Review Article | Published:

B cell checkpoints in autoimmune rheumatic diseases

Nature Reviews Rheumatology (2019) | Download Citation


B cells have important functions in the pathogenesis of autoimmune diseases, including autoimmune rheumatic diseases. In addition to producing autoantibodies, B cells contribute to autoimmunity by serving as professional antigen-presenting cells (APCs), producing cytokines, and through additional mechanisms. B cell activation and effector functions are regulated by immune checkpoints, including both activating and inhibitory checkpoint receptors that contribute to the regulation of B cell tolerance, activation, antigen presentation, T cell help, class switching, antibody production and cytokine production. The various activating checkpoint receptors include B cell activating receptors that engage with cognate receptors on T cells or other cells, as well as Toll-like receptors that can provide dual stimulation to B cells via co-engagement with the B cell receptor. Furthermore, various inhibitory checkpoint receptors, including B cell inhibitory receptors, have important functions in regulating B cell development, activation and effector functions. Therapeutically targeting B cell checkpoints represents a promising strategy for the treatment of a variety of autoimmune rheumatic diseases.

Key points

  • B cells have important pathogenic functions in autoimmune rheumatic diseases; they can produce antibodies, serve as professional antigen-presenting cells (APCs) and produce cytokines.

  • B cells express activating receptors and inhibitory receptors, which serve as immune checkpoints that regulate their activation and function.

  • Activating receptors include the B cell receptor, Toll-like receptors, cytokine receptors, CD19, CD40 and other co-stimulatory receptors.

  • Inhibitory receptors include the low-affinity immunoglobulin-γ Fc region receptor IIb (FcγRIIb), CD22, programmed cell death 1 (PD1) and other receptors, which transmit inhibitory signals to B cells.

  • Various B cell-targeting strategies could be used for the treatment of autoimmune rheumatic diseases, such as B cell depletion, blockade of activation checkpoints, inhibition of pro-inflammatory cytokines, triggering of B cell inhibitory checkpoints and trafficking blockade.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Chan, O. T., Madaio, M. P. & Shlomchik, M. J. The central and multiple roles of B cells in lupus pathogenesis. Immunol. Rev. 169, 107–121 (1999).

  2. 2.

    Townsend, M. J., Monroe, J. G. & Chan, A. C. B cell targeted therapies in human autoimmune diseases: an updated perspective. Immunol. Rev. 237, 264–283 (2010).

  3. 3.

    Yuseff, M. I., Pierobon, P., Reversat, A. & Lennon-Dumenil, A. M. How B cells capture, process and present antigens: a crucial role for cell polarity. Nat. Rev. Immunol. 13, 475–486 (2013).

  4. 4.

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

  5. 5.

    Specks, U. et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N. Engl. J. Med. 369, 417–427 (2013).

  6. 6.

    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).

  7. 7.

    Hauser, S. L. et al. B cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).

  8. 8.

    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).

  9. 9.

    Cambridge, G. et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum. 48, 2146–2154 (2003).

  10. 10.

    Cortazar, F. B. et al. Effect of continuous B cell depletion with rituximab on pathogenic autoantibodies and total IgG levels in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol. 69, 1045–1053 (2017).

  11. 11.

    Du, F. H., Mills, E. A. & Mao-Draayer, Y. Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment. Auto Immun. Highlights 8, 12 (2017).

  12. 12.

    Rehnberg, M., Amu, S., Tarkowski, A., Bokarewa, M. I. & Brisslert, M. Short- and long-term effects of anti-CD20 treatment on B cell ontogeny in bone marrow of patients with rheumatoid arthritis. Arthritis Res. Ther. 11, R123 (2009).

  13. 13.

    Martin-Garrido, I., Carmona, E. M., Specks, U. & Limper, A. H. Pneumocystis pneumonia in patients treated with rituximab. Chest 144, 258–265 (2013).

  14. 14.

    Elsegeiny, W., Eddens, T., Chen, K. & Kolls, J. K. Anti-CD20 antibody therapy and susceptibility to Pneumocystis pneumonia. Infect. Immun. 83, 2043–2052 (2015).

  15. 15.

    Wei, K. C. et al. Pneumocystis jirovecii pneumonia in HIV-uninfected, rituximab treated non-Hodgkin lymphoma patients. Sci. Rep. 8, 8321 (2018).

  16. 16.

    Shah, S., Jaggi, K., Greenberg, K. & Geetha, D. Immunoglobulin levels and infection risk with rituximab induction for anti-neutrophil cytoplasmic antibody-associated vasculitis. Clin. Kidney J. 10, 470–474 (2017).

  17. 17.

