleukin-6 production. Nat. Med. 20, 1334–1339 (2014).

  55. 55.

    Yoshizaki, A. et al. Regulatory B cells control T cell autoimmunity through IL-21-dependent cognate interactions. Nature 491, 264–268 (2012).

  56. 56.

    Blair, P. A. et al. CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 32, 129–140 (2010). This study is the first characterization of human B reg cells in PBMCs.

  57. 57.

    Iwata, Y. et al. Characterization of a rare IL-10-competent B cell subset in humans that parallels mouse regulatory B10 cells. Blood 117, 530–541 (2011). This study is the first to identify the human equivalent of mouse B10 B reg cells.

  58. 58.

    Matsumoto, M. et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity 41, 1040–1051 (2014). This is the first study to characterize B reg cells with a plasmablast phenotype.

  59. 59.

    Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 3, 944–950 (2002).

  60. 60.

    Burkett, P. R., Meyer zu Horste, G. & Kuchroo, V. K. Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. J. Clin. Invest. 125, 2211–2219 (2015).

  61. 61.

    Matsumoto, M. et al. The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. Immunity 34, 703–714 (2011).

  62. 62.

    Mauri, C., Gray, D., Mushtaq, N. & Londei, M. Prevention of arthritis by interleukin 10-producing B cells. J. Exp. Med. 197, 489–501 (2003).

  63. 63.

    Mizoguchi, A., Mizoguchi, E., Takedatsu, H., Blumberg, R. S. & Bhan, A. K. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16, 219–230 (2002). This study and references 59 and 62 are the first reports to demonstrate the importance of IL-10-producing B cells in the suppression of immune responses.

  64. 64.

    Blair, P. A. et al. 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. J. Immunol. 182, 3492–3502 (2009).

  65. 65.

    Liu, B. S., Cao, Y., Huizinga, T. W., Hafler, D. A. & Toes, R. E. TLR-mediated STAT3 and ERK activation controls IL-10 secretion by human B cells. Eur. J. Immunol. 44, 2121–2129 (2014).

  66. 66.

    Lampropoulou, V. et al. TLR-activated B cells suppress T cell-mediated autoimmunity. J. Immunol. 180, 4763–4773 (2008).

  67. 67.

    Tian, J. et al. Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J. Immunol. 167, 1081–1089 (2001).

  68. 68.

    Carter, N. A. et al. Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J. Immunol. 186, 5569–5579 (2011).

  69. 69.

    Carter, N. A., Rosser, E. C. & Mauri, C. Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis. Arthritis Res. Ther. 14, R32 (2012).

  70. 70.

    Sun, J. B., Flach, C. F., Czerkinsky, C. & Holmgren, J. B lymphocytes promote expansion of regulatory T cells in oral tolerance: powerful induction by antigen coupled to cholera toxin B subunit. J. Immunol. 181, 8278–8287 (2008).

  71. 71.

    Tadmor, T., Zhang, Y., Cho, H. M., Podack, E. R. & Rosenblatt, J. D. The absence of B lymphocytes reduces the number and function of T-regulatory cells and enhances the anti-tumor response in a murine tumor model. Cancer Immunol. Immunother. 60, 609–619 (2011).

  72. 72.

    Shen, P. et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014).

  73. 73.

    Wang, R. X. et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat. Med. 20, 633–641 (2014).

  74. 74.

    Bosma, A., Abdel-Gadir, A., Isenberg, D. A., Jury, E. C. & Mauri, C. Lipid-antigen presentation by CD1d+ B cells is essential for the maintenance of invariant natural killer T cells. Immunity 36, 477–490 (2012).

  75. 75.

    Flores-Borja, F. et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci. Transl Med. 5, 173ra23 (2013).

  76. 76.

    Knippenberg, S. et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission. J. Neuroimmunol. 239, 80–86 (2011).

  77. 77.

    Hayashi, M. et al. IL-10-producing regulatory B cells are decreased in patients with psoriasis. J. Dermatol. Sci. 81, 93–100 (2016).

  78. 78.

    Mauri, C. & Menon, M. Human regulatory B cells in health and disease: therapeutic potential. J. Clin. Invest. 127, 772–779 (2017).

