IgG1 glycosylation highlights premature aging in Down syndrome.

Down syndrome (DS) is characterized by lowered immune competence and premature aging. We previously showed decreased antibody response following SARS-CoV-2 vaccination in adults with DS. IgG1 Fc glycosylation patterns are known to affect the effector function of IgG and are associated with aging. Here, we compare total and anti-spike (S) IgG1 glycosylation patterns following SARS-CoV-2 vaccination in DS and healthy controls (HC). Total and anti-Spike IgG1 Fc N-glycan glycoprofiles were measured in non-exposed adults with DS and controls before and after SARS-CoV-2 vaccination by liquid chromatography-mass spectrometry (LC-MS) of Fc glycopeptides. We recruited N = 44 patients and N = 40 controls. We confirmed IgG glycosylation patterns associated with aging in HC and showed premature aging in DS. In DS, we found decreased galactosylation (50.2% vs. 59.0%) and sialylation (6.7% vs. 8.5%) as well as increased fucosylation (97.0% vs. 94.6%) of total IgG. Both cohorts showed similar bisecting GlcNAc of total and anti-S IgG1 with age. In contrast, anti-S IgG1 of DS and HC showed highly comparable glycosylation profiles 28 days post vaccination. The IgG1 glycoprofile in DS exhibits strong premature aging. The combination of an early decrease in IgG1 Fc galactosylation and sialylation and increase in fucosylation is predicted to reduce complement activity and decrease FcγRIII binding and subsequent activation, respectively. The altered glycosylation patterns, combined with decreased antibody concentrations, help us understand the susceptibility to severe infections in DS. The effect of premature aging highlights the need for individuals with DS to receive tailored vaccines and/or vaccination schedules.

Decreased Antibody Response After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Patients With Down Syndrome.

The risk of a severe course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults with Down syndrome is increased, resulting in an up to 10-fold increase in mortality, in particular in those >40 years of age. After primary SARS-CoV-2 vaccination, the higher risks remain. In this prospective observational cohort study, SARS-CoV-2 spike S1-specific antibody responses after routine SARS-CoV-2 vaccination (BNT162b2, messenger RNA [mRNA]-1273, or ChAdOx1) in adults with Down syndrome and healthy controls were compared. Adults with Down syndrome showed lower antibody concentrations after 2 mRNA vaccinations or after 2 ChAdOx1 vaccinations. After 2 mRNA vaccinations, lower antibody concentrations were seen with increasing age. CLINICAL TRIALS REGISTRATION: NCT05145348.

The risk of developing squamous cell carcinoma in patients with anogenital lichen sclerosis: A systematic review.

INTRODUCTION: Lichen sclerosis (LS) is a chronic inflammatory skin disease, mostly affecting the anogenital region. Patients with LS have a higher risk of developing anogenital squamous cell carcinoma (SCC), although exact numbers are not known. OBJECTIVE: To systematically review the absolute risk (AR) and incidence rate (IR) of developing SCC in patients with anogenital LS, as well as patient characteristics that influence the risk of developing LS associated SCC. METHODS: A search was performed through the databases of Pubmed and Embase. Five reviewers independently screened the articles on title/abstract and full text published before 31st of July 2019. The selected articles were critically appraised using the Quality In Prognostic Studies tool. RESULTS: Of 2238 titles and abstracts assessed, 15 studies were selected to be analysed. The AR of developing SCC in patients with LS varied between 0.21 and 3.88% for women and 0.00-0.91% for men across the included studies. The IR was 0.65-8.89/1000 person-years for women and 0.00-6.49/1000 person-years for men. This risk for women seemed to be increased by age, the presence of vulval intra-epithelial neoplasia (VIN), a long history of LS, late diagnosis of LS and partial compliance of treatment with topical corticosteroids. For men, no determinants were found. CONCLUSION: We found fair evidence that the AR of developing SCC in patients with anogenital LS varied between 0.21 and 3.88% for women and 0.00-0.91% for men. Therefore, we recommend regular follow up and compliant treatment with topical corticosteroids, especially in older women.