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Granzyme B is dispensable for immunologic tolerance to self in a murine model of systemic lupus erythematosus.

Publication ,  Journal Article
Graham, KL; Thibault, DL; Steinman, JB; Okeke, L; Kao, PN; Utz, PJ
Published in: Arthritis Rheum
June 2005

OBJECTIVE: Proteolytic autoantigen cleavage by the serine protease granzyme B has been implicated in the development of systemic autoimmune disease; however, there has been no conclusive demonstration of a pathogenic role for granzyme B in autoimmunity. In this study, we evaluated the role of granzyme B in a murine model of autoimmunity. METHODS: To identify potential novel granzyme B substrates, complementary DNAs encoding nuclear factor 45 (NF45) and NF90 were used to generate (35)S-methionine-labeled proteins by coupled in vitro transcription/translation. Radiolabeled proteins were then incubated with purified recombinant granzyme B or caspases, and the cleavage products were analyzed by autoradiography. We also immunized granzyme B-deficient and granzyme B-intact mice with the mineral oil pristane. Production of autoantibodies directed against granzyme B substrates in response to pristane was evaluated by Western blotting, immunoprecipitation, and enzyme-linked immunosorbent assay. RESULTS: The double-stranded RNA-binding protein NF90 was identified as a novel substrate for caspases and granzyme B, both in vitro and in vivo. NF90 is uniquely cleaved by granzyme B in vitro; however, pristane immunization still induced anti-NF90 antibodies in granzyme B-deficient mice. Pristane-treated granzyme B-deficient mice also produced antibodies directed against the U1-70-kd antigen, a previously identified granzyme B substrate. Last, antibodies directed against U1-70 kd arose spontaneously in granzyme B-deficient mice. CONCLUSION: These results demonstrate that granzyme B is not required for the production of autoantibodies directed against antigens that are granzyme B substrates in vitro. The data also suggest a protective role for this proapoptotic protease in systemic autoimmunity.

Duke Scholars

Published In

Arthritis Rheum

DOI

ISSN

0004-3591

Publication Date

June 2005

Volume

52

Issue

6

Start / End Page

1684 / 1693

Location

United States

Related Subject Headings

  • Serine Endopeptidases
  • Models, Animal
  • Mice
  • Lupus Erythematosus, Systemic
  • Immune Tolerance
  • Granzymes
  • Female
  • Autoimmunity
  • Autoantigens
  • Autoantibodies
 

Citation

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Graham, K. L., Thibault, D. L., Steinman, J. B., Okeke, L., Kao, P. N., & Utz, P. J. (2005). Granzyme B is dispensable for immunologic tolerance to self in a murine model of systemic lupus erythematosus. Arthritis Rheum, 52(6), 1684–1693. https://doi.org/10.1002/art.21092
Graham, Kareem L., Donna L. Thibault, Jonathan B. Steinman, Lance Okeke, Peter N. Kao, and Paul J. Utz. “Granzyme B is dispensable for immunologic tolerance to self in a murine model of systemic lupus erythematosus.Arthritis Rheum 52, no. 6 (June 2005): 1684–93. https://doi.org/10.1002/art.21092.
Graham KL, Thibault DL, Steinman JB, Okeke L, Kao PN, Utz PJ. Granzyme B is dispensable for immunologic tolerance to self in a murine model of systemic lupus erythematosus. Arthritis Rheum. 2005 Jun;52(6):1684–93.
Graham, Kareem L., et al. “Granzyme B is dispensable for immunologic tolerance to self in a murine model of systemic lupus erythematosus.Arthritis Rheum, vol. 52, no. 6, June 2005, pp. 1684–93. Pubmed, doi:10.1002/art.21092.
Graham KL, Thibault DL, Steinman JB, Okeke L, Kao PN, Utz PJ. Granzyme B is dispensable for immunologic tolerance to self in a murine model of systemic lupus erythematosus. Arthritis Rheum. 2005 Jun;52(6):1684–1693.
Journal cover image

Published In

Arthritis Rheum

DOI

ISSN

0004-3591

Publication Date

June 2005

Volume

52

Issue

6

Start / End Page

1684 / 1693

Location

United States

Related Subject Headings

  • Serine Endopeptidases
  • Models, Animal
  • Mice
  • Lupus Erythematosus, Systemic
  • Immune Tolerance
  • Granzymes
  • Female
  • Autoimmunity
  • Autoantigens
  • Autoantibodies