  79. 79.

    Barsotti, N. S. et al. IL-10-producing regulatory B cells are decreased in patients with common variable immunodeficiency. PLOS ONE 11, e0151761 (2016).

  80. 80.

    Nouel, A. et al. B-cells induce regulatory T cells through TGF-β/IDO production in a CTLA-4 dependent manner. J. Autoimmun. 59, 53–60 (2015).

  81. 81.

    Khan, A. R. et al. PD-L1hi B cells are critical regulators of humoral immunity. Nat. Commun. 6, 5997 (2015).

  82. 82.

    Kessel, A. et al. Human CD19+CD25high B regulatory cells suppress proliferation of CD4+ T cells and enhance Foxp3 and CTLA-4 expression in T-regulatory cells. Autoimmun. Rev. 11, 670–677 (2012).

  83. 83.

    van de Veen, W. et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J. Allergy Clin. Immunol. 131, 1204–1212 (2013).

  84. 84.

    Lindner, S. et al. Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells. Cancer Res. 73, 2468–2479 (2013).

  85. 85.

    Amu, S. et al. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model. J. Allergy Clin. Immunol. 125, 1114–1124.e8 (2010).

  86. 86.

    Novak, J. & Lehuen, A. Mechanism of regulation of autoimmunity by iNKT cells. Cytokine 53, 263–270 (2011).

  87. 87.

    Oleinika, K. et al. CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells. Nat. Commun. 9, 684 (2018).

  88. 88.

    Vivarelli, M., Massella, L., Ruggiero, B. & Emma, F. Minimal change disease. Clin. J. Am. Soc. Nephrol. 12, 332–345 (2017).

  89. 89.

    Kim, K. W. et al. B cell-associated immune profiles in patients with end-stage renal disease (ESRD). Exp. Mol. Med. 44, 465–472 (2012).

  90. 90.

    Newell, K. A. et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J. Clin. Invest. 120, 1836–1847 (2010).

  91. 91.

    Sagoo, P. et al. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J. Clin. Invest. 120, 1848–1861 (2010).

  92. 92.

    Chesneau, M., Michel, L., Degauque, N. & Brouard, S. Regulatory B cells and tolerance in transplantation: from animal models to human. Front. Immunol. 4, 497 (2013).

  93. 93.

    Chesneau, M. et al. Tolerant kidney transplant patients produce B cells with regulatory properties. J. Am. Soc. Nephrol. 26, 2588–2598 (2015).

  94. 94.

    Rebollo-Mesa, I. et al. Biomarkers of tolerance in kidney transplantation: are we predicting tolerance or response to immunosuppressive treatment? Am. J. Transplant. 16, 3443–3457 (2016).

  95. 95.

    Lozano, J. J. et al. Comparison of transcriptional and blood cell-phenotypic markers between operationally tolerant liver and kidney recipients. Am. J. Transplant. 11, 1916–1926 (2011).

  96. 96.

    Latorre, I. et al. Calcineurin and mTOR inhibitors have opposing effects on regulatory T cells while reducing regulatory B cell populations in kidney transplant recipients. Transpl. Immunol. 35, 1–6 (2016).

  97. 97.

    Shabir, S. et al. Transitional B lymphocytes are associated with protection from kidney allograft rejection: a prospective study. Am. J. Transplant. 15, 1384–1391 (2015).

  98. 98.

    Tebbe, B. et al. Renal transplant recipients treated with calcineurin-inhibitors lack circulating immature transitional CD19+CD24hiCD38hi regulatory B-lymphocytes. PLOS ONE 11, e0153170 (2016).

  99. 99.

    Schlosser, H. A. et al. Prospective analyses of circulating B cell subsets in ABO-compatible and ABO-incompatible kidney transplant recipients. Am. J. Transplant. 17, 542–550 (2017).

  100. 100.

    Cherukuri, A. et al. Immunologic human renal allograft injury associates with an altered IL-10/TNF-α expression ratio in regulatory B cells. J. Am. Soc. Nephrol. 25, 1575–1585 (2014). This study identified the cytokine profile of B reg cells as a potential biomarker of allograft function in renal transplantation.

  101. 101.

