title: Interleukin-4 produces a breakdown of tolerance in vivo with autoantibody formation and tissue damage.
abstract: B cell susceptibility to Fas-mediated apoptosis is downmodulated by engagement of IL-4 and sIg receptors. IL-4 produces Fas-resistance in both normal and tolerant B lymphocytes and has been associated with autoantibody production in mice expressing heterogeneous B cell receptors. To study the in vivo effects of IL-4 on autoreactive B cells in a more well-defined system, mice triply transgenic for IL-4, soluble HEL and anti-HEL B cell receptors were generated. Anti-HEL/sHEL/IL-4 triple transgenic mice matured normally but accumulated increasing amounts of serum anti-HEL antibodies over time, whereas anti-HEL/sHEL double transgenic mice lacked serum anti-HEL. Autoantibodies in triple transgenic mice were accompanied by gross evidence of renal pathology, characterized by both abnormal histology and marked proteinuria, along with microscopic evidence of immune complex-type hepatic damage. Proteinuria and histopathological changes were also observed in IL-4 transgenic control mice. These results suggest that IL-4 induced a breakdown in tolerance and autoreactive B cell activity manifested by the onset and accumulation of autoantibodies and the development of frank autoimmune disease.
authors.affiliation: Merrimack College, North Andover, MA, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Foote
authors.forename: John W
authors.initials: JW
authors.lastname: Evans
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cifuni
authors.forename: Mark C
authors.initials: MC
authors.lastname: Siracusa
authors.forename: Gina M
authors.initials: GM
authors.lastname: Monteforte
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McCole
authors.forename: Christian C
authors.initials: CC
authors.lastname: D'Orazio
authors.forename: William D
authors.initials: WD
authors.lastname: Hastings
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Rothstein
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes; D015847:Interleukin-4 / Q000276:immunology*; D007668:Kidney / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017634:Self Tolerance / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
chemical_list: D001323:Autoantibodies; D019014:fas Receptor; D015847:Interleukin-4