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  • Review Article
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B-cell targeting in rheumatoid arthritis and other autoimmune diseases

Nature Reviews Immunology volume 6, pages 394–403 (2006)Cite this article

Key Points

  • B-cell-depletion therapy has proved highly effective in rheumatoid arthritis and shows promise in several other autoantibody-associated diseases.

  • B-cell-depletion therapy was designed with the aim of breaking a vicious cycle of the two-way B-cell–T-cell interaction.

  • The CD20-specific monoclonal antibody rituximab is currently the main agent used in B-cell-depletion approaches.

  • Clinical benefit from B-cell depletion follows changes in levels of autoantibodies more closely than circulating B-cell numbers and can continue for months or years after B cells have returned.

  • Unwanted effects from immunosuppression seem to be minimal, although hypogammaglobulinaemia can occur after repeated therapy.

  • Several methods of B-cell targeting are now under investigation, including neutralization of B-cell-activating factor (BAFF) and blockade of B-cell-selective kinases.

Abstract

B-cell-targeted therapy for autoimmune disease emerged from theoretical proposition to practical reality between 1997 and 1998, with the availability of the B-cell-depleting monoclonal antibody rituximab. Since then, a score of autoantibody-associated disorders have been treated, with most convincing evidence of efficacy seen in subjects with rheumatoid arthritis. Several classes of B-cell-targeted agent are now under investigation. From the outset, a major goal of B-cell targeting has been the re-establishment of some form of immunological tolerance. In some subjects, the observed improvement of disease for years following therapy fuels hope that this goal might ultimately be achievable.

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Figure 1: B-cell–T-cell interactions.
Figure 2: B-cell development.
Figure 3: Model for self-perpetuation of autoreactive B cells.
Figure 4: Responses to rituximab treatment in patients with rheumatoid arthritis.

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  1. Department of Medicine, University College London, 46 Cleveland Street, London, W1P 6DB, UK

    Jonathan C. W. Edwards & Geraldine Cambridge

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The Edwards' research group has received financial support from Roche Pharmaceuticals for clinical infrastructure and advisory services.

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DATABASES

Medscape Drug Reference

rituximab

OMIM

multiple sclerosis

psoriatic arthropathy

rheumatoid arthritis

systemic lupus erythematosus

FURTHER INFORMATION

Jonathan Edwards' laboratory

Glossary

NOD proteins

Proteins that have a nucleotide-binding oligomerization domain and are involved in innate immune recognition systems.

Inflammasome

A complex of intracellular proteins that are involved in regulating cytokine and granzyme secretion in inflammation.

MRL/lpr mouse

A mouse strain that spontaneously develops glomerular nephritis and other symptoms of systemic lupus erythematosus ('lupus'). The lpr mutation causes a defect in FAS, preventing the apoptosis of activated lymphocytes; the MRL strain contributes disease-associated mutations that have yet to be identified.

K/BxN transgenic mouse

A mouse strain formed by crossing NOD/Lt mice with C57BL/6 x KRN T-cell-receptor-transgenic mice in which T cells recognize a peptide from the autoantigen glucose-6-phosphate isomerase (GPI). These mice develop an arthritis that is mediated, and transferable, by circulating antibody against GPI.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). A cytotoxic mechanism by which an antibody-coated target cell is directly killed by a leukocyte that expresses Fc receptors, such as a natural killer (NK) cell, macrophage or neutrophil. A specific receptor for the constant region of IgG, FcγRIII (also known as CD16), is expressed at the surface of most NK cells and mediates ADCC.

Methotrexate

An inhibitor of folate metabolism and other purine-related pathways that is widely used in rheumatoid arthritis to suppress synovitis and other features of the disease.

Cyclophosphamide

A DNA-alkylating agent that is used as an antitumour or immunosuppressive agent. Cyclophosphamide has been shown to destroy certain subsets of lymphocytes preferentially, including B cells and regulatory cells.

ACR50

An index of clinical improvement of at least 50%, based on several measures of disease activity, in rheumatoid arthritis, devised by the American College of Rheumatology.

C-reactive protein

An acute-phase plasma protein that belongs to the pentraxin family. It is produced in the liver during inflammation. For this reason, it is often used as a marker of inflammation and can prove useful in determining disease progress or the effectiveness of treatments.

Severe combined immunodeficiency mice

A naturally occurring mouse mutant with severe combined immune deficiency due to an inability to rearrange antigen-receptor chain genes.

Immune thrombocytopaenia

A condition in which a decrease in the number of platelets in the blood is due to increased destruction associated with coating of platelets with autoantibody.

Wegener's granulomatosis

A multisystem disorder characterized by necrotising granulomas, mainly of air passages, and vasculitis. It is frequently associated with anti-neutrophil cytoplasmic autoantibodies specific for protease 3.

Humanization

Conversion of a mouse antibody, by genetic engineering, into one with the structure of a human immunoglobulin in all domains other than the antigen-binding site (complementarity determining region).

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). This motif is present in the cytoplasmic domain of several inhibitory receptors. After ligand binding, ITIMs are tyrosine phosphorylated and recruit inhibitory phosphatases.

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Edwards, J., Cambridge, G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol 6, 394–403 (2006). https://doi.org/10.1038/nri1838

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