An early sympathetic nervous system influence exacerbates collagen-induced arthritis via CD4+CD25+ cells

Arthritis Rheum. 2008 Aug;58(8):2347-55. doi: 10.1002/art.23628.


Objective: Activation of the sympathetic nervous system (SNS) ameliorates collagen-induced arthritis (CIA) in the late phase of the disease but aggravates it in the presymptomatic phase. The aim of the present study was to determine whether CD4+CD25+ T cells are influenced by the SNS of mice and play a disease-modifying role in the early symptomatic phase of the disease.

Methods: We tested the effects of the SNS on arthritis by transferring CD4+CD25+ T cells from sympathectomized mice immunized with type II collagen and from immunized, SNS-intact animals (controls). We further characterized transferred cells by studying forkhead box P3 (FoxP3) expression, cell proliferation, and cytokine secretion.

Results: Using anti-dopamine-beta-hydroxylase antibodies for systemic sympathectomy, we noticed a time-dependent disease amelioration (strongest when sympathectomy was performed 7 days before immunization, with no effect 30 days after immunization). When CD4+CD25+ T cells from immunized and sympathectomized animals were transferred into mice with CIA (on day 32), disease severity was reduced compared with that in controls. However, the number of CD4+CD25+FoxP3+ cells and the FoxP3 expression level in CD4+CD25+ cells were not changed by sympathectomy. In a mixed assay of donor CD4+CD25- and CD4+CD25+ cells, proliferation was reduced when cells from sympathectomized animals were studied. In the same assay, secretion of tumor necrosis factor, interleukin-17 (IL-17), IL-10, and IL-4 (not interferon-gamma) was markedly reduced when cells were taken from sympathectomized animals. Culture of CD4+CD25+ cells with norepinephrine (10(-5)M) for 24 hours before transfer worsened the arthritis.

Conclusion: The SNS increases disease severity in the early phase of symptomatic CIA by stimulating several proinflammatory aspects of CD4+CD25+ T cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / pathology*
  • Arthritis, Experimental / physiopathology*
  • B-Cell Activating Factor / metabolism*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology*
  • CD4-Positive T-Lymphocytes / physiology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Forkhead Transcription Factors / metabolism
  • Immunotherapy, Adoptive
  • Mice
  • Mice, Inbred DBA
  • Norepinephrine / pharmacology
  • Severity of Illness Index
  • Sympathectomy, Chemical
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / physiopathology*
  • Sympathomimetics / pharmacology


  • B-Cell Activating Factor
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Sympathomimetics
  • Norepinephrine