A new site-directed transgenic rheumatoid factor mouse model demonstrates extrafollicular class switch and plasmablast formation.
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.
Sweet
Rebecca A
RA
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 6520-8035, USA.
Christensen
Sean R
SR
Harris
Michelle L
ML
Shupe
Jonathan
J
Sutherland
Jaime L
JL
Shlomchik
Mark J
MJ
D000818:Animals; D001323:Autoantibodies / Q000032:analysis / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D012217:Rheumatoid Factor / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology*
D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains; D012217:Rheumatoid Factor