Perforin deficiency attenuates collagen-induced arthritis.
Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8+ T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8+ T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp-/-, and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp+/+, 64%; DBA/1J-pfp-/-, 54%), a slightly delayed onset (onset of disease: DBA/1J-pfp+/+, 53 +/- 3.6; DBA/1J-pfp-/-, 59 +/- 4.9 (mean +/- SEM), and milder form of the disease (maximum disease score: DBA/1J-pfp+/+, 7.3 +/- 1.1; DBA/1J-pfp-/-, 3.4 +/- 1.4 (mean +/- SEM); P < 0.05). Concomitantly, peripheral T cell proliferation in response to the specific antigen bovine collagen II was increased in pfp-/- mice compared with pfp+/+ mice, arguing for an impaired killing of autoreactive T cells caused by pfp deficiency. Thus, pfp-mediated cytotoxicity is involved in the initiation of tissue damage in arthritis, but pfp-independent cytotoxic death pathways might also contribute to CIA.
Bauer
Kristin
K
Institute of Immunology, University of Rostock, Rostock, Germany. kristin.bauer@med.uni-rostock.de
Knipper
Annika
A
Tu-Rapp
Hoang
H
Koczan
Dirk
D
Kreutzer
Hans-Jürgen
HJ
Nizze
Horst
H
Mix
Eilhard
E
Thiesen
Hans-Juergen
HJ
Holmdahl
Rikard
R
Ibrahim
Saleh M
SM
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D003094:Collagen