Th17/1 and ex-Th17 cells are detected in patients with polyarticular juvenile arthritis and increase following treatment.

BACKGROUND: A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. METHODS: Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann-Whitney U and Wilcoxon matched-pairs signed rank tests. RESULTS: Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p < 0.05), but Tregs (CD3 + CD4 + CD25 + FOXP3 +) from patients did not differ from controls. Changes in STAT3 phosphorylation in CD4 + T cells following ex vivo stimulation were not significantly different in patients compared to controls. We identified dual IL-17 + and interferon (IFN)γ + expressing CD4 + T cells in patients, but not controls. Further, both Th17/1 s (CCR6 + CD161 + IFNγ + IL-17 +) and ex-Th17s (CCR6 + CD161 + IFNγ + IL-17neg) were increased in patients' post-treatment (Th17/1: 0.3% v 0.07%, p < 0.05 and ex-Th17s: 2.3% v 1.4%, p < 0.05). The patients with the highest IL-17 expressing cells post-treatment remained therapy-bound. CONCLUSIONS: Patients with polyJIA have increased baseline Th17 cells, potentially reflecting higher tonic STAT3 activation in vivo. These quantifiable immune markers may identify patients that would benefit upfront from pathway-focused biologic therapies. Our data also suggest that inflammatory CD4 + T cell subsets not detected in controls but increased in post-treatment samples should be further evaluated as a tool to stratify patients in remission on medication. Future work will explore these proposed diagnostic and prognostic biomarkers.

Associations of Allostatic Load with Level of and Change in Cognitive Function Among Middle-Aged and Older Hispanic/Latino Adults: The Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA).

Background: Higher allostatic load (AL), a multi-system measure of physiological dysregulation considered a proxy for chronic stress exposure, is associated with poorer global cognition (GC) in older non-Hispanic white adults. However, evidence of these associations in middle-aged and older US-based Hispanic/Latino adults is limited. Objective: To examine associations of AL with level of cognition, performance in cognition 7 years later, and change in cognition over 7 years among middle-aged and older US-based Hispanic/Latino adults. Methods: We used data (n = 5,799, 45-74 years at baseline) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL-Investigation of Neurocognitive Aging (SOL-INCA). The AL score comprised 16 biomarkers representing cardiometabolic, glucose, cardiopulmonary, parasympathetic, and inflammatory systems (higher scores = greater dysregulation). Cognitive outcomes included GC and individual tests of verbal learning and memory, world fluency (WF), Digit Symbol Substitution (DSS), and Trail Making (Parts A & B). Survey-linear regressions assessed associations of AL with performance in cognition at baseline, 7 years later, and via 7-year cognitive change scores adjusting for sociodemographic characteristics, lifestyle factors, and depressive symptoms. Results: Higher AL was associated with lower baseline performance in GC and WF; and lower 7-year follow-up performance in these same measures plus DSS and Trail Making Parts A & B. Higher AL was associated with more pronounced 7-year change (reduction) in GC and on WF and DSS tests. Conclusions: Findings extend previous evidence in predominantly older non-Hispanic white cohorts to show that AL is related to level of and change in GC (as well as WF and DSS) among middle-aged and older US-based Hispanic/Latino adults.