    Cherukuri, A. et al. An analysis of lymphocyte phenotype after steroid avoidance with either alemtuzumab or basiliximab induction in renal transplantation. Am. J. Transplant. 12, 919–931 (2012).

  102. 102.

    Clatworthy, M. R. et al. B cell-depleting induction therapy and acute cellular rejection. N. Engl. J. Med. 360, 2683–2685 (2009).

  103. 103.

    Barnett, A. N., Hadjianastassiou, V. G. & Mamode, N. Rituximab in renal transplantation. Transpl. Int. 26, 563–575 (2013).

  104. 104.

    Tyden, G. et al. A randomized, doubleblind, placebo-controlled, study of single-dose rituximab as induction in renal transplantation. Transplantation 87, 1325–1329 (2009).

  105. 105.

    McGregor, J. G. et al. Rituximab as an immunosuppressant in antineutrophil cytoplasmic antibody-associated vasculitis. Nephrol. Dial. Transplant. 30 (Suppl. 1), i123–i131 (2015).

  106. 106.

    Steinmetz, O. M. et al. Analysis and classification of B cell infiltrates in lupus and ANCA-associated nephritis. Kidney Int. 74, 448–457 (2008).

  107. 107.

    Ferraro, A. J., Smith, S. W., Neil, D. & Savage, C. O. Relapsed Wegener’s granulomatosis after rituximab therapy — B cells are present in new pathological lesions despite persistent ‘depletion’ of peripheral blood. Nephrol. Dial. Transplant. 23, 3030–3032 (2008).

  108. 108.

    Eriksson, P., Sandell, C., Backteman, K. & Ernerudh, J. B cell abnormalities in Wegener’s granulomatosis and microscopic polyangiitis: role of CD25+-expressing B cells. J. Rheumatol. 37, 2086–2095 (2010).

  109. 109.

    Lepse, N. et al. Altered B cell balance, but unaffected B cell capacity to limit monocyte activation in anti-neutrophil cytoplasmic antibody-associated vasculitis in remission. Rheumatology 53, 1683–1692 (2014).

  110. 110.

    Todd, S. K. et al. Regulatory B cells are numerically but not functionally deficient in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 53, 1693–1703 (2014).

  111. 111.

    Wilde, B. et al. Regulatory B cells in ANCA-associated vasculitis. Ann. Rheum. Dis. 72, 1416–1419 (2013).

  112. 112.

    Wilde, B., Witzke, O. & Cohen Tervaert, J. W. Rituximab and B cell return in ANCA-associated vasculitis. Am. J. Kidney Dis. 63, 1066 (2014).

  113. 113.

    Gary-Gouy, H. et al. Human CD5 promotes B cell survival through stimulation of autocrine IL-10 production. Blood 100, 4537–4543 (2002).

  114. 114.

    Bunch, D. O. et al. Decreased CD5+ B cells in active ANCA vasculitis and relapse after rituximab. Clin. J. Am. Soc. Nephrol. 8, 382–391 (2013).

  115. 115.

    Bunch, D. O. et al. Gleaning relapse risk from B cell phenotype: decreased CD5+ B cells portend a shorter time to relapse after B cell depletion in patients with ANCA-associated vasculitis. Ann. Rheum. Dis. 74, 1784–1786 (2015).

  116. 116.

    Unizony, S. et al. Peripheral CD5+ B cells in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol. 67, 535–544 (2015).

  117. 117.

    Rahman, A. & Isenberg, D. A. Systemic lupus erythematosus. N. Engl. J. Med. 358, 929–939 (2008).

  118. 118.

    Karrar, S. & Cunninghame Graham, D. S. Abnormal B cell development in systemic lupus erythematosus: what the genetics tell us. Arthritis Rheumatol. 70, 496–507 (2018).

  119. 119.

    Merrill, J. T. et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 62, 222–233 (2010).

  120. 120.

    Rovin, B. H. et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 64, 1215–1226 (2012).

  121. 121.

    Reddy, V., Jayne, D., Close, D. & Isenberg, D. B cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design. Arthritis Res. Ther. 15 (Suppl.1), S2 (2013).

  122. 122.

    Manzi, S. et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann. Rheum. Dis. 71, 1833–1838 (2012).