    Bingham, C. O. 3rd et al. Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis Rheum. 62, 64–74 (2010).

  18. 18.

    van Assen, S. et al. Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab. Arthritis Rheum. 62, 75–81 (2010).

  19. 19.

    Kapetanovic, M. C. Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis. Arthritis Res. Ther. 15, R171 (2013).

  20. 20.

    Suurmond, J. & Diamond, B. Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity. J. Clin. Invest. 125, 2194–2202 (2015).

  21. 21.

    Schiffer, L. et al. Short term administration of costimulatory blockade and cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice by a mechanism downstream of renal immune complex deposition. J. Immunol. 171, 489–497 (2003).

  22. 22.

    Okroj, M., Heinegard, D., Holmdahl, R. & Blom, A. M. Rheumatoid arthritis and the complement system. Ann. Med. 39, 517–530 (2007).

  23. 23.

    Anquetil, F., Clavel, C., Offer, G., Serre, G. & Sebbag, M. IgM and IgA rheumatoid factors purified from rheumatoid arthritis sera boost the Fc receptor- and complement-dependent effector functions of the disease-specific anti-citrullinated protein autoantibodies. J. Immunol. 194, 3664–3674 (2015).

  24. 24.

    Clynes, R., Dumitru, C. & Ravetch, J. V. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279, 1052–1054 (1998).

  25. 25.

    Sokolove, J. et al. Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. Arthritis Rheumatol. 66, 813–821 (2014).

  26. 26.

    Daniels, R. H., Williams, B. D. & Morgan, B. P. Human rheumatoid synovial cell stimulation by the membrane attack complex and other pore-forming toxins in vitro: the role of calcium in cell activation. Immunology 71, 312–316 (1990).

  27. 27.

    Hay, F. C., Jones, M. G., Bond, A. & Soltys, A. J. Rheumatoid factors and complex formation. The role of light-chain framework sequences and glycosylation. Clin Orthop. Relat. Res. 265, 54–62 (1991).

  28. 28.

    Regnault, A. et al. Fcγ receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J. Exp. Med. 189, 371–380 (1999).

  29. 29.

    Hamano, Y., Arase, H., Saisho, H. & Saito, T. Immune complex and Fc receptor-mediated augmentation of antigen presentation for in vivo Th cell responses. J. Immunol. 164, 6113–6119 (2000).

  30. 30.

    Schuurhuis, D. H. et al. Antigen-antibody immune complexes empower dendritic cells to efficiently prime specific CD8+ CTL responses in vivo. J. Immunol. 168, 2240–2246 (2002).

  31. 31.

    Ise, W. et al. T follicular helper cell-germinal center B cell interaction strength regulates entry into plasma cell or recycling germinal center cell fate. Immunity 48, 702–715 (2018).

  32. 32.

    Stebegg, M. et al. Regulation of the germinal center response. Front. Immunol. 9, 2469 (2018).

  33. 33.

    Ting, Y. T. et al. The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis. J. Biol. Chem. 293, 3236–3251 (2018).

  34. 34.

    McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).

  35. 35.

    Grumet, F. C., Coukell, A., Bodmer, J. G., Bodmer, W. F. & McDevitt, H. O. Histocompatibility (HL-A) antigens associated with systemic lupus erythematosus. A possible genetic predisposition to disease. N. Engl. J. Med. 285, 193–196 (1971).

  36. 36.

    Gaffney, P. M. et al. Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analyses of 187 sib-pair families. Am. J. Hum. Genet. 66, 547–556 (2000).

  37. 37.

    Brown, M. A. et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann. Rheum. Dis. 55, 268–270 (1996).

  38. 38.

    Brown, M. A. et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum. 40, 1823–1828 (1997).

  39. 39.

    Shipman, W. D., Dasoveanu, D. C. & Lu, T. T. Tertiary lymphoid organs in systemic autoimmune diseases: pathogenic or protective? F1000Res. 6, 196 (2017).

  40. 40.

    Detanico, T. et al. Somatic mutagenesis in autoimmunity. Autoimmunity 46, 102–114 (2013).

  41. 41.

    Elliott, S. E. et al. Affinity maturation drives epitope spreading and generation of pro-inflammatory anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis Rheumatol. 70, 1946–1958 (2018).

  42. 42.

    Lu, D. R. et al. T cell-dependent affinity maturation and innate immune pathways differentially drive autoreactive B cell responses in rheumatoid arthritis. Arthritis Rheumatol. 70, 1732–1744 (2018).

  43. 43.

