Visualizing the onset and evolution of an autoantibody response in systemic autoimmunity.
The onset of systemic autoimmunity is variable, making it difficult to identify early events. In this study, we show in rheumatoid factor (RF) Ig-transgenic autoimmune-prone mice that the appearance of RF B cells in blood signifies the onset of RF B cell activation in spleen, providing a novel window into the initiation of an autoantibody response. This allowed us to study the early and late phases of spontaneous induction of the B cell autoimmune response. Using this approach we showed that extensive Ab-forming cell generation in spleen, accompanied by somatic hypermutation, occurred despite the lack of an early germinal center response. The onset of the RF response correlated with the levels of IgG2a-containing immune complexes but not total IgG2a. By identifying the time of onset in individual mice, we were able to track progression of disease. We found remissions of RF Ab-forming cell production in some mice, suggesting that at the clonal level, chronic autoantibody responses are dynamic and episodic, much like acute pathogen responses. Surprisingly, there was little accumulation of long-lived plasma cells in bone marrow of mice with long-standing RF responses in spleen. These studies are among the first to define the early events of a spontaneous B cell autoimmune response.
William
Jacqueline
J
Section of Immunobiology and Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Euler
Chad
C
Leadbetter
Elizabeth
E
Marshak-Rothstein
Ann
A
Shlomchik
Mark J
MJ
D000818:Animals; D000921:Antibody-Producing Cells / Q000378:metabolism / Q000473:pathology; D000936:Antigen-Antibody Complex / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D019143:Evolution, Molecular; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007126:Immunoglobulin Allotypes / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis; D007700:Kinetics; D018655:Lymphocyte Count; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D012217:Rheumatoid Factor / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000936:Antigen-Antibody Complex; D007126:Immunoglobulin Allotypes; D007074:Immunoglobulin G; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D012217:Rheumatoid Factor