Interleukin-4 produces a breakdown of tolerance in vivo with autoantibody formation and tissue damage.
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.
Foote
Linda C
LC
Merrimack College, North Andover, MA, USA.
Evans
John W
JW
Cifuni
Justin M
JM
Siracusa
Mark C
MC
Monteforte
Gina M
GM
McCole
Jennifer L
JL
D'Orazio
Christian C
CC
Hastings
William D
WD
Rothstein
Thomas L
TL
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
D001323:Autoantibodies; D019014:fas Receptor; D015847:Interleukin-4