    Lindhout, E. et al. Fibroblast-like synoviocytes from rheumatoid arthritis patients have intrinsic properties of follicular dendritic cells. J. Immunol. 162, 5949–5956 (1999).

  44. 44.

    Harris, D. P. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat. Immunol. 1, 475–482 (2000).

  45. 45.

    Yanaba, K. et al. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 28, 639–650 (2008).

  46. 46.

    Piancone, F. et al. B lymphocytes in multiple sclerosis: bregs and BTLA/CD272 expressing-CD19+ lymphocytes modulate disease severity. Sci. Rep. 6, 29699 (2016).

  47. 47.

    Grammer, A. C. & Lipsky, P. E. B cell abnormalities in systemic lupus erythematosus. Arthritis Res. Ther. 5 (Suppl. 4), 22–27 (2003).

  48. 48.

    Hirano, T. et al. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur. J. Immunol. 18, 1797–1801 (1988).

  49. 49.

    Arkatkar, T. et al. B cell-derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity. J. Exp. Med. 214, 3207–3217 (2017).

  50. 50.

    Dienz, O. & Rincon, M. The effects of IL-6 on CD4 T cell responses. Clin. Immunol. 130, 27–33 (2009).

  51. 51.

    Kalampokis, I., Yoshizaki, A. & Tedder, T. F. IL-10-producing regulatory B cells (B10 cells) in autoimmune disease. Arthritis Res. Ther. 15 (Suppl. 1), 1 (2013).

  52. 52.

    Lee, K. M. et al. TGF-β-producing regulatory B cells induce regulatory T cells and promote transplantation tolerance. Eur. J. Immunol. 44, 1728–1736 (2014).

  53. 53.

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

  54. 54.

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

  55. 55.

    Egwuagu, C. E. & Yu, C. R. Interleukin 35-producing B cells (i35-Breg): a new mediator of regulatory B-cell functions in CNS autoimmune diseases. Crit. Rev. Immunol. 35, 49–57 (2015).

  56. 56.

    Rosser, E. C. & Mauri, C. Regulatory B cells: origin, phenotype, and function. Immunity 42, 607–612 (2015).

  57. 57.

    Meffre, E. & Wardemann, H. B cell tolerance checkpoints in health and autoimmunity. Curr. Opin. Immunol. 20, 632–638 (2008).

  58. 58.

    Kuokkanen, E., Sustar, V. & Mattila, P. K. Molecular control of B cell activation and immunological synapse formation. Traffic 16, 311–326 (2015).

  59. 59.

    Yang, J. & Reth, M. in B Cell Receptor Signaling (eds Kurosaki, T. & Wienands, J.) 27–43 (Springer International Publishing, 2016).

  60. 60.

    Avalos, A. M., Meyer-Wentrup, F. & Ploegh, H. L. B cell receptor signaling in lymphoid malignancies and autoimmunity. Adv. Immunol. 123, 1–49 (2014).

  61. 61.

    Dal Porto, J. M. et al. B cell antigen receptor signaling 101. Mol. Immunol. 41, 599–613 (2004).

  62. 62.

    Lane, P. et al. Activated human T cells express a ligand for the human B cell-associated antigen CD40 which participates in T cell-dependent activation of B lymphocytes. 22, 2573–2578 (1992).

  63. 63.

    Bishop, G. A. & Hostager, B. S. The CD40–CD154 interaction in B cell–T cell liaisons. Cytokine Growth Factor Rev. 14, 297–309 (2003).

  64. 64.

    Hokazono, Y. et al. Inhibitory coreceptors activated by antigens but not by Anti-Ig heavy chain antibodies install requirement of costimulation through CD40 for survival and proliferation of B cells. J. Immunol. 171, 1835–1843 (2003).

  65. 65.

    Voynova, E. et al. Requirement for CD40/CD40L interactions for development of autoimmunity differs depending on specific checkpoint and costimulatory pathways. ImmunoHorizons 2, 54–66 (2018).

  66. 66.

    Peters, A. L., Stunz, L. L. & Bishop, G. A. CD40 and autoimmunity: the dark side of a great activator. Semin. Immunol. 21, 293–300 (2009).

  67. 67.

    Toubi, E. & Shoenfeld, Y. The role of CD40-CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity 37, 457–464 (2004).

  68. 68.

    Vinuesa, C. G. & Goodnow, C. C. Immunology: DNA drives autoimmunity. Nature 416, 595–598 (2002).

  69. 69.

    Pelka, K., Shibata, T., Miyake, K. & Latz, E. Nucleic acid-sensing TLRs and autoimmunity: novel insights from structural and cell biology. Immunol. Rev. 269, 60–75 (2016).

  70. 70.

