Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis

Arthritis Rheum. 1999 Jun;42(6):1168-78. doi: 10.1002/1529-0131(199906)42:6<1168::AID-ANR13>3.0.CO;2-L.


Objective: This study addresses the hypothesis that a profibrotic pattern of cytokines is produced in the lungs of patients with systemic sclerosis (SSc) and causes fibrosis.

Methods: Using a reverse transcriptase-polymerase chain reaction technique, interleukin-4 (IL-4), IL-5, and interferon-gamma (IFNgamma) messenger RNA (mRNA) were measured in unseparated CD8+ and CD4+ bronchoalveolar lavage (BAL) cells from SSc patients and healthy controls. To confirm the results, CD8+ T cells were cloned from BAL fluids, and the pattern of cytokine mRNA made by these cells was determined. Serial pulmonary function tests were done.

Results: BAL cells from healthy controls made IFNgamma mRNA, with no or little IL-4 or IL-5 mRNA. In contrast, BAL cells from the majority of SSc patients made IL-4 and/or IL-5 mRNA, with or without approximately equal amounts of IFNgamma mRNA. This pattern of cytokines was made by CD8+ T cells, which were increased in the lungs of these SSc patients. Patients whose BAL cells made this type 2 pattern of cytokine mRNA had a significant decline in forced vital capacity over time after the BAL, whereas patients whose BAL cells made IFNgamma mRNA alone did not. Both wild-type and an alternative splice variant of IL-4 mRNA were increased in BAL cells from SSc patients. Both forms of IL-4 stimulated alpha2(I) collagen mRNA in human dermal and lung fibroblasts.

Conclusion: The type 2 pattern of cytokine mRNA produced by BAL cells from SSc patients differs from unopposed IFNgamma production found in healthy BAL cells. This production of type 2 cytokine mRNA by CD8+ T cells is associated with a significant decline in lung function over time, which suggests a pathologic role for these T cells in interstitial fibrosis in SSc.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Count
  • DNA Primers / chemistry
  • Female
  • Flow Cytometry
  • Humans
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / genetics
  • Interleukin-4 / biosynthesis*
  • Interleukin-4 / genetics
  • Interleukin-5 / biosynthesis*
  • Interleukin-5 / genetics
  • Male
  • Middle Aged
  • Prospective Studies
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / physiopathology
  • RNA, Messenger / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Scleroderma, Systemic / metabolism*
  • Scleroderma, Systemic / physiopathology


  • DNA Primers
  • Interleukin-5
  • RNA, Messenger
  • Interleukin-4
  • Interferon-gamma