  123. 123.

    Mota, P., Reddy, V. & Isenberg, D. Improving B cell depletion in systemic lupus erythematosus and rheumatoid arthritis. Expert Rev. Clin. Immunol. 13, 667–676 (2017).

  124. 124.

    Heinemann, K. et al. Decreased IL-10+ regulatory B cells (Bregs) in lupus nephritis patients. Scand. J. Rheumatol. 45, 312–316 (2016).

  125. 125.

    Sim, J. H. et al. Autoregulatory function of interleukin-10-producing pre-naive B cells is defective in systemic lupus erythematosus. Arthritis Res. Ther. 17, 190 (2015).

  126. 126.

    Wang, S. et al. IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet+ B cells in SLE. Nat. Commun. 9, 1758 (2018).

  127. 127.

    Kojo, S., Adachi, Y., Keino, H., Taniguchi, M. & Sumida, T. Dysfunction of T cell receptor AV24AJ18+, BV11+ double-negative regulatory natural killer T cells in autoimmune diseases. Arthritis Rheum. 44, 1127–1138 (2001).

  128. 128.

    Green, M. R. et al. Natural killer T cells in families of patients with systemic lupus erythematosus: their possible role in regulation of IGG production. Arthritis Rheum. 56, 303–310 (2007).

  129. 129.

    Cho, Y. N. et al. Numerical and functional deficiencies of natural killer T cells in systemic lupus erythematosus: their deficiency related to disease activity. Rheumatology 50, 1054–1063 (2011).

  130. 130.

    Jego, G. et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19, 225–234 (2003).

  131. 131.

    Poeck, H. et al. Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T cell help. Blood 103, 3058–3064 (2004).

  132. 132.

    Fleischer, V. et al. Epratuzumab inhibits the production of the proinflammatory cytokines IL-6 and TNF-alpha, but not the regulatory cytokine IL-10, by B cells from healthy donors and SLE patients. Arthritis Res. Ther. 17, 185 (2015).

  133. 133.

    Anolik, J. H. et al. Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. Arthritis Rheum. 56, 3044–3056 (2007).

  134. 134.

    Wallace, Z. S. et al. Predictors of disease relapse in IgG4-related disease following rituximab. Rheumatology 55, 1000–1008 (2016).

  135. 135.

    Collins, M. et al. Rituximab treatment of fibrillary glomerulonephritis. Am. J. Kidney Dis. 52, 1158–1162 (2008).

  136. 136.

    Maritati, F. et al. Brief Report: Rituximab for the treatment of adult-onset IgA Vasculitis (Henoch-Schonlein). Arthritis Rheumatol. 70, 109–114 (2018).

  137. 137.

    Comstock, E. et al. Transcriptional profiling of PBMCs unravels B cell mediated immunopathogenic imprints of HCV vasculitis. PLOS ONE 12, e0188314 (2017).

  138. 138.

    Comarmond, C. et al. Direct-acting antiviral therapy restores immune tolerance to patients with hepatitis C virus-induced cryoglobulinemia vasculitis. Gastroenterology 152, 2052–2062.e2 (2017).

  139. 139.

    Lin, W. et al. B cell subsets and dysfunction of regulatory B cells in IgG4-related diseases and primary Sjogren’s syndrome: the similarities and differences. Arthritis Res. Ther. 16, R118 (2014).

  140. 140.

    Wallace, Z. S. et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann. Rheum. Dis. 74, 190–195 (2015).

  141. 141.

    Wang, Y. Y. et al. Functional implications of regulatory B cells in human IgA nephropathy. Scand. J. Immunol. 79, 51–60 (2014).

  142. 142.

    Lafayette, R. A. et al. A randomized, controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction. J. Am. Soc. Nephrol. 28, 1306–1313 (2017).

  143. 143.

    Dahan, K. et al. Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up. J. Am. Soc. Nephrol. 28, 348–358 (2017).

  144. 144.

    Rosenzwajg, M. et al. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab. Kidney Int. 92, 227–237 (2017).

  145. 145.

    van den Brand, J. et al. Safety of rituximab compared with steroids and cyclophosphamide for idiopathic membranous nephropathy. J. Am. Soc. Nephrol. 28, 2729–2737 (2017).

