Arthritis in mice that are deficient in interleukin-1 receptor antagonist is dependent on genetic background.
OBJECTIVE
To determine the effect of deletion of interleukin-1 receptor antagonist (IL-1Ra) protein in an animal model of rheumatoid arthritis.


METHODS
BALB/c mice deficient in IL-1Ra (IL-1Ra(-/-)) were bred with collagen-induced arthritis (CIA)-susceptible DBA/1 mice and B10 mice transgenic for HLA-DRB1*0101 (B10.DR1). After generation of IL-1Ra(-/-) mice on the DBA/1 and B10.DR1 backgrounds, the mice were observed for the development of spontaneous arthritis and immunized for induction of CIA.


RESULTS
We found that although BALB/c mice deficient in IL-1Ra (BALB/c(-/-)) spontaneously developed chronic inflammatory arthritis, DBA/1 IL-1Ra-deficient (DBA/1(-/-)) and B10.DR1 IL-1Ra-deficient (B10.DR1(-/-)) mice did not. Splenocytes from BALB/c(-/-) mice produced elevated levels of IL-2, IL-4, IL-6, IL-10, IL-17, and granulocyte-macrophage colony-stimulating factor in response to anti-CD3 stimulation. After immunization with type II collagen (CII), DBA/1(-/-) and B10.DR1(-/-) mice had a significantly earlier onset of CIA, and with increased severity compared with IL-1Ra(+/+) mice. Immunization of BALB/c(-/-) mice with CII did not aggravate spontaneous arthritis. All of the immunized mice developed antibodies to CII that correlated with arthritis severity. Levels of antibody to CII in the BALB/c(-/-) strain were relatively low.


CONCLUSIONS
These data indicate that the spontaneous arthritis of IL-1Ra deficiency is highly dependent on non-major histocompatibility complex genes and that autoimmunity to CII is not the major disease-inducing event. Class II immune response genes are more important for the regulation of CIA, and although these 2 models of arthritis share many pathogenic mechanisms, they also have significant differences.
Zhou
Fang
F
Veterans Affairs Medical Center, University of Tennessee Health Science Center, Memphis, Tennessee 38104, USA.
He
Xiaowen
X
Iwakura
Yoichiro
Y
Horai
Reiko
R
Stuart
John M
JM
D000818:Animals; D000906:Antibodies / Q000097:blood; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D017252:CD3 Complex / Q000276:immunology; D024043:Collagen Type II / Q000276:immunology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D053590:Interleukin 1 Receptor Antagonist Protein; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C / Q000276:immunology*; D008811:Mice, Inbred DBA / Q000276:immunology*; D008822:Mice, Transgenic; D012795:Sialoglycoproteins / Q000235:genetics*; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000906:Antibodies; D017252:CD3 Complex; D024043:Collagen Type II; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins