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This article is part of the supplement: New therapeutic targets in systemic lupus

Highly Accessed Review

B-cell selection and the development of autoantibodies

Natalia V Giltiay1, Craig P Chappell1 and Edward A Clark12*

Author Affiliations

1 Department of Immunology, 1959 NE Pacific Street, University of Washington, Seattle, WA 98195, USA

2 Division of Rheumatology, Department of Medicine, 1959 NE Pacific Street, University of Washington, Seattle, WA 98195, USA

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Arthritis Research & Therapy 2012, 14(Suppl 4):S1  doi:10.1186/ar3918

Published: 2 November 2012

Abstract

The clearest evidence that B cells play an important role in human autoimmunity is that immunotherapies that deplete B cells are very effective treatments for many autoimmune diseases. All people, healthy or ill, have autoreactive B cells, but not at the same frequency. A number of genes influence the level of these autoreactive B cells and whether they are eliminated or not during development at a central checkpoint in the bone marrow (BM) or at a later checkpoint in peripheral lymphoid tissues. These genes include those encoding proteins that regulate signaling through the B-cell receptor complex such as Btk and PTPN22, proteins that regulate innate signaling via Toll-like receptors (TLRs) such as MyD88 and interleukin-1 receptor-associated kinase 4, as well as the gene encoding the activation-induced deaminase (AID) essential for B cells to undergo class switch recombination and somatic hypermutation. Recent studies have revealed that TLR signaling elements and AID function not only in peripheral B cells to help mediate effective antibody responses to foreign antigens, but also in the BM to help remove autoreactive B-lineage cells at a very early point in B-cell development. Newly arising B cells that leave the BM and enter the blood and splenic red pulp can express both AID and TLR signaling elements like TLR7, and thus are fully equipped to respond rapidly to antigens (including autoantigens), to isotype class switch, and to undergo somatic hypermutation. These red pulp B cells may thus be an important source of autoantibody-producing cells arising particularly in extrafollicular sites, and indeed may be as significant a source of autoantibody-producing cells as B cells arising from germinal centers.