Identification of new telomere- and telomerase-associated autoantigens in systemic sclerosis.

PURPOSE: In up to 20% of patients with systemic sclerosis (SSc) no known autoantibody specificity can be identified. Recently discovered autoantigens, such as telomeric repeat binding factor 1 (TERF1), as well as established autoantigens, like RuvBL1/2, are associated with telomere and telomerase biology. We aimed to identify new telomere- and telomerase-associated autoantigens in patients with SSc without known autoantibody specificity. METHODS: Unlabelled protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) was performed with sera of 106 patients with SSc from two tertiary referral centres that had a nuclear pattern on HEp-2 indirect immunofluorescence without previously identified autoantibody. Telomere- or telomerase-associated proteins or protein complexes precipitated by individual sera were identified. Candidate autoantigens were confirmed through immunoprecipitation-western blot (IP-WB). A custom Luminex xMAP assay for 5 proteins was evaluated with sera from persons with SSc (n = 467), other systemic autoimmune rheumatic diseases (n = 923), non-rheumatic disease controls (n = 187) and healthy controls (n = 199). RESULTS: Eight telomere- and telomerase-associated autoantigens were identified in a total of 11 index patients, including the THO complex (n = 3, all with interstitial lung disease and two with cardiac involvement), telomeric repeat-binding factor 2 (TERF2, n = 1), homeobox-containing protein 1 (HMBOX1, n = 2), regulator of chromosome condensation 1 (RCC1, n = 1), nucleolar and coiled-body phosphoprotein 1 (NOLC1, n = 1), dyskerin (DKC1, n = 1), probable 28S rRNA (cytosine(4447)-C(5))-methyltransferase (NOP2, n = 1) and nuclear valosin-containing protein-like (NVL, n = 2). A Luminex xMAP assay for THO complex subunit 1 (THOC1), TERF2, NOLC1, NOP2 and NVL revealed high reactivity in all index patients, but also in other patients with SSc and disease controls. However, the reactivity by xMAP assay in these other patients was not confirmed by IP-WB. CONCLUSION: IP-MS revealed key telomere- and telomerase-associated proteins and protein complexes as autoantigens in patients with SSc.

The long-term metabolic and neurocognitive risks in offspring of women with type 1 diabetes mellitus.

AIMS: Previous studies have evaluated long-term metabolic and neurocognitive outcomes in offspring of women with diabetes. However, many studies did not differentiate between different types of diabetes. We aimed to specifically evaluate both metabolic and neurocognitive outcomes in offspring of women with type 1 diabetes mellitus (OT1D). METHODS: We conducted an extensive literature search on PubMed between February 2020 and September 2020. We performed a scoping review including 12 retrospective cohort studies, 15 prospective cohort studies, one case-control study and one cross-sectional study, comparing long-term metabolic and neurocognitive outcomes between OT1D and a control group. RESULTS: OT1D had a higher body mass index and an increased risk for overweight and obesity compared to offspring of mothers without diabetes. A limited number of studies showed a higher risk for (pre)diabetes, higher rates of non-alcoholic fatty liver disease and metabolic syndrome in OT1D. Index offspring had in general similar intelligence and academic achievement as control children but a higher risk for attention deficit and hyperactivity disorders. Data were conflicting concerning the increased risk for autism spectrum disorders. There is limited evidence suggesting that female offspring have more often unfavorable metabolic parameters, while male offspring are more at risk for hyperactivity/impulsivity. CONCLUSION: Maternal type 1 diabetes mellitus is associated with an increased risk of several metabolic complications and neurobehavioral disorders in the offspring. Increased attention for long-term complications in this population is needed. Further research is needed to evaluate whether improved glycemic control in pregnancy can reduce these long-term complications.