Development of autoimmune hepatitis-like disease and production of autoantibodies to nuclear antigens in mice lacking B and T lymphocyte attenuator.
OBJECTIVE
B and T lymphocyte attenuator (BTLA), a coreceptor expressed on lymphocytes, was recently described as an inhibitory coreceptor that negatively regulates lymphocyte activation. The purpose of this study was to investigate the role of BTLA in the regulation of immune homeostasis and the pathogenesis of autoimmunity.


METHODS
We examined the levels of immunoglobulins and autoantibodies to nuclear antigens and the activation status of T cells in BTLA(-/-) mice. We also examined histopathologic changes in the organs of BTLA(-/-) mice.


RESULTS
We observed that BTLA(-/-) mice gradually developed hypergammaglobulinemia, antinuclear antibodies, anti-SSA antibodies, anti-double-stranded DNA antibodies, and an increased number of activated CD4+ T cells in the periphery with age. Lack of BTLA led to spontaneous development of autoimmune hepatitis-like disease characterized by an elevation in the level of transaminases, interface hepatitis, and spotty necrosis of the liver. BTLA(-/-) mice also showed inflammatory cell infiltration of multiple organs, including the salivary glands, lungs, and pancreas; these features are similar to those of Sjögren's syndrome, which is a frequent complication of autoimmune hepatitis. Furthermore, the survival rate of BTLA(-/-) mice was significantly reduced after the age of 7 months.


CONCLUSIONS
Our results indicate that BTLA plays an important role in the maintenance of immune tolerance and the prevention of autoimmune diseases.
Oya
Yoshihiro
Y
Graduate School of Medicine, Chiba University, Chiba, Japan.
Watanabe
Norihiko
N
Owada
Takayoshi
T
Oki
Mie
M
Hirose
Koichi
K
Suto
Akira
A
Kagami
Shin-Ichiro
S
Nakajima
Hiroshi
H
Kishimoto
Takashi
T
Iwamoto
Itsuo
I
Murphy
Theresa L
TL
Murphy
Kenneth M
KM
Saito
Yasushi
Y
D000818:Animals; D034961:Antigens, Nuclear / Q000276:immunology*; D001323:Autoantibodies / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D019693:Hepatitis, Autoimmune / Q000209:etiology / Q000276:immunology* / Q000378:metabolism*; D006706:Homeostasis / Q000276:immunology; D006942:Hypergammaglobulinemia / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology
D034961:Antigens, Nuclear; D001323:Autoantibodies; C488868:BTLA protein, mouse; D011971:Receptors, Immunologic