CD4+CXCR4+ T cells as a novel prognostic biomarker in patients with idiopathic inflammatory myopathy-associated interstitial lung disease

Background. There is an unmet need for the development of new biomarkers for idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD). Methods. Peripheral CD4(+)CXCR4(+) T cells, stromal cell-derived factor-1 and Krebs von den Lungen-6 were measured in patients with IIM-ILD (n=85) and controls. The relation to pulmonary functions, high-resolution CT scores, specific clinical phenotypes and survival was analysed. Cytokine-expression profiling of these CD4(+)CXCR4(+) T cells and their co-culture with pulmonary fibroblasts were conducted. Results. The peripheral percentages of CD4(+)CXCR4(+) T cells were significantly elevated in IIM-ILD patients, and correlated with high-resolution CT score (r= 0.7136, P < 0.0001) and pulmonary function impairments, such as percentage of forced volume vital capacity (r= -0.4734, P = 0.0005). They were associated with anti-melanoma differentiation-associated gene 5 autoantibodies and the amyopathic DM phenotype. In IIM-ILD, peripheral percentages of CD4(+)CXCR4(+) T cells >= 30% revealed a 6-month mortality as high as 47%. These CD4(+)CXCR4(+) T cells express high levels of IL-21 and IL-6. In vitro blockade of IL-21 signalling by neutralization of IL-21 or Janus kinase inhibitor could abolished the fibroblast proliferation. Conclusion. Overall, peripheral CD4(+)CXCR4(+) T cells appear to be a potentially valuable novel biomarker associated with the severity and prognosis of IIM-ILD. They promote pulmonary fibroblast proliferation via IL-21, which may herald future targeted treatments for this severe disease.