Deep immunophenotyping reveals that autoimmune and autoinflammatory disorders are spread along two immunological axes capturing disease inflammation levels and types.

OBJECTIVES: Based on genetic associations, McGonagle and McDermott suggested a classification of autoimmune and autoinflammatory diseases as a continuum ranging from purely autoimmune to purely autoinflammatory diseases and comprising diseases with both components. We used deep immunophenotyping to identify immune cell populations and molecular targets characterising this continuum. METHODS: We collected blood from 443 patients with one of 15 autoimmune or autoinflammatory diseases and 71 healthy volunteers. Deep phenotyping was performed using 13 flow cytometry panels characterising over 600 innate and adaptive cell populations. Unsupervised and supervised analyses were conducted to identify disease clusters with their common and specific cell parameters. RESULTS: Unsupervised clustering categorised these diseases into five clusters. Principal component analysis deconvoluted this clustering into two immunological axes. The first axis was driven by the ratio of LAG3+ to ICOS+ in regulatory T lymphocytes (Tregs), and segregated diseases based on their inflammation levels. The second axis was driven by activated Tregs and type 3 innate lymphoid cells (ILC3s), and segregated diseases based on their types of affected tissues. We identified a signature of 23 cell populations that accurately characterised the five disease clusters. CONCLUSIONS: We have refined the monodimensional continuum of autoimmune and autoinflammatory diseases as a continuum characterised by both disease inflammation levels and targeted tissues. Such classification should be helpful for defining therapies. Our results call for further investigations into the role of the LAG3+/ICOS+ balance in Tregs and the contribution of ILC3s in autoimmune and autoinflammatory diseases. TRIAL REGISTRATION NUMBER: NCT02466217.

Dose-dependent neuroprotective effect of the JNK inhibitor Brimapitide in 5xFAD transgenic mice.

Alzheimer's disease (AD) is a neurodegenerative disease mainly affecting old people. According to the "amyloid cascade hypothesis", the accumulation of Aß oligomers could lead to kinase activation and Tau phosphorylation. Activated kinases include c-Jun N-terminal kinase (JNK) and previous studies highlighted the beneficial effects of the JNK-specific inhibitor Brimapitide (10 mg/kg) in 5xFAD transgenic mice. Our aim was to evaluate the effects of decreasing doses of Brimapitide on cognition and neurodegeneration in early treated 5xFAD mice. Three month-old 5xFAD were intravenously treated for 6 months with either Brimapitide (3 mg/kg or 0.3 mg/kg) or Nacl. Cognition and amyloid burden, neuronal and synaptic impairments were evaluated. Low doses of Brimapitide (0.3 mg/kg) reduced neuronal degeneration and improved cognition in treated mice compared to non-treated mice. Amyloid burden and synaptic degeneration only decreased with the 3 mg/kg dose. This JNK inhibitor can afford neuroprotection but with a differential effect on amyloid deposition in 5xFAD mice. Brimapitide might partially prevent ongoing neurodegeneration in 5xFAD mice.