    Hoffmann, M. H. & Steiner, G. A common pathway for all autoimmune diseases? The unholy alliance of environment, cell death and nucleic acids. Curr. Immunol. Rev. 5, 69–88 (2009).

  71. 71.

    Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

  72. 72.

    Lau, C. M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005).

  73. 73.

    Uckun, F. M., Sun, L., Qazi, S., Ma, H. & Ozer, Z. Recombinant human CD19-ligand protein as a potent anti-leukaemic agent. Br. J. Haematol. 153, 15–23 (2011).

  74. 74.

    Liu, Z. et al. Peripheral CD19(hi) B cells exhibit activated phenotype and functionality in promoting IgG and IgM production in human autoimmune diseases. Sci. Rep. 7, 13921 (2017).

  75. 75.

    Abraham, P. M., Quan, S. H., Dukala, D. & Soliven, B. CD19 as a therapeutic target in a spontaneous autoimmune polyneuropathy. Clin. Exp. Immunol. 175, 181–191 (2014).

  76. 76.

    Stuve, O. et al. CD19 as a molecular target in CNS autoimmunity. Acta Neuropathol. 128, 177–190 (2014).

  77. 77.

    Ng, L. G. et al. B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J. Immunol. 173, 807–817 (2004).

  78. 78.

    Mackay, F. & Browning, J. L. BAFF: a fundamental survival factor for B cells. Nat. Rev. Immunol. 2, 465–475 (2002).

  79. 79.

    Salazar-Camarena, D. C. et al. Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B cell subsets with clinical manifestations in systemic lupus erythematosus. Lupus 25, 582–592 (2016).

  80. 80.

    Wallace, D. J. et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 61, 1168–1178 (2009).

  81. 81.

    Steri, M. et al. Overexpression of the cytokine BAFF and autoimmunity risk. N. Engl. J. Med. 376, 1615–1626 (2017).

  82. 82.

    Touma, Z. & Gladman, D. D. Current and future therapies for SLE: obstacles and recommendations for the development of novel treatments. Lupus Sci. Med. 4, e000239 (2017).

  83. 83.

    Vincent, F. B., Morand, E. F., Schneider, P. & Mackay, F. The BAFF/APRIL system in SLE pathogenesis. Nat. Rev. Rheumatol. 10, 365–373 (2014).

  84. 84.

    Dienz, O. et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J. Exp. Med. 206, 69–78 (2009).

  85. 85.

    Maeda, K., Mehta, H., Drevets, D. A. & Coggeshall, K. M. IL-6 increases B cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production. Blood 115, 4699–4706 (2010).

  86. 86.

    Axmann, R. et al. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum. 60, 2747–2756 (2009).

  87. 87.

    Wu, Q., Zhou, X., Huang, D., Ji, Y. & Kang, F. IL-6 enhances osteocyte-mediated osteoclastogenesis by promoting JAK2 and RANKL activity in vitro. Cell Physiol. Biochem. 41, 1360–1369 (2017).

  88. 88.

    Smolen, J. S. & Maini, R. N. Interleukin-6: a new therapeutic target. Arthritis Res. Ther. 8 (Suppl. 2), 5 (2006).

  89. 89.

    Scott, L. J. Tocilizumab: a review in rheumatoid arthritis. Drugs 77, 1865–1879 (2017).

  90. 90.

    Illei, G. G. et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 62, 542–552 (2010).

  91. 91.

    Wallace, D. J. et al. Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial. Ann. Rheum. Dis. 76, 534–542 (2017).

  92. 92.

    Liu, S. M. & King, C. IL-21-producing Th cells in immunity and autoimmunity. J. Immunol. 191, 3501–3506 (2013).

  93. 93.

    Konforte, D., Simard, N. & Paige, C. J. IL-21: an executor of B cell fate. J. Immunol. 182, 1781–1787 (2009).

  94. 94.

    Kuchen, S. et al. Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration. J. Immunol. 179, 5886–5896 (2007).

  95. 95.

    Wu, Y. et al. The biological effects of IL-21 signaling on B-cell-mediated responses in organ transplantation. Front. Immunol. 7, 319 (2016).

  96. 96.

    Pritchard, N. R. & Smith, K. G. B cell inhibitory receptors and autoimmunity. Immunology 108, 263–273 (2003).

  97. 97.

    Gagneux, P. et al. Human-specific regulation of α2-6-linked sialic acids. J. Biol. Chem. 278, 48245–48250 (2003).

  98. 98.

    Tedder, T. F., Poe, J. C. & Haas, K. M. CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction. Adv. Immunol. 88, 1–50 (2005).

  99. 99.

