ARTHRITIS & RHEUMATISM Vol. 42, No. 6, June 1999, pp 1168–1178 © 1999, American College of Rheumatology PRODUCTION OF TYPE 2 CYTOKINES BY CD8+ LUNG CELLS IS ASSOCIATED WITH GREATER DECLINE IN PULMONARY FUNCTION IN PATIENTS WITH SYSTEMIC SCLEROSIS SERGEI P. ATAMAS, VLADIMIR V. YUROVSKY, ROBERT WISE, FREDRICK M. WIGLEY, CAROL J. GOTER ROBINSON, PATRICIA HENRY, WILLIAM J. ALMS, and BARBARA WHITE 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- (IFN) 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 IFN 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 approx- imately equal amounts of IFN 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 IFN 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 2(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 IFN 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. Interstitial lung disease is the major cause of death in systemic sclerosis (SSc) (1). The pathobiology of this aspect of SSc remains poorly understood, but involves pulmonary inflammation, followed by fibrosis. The pulmonary inflammation is a cellular process in which alveolar spaces and the pulmonary interstitium are filled with T cells, macrophages, neutrophils, eosino- phils, and plasma cells (2). The cells and lining fluid in the alveoli and airways can be sampled by bronchoal- veolar lavage (BAL). The phenotype of cells in BAL fluids correlates well with that of cells obtained from tissue in both normal and diseased lungs (3), although BAL lymphocytes may be relatively underrepresented in interstitial lung disease (4,5). Inflammatory cells in the lungs of SSc patients could promote pulmonary fibrosis through the produc- tion of soluble mediators that stimulate inflammation or activate fibroblasts. Chemokines such as interleukin-8 (IL-8), macrophage inhibitory protein 1 (MIP-1), and RANTES could attract T cells, macrophages, neutro- phils, and eosinophils to the lungs. Through this inflam- mation, chemokines might indirectly stimulate fibrosis. The type 2 cytokines IL-4 and IL-5 could stimulate pulmonary inflammation and fibrosis. For example, in Dr. Atamas’ work was supported by a Herbert J. Zarkin Fellowship in Scleroderma. Dr. Yurovsky’s work was supported by an Arthritis Investigator Award. Dr. White’s work was supported by a Career Investigator Award from the Veterans Administration and grant no. R01HL-54163 from the NIH. Sergei P. Atamas, MD, PhD, Vladimir V. Yurovsky, PhD, Carol J. Goter Robinson, PhD, Patricia Henry, BA, William J. Alms, MD, PhD, Barbara White, MD: University of Maryland School of Medicine, and Veterans Affairs Maryland Health Care System, Balti- more; Robert Wise, MD, Fredrick M. Wigley, MD: Johns Hopkins University School of Medicine, Baltimore, Maryland. Address reprint requests to Sergei P. Atamas, MD, PhD, University of Maryland School of Medicine, Veterans Affairs Medical Center 3C-125, Research Service (151), 10 North Greene Street, Baltimore, MD 21201. Submitted for publication May 26, 1998; accepted in revised form January 7, 1999. 1168