Role of Crk-associated substrate lymphocyte type in the pathophysiology of rheumatoid arthritis in tax transgenic mice and in humans.
OBJECTIVE
To investigate the role of Crk-associated substrate lymphocyte type (Cas-L), a downstream signaling molecule of beta1 integrins, in the pathophysiology of rheumatoid arthritis (RA).


METHODS
We analyzed human T lymphotropic virus type I (HTLV-I) tax transgenic mice as well as samples from human RA patients. Splenocytes from tax transgenic mice were cultured on mouse endothelial cell-covered Transwell inserts, and cells migrating through the endothelial monolayer were counted. Biochemical studies were performed to analyze the protein expression and tyrosine phosphorylation of Cas-L. Immunohistochemical analysis was performed to detect Cas-L-positive cells that had infiltrated into the joints.


RESULTS
Migratory activity of splenocytes from tax transgenic mice with arthritis (ATg) was much higher than that of tax transgenic mice without arthritis (NTg) and littermate control mice. The expression of Cas-L protein and its tyrosine phosphorylation were increased in ATg mice compared with NTg and control mice, and this was accompanied by enhanced autophosphorylation of Fyn and Lck. Immunohistochemical analysis demonstrated a large number of Cas-L-positive lymphocytes migrating into the affected joints. Furthermore, in human RA, Cas-L-positive lymphocytes were shown to infiltrate to the inflammatory lesions.


CONCLUSIONS
These results strongly suggest that Cas-L plays an important role in the pathophysiology of RA.
Miyake-Nishijima
Rikako
R
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Iwata
Satoshi
S
Saijo
Shinobu
S
Kobayashi
Hiroshi
H
Kobayashi
Seiji
S
Souta-Kuribara
Akiko
A
Hosono
Osamu
O
Kawasaki
Hiroshi
H
Tanaka
Hirotoshi
H
Ikeda
Eiji
E
Okada
Yasunori
Y
Iwakura
Yoichiro
Y
Morimoto
Chikao
C
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology*; D017252:CD3 Complex / Q000032:analysis; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D007596:Joints / Q000166:cytology / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D014759:Viral Envelope Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases