Transition readiness in adolescents and young adults with chronic genetic skin conditions.

BACKGROUND/OBJECTIVES: Healthcare transition (HCT) refers to movement from pediatric to adult healthcare models. Lack of HCT preparation contributes to poor health outcomes. This study measures readiness to transition in individuals with genetic skin conditions. METHODS: Participants signed IRB-approved consents/assents. Participants ages 14-22 years with genetic skin disorders were surveyed with measures of QoL (Children's Dermatology Life Quality Index/CDLQI or DLQI) and HCT readiness using the Transition Readiness Assessment Questionnaire (TRAQ) and adapted non-validated measures of Skin Knowledge and Psychosocial Factors (5 = highest readiness). Mean TRAQ was compared with historical data on controls and other chronic conditions (t-tests) and correlated (Pearson) with Skin Knowledge and Psychosocial. Multivariable regression compared demographics and QoL with transition readiness. RESULTS: A total of 45 participants were enrolled (mean age 17.8 years, 67% female, 71% White; disorders of cornification [n = 31], ectodermal dysplasias [n = 7], epidermolysis bullosa [n = 4], tuberous sclerosis [n = 3]). Mean TRAQ (3.3 ± 0.9) was lower than controls (3.9; p < .001) and some chronic disorders (sickle cell [3.7; p < .05], type 1 diabetes [3.7; p < .01]), but higher than with spina bifida (2.8; p < .001) and congenital heart disease (2.9; p < .01). Mean Skin Knowledge was 4.2 ± 1.0, and mean Psychosocial was 3.4 ± 0.8. TRAQ correlated strongly with Skin Knowledge (r = .61; p < .05), but not Psychosocial (r = .12; p = .6). Ages 14-17 years versus 18-22 years and public versus private insurance predicted lower TRAQ scores. Poor DLQI predicted higher TRAQ and Skin Knowledge, but poor DLQI and CDLQI predicted lower Psychosocial. CONCLUSIONS: Adolescents and young adults with genetic skin disorders demonstrated low transition readiness, especially among younger-aged and lower socioeconomic groups. We recommend a HCT intervention to improve health outcomes.

A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome.

Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi-ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon-driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.

A Defect in Thymic Tolerance Causes T Cell-Mediated Autoimmunity in a Murine Model of COPA Syndrome.

COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the coatomer protein complex subunit α (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis, which requires life-saving measures, such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a CopaE241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells. In this study, we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from CopaE241K/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, to our knowledge, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.