  146. 146.

    Colucci, M. et al. B cell reconstitution after rituximab treatment in idiopathic nephrotic syndrome. J. Am. Soc. Nephrol. 27, 1811–1822 (2016).

  147. 147.

    Kim, A. H. et al. B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. JCI Insight 2, 81836 (2017).

  148. 148.

    Cho, B. S., Yoon, S. R., Jang, J. Y., Pyun, K. H. & Lee, C. E. Up-regulation of interleukin-4 and CD23/FcεRII in minimal change nephrotic syndrome. Pediatr. Nephrol. 13, 199–204 (1999).

  149. 149.

    Edwards, J. C. et al. Efficacy of B cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).

  150. 150.

    Weiner, G. J. Rituximab: mechanism of action. Semin. Hematol. 47, 115–123 (2010).

  151. 151.

    Dorner, T. & Lipsky, P. E. B cell targeting: a novel approach to immune intervention today and tomorrow. Expert Opin. Biol. Ther. 7, 1287–1299 (2007).

  152. 152.

    Ward, E. et al. A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo. Br. J. Haematol. 155, 426–437 (2011).

  153. 153.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02260934 (2018).

  154. 154.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02284984 (2018).

  155. 155.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03312907 (2018).

  156. 156.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02284984 (2017).

  157. 157.

    Holden, N. J. et al. ANCA-stimulated neutrophils release BLyS and promote B cell survival: a clinically relevant cellular process. Ann. Rheum. Dis. 70, 2229–2233 (2011).

  158. 158.

    Mahevas, M. et al. B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells. J. Clin. Invest. 123, 432–442 (2013).

  159. 159.

    Vital, E. M., Kay, J. & Emery, P. Rituximab biosimilars. Expert Opin. Biol. Ther. 13, 1049–1062 (2013).

  160. 160.

    Chen, D. et al. Autoreactive CD19+CD20 plasma cells contribute to disease severity of experimental autoimmune encephalomyelitis. J. Immunol. 196, 1541–1549 (2016).

  161. 161.

    Eskandary, F. et al. A randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. J. Am. Soc. Nephrol. 29, 591–605 (2018).

  162. 162.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02102594 (2018).

  163. 163.

    Ratnasingam, S. et al. Bortezomib-based antibody depletion for refractory autoimmune hematological diseases. Blood Adv. 1, 31–35 (2016).

  164. 164.

    Jelinek, T. & Hajek, R. Monoclonal antibodies — a new era in the treatment of multiple myeloma. Blood Rev. 30, 101–110 (2016).

  165. 165.

    Watkins, M. P. & Bartlett, N. L. CD19-targeted immunotherapies for treatment of patients with non-Hodgkin B cell lymphomas. Expert Opin. Investig. Drugs. 27, 1–11 (2018).

  166. 166.

    Amrouche, K. & Jamin, C. Influence of drug molecules on regulatory B cells. Clin. Immunol. 184, 1–10 (2017).

  167. 167.

    Wallin, E. F. et al. Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers. Blood 124, 2666–2674 (2014).

  168. 168.

    Wei, C. et al. A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus. J. Immunol. 178, 6624–6633 (2007).

  169. 169.

    Dorner, T., Shock, A., Goldenberg, D. M. & Lipsky, P. E. The mechanistic impact of CD22 engagement with epratuzumab on B cell function: Implications for the treatment of systemic lupus erythematosus. Autoimmun. Rev. 14, 1079–1086 (2015).

  170. 170.

    European Association for the Study of the Liver et al. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol. 67, 370–398 (2017).

  171. 171.

    Molloy, E. S. & Calabrese, L. H. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum. 64, 3043–3051 (2012).

  172. 172.

    Thiel, J. et al. B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients. Arthritis Res. Ther. 19, 101 (2017).

  173. 173.

    Roberts, D. M. et al. Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease. J. Autoimmun. 57, 60–65 (2015).

  174. 174.

    Merrill, J. T. et al. Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Arthritis Rheum. 64, 3364–3373 (2012).

  175. 175.

    Mok, C. C. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des. Devel. Ther. 8, 87–100 (2013).

