title: MRL Strains Have a BAFFR Mutation without Functional Consequence.
abstract: It has been shown that B cell activating factor receptor (BAFFR) is critical for B cell development and survival. In this study, we sought to evaluate the expression and function of BAFFR across multiple stains of mice that vary in their potential to develop systemic autoimmune disease. The inability of a commercial antibody to bind to BAFFR in the autoimmune prone mouse strains, MRL and MRL/Lpr led to the discovery of a mutation in TNFRSF13C gene (encoding BAFFR) that resulted in a Pro44Ser substitution in the N-terminus near the BAFF binding site in these strains. To define the biological consequences of mutant BAFFR, we compared the expression and activity of BAFFR in MRL and MRL/Lpr mice to BALB/c, which express the consensus version of TNFRSF13C. B cells from MRL and MRL/Lpr mice expressed mutant BAFFR on surface and were capable of responding to BAFF as exhibited by BAFF-mediated reduction in apoptosis and NF-κB2 activation. Signaling through MAPK ERK1/2 was not significantly induced by BAFF in MRL/Lpr mice; however, MAPK ERK1/2 signaling was intact in MRL mice. The inability of MRL/Lpr B cells to significantly activate ERK1/2 in response to BAFF was due to the high basal activity of the signaling pathway in these cells. In fact, basal activity of ERK1/2 in B cells correlated with the degree of autoimmune susceptibility exhibited by each strain. In addition, aged MRL/Lpr mice with severe autoimmune disease had high BAFF levels, low surface BAFFR, and high basal NF-κB2 activation, a pattern which is attributed to the high frequency of antibody secreting cells. We conclude that P44S BAFFR mutation does not hinder BAFFR function or enhance B cell activity in MRL/Lpr and MRL mice and that other susceptibility loci on the MRL background contributed to the hyperactivity of these cells.
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993-0002, United States of America.
authors.forename: Windy R
authors.initials: WR
authors.lastname: Allman
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993-0002, United States of America.
authors.forename: Lunhua
authors.initials: L
authors.lastname: Liu
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993-0002, United States of America.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Coleman
authors.affiliation: Laboratory of Bacterial Polysaccharides, Division of Bacterial Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993-0002, United States of America.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Akkoyunlu
mesh_terms: D000818:Animals; D053265:B-Cell Activation Factor Receptor / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053265:B-Cell Activation Factor Receptor; D016328:NF-kappa B; C486662:Tnfrsf13c protein, mouse