    Lumb, S. et al. Engagement of CD22 on B cells with the monoclonal antibody epratuzumab stimulates the phosphorylation of upstream inhibitory signals of the B cell receptor. J. Cell Commun. Signal 10, 143–151 (2016).

  100. 100.

    Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).

  101. 101.

    Sohn, H. W., Pierce, S. K. & Tzeng, S. J. Live cell imaging reveals that the inhibitory FcγRIIB destabilizes B cell receptor membrane-lipid interactions and blocks immune synapse formation. J. Immunol. 180, 793–799 (2008).

  102. 102.

    Kleinau, S. The impact of Fc receptors on the development of autoimmune diseases. Curr. Pharm. Des. 9, 1861–1870 (2003).

  103. 103.

    Meyaard, L. The inhibitory collagen receptor LAIR-1 (CD305). J. Leukoc. Biol. 83, 799–803 (2008).

  104. 104.

    Franks, S. E., Getahun, A., Hogarth, P. M. & Cambier, J. C. Targeting B cells in treatment of autoimmunity. Curr. Opin. Immunol. 43, 39–45 (2016).

  105. 105.

    Chatenoud, L. Biotherapies targeting T and B cells: from immune suppression to immune tolerance. Curr. Opin. Pharmacol. 23, 92–97 (2015).

  106. 106.

    Hardy, I. R. et al. Anti-CD79 antibody induces B cell anergy that protects against autoimmunity. J. Immunol. 192, 1641–1650 (2014).

  107. 107.

    Rossi, E. A., Chang, C. H. & Goldenberg, D. M. Anti-CD22/CD20 Bispecific antibody with enhanced trogocytosis for treatment of Lupus. PLOS ONE 9, e98315 (2014).

  108. 108.

    Donahue, A. C. & Fruman, D. A. Proliferation and survival of activated B cells requires sustained antigen receptor engagement and phosphoinositide 3-kinase activation. J. Immunol. 170, 5851–5860 (2003).

  109. 109.

    Galinier, A., Delwail, V. & Puyade, M. Ibrutinib is effective in the treatment of autoimmune haemolytic anaemia in mantle cell lymphoma. Case Rep. Oncol. 10, 127–129 (2017).

  110. 110.

    Muschen, M. Autoimmunity checkpoints as therapeutic targets in B cell malignancies. Nat. Rev. Cancer 18, 103–116 (2018).

  111. 111.

    Ryden-Aulin, M. et al. Off-label use of rituximab for systemic lupus erythematosus in Europe. Lupus Sci. Med. 3, e000163 (2016).

  112. 112.

    Hauser, S. L. et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N. Engl. J. Med. 376, 221–234 (2017).

  113. 113.

    Kappos, L. et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378, 1779–1787 (2011).

  114. 114.

    Mysler, E. F. et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis Rheum. 65, 2368–2379 (2013).

  115. 115.

    Stashenko, P., Nadler, L. M., Hardy, R, & Schlossman, S. F. Expression of cell surface markers after human B lymphocyte activation. Proc. Natl Acad. Sci. USA 78, 3848–3852 (1981).

  116. 116.

    DiLillo, D. J. et al. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J. Immunol. 180, 361–371 (2007).

  117. 117.

    Forsthuber, T. G., Cimbora, D. M., Ratchford, J. N., Katz, E. & Stuve, O. B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets. Ther. Adv. Neurol. Disord. 11, 1756286418761697 (2018).

  118. 118.

    Herbst, R. et al. B cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J. Pharmacol. Exp. Ther. 335, 213–222 (2010).

  119. 119.

    Chen, D. et al. Single dose of glycoengineered anti-CD19 antibody (MEDI551) disrupts experimental autoimmune encephalomyelitis by inhibiting pathogenic adaptive immune responses in the bone marrow and spinal cord while preserving peripheral regulatory mechanisms. J. Immunol. 193, 4823–4832 (2014).

  120. 120.

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

  121. 121.

    Agius, M. A. et al. Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study. Mult. Scler. 25, 235–245 (2019).

  122. 122.

    Mei, H. E. et al. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood 125, 1739–1748 (2015).

  123. 123.

    Ruck, T., Bittner, S., Wiendl, H. & Meuth, S. G. Alemtuzumab in multiple sclerosis: mechanism of action and beyond. Int. J. Mol. Sci. 16, 16414–16439 (2015).

  124. 124.

    Tolbert, V. P. et al. Daratumumab is effective in the treatment of refractory post-transplant autoimmune hemolytic anemia: a pediatric case report. Blood 128, 4819–4819 (2016).

  125. 125.

