👤 Karen Hildenbrand

In CLN3 disease, impairments in motor function are frequently reported to have later onset compared to visual and cognitive decline, but upper limb motor function has yet to be explored in this population. In a cohort of 22 individuals with CLN3, we used a novel application of multiple measures to (1) characterize motor function, particularly of the upper limbs, in activities of daily living (ADLs), and (2) explore associations between motor function and age as well as visual ability, disease severity, and cognitive function, as evaluated by the Unified Batten Disease Rating Scale (UBDRS), a validated CLN3 disease measure. ADLs that required coordination, speed, and fine motor control were particularly challenging for children with CLN3 based on item-level performance across direct assessments (Jebsen-Taylor Hand Function Test [JTHFT] and MyoSet Tools) and caregiver reports (Pediatric Evaluation of Disability Inventory-Computer Adaptive Testing [PEDI-CAT] and Patient-Reported Outcomes Measurement Information System [PROMIS] Pediatric Upper Extremity). Poorer visual ability, disease severity, and cognitive function were associated with worse performance on these measures, whereas age had limited impact. These findings support the need for children with CLN3 to receive skilled clinical evaluation and treatment tailored to their individual needs, particularly in the context of ADLs, as their symptom profile progresses. Show less

The interleukin 12 (IL-12) family of cytokines regulates T cell functions and is key for the orchestration of immune responses. Each heterodimeric IL-12 family member is a glycoprotein. However, the impact of glycosylation on biogenesis and function of the different family members has remained incompletely defined. Here, we identify glycosylation sites within human IL-12 family subunits that become modified upon secretion. Building on these insights, we show that glycosylation is dispensable for secretion of human IL-12 family cytokines except for IL-35. Furthermore, our data show that glycosylation differentially influences IL-12 family cytokine functionality, with IL-27 being most strongly affected. Taken together, our study provides a comprehensive analysis of how glycosylation affects biogenesis and function of a key human cytokine family and provides the basis for selectively modulating their secretion via targeting glycosylation. Show less

IL-27 is a cytokine of the IL-12 family, composed of EBI3 and IL-27p28. IL-27 regulates immune responses and also other physiological processes including hematopoiesis, angiogenesis, and bone formation. Its receptor, composed of IL-27Rα and gp130, activates the STAT pathway. Here, we show that different glycosaminoglycans (GAGs) modulate human IL-27 activity in vitro. We find that soluble heparin and heparan sulfate efficiently inhibit human IL-27 activity as shown by decreased STAT signaling and downstream biological effects. In contrast, membrane-bound heparan sulfate seems to positively regulate IL-27 activity. Our biochemical studies demonstrate that soluble GAGs directly bind to human IL-27, consistent with in silico analyses, and prevent its binding to IL-27Rα. Although murine IL-27 also bound to GAGs in vitro, its activity was less efficiently inhibited by soluble GAGs. Lastly, we show that two heparin-derivatives, low molecular weight heparin and fondaparinux, that like unfractionated heparin are used in clinics, had weaker or no effect on human IL-27 activity. Together, our data identify GAGs as new players in the regulation of human IL-27 activity that might act under physiological conditions and may also have a clinical impact in heparin-treated patients. Show less