Dominant negative OTULIN-related autoinflammatory syndrome.

OTU deubiquitinase with linear linkage specificity (OTULIN) regulates inflammation and cell death by deubiquitinating linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC). Biallelic loss-of-function mutations causes OTULIN-related autoinflammatory syndrome (ORAS), while OTULIN haploinsuffiency has not been associated with spontaneous inflammation. However, herein, we identify two patients with the heterozygous mutation p.Cys129Ser in OTULIN. Consistent with ORAS, we observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells. While the C129S mutation did not affect OTULIN protein stability or binding capacity to LUBAC and linear ubiquitin chains, it did ablate OTULIN deubiquitinase activity. Loss of activity facilitated the accumulation of autoubiquitin chains on LUBAC. Altered ubiquitination of LUBAC inhibits its recruitment to the TNF receptor signaling complex, promoting TNF-induced cell death and disease pathology. By reporting the first dominant negative mutation driving ORAS, this study expands our clinical understanding of OTULIN-associated pathology.

A necroptosis-independent function of RIPK3 promotes immune dysfunction and prevents control of chronic LCMV infection.

Necroptosis is a lytic and inflammatory form of cell death that is highly constrained to mitigate detrimental collateral tissue damage and impaired immunity. These constraints make it difficult to define the relevance of necroptosis in diseases such as chronic and persistent viral infections and within individual organ systems. The role of necroptotic signalling is further complicated because proteins essential to this pathway, such as receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), have been implicated in roles outside of necroptotic signalling. We sought to address this issue by individually defining the role of RIPK3 and MLKL in chronic lymphocytic choriomeningitis virus (LCMV) infection. We investigated if necroptosis contributes to the death of LCMV-specific CD8+ T cells or virally infected target cells during infection. We provide evidence showing that necroptosis was redundant in the pathogenesis of acute forms of LCMV (Armstrong strain) and the early stages of chronic (Docile strain) LCMV infection in vivo. The number of immune cells, their specificity and reactivity towards viral antigens and viral loads are not altered in the absence of either MLKL or RIPK3 during acute and during the early stages of chronic LCMV infection. However, we identified that RIPK3 promotes immune dysfunction and prevents control of infection at later stages of chronic LCMV disease. This was not phenocopied by the loss of MLKL indicating that the phenotype was driven by a necroptosis-independent function of RIPK3. We provide evidence that RIPK3 signaling evoked a dysregulated type 1 interferone response which we linked to an impaired antiviral immune response and abrogated clearance of chronic LCMV infection.

Patient experience and physiological response to two commercially available daily disposable myopia control contact lenses.

BACKGROUND: A range of myopia management (MM) contact lenses are becoming available to practitioners. These lenses are designed to slow myopia progression and axial elongation. This study explored the initial experience of participants wearing daily disposable MM contact lenses to investigate established factors previously associated with successful lens wear. METHODS: This was a prospective, double-masked, crossover study. Twenty participants aged 18-30 years old were assigned to wear two daily disposable MM lenses in a randomised order. Visual acuity, contrast sensitivity, and amplitude/lag of accommodation were assessed at baseline, post-insertion, and after 2 and 6 h of lens wear. Self-reported lens comfort and vision quality were recorded at the same timepoints, and at 10 h post-insertion. Pairwise comparisons were performed between the two lenses at each timepoint, as well as assessing changes throughout wear. The relationship of the measured parameters to overall lens satisfaction was also assessed. RESULTS: There were no significant differences between the two MM lenses at any timepoint for any of the participant-reported parameters, including overall satisfaction. A small difference in visual acuity was noted at 6 h post-insertion, although this is unlikely to be clinically significant. Comfort decreased throughout the day, most notably at 10 h post-insertion. A moderate positive correlation was observed between participant-reported visual quality and overall satisfaction. A similar pattern was seen for comfort and overall satisfaction. Self-reported vision quality and measured visual acuity were poorly correlated, highlighting the benefit of subjectively assessing the quality of vision with these lenses. CONCLUSIONS: The participants demonstrated comparable measures across a range of measures between the two MM lenses. Notably, half of the participants demonstrated a clear lens preference, although the preferred lens varied between individuals. Candidates for MM may benefit from trialling more than one MM lens design, to maximise initial wearing satisfaction.