    Jagannath, S. et al. Indatuximab ravtansine (BT062) monotherapy in patients with relapsed and/or refractory multiple myeloma. Clin. Lymphoma Myeloma Leuk. (2019).

  126. 126.

    Usmani, S. Z. et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood 128, 37–44 (2016).

  127. 127.

    Sidiropoulos, P. I. & Boumpas, D. T. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 13, 391–397 (2004).

  128. 128.

    Chamberlain, C. et al. Repeated administration of dapirolizumab pegol in a randomised phase I study is well tolerated and accompanied by improvements in several composite measures of systemic lupus erythematosus disease activity and changes in whole blood transcriptomic profiles. Ann. Rheum. Dis. 76, 1837–1844 (2017).

  129. 129.

    Fisher, B. et al. The novel anti-CD40 monoclonal antibody CFZ533 shows beneficial effects in patients with primary Sjögren’s syndrome: a phase IIa double-blind, placebo-controlled randomized trial. Abstract presented at 2017 ACR/ARHP Annual Meeting (San Diego, CA).

  130. 130.

    Johnson, P. et al. Clinical and biological effects of an agonist anti-CD40 antibody: a Cancer Research UK phase I study. Clin. Cancer Res. 21, 1321–1328 (2015).

  131. 131.

    Dahan, R. et al. Therapeutic activity of agonistic, human anti-CD40 monoclonal antibodies requires selective FcγR engagement. Cancer Cell 29, 820–831 (2016).

  132. 132.

    Cheng, L. E. et al. Brief report: a randomized, double-blind, parallel-group, placebo-controlled, multiple-dose study to evaluate AMG 557 in patients with systemic lupus erythematosus and active lupus arthritis. Arthritis Rheumatol. 70, 1071–1076 (2018).

  133. 133.

    Bluml, S., McKeever, K., Ettinger, R., Smolen, J. & Herbst, R. B cell targeted therapeutics in clinical development. Arthritis Res. Ther. 15 (Suppl. 1), 4 (2013).

  134. 134.

    Clowse, M. E. et al. Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus: results from two phase III randomized, double-blind, placebo-controlled trials. Arthritis Rheumatol. 69, 362–375 (2017).

  135. 135.

    Chu, S. Y. et al. Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcγRIIb with Fc-engineered antibodies. Mol. Immunol. 45, 3926–3933 (2008).

  136. 136.

    US National Library of Medicine. (2018).

  137. 137.

    US National Library of Medicine. (2018).

  138. 138.

    Horton, H. M. et al. Antibody-mediated coengagement of FcγRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus. J. Immunol. 186, 4223–4233 (2011).

  139. 139.

    Chu, S. Y. et al. Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcγ receptor IIb inhibitory receptor. Arthritis Rheumatol. 66, 1153–1164 (2014).

  140. 140.

    Veri, M. C. et al. Therapeutic control of B cell activation via recruitment of Fcγ receptor IIb (CD32B) inhibitory function with a novel bispecific antibody scaffold. Arthritis Rheum. 62, 1933–1943 (2010).

  141. 141.

    US National Library of Medicine. (2017).

  142. 142.

    Pal Singh, S., Dammeijer, F. & Hendriks, R. W. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol. Cancer 17, 57 (2018).

  143. 143.

    Gillooly, K. M. et al. Bruton’s tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care. PLOS ONE 12, e0181782 (2017).

  144. 144.

    Lee, S. K. et al. Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants. Eur. J. Clin. Pharmacol. 73, 689–698 (2017).

  145. 145.

    Crawford, J. J. et al. Discovery of GDC-0853: a potent, selective, and noncovalent Bruton’s tyrosine kinase inhibitor in early clinical development. J. Med. Chem. 61, 2227–2245 (2018).

  146. 146.

    Akinleye, A., Chen, Y., Mukhi, N., Song, Y. & Liu, D. Ibrutinib and novel BTK inhibitors in clinical development. J. Hematol. Oncol. 6, 59 (2013).

  147. 147.

    Katewa, A. et al. Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell-associated damage in IFNα-driven lupus nephritis. JCI Insight 2, e90111 (2017).

  148. 148.

    Gopal, A. K. et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 1008–1018 (2014).

  149. 149.

    Stark, A. K., Sriskantharajah, S., Hessel, E. M. & Okkenhaug, K. PI3K inhibitors in inflammation, autoimmunity and cancer. Curr. Opin. Pharmacol. 23, 82–91 (2015).

  150. 150.

    Baker, K. P. et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 48, 3253–3265 (2003).

  151. 151.

    Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721–731 (2011).

  152. 152.

    Dall’Era, M. et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum. 56, 4142–4150 (2007).

