Short-lived plasmablasts dominate the early spontaneous rheumatoid factor response: differentiation pathways, hypermutating cell types, and affinity maturation outside the germinal center.
We used a newly validated approach to identify the initiation of an autoantibody response to identify the sites and cell differentiation pathways at early and late stages of the rheumatoid factor response. The autoimmune response is mainly comprised of rapidly turning over plasmablasts that, according to BrdU labeling, TUNEL, and hypermutation data, derive from an activated B cell precursor. Surprisingly, few long-lived plasma cells were generated. The response most likely initiates at the splenic T-B zone border and continues in the marginal sinus bridging channels. Both activated B cells and plasmablasts harbor V gene mutations; large numbers of mutations in mice with long-standing response indicate that despite the rapid turnover of responding cells, clones can persist for many weeks. These studies provide insights into the unique nature of an ongoing autoimmune response and may be a model for understanding the response to therapies such as B cell depletion.
William
Jacqueline
J
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Euler
Chad
C
Shlomchik
Mark J
MJ
D000818:Animals; D000921:Antibody-Producing Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015703:Antigens, CD / Q000096:biosynthesis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001666:Binding Sites, Antibody / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D037102:Lectins / Q000096:biosynthesis; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000378:metabolism; D012217:Rheumatoid Factor / Q000096:biosynthesis* / Q000235:genetics; D051918:Sialic Acid Binding Ig-like Lectin 2; D027041:Somatic Hypermutation, Immunoglobulin; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D037102:Lectins; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D012217:Rheumatoid Factor