Gene expression profiling of peripheral blood from patients with untreated new‐onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome

Abstract

Objective. Systemic juvenile idiopathic arthritis (JIA) is frequently associated with the development of macrophage activation syndrome. This study was undertaken to better understand the relationship between systemic JIA and macrophage activation syndrome.Methods. Gene expression profiles were examined in 17 patients with untreated new-onset systemic JIA, 5 of whom showed evidence of subclinical macrophage activation syndrome (of whom 2 eventually developed overt macrophage activation syndrome). Peripheral blood mononuclear cells (PBMCs) were separated on Ficoll gradients, and purified RNA was analyzed using Affymetrix GeneChip expression arrays. A fraction of the PBMCs were used for flow cytometry to define the cellular composition of the samples.Results. Two hundred twenty-five differentially expressed genes (P < 0.05) that distinguished patients with systemic JIA from healthy controls (n ‫؍‬ 30) were identified. Clustering analysis indicated that expression patterns correlated with serum ferritin levels. Three main clusters distinguished systemic JIA patients with highly elevated ferritin levels (including those with subclinical macrophage activation syndrome) from those with normal or only moderately elevated ferritin levels. The first cluster comprised genes involved in the synthesis of hemoglobins and structural proteins of erythrocytes. This transcriptional profile was consistent with immature nucleated red blood cells, likely reflective of high red blood cell turnover. Also included were transcripts indicating immature granulocytes. The second cluster was enriched for genes involved in cell cycle regulation. The third cluster was enriched for genes involved in innate immune responses, including those involved in the negative regulation of Toll-like receptor/ interleukin-1 receptor-triggered inflammatory cascades and markers of the alternative pathway of macrophage differentiation. Additional differentially expressed genes of interest were those involved in the cytolytic pathway, including SH2D1A and Rab27a. Conclusion. These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.At onset, systemic juvenile idiopathic arthritis (JIA), which constitutes ϳ10% of all cases of JIA, is distinguished from other forms of JIA by the prominence of extraarticular features, such as spiking fevers,

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

“…Gene signatures consistent with chronic TLR/IL-1b signaling are present in sJIA patients. 53 Lupus, another rheumatic condition associated with MAS, 4 has also long been associated with hyperactive TLR9 function. 54 EBV, perhaps the most common infectious trigger of secondary HLH, is a DNA virus that triggers TLR9.…”

Heterogeneity in juvenile idiopathic arthritis: Impact of molecular profiling based on DNA polymorphism and gene expression patterns

“…Nevertheless, gene expression profiles in peripheral blood mononuclear cells obtained prior to therapy with disease-modifying antirheumatic drugs can identify gene expression differences between groups of samples from patients with several JIA subtypes and those from normal controls (17). Further, gene expression analyses can identify phenotypically distinguishable subsets within JIA subtypes, including polyarticular JIA (18), systemic JIA (19), and oligoarticular JIA (20).…”

“…Gene expression studies have also provided additional evidence that the role of the adaptive immune system is rather limited in systemic JIA as compared with the other JIA subtypes, whereas the contribution of the innate immunity may be much more prominent (19,25,26). Several recent gene expression (microarray) studies, for example, have shown that systemic JIA can be distinguished from other subtypes of JIA by the presence of an up-regulation of the innate immune pathways, including interleukin-6, Toll-like receptor/ interleukin-1 receptor, as well as a down-regulation of the gene networks involving T cell-related and MHCrelated biologic processes, including antigen presentation (19).…”

“…Several recent gene expression (microarray) studies, for example, have shown that systemic JIA can be distinguished from other subtypes of JIA by the presence of an up-regulation of the innate immune pathways, including interleukin-6, Toll-like receptor/ interleukin-1 receptor, as well as a down-regulation of the gene networks involving T cell-related and MHCrelated biologic processes, including antigen presentation (19). This pattern is strikingly similar to that seen in patients with autoinflammatory syndromes such as neonatal-onset multisystem inflammatory disease (NOMID).…”

Comparison of biomarkers for systemic juvenile idiopathic arthritis

“…The innate immune system is believed to play an important role. An expansion of cells of monocyte/macrophage lineage during SJIA flare (9)(10)(11), with increased expression of corresponding genes, has been reported (8,9,(12)(13)(14). Crosstalk between the innate and adaptive immune system regulates a healthy inflammatory response.…”