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Tumor Necrosis Factor Receptor-associated Factor 1 influences KRN/I-Ag7 Mouse Arthritis Autoantibody Production

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Abstract

Purpose

Recently, genomewide association analysis has revealed that the Tumor Necrosis Factor Receptor-associated factor 1-Complement 5 (TRAF1-C5) containing locus on chromosome 9 was associated with an increased risk for RA. Studies in model systems suggested that either gain- or loss-of-function TRAF1 mutations have immune effects that could plausibly lead to or exacerbate the arthritis phenotype. KRN/I-Ag7 (KxB/N) is a genetic mouse model of inflammatory arthritis. We aimed to assess the impact of TRAF1 deficiency on KRN/I-Ag7 mice.

Methods

We have bred KRN/I-Ag7 mice onto a TRAF1-deficient background and followed cohorts for the spontaneous appearance of arthritis. We have also transferred KxB/N serum to B6.I-Ag7 TRAF1KO recipients. In addition, systemic autoimmunity was induced through cGVH by injecting bm12 splenocytes into TRAF1KO recipient mice.

Results

TRAF1-deficient KRN/I-Ag7 mice spontaneously developed severe, progressive arthritis, comparable to that seen in TRAF1-intact KRN/I-Ag7 mice. However, the anti-GPI antibody titer was significantly lower in the former group. Interestingly, the TRAF1KO mice that had background levels of anti-GPI antibodies still showed severe arthritis, although with a brief delay compared to TRAF1 sufficient mice. In addition, TRAF1KO mice were fully susceptible to passive, serum transfer experiments. In another model of autoimmunity, TRAF1KO had no effect on cGVH autoantibodies production; nor was the response to an exogenous antigen impaired.

Conclusion

The pathogenesis of spontaneous KRN/I-Ag7 arthritis can largely proceed by TRAF1-independent pathways. The production of anti-GPI autoantibody, but not other autoantibody or antibody responses, was markedly impaired by TRAF1 deficiency. The spontaneous arthritis model in KRN mice appears to be much less antibody dependent than previously believed.

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Acknowledgments

We thank Xin Tian for helpful mouse bleeding.

Disclosures

The authors have no financial conflicts of interest.

Author information

Author notes

  1. Terri H. Finkel

    Present address: University of Central Florida College of Medicine, Orlando, FL, USA

Authors and Affiliations

  1. Department of Rheumatology, First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China

    Tao Cheng

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Yongwon Choi

  3. Department of Pediatrics, Division of Rheumatology, The Children’s Hospital of Philadelphia, University of Pennsylvania, Pennsylvania, USA

    Terri H. Finkel

  4. Department of Medicine, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, USA

    Patricia Y. Tsao, Mei Qing Ji & Robert A. Eisenberg

Authors
  1. Tao Cheng
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  2. Yongwon Choi
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  4. Patricia Y. Tsao
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  5. Mei Qing Ji
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Corresponding author

Correspondence to Robert A. Eisenberg.

Additional information

This work was supported by the Arthritis Foundation, the American Autoimmune Related Disease Association, and the NIH (R01-AR-34156; R01-AI063626; R01-EB012065).

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Cheng, T., Choi, Y., Finkel, T.H. et al. Tumor Necrosis Factor Receptor-associated Factor 1 influences KRN/I-Ag7 Mouse Arthritis Autoantibody Production. J Clin Immunol 33, 759–766 (2013). https://doi.org/10.1007/s10875-013-9866-5

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  • DOI: https://doi.org/10.1007/s10875-013-9866-5

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