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Science 12 January 2001:
Vol. 291. no. 5502, pp. 319 - 322
DOI: 10.1126/science.291.5502.319
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Reports

Autoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice

Hiroyuki Nishimura,1 Taku Okazaki,1 Yoshimasa Tanaka,2 Kazuki Nakatani,6 Masatake Hara,3 Akira Matsumori,3 Shigetake Sasayama,3 Akira Mizoguchi,4 Hiroshi Hiai,5 Nagahiro Minato,2 Tasuku Honjo1*

Dilated cardiomyopathy is a severe pathology of the heart with poorly understood etiology. Disruption of the gene encoding the negative immunoregulatory receptor PD-1 in BALB/c mice, but not in BALB/c RAG-2-/- mice, caused dilated cardiomyopathy with severely impaired contraction and sudden death by congestive heart failure. Affected hearts showed diffuse deposition of immunoglobulin G (IgG) on the surface of cardiomyocytes. All of the affected PD-1-/- mice exhibited high-titer circulating IgG autoantibodies reactive to a 33-kilodalton protein expressed specifically on the surface of cardiomyocytes. These results indicate that PD-1 may be an important factor contributing to the prevention of autoimmune diseases.

1 Department of Medical Chemistry,
2 Department of Immunology and Cell Biology,
3 Department of Cardiovascular Medicine,
4 Department of Anatomy and Neurobiology,
5 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo, Kyoto, 606-8501, Japan.
6 Second Department of Anatomy, Osaka City University Medical School, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan.
*   To whom correspondence should be addressed. E-mail: honjo{at}mfour.med.kyoto-u.ac.jp

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A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients.
C Nielsen, H Laustrup, A Voss, P Junker, S Husby, and S T Lillevang (2004)
Lupus 13, 510-516
   Abstract »    PDF »
Regulation of Postsurgical Fibrosis by the Programmed Death-1 Inhibitory Pathway.
M. A. Holsti, T. Chitnis, R. J. Panzo, R. T. Bronson, H. Yagita, M. H. Sayegh, and A. O. Tzianabos (2004)
J. Immunol. 172, 5774-5781
   Abstract »    Full Text »    PDF »
Altering immune tolerance therapeutically: the power of negative thinking.
G. J. Prud'homme (2004)
J. Leukoc. Biol. 75, 586-599
   Abstract »    Full Text »    PDF »
The genetic basis of systemic lupus erythematosus--knowledge of today and thoughts for tomorrow.
L. Prokunina and M. Alarcon-Riquelme (2004)
Hum. Mol. Genet. 13, R143-148
   Abstract »    Full Text »    PDF »
B7-DC Regulates Asthmatic Response by an IFN-{gamma}-Dependent Mechanism.
K. Matsumoto, H. Inoue, T. Nakano, M. Tsuda, Y. Yoshiura, S. Fukuyama, F. Tsushima, T. Hoshino, H. Aizawa, H. Akiba, et al. (2004)
J. Immunol. 172, 2530-2541
   Abstract »    Full Text »    PDF »
A Spontaneous Model for Autoimmune Myocarditis Using the Human MHC Molecule HLA-DQ8.
J. A. Taylor, E. Havari, M. F. McInerney, R. Bronson, K. W. Wucherpfennig, and M. A. Lipes (2004)
J. Immunol. 172, 2651-2658
   Abstract »    Full Text »    PDF »
PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells.
C. Blank, I. Brown, A. C. Peterson, M. Spiotto, Y. Iwai, T. Honjo, and T. F. Gajewski (2004)
Cancer Res. 64, 1140-1145
   Abstract »    Full Text »    PDF »
Current Perspective on the Pathogenesis of Graves' Disease and Ophthalmopathy.
B. S. Prabhakar, R. S. Bahn, and T. J. Smith (2003)
Endocr. Rev. 24, 802-835
   Abstract »    Full Text »    PDF »
Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IA{beta} knockout NOD mice.
J. F. Elliott, J. Liu, Z.-N. Yuan, N. Bautista-Lopez, S. L. Wallbank, K. Suzuki, D. Rayner, P. Nation, M. A. Robertson, G. Liu, et al. (2003)
PNAS 100, 13447-13452
   Abstract »    Full Text »    PDF »
Absence of Programmed Death Receptor 1 Alters Thymic Development and Enhances Generation of CD4/CD8 Double-Negative TCR-Transgenic T Cells.
C. Blank, I. Brown, R. Marks, H. Nishimura, T. Honjo, and T. F. Gajewski (2003)
J. Immunol. 171, 4574-4581
   Abstract »    Full Text »    PDF »
Blockade of B7-H1 Suppresses the Development of Chronic Intestinal Inflammation.
T. Kanai, T. Totsuka, K. Uraushihara, S. Makita, T. Nakamura, K. Koganei, T. Fukushima, H. Akiba, H. Yagita, K. Okumura, et al. (2003)
J. Immunol. 171, 4156-4163
   Abstract »    Full Text »    PDF »
T Cell Rewiring in Differentiation and Disease.
S. Krishnan, D. L. Farber, and G. C. Tsokos (2003)
J. Immunol. 171, 3325-3331
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Vav1 Dephosphorylation by the Tyrosine Phosphatase SHP-1 as a Mechanism for Inhibition of Cellular Cytotoxicity.
C. C. Stebbins, C. Watzl, D. D. Billadeau, P. J. Leibson, D. N. Burshtyn, and E. O. Long (2003)
Mol. Cell. Biol. 23, 6291-6299
   Abstract »    Full Text »    PDF »
Blockade of Programmed Death-1 Engagement Accelerates Graft-Versus-Host Disease Lethality by an IFN-{gamma}-Dependent Mechanism.
B. R. Blazar, B. M. Carreno, A. Panoskaltsis-Mortari, L. Carter, Y. Iwai, H. Yagita, H. Nishimura, and P. A. Taylor (2003)
J. Immunol. 171, 1272-1277
   Abstract »    Full Text »    PDF »
PD-1 Inhibits Antiviral Immunity at the Effector Phase in the Liver.
Y. Iwai, S. Terawaki, M. Ikegawa, T. Okazaki, and T. Honjo (2003)
J. Exp. Med. 198, 39-50
   Abstract »    Full Text »    PDF »
The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice.
M. J. I. Ansari, A. D. Salama, T. Chitnis, R. N. Smith, H. Yagita, H. Akiba, T. Yamazaki, M. Azuma, H. Iwai, S. J. Khoury, et al. (2003)
J. Exp. Med. 198, 63-69
   Abstract »    Full Text »    PDF »
Critical Role of the Programmed Death-1 (PD-1) Pathway in Regulation of Experimental Autoimmune Encephalomyelitis.
A. D. Salama, T. Chitnis, J. Imitola, M. J. I. Ansari, H. Akiba, F. Tushima, M. Azuma, H. Yagita, M. H. Sayegh, and S. J. Khoury (2003)
J. Exp. Med. 198, 71-78
   Abstract »    Full Text »    PDF »


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