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

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Abstract
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‐γ (IFNγ) 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 IFNγ 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 IFNγ 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 IFNγ 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 α2(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 IFNγ 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.