Anti-chromatin antibodies drive in vivo antigen-specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites
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2007-11-29
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Herlands, Robin A., Jacqueline William, Uri Hershberg, and Mark J. Shlomchik. “Anti-Chromatin Antibodies Drive in Vivo Antigen-Specific Activation and Somatic Hypermutation of Rheumatoid Factor B Cells at Extrafollicular Sites.” European Journal of Immunology 37, no. 12 (2007): 3339–51. https://doi.org/10.1002/eji.200737752.
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This is the peer reviewed version of the following article: Herlands, Robin A., Jacqueline William, Uri Hershberg, and Mark J. Shlomchik. “Anti-Chromatin Antibodies Drive in Vivo Antigen-Specific Activation and Somatic Hypermutation of Rheumatoid Factor B Cells at Extrafollicular Sites.” European Journal of Immunology 37, no. 12 (2007): 3339–51. https://doi.org/10.1002/eji.200737752., which has been published in final form at https://doi.org/10.1002/eji.200737752. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
Abstract
A dominant type of spontaneous autoreactive B cell activation in murine lupus is the extrafollicular generation of plasmablasts. The factors governing such activation have been difficult to identify due to the stochastic onset and chronic nature of the response. Thus, the ability to induce a similar autoreactive B cell response with a known autoantigen in vivo would be a powerful tool in deciphering how autoimmune responses are initiated. We report here the establishment and characterization of a system to initiate autoreactive extrafollicular B cell responses, using IgG anti-chromatin antibodies, that closely mirrors the spontaneous response. We demonstrate that exogenously administered anti-chromatin antibody, presumably by forming immune complexes with released nuclear material, drives activation of rheumatoid factor B cells in AM14 Tg mice. Anti-chromatin elicits autoreactive B cell activation and development into antibody-forming cells at the T zone/red pulp border. Plasmablast generation occurs equally in BALB/c, MRL/+ and MRL/lpr mice, indicating that an autoimmune-prone genetic background is not required for the induced response. Importantly, infused IgG anti-chromatin induces somatic hypermutation in the absence of a GC response, thus proving the extrafollicular somatic hypermutation pathway. This system provides a window on the initiation of an autoantibody response and reveals authentic initiators of it.