Abstract
IntroductionPrevious observations suggest that active systemic juvenile idiopathic arthritis (sJIA) is associated with a prominent erythropoiesis gene-expression signature. The aim of this study was to determine the association of this signature with peripheral blood mononuclear cell (PBMC) subpopulations and its specificity for sJIA as compared with related conditions.MethodsThe 199 patients with JIA (23 sJIA and 176 non-sJIA) and 38 controls were studied. PBMCs were isolated and analyzed for multiple surface antigens with flow cytometry and for gene-expression profiles. The proportions of different PBMC subpopulations were compared among sJIA, non-sJIA patients, and controls and subsequently correlated with the strength of the erythropoiesis signature. Additional gene-expression data from patients with familial hemophagocytic lymphohistiocytosis (FHLH) and from a published sJIA cohort were analyzed to determine whether the erythropoiesis signature was present.ResultsPatients with sJIA had significantly increased proportions of immature cell populations, including CD34+ cells, correlating highly with the strength of the erythropoiesis signature. The erythropoiesis signature strongly overlapped with the gene-expression pattern in purified immature erythroid precursors. The expansion of immature cells was most prominently seen in patients with sJIA and anemia, even in the absence of reticulocytosis. Patients with non-sJIA and anemia did not exhibit the erythropoiesis signature. The erythropoiesis signature was found to be prominent in patients with FHLH and in a published cohort of patients with active sJIA, but not in patients with inactive sJIA.ConclusionsAn erythropoiesis signature in active sJIA is associated with the expansion of CD34+ cells, also is seen in some patients with FHLH and infection, and may be an indicator of ineffective erythropoiesis and hemophagocytosis due to hypercytokinemia.
Highlights
Previous observations suggest that active systemic juvenile idiopathic arthritis is associated with a prominent erythropoiesis gene-expression signature
We demonstrate that a link exists between the expansion of immature peripheral blood mononuclear cells (PBMCs) subpopulations and characteristic gene-expression signatures in systemic juvenile idiopathic arthritis (sJIA) and that the erythropoiesis signature is seen in patients with familial hemophagocytic lymphohistiocytosis (FHLH) and in some patients with systemic lupus erythematosus (SLE) and bacterial infections
PBMC subpopulations in non-sJIA, sJIA, and controls In a previous study, by comparing PBMC gene expression between sJIA patients and healthy controls, we identified a group of 67 probe sets that we defined as an erythropoiesis signature [14]
Summary
Previous observations suggest that active systemic juvenile idiopathic arthritis (sJIA) is associated with a prominent erythropoiesis gene-expression signature. Other findings supporting a different underlying pathogenic mechanism in sJIA are the absence of reproducible HLA associations, autoreactive B and T cells, and autoantibodies This has led some investigators to postulate that sJIA represents an autoinflammatory rather than an autoimmune condition [2]. MAS shares many features with familial HLH (FHLH), including clinical and laboratory features, and immunologic abnormalities such as natural killer (NK) cell dysfunction and elevated levels of soluble IL2Ra and soluble CD163 [8,9]. Both conditions are characterized by a marked increase in serum ferritin levels [10,11]. About 50% of patients with new-onset sJIA have elevated serum ferritin levels of > 500 ng/ml [8], which is used as a cut-off in the diagnostic criteria for HLH [12]
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