Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1) results in a systemic vasculitis known as deficiency of ADA2 (DADA2). Neutrophils and a subset of neutrophils known as low-density granulocytes (LDGs) have been implicated in the pathogenesis of vasculitis, at least in part, through the formation of neutrophil extracellular traps (NETs). The study objective was to determine whether neutrophils and NETs play a pathogenic role in DADA2. In vivo evidence demonstrated NETs and macrophages in affected gastrointestinal tissue from patients with DADA2. An abundance of circulating LDGs prone to spontaneous NET formation was observed during active disease in DADA2 and were significantly reduced after remission induction by anti–tumor necrosis factor (TNF) therapy. Increased circulating LDGs were identified in unaffected family members with monoallelic ADA2 mutations. Adenosine triggered NET formation, particularly in neutrophils from female patients, by engaging A1 and A3 adenosine receptors (ARs) and through reactive oxygen species– and peptidylarginine deiminase–dependent pathways. Adenosine-induced NET formation was inhibited by recombinant ADA2, A1/A3 AR antagonists, or by an A2A agonist. M1 macrophages incubated with NETs derived from patients with DADA2 released significantly greater amounts of TNF-α. Treatment with an A2AAR agonist decreased nuclear translocation of NF-κB and subsequent production of inflammatory cytokines in DADA2 monocyte-derived macrophages. These results suggest that neutrophils may play a pathogenic role in DADA2. Modulation of adenosine-mediated NET formation may contribute a novel and directed therapeutic approach in the treatment of DADA2 and potentially other inflammatory diseases.

No abstract

We made a coupled genetic reporter that detects rare transcription misincorporation errors to measure RNA polymerase transcription fidelity in Escherichia coli. Using this reporter, we demonstrated in vivo that the transcript cleavage factor GreA, but not GreB, is essential for proofreading of a transcription error where a riboA has been misincorporated instead of a riboG. A greA mutant strain had more than a 100-fold increase in transcription errors relative to wild-type or a greB mutant. However, overexpression of GreB in ΔgreA cells reduced the misincorporation errors to wild-type levels, demonstrating that GreB at high concentration could substitute for GreA in RNA proofreading activity in vivo.

Medications commonly implicated in drug-induced autoimmunity trigger NET formation displaying distinct protein cargo, via common and specific pathways. NETosis may play a role in the pathogenesis of drug-induced autoimmunity.

No abstract

Key Points Question What is the prevalence of hypothalamic-pituitary-thyroid dysfunction in patients with Erdheim-Chester disease (ECD)? Findings In this cross-sectional study of 61 patients with ECD, the prevalence of central and primary hypothyroidism was 9.8% and 18.0%, respectively, in patients with ECD, higher than the corresponding rates of 0.1% and 4.7%, respectively, in the community. Meaning The findings of this study suggest that clinicians should consider screening for hypothyroidism in patients with ECD.

No abstract

Purpose: We examined abnormal pituitary imaging (API) and associated endocrine dysfunction in subjects with ECD. Methods: A cross-sectional descriptive examination of a natural history cohort study diagnosed with ECD was conducted at a clinical research center. Subjects underwent baseline endocrine tests of anterior and posterior pituitary function and dedicated pituitary gland MRI scans. We determined the frequency of various pituitary imaging abnormalities in ECD and assessed its relationships with age, sex, body mass index (BMI), BRAF V600E status, high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), pituitary hormone deficits and number, diabetes insipidus (DI), and panhypopituitarism. Results: Our cohort included 61 subjects with ECD [age (SD): 54.3 (10.9) y, 46 males/15 females]. API was present in 47.5% (29/61) of ECD subjects. Loss of the posterior pituitary bright spot (36.1%) followed by thickened pituitary stalk (24.6%), abnormal enhancement (18.0%), and pituitary atrophy (14.8%) were the most common abnormalities. DI and panhypopituitarism were more frequent in subjects with API without differences in age, sex distribution, hsCRP, ESR, and BRAF V600E status compared to normal pituitary imaging. Conclusions: We noted a high burden of API and endocrinopathies in ECD. API was highly associated with the presence of panhypopituitarism and DI. Therefore, a thorough assessment of hypothalamic–pituitary integrity should be considered in subjects with ECD.