A new site-directed transgenic rheumatoid factor mouse model demonstrates extrafollicular class switch and plasmablast formation

Authors: Sweet, Rebecca A.; Christensen, Sean R.; Harris, Michelle L.; Shupe, Jonathan; Sutherland, Jaime L.; Shlomchik, Mark J.

Source: Autoimmunity, Volume 43, Number 8, December 2010 , pp. 607-618(12)

Publisher: Informa Healthcare

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Abstract:

The AM14 rheumatoid factor (RF) transgenic (Tg) mouse has been valuable for studying how self-reactive B cells are regulated beyond central tolerance, because they remain ignorant in normal mice. AM14 B-cell activation can be studied on autoimmune-prone strains or by inducing activation with IgG2a anti-chromatin antibodies (Abs). Despite the utility of conventional Ig-Tg mice, site-directed Ig-Tg (sd-Tg) mice provide a more physiological model for B-cell responses, allowing class switch and somatic hypermutation. We report here the creation of an AM14 sd-Tg mouse and describe its phenotype on both normal and autoimmune-prone backgrounds. AM14 sd-Tg B cells develop normally but remain unactivated in the BALB/c background, even after significant aging. In contrast, in the autoimmune-prone strain MRL/lpr, AM14 sd-Tg B cells become activated and secrete large amounts of IgG RF Ab into the serum. Class-switched Ab-forming cells were found in the spleen and bone marrow. IgG RF plasmablasts were also observed in extrafollicular clusters in the spleens of aged AM14 sd-Tg MRL/lpr mice. Class switch and Ab secretion were observed additionally in AM14 sd-Tg BALB/c B cells activated in vivo using IgG2a anti-chromatin Abs. Development of IgG auto-Abs is a hallmark of severe autoimmunity and is related to pathogenesis. Using the AM14 sd-Tg, we now show that switched auto-Ab-forming cells develop robustly outside germinal centers, further confirming the extrafollicular expression of activation induced cytidine deaminase (AID). This model will allow more physiological studies of B-cell biology in the future, including memory responses marked by class switch.

Keywords: Plasmablast; isotype switch; lupus; extrafollicular response

Document Type: Research article

DOI: http://dx.doi.org/10.3109/08916930903567500

Affiliations: 1: 2Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA

Publication date: 2010-12-01

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