A new murine model to define the critical pathologic and therapeutic mediators of polymyositis.
OBJECTIVE
To establish a new murine model of polymyositis (PM) for the understanding of its pathologic mechanisms and the development of new treatment strategies.


METHODS
C protein-induced myositis (CIM) was induced by a single immunization of recombinant human skeletal C protein in C57BL/6 mice, as well as in CD4-depleted, CD8-depleted, and mutant mice as controls. Some mice were treated with high-dose intravenous immunoglobulin (IVIG) after disease induction. Muscle tissues were examined histologically.


RESULTS
In mice with CIM, inflammation was confined to the skeletal muscles. Histologic examination revealed a common pathologic feature of CIM and PM, involving abundant infiltration of CD8 and perforin-expressing cells in the endomysial site of the injured muscle. Suppression of myositis was achieved by depletion of both CD4 and CD8 T cells. Despite the development of serum anti-C protein antibodies in wild-type mice, severe myositis was induced in mice deficient in B cells. Induction of myositis was suppressed in interleukin-1alpha/beta (IL-1alpha/beta)-null mutant mice, but not in tumor necrosis factor alpha (TNFalpha)-null mutant mice. Use of IVIG, a treatment with proven efficacy in PM, suppressed CIM in the subgroup of treated mice.


CONCLUSIONS
CIM mimics PM pathologically and clinically. Infiltration of CD8 T cells is the most likely mechanism of muscle injury, and IL-1, but not B cells or TNFalpha, is crucial in the development of CIM. IVIG has therapeutic effects in CIM, suggesting that the effects of IVIG are not mediated by suppression of antibody-mediated tissue injury. This murine model provides a useful tool for understanding the pathologic mechanisms of PM and for developing new treatment strategies.
Sugihara
Takahiko
T
Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Sekine
Chiyoko
C
Nakae
Takashi
T
Kohyama
Kuniko
K
Harigai
Masayoshi
M
Iwakura
Yoichiro
Y
Matsumoto
Yoh
Y
Miyasaka
Nobuyuki
N
Kohsaka
Hitoshi
H
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D017285:Polymyositis / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins; D012420:Running; D000099163:Myosin Binding Protein C
D016827:CD8 Antigens; D002352:Carrier Proteins; D016756:Immunoglobulins, Intravenous; D011994:Recombinant Proteins; D000099163:Myosin Binding Protein C