  153. 153.

    Furie, R. et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918–3930 (2011).

  154. 154.

    Merrill, J. T. et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study. Arthritis Rheumatol. 70, 266–276 (2018).

  155. 155.

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

  156. 156.

    Yao, X. et al. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol. Ther. 141, 125–139 (2014).

  157. 157.

    Wallace, D. J. et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 392, 222–231 (2018).

  158. 158.

    Ghoreschi, K. et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J. Immunol. 186, 4234–4243 (2011).

  159. 159.

    Kubo, S., Nakayamada, S. & Tanaka, Y. Baricitinib for the treatment of rheumatoid arthritis. Expert Rev. Clin. Immunol. 12, 911–919 (2016).

  160. 160.

    Tanaka, Y. & Yamaoka, K. JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical. Mod. Rheumatol. 23, 415–424 (2013).

  161. 161.

    Wang, S. P. et al. Tofacitinib, a JAK inhibitor, inhibits human B cell activation in vitro. Ann. Rheum. Dis. 73, 2213–2215 (2014).

  162. 162.

    Rizzi, M. et al. Impact of tofacitinib treatment on human B cells in vitro and in vivo. J. Autoimmun. 77, 55–66 (2017).

  163. 163.

    Ignatenko, S., Skrumsager, B. K., Steensberg, A. & Mouritzen, U. First in human study with recombinant anti-IL-21 monoclonal antibody in healthy subjects and patients with rheumatoid arthritis. Abstract presented at 2012 ACR/ARHP Annual Meeting (Washington, DC).

  164. 164.

    Wagner, F., Skrumsager, B. K. & Fitilev, S. Safety and tolerability of NNC01140006, an anti-IL-21 monoclonal antibody, at multiple s.c. dose levels in patients with rheumatoid arthritis. Abstract presented at 2014 ACR/ARHP Annual Meeting (Boston, MA).

  165. 165.

    Ignatenko, S., Skrumsager, B. K. & Mouritzen, U. Safety, PK, and PD of recombinant anti-interleukin-21 monoclonal antibody in a first-in-human trial. Int. J. Clin. Pharmacol. Ther. 54, 243–252 (2016).

  166. 166.

    Yednock, T. A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrin. Nature 356, 63–66 (1992).

  167. 167.

    Guagnozzi, D. & Caprilli, R. Natalizumab in the treatment of Crohn’s disease. Biologics 2, 275–284 (2008).

  168. 168.

    Yaldizli, O. & Putzki, N. Natalizumab in the treatment of multiple sclerosis. Ther. Adv. Neurol. Disord. 2, 115–128 (2009).

  169. 169.

    Stuve, O. et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann. Neurol. 59, 743–747 (2006).

  170. 170.

    Stüve, O. The effects of natalizumab on the innate and adaptive immune system in the central nervous system. J. Neurol. Sci. 274, 39–41 (2008).

  171. 171.

    Tocheva, A. S. & Mor, A. Checkpoint inhibitors: applications for autoimmunity. Curr. Allergy Asthma Rep. 17, 72 (2017).

  172. 172.

    Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996).

  173. 173.

    Okazaki, T., Iwai, Y. & Honjo, T. New regulatory co-receptors: inducible co-stimulator and PD-1. Curr. Opin. Immunol. 14, 779–782 (2002).

  174. 174.

    Thibult, M. L. et al. PD-1 is a novel regulator of human B cell activation. Int. Immunol. 25, 129–137 (2013).

  175. 175.

    Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

  176. 176.

    Hess, K. L. et al. Engineering immunological tolerance using quantum dots to tune the density of self-antigen display. Adv. Funct. Mater. 27, 1700290 (2017).

  177. 177.

    Ortiz, D. F. et al. Elucidating the interplay between IgG-Fc valency and Fcγ activation for the design of immune complex inhibitors. Sci. Transl Med. 8, 365ra158 (2016).

  178. 178.

    Karnell, J. L. et al. CD19 and CD32b differentially regulate human B cell responsiveness. J. Immunol. 192, 1480–1490 (2014).

  179. 179.

    Wu, X. & Demarest, S. J. Building blocks for bispecific and trispecific antibodies. Methods 154, 3–9 (2019).

  180. 180.

    Moore, P. A. et al. Application of dual affinity retargeting molecules to achieve optimal redirected T cell killing of B cell lymphoma. Blood 117, 4542–4551 (2011).

  181. 181.

    Huehls, A. M., Coupet, T. A. & Sentman, C. L. Bispecific T cell engagers for cancer immunotherapy. Immunol. Cell Biol. 93, 290–296 (2015).

