Aberrant Naive CD4-Positive T Cell Differentiation in Systemic Juvenile Idiopathic Arthritis Committed to B Cell Help.

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. In this study, we hypothesized that aberrant or incomplete polarization of T helper cells contributes to disease pathology. METHODS: Cells or serum samples were obtained from healthy controls (n = 72) and systemic JIA patients (n = 171). Isolated naive T helper cells were cultured under Th1, Th17, and T follicular helper (Tfh) or T peripheral helper (Tph)-polarizing conditions and were partly cocultured with allogenic memory B cells. Cell samples were then analyzed for surface marker, transcription factor, and cytokine expression, as well as plasmablast generation. Serum samples were subjected to multiplexed bead and self-antigen arrays and enzyme-linked immunosorbent assays, and all data were compared to retrospective RNA profiling analyses. RESULTS: Differentiation of systemic JIA-naive T helper cells toward Th1 cells resulted in low expression levels of interferon-γ (IFNγ) and eomesodermin, which was associated in part with disease duration. In contrast, developing Th1 cells in patients with systemic JIA were found to produce elevated levels of interleukin-21 (IL-21), which negatively correlated with cellular expression of IFNγ and eomesodermin. In both in vitro and ex vivo analyses, IL-21 together with programmed cell death 1 (PD-1), inducible T cell costimulator (ICOS), and CXCR5 expression induced naive T helper cells from systemic JIA patients to polarize toward a Tfh/Tph cell phenotype. Retrospective analysis of whole-blood RNA-sequencing data demonstrated that Bcl-6, a master transcription factor in Tfh/Tph cell differentiation, was overexpressed specifically in patients with systemic JIA. Naive T helper cells from systemic JIA patients which were stimulated in vitro promoted B cellular plasmablast generation, and self-antigen array data indicated that IgG reactivity profiles of patients with systemic JIA differed from those of healthy controls. CONCLUSION: In the pathogenesis of systemic JIA, skewing of naive T helper cell differentiation toward a Tfh/Tph cell phenotype may represent an echo of autoimmunity, which may indicate the mechanisms driving progression toward chronic destructive arthritis.

Value of speckle-tracking echocardiography and MRI-based feature tracking analysis in adult patients after Fontan-type palliation.

BACKGROUND: Patients are commonly affected by ventricular dysfunction and heart failure after Fontan palliation. Reliable quantification of ventricular function is of interest but hampered by complex ventricular anatomy and physiology. OBJECTIVES: We aimed to assess myocardial function using a novel cardiac magnetic resonance imaging (CMR)-based feature-tracking (FT) technique and to study its clinical utility in Fontan patients. METHODS: Retrospective study in consecutive patients attending our service. RESULTS: We included 15 adult Fontan patients (age 27 ± 7 years) who underwent a standardized transthoracic echocardiographic investigation (TTE) with measurement of global strain using speckle tracking. Thirteen patients also underwent CMR, with assessment of myocardial deformation by FT, providing longitudinal and circumferential global strain for the single ventricle. The value of TTE-based strain measurements was limited by the fact that in 63% of patients at least one myocardial segment could not be adequately quantified due to limited acoustic windows. In contrast, CMR allowed for a complete visualization of all wall segments. Not surprisingly, there was poor agreement between the techniques but good or moderate interobserver variability for FT (coefficients of variability 6.6% and 14.3% for circumferential and longitudinal strain). Unlike ejection fraction, FT parameters correlated significantly with age at Fontan completion, New York Heart Association (NYHA) class, and peak oxygen uptake on cardiopulmonary exercise testing. CONCLUSIONS: Assessment of myocardial function using CMR cine-based feature tracking is feasible in Fontan patients. Unlike echocardiographic techniques, FT is independent of inadequate acoustic windows and FT measurements relate to clinical parameters, suggesting that this approach could have clinical relevance in future.