  176. 176.

    Saze, Z. et al. Adenosine production by human B cells and B cell-mediated suppression of activated T cells. Blood 122, 9–18 (2013).

  177. 177.

    Venhoff, N. et al. Reconstitution of the peripheral B lymphocyte compartment in patients with ANCA-associated vasculitides treated with rituximab for relapsing or refractory disease. Autoimmunity 47, 401–408 (2014).

  178. 178.

    von Borstel, A. et al. Increased CD38hiCD27+ plasmablast frequency in remission predicts relapsing disease in granulomatosis with polyangiitis patients. Arthritis Rheumatol. 69 (suppl. 10) (2017).

  179. 179.

    Morelon, E. et al. Preferential increase in memory and regulatory subsets during T-lymphocyte immune reconstitution after Thymoglobulin induction therapy with maintenance sirolimus versus cyclosporine. Transpl. Immunol. 23, 53–58 (2010).

  180. 180.

    Song, J. et al. The role of regulatory B cells (Bregs) in the Tregs-amplifying effect of Sirolimus. Int. Immunopharmacol. 38, 90–96 (2016).

  181. 181.

    Heidt, S., Hester, J., Shankar, S., Friend, P. J. & Wood, K. J. B cell repopulation after alemtuzumab induction-transient increase in transitional B cells and long-term dominance of naive B cells. Am. J. Transplant. 12, 1784–1792 (2012).

  182. 182.

    Picchianti Diamanti, A. et al. Abatacept (cytotoxic T lymphocyte antigen 4-immunoglobulin) improves B cell function and regulatory T cell inhibitory capacity in rheumatoid arthritis patients non-responding to anti-tumour necrosis factor-α agents. Clin. Exp. Immunol. 177, 630–640 (2014).

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Acknowledgements

A.D.S. is supported by Kidney Research UK.

Reviewer information

Nature Reviews Nephrology thanks S. Hillion and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Author notes

  1. These authors contributed equally: Claudia Mauri and Alan D. Salama

Affiliations

  1. Division of Medicine, University College London, London, UK

    • Kristine Oleinika
    •  & Claudia Mauri
  2. UCL Centre for Nephrology, Royal Free Hospital, London, UK

    • Alan D. Salama

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Contributions

All authors contributed to researching data for the article, discussing the article’s content, writing the article and reviewing and editing the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Alan D. Salama.

Glossary

Nephrotic syndrome

A triad of symptoms, namely oedema, proteinuria >3.5 g/day and hypoalbuminaemia, which result from glomerular podocyte damage. Patients often present with marked hypercholesterolaemia.

Minimal change disease

A common cause of nephrotic syndrome in children and adults, which is characterized by minimal histological abnormalities visible by light microscopy, but in which podocyte effacement can be observed by electron microscopy.

Membranous glomerulonephritis

A glomerular disease that is characterized by subepithelial immune complexes, which cause nephrotic syndrome and is frequently associated with the presence of autoantibodies to phospholipase A2 receptor or thrombospondin type 1 domain-containing protein 7A.

Induction therapy

The initial immunosuppressive therapy used at the time of transplantation or the initial therapy used to treat autoimmune diseases.

Germinal centre reaction

The process through which high-affinity, class-switched plasma cells and memory B cells are generated.

Type 1 response

An immune response in which mainly T helper 1 (TH1) cells produce cytokines, such as IFNγ and IL-12.

Type 2 response

An immune response in which mainly T helper 2 (TH2) cells produce cytokines, such as IL-4.

Tertiary lymphoid tissue

Organized lymphoid structures that develop in non-lymphoid tissues.

Invariant natural killer T cell

(iNKT cell). A CD1d-restricted T cell that expresses a semi-invariant T cell receptor and recognizes lipid antigens.

Operational tolerance

Long-term allograft acceptance without the requirement for continuous immunosuppression.

Maintenance therapy

Continuous immunosuppression to maintain stable graft function or remission in cases of autoimmunity.

Cryoglobulinaemia

A syndrome of circulating cryoglobulins, which are immunoglobulins that precipitate at temperatures below 37oC, leading to skin, kidney and neurological disease.

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https://doi.org/10.1038/s41581-018-0074-7