  182. 182.

    US National Library of Medicine. (2018).

  183. 183.

    Ikeda, H. et al. The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin. Cancer Res. 15, 4028–4037 (2009).

  184. 184.

    US National Library of Medicine. (2017).

  185. 185.

    US National Library of Medicine. (2019).

  186. 186.

    US National Library of Medicine. (2018).

  187. 187.

    US National Library of Medicine. (2018).

  188. 188.

    US National Library of Medicine. (2019).

  189. 189.

    US National Library of Medicine. (2014).

  190. 190.

    US National Library of Medicine. (2019).

  191. 191.

    US National Library of Medicine. (2017).

  192. 192.

    US National Library of Medicine. (2013).

  193. 193.

    US National Library of Medicine. (2015).

  194. 194.

    US National Library of Medicine. (2018).

  195. 195.

    Byrd, J. C. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 369, 32–42 (2013).

  196. 196.

    US National Library of Medicine. (2013).

  197. 197.

    Stohl, W. et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two-week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 69, 1016–1027 (2017).

  198. 198.

    US National Library of Medicine. (2018).

  199. 199.

    US National Library of Medicine. (2016).

  200. 200.

    US National Library of Medicine. (2016).

  201. 201.

    US National Library of Medicine. (2016).

  202. 202.

    US National Library of Medicine. (2017).

  203. 203.

    US National Library of Medicine. (2019).

  204. 204.

    Khanna, D. et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 387, 2630–2640 (2016).

  205. 205.

    US National Library of Medicine. (2018).

  206. 206.

    US National Library of Medicine. (2017).

  207. 207.

    Fleischmann, R. et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 390, 457–468 (2017).

  208. 208.

    US National Library of Medicine. (2019).

  209. 209.

    US National Library of Medicine. (2018).

  210. 210.

    US National Library of Medicine. (2017).

  211. 211.

    Taylor, P. C. et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N. Engl. J. Med. 376, 652–662 (2017).

  212. 212.

    US National Library of Medicine. (2017).

  213. 213.

    US National Library of Medicine. (2019).

  214. 214.

    US National Library of Medicine. (2019).

  215. 215.

    US National Library of Medicine. (2019).

  216. 216.

    US National Library of Medicine. (2016).

  217. 217.

    US National Library of Medicine. (2016).

  218. 218.

    Polman, C. H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

  219. 219.

    US National Library of Medicine. (2017).

Download references


S.J.S.R. thanks the National Science Foundation Graduate Research Fellowship and the Stanford Graduate Fellowship for their generous support. This Review is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under grant no. DGE–1656518. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. Research in the laboratory of W.H.R. is supported by US National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants R01 AR063676, U19 AI11049103 and U01 AI101981.

Author information


  1. Immunology Program, Stanford University School of Medicine, Stanford, CA, USA

    • Samuel J. S. Rubin
    • , Michelle S. Bloom
    •  & William H. Robinson
  2. Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    • Samuel J. S. Rubin
    • , Michelle S. Bloom
    •  & William H. Robinson
  3. VA Palo Alto Health Care System, Palo Alto, CA, USA

    • Samuel J. S. Rubin
    • , Michelle S. Bloom
    •  & William H. Robinson


  1. Search for Samuel J. S. Rubin in:

  2. Search for Michelle S. Bloom in:

  3. Search for William H. Robinson in:


The authors contributed equally to all aspects of the article.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to William H. Robinson.


Antibody-dependent cell-mediated cytotoxicity

(ADCC). A mechanism by which antibodies direct immune cells via Fc receptor (FcR) engagement to lyse a target cell bound by specific antibodies.

Complement-dependent cytotoxicity

(CDC). A mechanism by which the complement system kills pathogens or cells bound by specific antibodies by insertion of the membrane attack complex (MAC) to form pores that mediate lysis.

Fc region

The tail region of an antibody, containing two heavy chain constant domains, that interacts with Fc receptors (FcRs) to mediate immune cell effector functions.

Ectopic lymphoid structures

Also known as tertiary lymphoid structures; organized aggregates of lymphocytes and other cells that possess some features of germinal centres. These structures can develop in chronically inflamed nonlymphoid tissues such as the synovium in rheumatoid arthritis.

Affinity maturation

A process in the germinal centre by which B cells, following interaction and activation by follicular helper T cells, undergo immunoglobulin gene mutation and subsequent selection to generate B cells that express antibodies with increased affinity for the target antigen.

Single-chain variable fragments

Single polypeptide fusion proteins of the variable regions of the heavy and light chains of an antibody connected by a peptide linker.

About this article

Publication history