Schulert Lab

Schulert Lab

Current Projects

Monocyte and macrophage polarization in systemic juvenile idiopathic arthritis and macrophage activation syndrome

Systemic juvenile idiopathic arthritis is a severe inflammatory disease of childhood conferring significant risk for fatal complications including Macrophage Activation Syndrome (MAS). The phenotype and function of the key effector monocytes and macrophages in systemic JIA remains unclear. These cells adopt distinct polarization states based on specific activating signals, modified by microRNA to “fine-tune” these transcriptional responses.  Circulating monocytes in systemic JIA appear to display a unique mixed polarization phenotype, and little is known regarding how tissue resident macrophages are further altered during emergence of MAS (Image 1).  Notably, despite effective treatment children with systemic JIA remain at risk for MAS. Thus, there is a critical need to characterize the phenotype of monocytes and tissue macrophages in systemic JIA, and particularly how they contribute to emergence of MAS. In the absence of such knowledge, developing novel strategies to effectively prevent and treat MAS will remain a formidable challenge.

The objective in this project is to define polarization-specific gene expression signatures and functional roles of microRNA in monocytes and macrophages from children with systemic JIA and a mouse model of systemic JIA/MAS. Our central hypothesis is monocytes from children with systemic JIA have a distinct polarized pattern which is regulated by microRNA, and further dysregulated during MAS. This project will utilize emerging technologies to define the molecular control of polarization-specific transcriptional signatures in monocytes and macrophages in children with systemic JIA and MAS. Together these findings are expected to have positive translational impact, through providing new targets to modulate inflammation in systemic JIA and reduce the risk for MAS.

Funding: NIAMS/NIH, K08-AR072075

Genomic approaches to systemic juvenile idiopathic arthritis and macrophage activation syndrome

Patients with systemic JIA have significant clinical heterogeneity as regards their disease course and complications.  However, the genetic basis of the variability is largely unknown.  Approximately 10-30% of systemic JIA patients experience macrophage activation syndrome. Interestingly, previous work has found numerous variants in genes associated with the phenotypically similar familial hemophagocytic lymphohistiocytosis in children with systemic JIA (Image 2), and these variants were significantly enriched in patients who experienced MAS.

The objective of this project is to identify rare functional genetic variants in patients with distinct clinical subtypes and severe manifestations of systemic JIA.  This project will utilize genomic approaches in a large cohort of systemic JIA patients with diverse clinical subtypes to identify rare genetic variants, including those of modest effect and incomplete penetrance, which collectively may lead to disease phenotypes. This work will also examine non-coding genetic variants, which we have recently shown can be associated with MAS (Image 3). Further understanding of the genetic basis of MAS in systemic JIA will allow for a personalized medicine approach to the management of this disease, including personalized disease surveillance and preventative treatments.

Funding: Cincinnati Children’s Research Foundation Academic Research and Teaching (ARC) Grant.

Severe lung disease associated with systemic juvenile idiopathic arthritis (SJIA-LD)

Severe lung disease is a life-threatening complication of the autoinflammatory disorder systemic juvenile idiopathic arthritis (SJIA-LD). Chronic pulmonary involvement in SJIA was only rarely reported prior to 2004, but the incidence has markedly increased in parallel with introduction of biologic therapy, and currently affects as many as 1 in 20 SJIA patients. However, the immunopathogenesis of SJIA-LD are unknown. An international collaboration including Cincinnati Children's Hospital Medical Center has defined clinical features of SJIA-LD, most notably that nearly 70% exhibited recurrent/persistent macrophage activation syndrome (MAS), characterized by overwhelming hyperinflammation driven by IFNγ. In support of this, our preliminary data shows highly overlapping biomarker profiles between patients with SJIA-LD and those with MAS. There represents a critical need to define the pathogenesis of SJIA-LD, which is essential for development of targeted treatment strategies. The objective of this project is to characterize and map pulmonary pathology in SJIA-LD. The central hypothesis is that SJIA-LD and MAS are defined by specific shared immunopathologic features including IFNγ pathway activation. Our rationale for the proposed research is that defining specific inflammatory features in SJIA-LD will provide key mechanistic insights into disease pathogenesis, and support new approaches to prevent and treat this often fatal complication.

Funding: Cincinnati Children's Research Foundation Academic Research and Teaching (ARC) Grant; Systemic JIA Foundation
Monocyte microRNA profiling in active systemic juvenile idiopathic arthritis implicates microRNA-125a-5p in polarized monocyte phenotypes. Ref: Arthritis & Rheumatology (2016) Vol 68(9): A22.
Fig. 1 - Click for caption & to enlarge.
Representative examples of hemophagocytosis characterized by macrophages with engulfed red blood cells in lymph node (A and B) and spleen (C and D) in patients with macrophage activation syndrome.
Fig. 2 - Click for caption & to enlarge.
Genomic view of novel UNC13D intronic variant c.117+143A>G
Fig. 3 - Click for caption & to enlarge.