Fas/Fas ligand deficiency results in altered localization of anti-double-stranded DNA B cells and dendritic cells.
Autoantibodies directed against dsDNA are found in patients with systemic lupus erythematosus as well as in mice functionally deficient in either Fas or Fas ligand (FasL) (lpr/lpr or gld/gld mice). Previously, an IgH chain transgene has been used to track anti-dsDNA B cells in both nonautoimmune BALB/c mice, in which autoreactive B cells are held in check, and MRL-lpr/lpr mice, in which autoantibodies are produced. In this study, we have isolated the Fas/FasL mutations away from the autoimmune-prone MRL background, and we show that anti-dsDNA B cells in Fas/FasL-deficient BALB/c mice are no longer follicularly excluded, and they produce autoantibodies. Strikingly, this is accompanied by alterations in the frequency and localization of dendritic cells as well as a global increase in CD4 T cell activation. Notably, as opposed to MRL-lpr/lpr mice, BALB-lpr/lpr mice show no appreciable kidney pathology. Thus, while some aspects of autoimmune pathology (e.g., nephritis) rely on the interaction of the MRL background with the lpr mutation, mutations in Fas/FasL alone are sufficient to alter the fate of anti-dsDNA B cells, dendritic cells, and T cells.
Fields
M L
ML
Wistar Institute, Philadelphia, PA 19104, USA.
Sokol
C L
CL
Eaton-Bassiri
A
A
Seo
S
S
Madaio
M P
MP
Erikson
J
J
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D053222:Fas Ligand Protein; D005260:Female; D016130:Immunophenotyping; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D008218:Lymphocytosis / Q000235:genetics / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009393:Nephritis / Q000235:genetics / Q000276:immunology; D013045:Species Specificity; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
D000974:Antibodies, Antinuclear; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor