Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity

Reduced intracellular T-helper 1 interferon-gamma in blood of newly diagnosed children with Crohn's disease and age-related changes in Th1/Th2 cytokine profiles.

Abnormal cytokine production by T-helper 1 (Th1)/T-helper 2 (Th2) lymphocytes has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Few studies have examined Th1/Th2 cytokine status in pediatric IBD patients, and results have been inconsistent. We used flow cytometric detection of intracellular IFN-gamma/IL-4 cytokine production to investigate CD4+, Th1, and Th2 cells in the peripheral blood of children with untreated, newly diagnosed Crohn's disease (CD) (n = 23) and matched healthy controls (n = 49). Th1 cytokine levels were lower in CD patients compared with controls (p = 0.006) and strongly correlated with levels of albumin and hematocrit (r = 0.51, p = 0.007 and r = 0.35, p = 0.052, respectively). An age-dependent increase in Th1 cells was observed (p < 0.0005); however, no correlation was found between age, clinical end points, %CD4+, or Th2 cell numbers. In conclusion, the Th1 cytokine levels in blood are lower in early onset CD patients than in healthy children and are directly associated with disease-related clinical parameters. In future studies of pediatric IBD patients, it will be critical to consider the effect of age and disease progression on cytokine status in intestinal mucosa and peripheral blood