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Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse
  1. K Komura1,2,
  2. M Fujimoto1,
  3. K Yanaba1,
  4. T Matsushita1,
  5. Y Matsushita1,
  6. M Horikawa1,
  7. F Ogawa2,
  8. K Shimizu2,
  9. M Hasegawa1,
  10. K Takehara1,
  11. S Sato2
  1. 1
    Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
  2. 2
    Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  1. Dr Shinichi Sato. Department of Dermatology Nagasaki University Graduate School of Biomedical Sciences. 1-7-1 Sakamoto Nagasaki 852-8501, Japan; s-sato{at}


Objective : To assess the association of CD40/CD40 ligand (CD40L) interactions with the development of skin fibrosis and autoimmunity in tight-skin (TSK/+) mouse, which is a mouse model for human systemic sclerosis.

Methods: Newly born TSK/+ mice were treated with murine anti-CD40L monoclonal antibody (100 μg intraperitoneally weekly). Hypodermal thickness of 8-week-old female mice (defined as the thickness of a subcutaneous loose connective tissue layer beneath the panniculus carnosus) was measured under a light microscope. All skin sections were taken from the para-midline, upper back region. Serum anti-topoisomerase I autoantibody levels, serum immunoglobulin levels and plasma soluble CD40L levels were determined by enzyme-linked immunosorbent assay. For analysis of lymphocyte surface molecules, single cell suspensions of lymphocytes were stained by monoclonal antibodies. Proliferation of TSK/+ B cells and fibroblasts to anti-CD40 antibodies was assessed by the uptake of [3H]-labelled thymidine and bromodeoxyuridine, respectively.

Results: The blockade of CD40/CD40L interactions by anti-CD40L monoclonal antibody significantly reduced cutaneous fibrosis (65%) and anti-topoisomerase I autoantibody in TSK/+ mice. Anti-CD40L monoclonal antibody also normalised B lymphocyte abnormal activation in TSK/+ mice, demonstrated by hyper-γ-globulinaemia. Furthermore, augmented CD40/CD40L interactions in TSK/+ mice were suggested by upregulated expression of CD40L on CD4+ T cells, elevated plasma soluble CD40L levels. The hyperresponsiveness to CD40 stimulation was also observed in TSK/+ B cells and fibroblasts.

Conclusions: Cutaneous fibrosis and autoimmunity in TSK/+ mice are closely correlated with CD40/CD40L interactions.

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  • Competing interests: None.