Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 37, Issue 12, Pages 3339-3351Publisher
WILEY
DOI: 10.1002/eji.200737752
Keywords
autoantibodies; B cells; systemic lupus erythematosus
Categories
Funding
- NIAID NIH HHS [R01 AI073722, P01-AI36529, P01 AI036529, R01 AI061090] Funding Source: Medline
- NIAMS NIH HHS [P01-AR050256, P01 AR050256] Funding Source: Medline
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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 autoimmuneprone 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.
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