Transcription factor motif enrichment in whole transcriptome analysis identifies STAT4 and BCL6 as the most prominent binding motif in systemic juvenile idiopathic arthritis

Abstract

BackgroundThe term systemic juvenile idiopathic arthritis (sJIA) describes an autoinflammatory condition characterized by arthritis and severe systemic inflammation, which in later stages can transform into interleukin (IL)-17-driven autoimmune arthritis. IL-1 antagonists have been used with good efficacy in the early stages of sJIA.MethodsA whole transcriptome analysis of peripheral blood RNA samples was performed in six patients with sJIA and active systemic disease, before initiating treatment with the IL-1β receptor antagonist anakinra, and after induction of inactive disease, compared with a single-sample control cohort of 21 patients in several clinical stages of sJIA activity. Whole transcriptomes were compared longitudinally and interindividually including gene ontology and motif enrichment analysis of differentially expressed genes.ResultsThere were 741 transcripts were identified using a threshold with a p value <0.01 and a fold change > 2. HLADRB1 and CD74 were identified as the most strongly upregulated genes in inactive compared to active disease; CD177 expression was significantly enhanced in active disease compared to inactive disease. Motif enrichment analysis revealed STAT4, BCL6, and STAT3 as the most prominent transcription factors that were present during active disease. In addition, strong upregulation of the major histocompatability complex II (MHCII) ligand CD74 was found in both active and inactive sJIA compared to healthy controls.ConclusionUsing transcription factor motif enrichment, this study identifies novel putative pathways in sJIA (STAT4, BCL6) implicating B cell activation at an earlier stage than predicted in refractory disease. The implication of BCL-6 dependent pathways argues for occurrence of autoimmunity early within the process of sJIA chronification. Transcriptional regulation of HLA-DRB1, a recently described independent genetic risk factor, in combination with its cooperating partner CD74 in patients where sJIA is confirmed, supports pathogenic involvement in alterations in antigen presentation during sJIA.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1603-2) contains supplementary material, which is available to authorized users.

Adult-Onset Still’s Disease: Clinical Aspects and Therapeutic Approach

“…Additionally, unstimulated cells from patients with active SoJIA and AOSD express genes related to innate immunity including members of the IL-1 pathway [ 3 , 122 ]. This perspective is broadened by recent work, which demonstrate an association of high expression of certain transcription factors with early active SoJIA, indicating a role of B-cell activation and autoimmunity during that phase of disease [ 123 ].…”

HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications

“…A recent study in HLA-B*27 transgenic rats emphasizes the relationship between the host genetic background and associated changes in multiple microbes in establishing an inflammatory environment that promotes arthritis 171 173 , and the absence of RF and ACPA autoantibodies (as well as the absence of anti-nuclear antibodies in most patients) 174 . However, some evidence supports a contribution from CD4 + T cells to established sJIA [175][176][177][178] , and a subset of patients with sJIA develop chronic erosive arthritis without continued systemic features 179 . Thus, one model is that the initial phase of sJIA is dominated by innate immune activation and a subsequent phase is T cell dominant 180 .…”

Epigenetic programming underpins B‐cell dysfunction in peanut and multi‐food allergy

“…Notably, the differential enrichment for motifs binding OCT2, NFAT, BATF and Bcl6 indicates differential pathways regulating B‐ and T‐cell development in MA individuals, with the differential expression of BATF providing further evidence for disruptions in immune cell development in MA patients. 48 , 49 , 50 , 52 , 53 , 54 , 55 Enrichment of Bcl6 motifs has previously been associated with chronic inflammatory disorders such as juvenile arthritis, 76 and previous studies report the combined roles of OCT2 and NFAT in promoting a proinflammatory response to pathogens in B‐ and T‐cell populations via the production of IL‐6 and IL‐21. 48 , 49 Differential enrichment of binding sites for TFs determining B‐cell lineage (KLF3, Bcl11a and PU.1:IRF8) and regulating B‐cell receptor signalling pathways (SpiB and Pu.1) suggests that MA individuals may possess unique B‐cell subpopulations and exhibit differential activation responses compared with SA individuals.…”