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The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease

Nature Reviews Rheumatology volume 10, pages 422–428 (2014)Cite this article

Subjects

Key Points

  • On B cells, CD22 and Siglec-G mediate inhibition of B-cell antigen receptor-induced signalling; Siglec-G is an inhibitory receptor for B1 cells

  • Ligand-binding of CD22 and Siglec-G to other membrane glycoproteins in cis regulate their association to the B-cell receptor and the degree of inhibition

  • CD22-deficiency or Siglec-G-deficiency does not result in autoimmunity, whereas CD22 and Siglec-G double-deficient mice develop a systemic lupus erythematosus (SLE)-like disease

  • The immunomodulatory CD22-specific antibody, epratuzumab, reduces disease activity in patients with SLE, although the exact mechanism is unknown

  • Attaching CD22-specific or Siglec-G-specific sialic acids with antigens on liposomes induces antigen-specific tolerance in mice and could be a new autoantigen-specific treatment strategy

Abstract

A high proportion of peripheral human B cells produce polyreactive or autoreactive antibodies, which indicates that they have escaped the elimination of self-reactive B cells in the bone marrow. CD22 and Siglec-G are two inhibitory receptors of the sialic-acid-binding immunoglobulin-like lectin (Siglec) family that inhibit the B-cell antigen receptor (BCR) signal. The ability of these two receptors to bind sialic acids is crucial for regulating inhibition and inducing tolerance to self-antigens. Sialylated glycans are usually absent on microbes (although several pathogenic microorganisms have evolved strategies to mimic self by decorating their surfaces with sialic acids) but abundant in higher vertebrates and might, therefore, provide an important tolerogenic signal. Combined Siglec-G deficiency and CD22 deficiency leads to spontaneous autoimmunity in mice, and mutations in an enzyme that modifies Siglec ligands are directly linked to several autoimmune diseases in humans. New data show that high-affinity ligands for CD22 and Siglec-G can be used to induce antigen-specific B-cell tolerance, which might be one strategy for the treatment of autoimmune diseases in the future.

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Figure 1: Regulation of BCR signalling by CD22 and Siglec-G binding to cis ligands.
Figure 2: CD22 and Siglec-G maintain tolerance to self-antigens.
Figure 3: Targeting CD22 by antibodies and liposomes.

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Acknowledgements

The authors are supported by grants from the Deutsche Forschungsgemeinschaft (SFB643, TRR130).

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  1. Department of Biology, Chair of Genetics, University of Erlangen, Staudtstrasse 5, Erlangen, 91058, Germany

    Jennifer Müller & Lars Nitschke

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J.M. and L.N. contributed equally to researching data for the article and writing the article. L.N. reviewed and edited the manuscript before submission.

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Correspondence to Lars Nitschke.

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L.N. received grants for research from UCB Pharma. J.M. declares no competing interests.

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Müller, J., Nitschke, L. The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease. Nat Rev Rheumatol 10, 422–428 (2014). https://doi.org/10.1038/nrrheum.2014.54

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