Vanderschueren, S. | bioRxiv Science

bioRxiv2024

Adults patients with autoinflammation of unknown origin partially phenocopy the immune presentation of Still's disease

Autoinflammation of unknown origin remains amongst the most enigmatic of systemic autoinflammatory disorders (SAIDs), immunological disorders characterized by inappropriate activation of the innate immune response. Recent clinical research has identified multiple distinct disorders, although overlap in clinical characteristics and genetic drivers impede rapid and precise diagnosis, and the immunological underpinning of disease is poorly understood. Here we aimed to understand the immunological process behind patients with autoinflammation of unknown origin. In a multi-center European trial, we collected samples from 36 patients with recent disease activity, and used deep immunophenotyping and plasma proteomics to compare to 58 healthy controls and an additional demographically-similar 92 SAID patients. Key immunological changes were upregulation of CD38 and HLA across T cell subsets and upregulation of acute phase plasma proteins in autoinflammation of unknown origin patients. These previously poorly characterised patients partially phenocopied the Stills disease presentation. Together this study identifies potential biomarkers and disease-mediators in autoinflammation of unknown origin.

immunology↗

bioRxiv2023

Aberrant N-glycosylation in pathogenic variants of adenosine deaminase 2 underlying human ADA2 deficiency

Human deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by pathogenic variants in ADA2 that lead to impaired deaminase activity. Recently, a lysosomal function of ADA2 has been proposed but an intracellular form of the protein has not yet been characterized. Here, we analyze protein expression of mutant ADA2 in human monocyte-derived macrophages from 10 DADA2 patients. We identify an intracellular low-molecular-weight (LMW) form of ADA2 that undergoes glycan trimming by -mannosidases and is absent in DADA2 macrophages. Subcellular fractionation and immunofluorescence microscopy demonstrate that LMW-ADA2 is localized in the lysosomes. By overexpression of 34 ADA2 variants in HEK293T and U-937 cells, we show that absence of LMW-ADA2 strongly correlates with reduced deaminase activity and predicts variant pathogenicity. In conclusion, we describe a previously unreported intracellular hypoglycosylated form of ADA2 and establish the absence of this LMW-ADA2 as a cellular characteristic of DADA2. Thereby, we introduce a protein correlate of the recently described lysosomal form of ADA2. SummaryEhlers et al. demonstrate that mutant ADA2 fails to undergo glycan processing beyond the ER leading to the absence of intracellular low-molecular-weight (LMW) ADA2 in DADA2 patients macrophages. LMW-ADA2 localizes to the lysosomes and can be generated from extracellular wild-type ADA2.

immunology↗