Review Article | Published:

B cell checkpoints in autoimmune rheumatic diseases

Nature Reviews Rheumatology (2019) | Download Citation

Abstract

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.

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Acknowledgements

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.

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Affiliations

  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

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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.

Glossary

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.

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https://doi.org/10.1038/s41584-019-0211-0