Rheumatoid factor B cell memory leads to rapid, switched antibody-forming cell responses.
B cells are critical in the initiation and maintenance of lupus. Autoreactive B cells clonally expand, isotype switch, and mutate--properties associated with memory B cells (MBCs), which are typically generated via germinal centers. The development and functions of autoreactive MBCs in lupus are poorly understood. Moreover, mounting evidence implicates the extrafollicular (EF) response in the generation of switched and mutated autoantibodies that are driven by BCR and TLR corecognition, raising the question of whether MBCs are generated in this context. In this study, we investigated autoreactive MBC generation associated with this type of response. We transferred B cells from AM14 site-directed BCR transgenic mice into nontransgenic normal recipients and elicited an EF response with anti-chromatin Ab, as in prior studies. By following the fate of the stimulated cells at late time points, we found that AM14 B cells persisted at increased frequency for up to 7 wk. Furthermore, these cells had divided in response to Ag but were subsequently quiescent, with a subset expressing the memory marker CD73. These cells engendered rapid, isotype-switched secondary plasmablast responses upon restimulation. Both memory and rapid secondary responses required T cell help to develop, emphasizing the need for T-B collaboration for long-term self-reactivity. Thus, using this model system, we show that the EF response generated persistent and functional MBCs that share some, but not all, of the characteristics of traditional MBCs. Such cells could play a role in chronic or flaring autoimmune disease.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Rebecca A
RA
Sweet
Jaime L
JL
Cullen
Mark J
MJ
Shlomchik
D015720:5'-Nucleotidase / Q000235:genetics / Q000276:immunology; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001323:Autoantibodies / Q000096:biosynthesis*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002450:Cell Communication; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D012217:Rheumatoid Factor / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000906:Antibodies; D001323:Autoantibodies; D002843:Chromatin; D011948:Receptors, Antigen, T-Cell; D012217:Rheumatoid Factor; D015720:5'-Nucleotidase