title: Autoimmune lpr/lpr mice deficient in CD40 ligand: spontaneous Ig class switching with dichotomy of autoantibody responses.
abstract: Fas-deficient MRL/Mp-lpr/lpr mice develop a syndrome that resembles human systemic lupus erythematosus, including production of IgG autoantibodies against small nuclear ribonucleoproteins (snRNPs), dsDNA, and self IgG (rheumatoid factor). To investigate the necessity for T-B cell contact in MRL autoimmunity, mice deficient in CD40 ligand (CD40L) were backcrossed onto this background, and Ab synthesis was assessed. In comparison to their CD40L-intact lpr/lpr counterparts, CD40L-deficient lpr/lpr mice had elevated levels of serum IgM and lower levels of IgG; however, a subset of animals had IgG2a, and to a lesser extent, IgG2b levels similar to those found in wild-type lpr/lpr mice. Levels of both isotypes in CD40L-deficient lpr/lpr mice were significantly greater than those found in nonautoimmune CD40L-deficient animals. IgG autoantibodies, including those directed against small nuclear ribonucleoproteins, also arose in CD40L-deficient lpr/lpr mice; however, they did not develop IgG rheumatoid factors or anti-dsDNA, and lacked histologic evidence of overt glomerulonephritis at age 3 mo, in contrast to CD40L-intact lpr/lpr animals. These results indicate that isotype switching occurs in lpr/lpr mice deficient in CD40L, and that production of IgG autoantibodies to ribonucleoproteins is at least partially preserved. They also suggest that different mechanisms may be responsible for eliciting autoantibody responses in lpr/lpr mice.
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8031, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: M P
authors.initials: MP
authors.lastname: Madaio
authors.forename: Q
authors.initials: Q
authors.lastname: Peng
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: I S
authors.initials: IS
authors.lastname: Grewal
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: J
authors.initials: J
authors.lastname: Craft
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001483:Base Sequence; D019013:CD40 Antigens / Q000235:genetics*; D023201:CD40 Ligand; D003433:Crosses, Genetic; D005921:Glomerulonephritis / Q000209:etiology; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000145:classification; D007075:Immunoglobulin M / Q000096:biosynthesis; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000235:genetics* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data
chemical_list: D001323:Autoantibodies; D019013:CD40 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand