Circulating plasmablasts are elevated and produce pathogenic anti-endothelial cell autoantibodies in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a devastating pulmonary vascular disease in which autoimmune and inflammatory phenomena are implicated. B cells and autoantibodies have been associated with IPAH and identified as potential therapeutic targets. However, the specific populations of B cells involved and their roles in disease pathogenesis are not clearly defined. We aimed to assess the levels of activated B cells (plasmablasts) in IPAH, and to characterize recombinant antibodies derived from these plasmablasts. Blood plasmablasts are elevated in IPAH, remain elevated over time, and produce IgA autoantibodies. Single-cell sequencing of plasmablasts in IPAH revealed repertoires of affinity-matured antibodies with small clonal expansions, consistent with an ongoing autoimmune response. Recombinant antibodies representative of these clonal lineages bound known autoantigen targets and displayed an unexpectedly high degree of polyreactivity. Representative IPAH plasmablast recombinant antibodies stimulated human umbilical vein endothelial cells to produce cytokines and overexpress the adhesion molecule ICAM-1. Together, our results demonstrate an ongoing adaptive autoimmune response involving IgA plasmablasts that produce anti-endothelial cell autoantibodies in IPAH. These antibodies stimulate endothelial cell production of cytokines and adhesion molecules, which may contribute to disease pathogenesis. These findings suggest a role for mucosally-driven autoimmunity and autoimmune injury in the pathogenesis of IPAH.

Acanthosis nigricans and diabetes risk factors: prevalence in young persons seen in southwestern US primary care practices.

PURPOSE: Evidence shows acanthosis nigricans is often associated with hyperinsulinemia and may indicate increased risk of type 2 diabetes mellitus. The purpose of this study was to determine the association of acanthosis nigricans with type 2 diabetes risk factors and disease in young persons. METHODS: We conducted a cross-sectional study in the Research in Outpatient Settings Network, a practice-based research network in southwestern US communities. Participating clinicians (N = 96) collected data on children and young adults aged 7 to 39 years seen during a 2-week sampling period. The main outcomes were the prevalence of acanthosis nigricans, type 2 diabetes risk factors (ethnicity, family history of type 2 diabetes, hypertension, overweight/obesity), type 2 diabetes, and the relationships among these. RESULTS: Among 1,133 patients sampled, risk factors for type 2 diabetes were common: 69% had a family history of the disease; 3% of children (aged 7 to 19 years) and 12% of adults had hypertension; 43% of children and 73% of adults were overweight or obese; and 80% were members of ethnic minorities. Acanthosis nigricans was found in 17% of children and 21% of adults. Among children and adults alike, the more type 2 diabetes risk factors that were present, the higher the prevalence of acanthosis nigricans (P <.001). The prevalence ratio for type 2 diabetes in patients with acanthosis nigricans was 1.97 (95% confidence interval, 1.18-3.27; P = .01) after controlling for age, body mass index, and the number of type 2 diabetes risk factors. Clinicians reported that the identification of acanthosis nigricans frequently led to discussions about lifestyle modification for decreasing the risk of type 2 diabetes. CONCLUSIONS: Patients with acanthosis nigricans are likely to have multiple risk factors for type 2 diabetes. Acanthosis nigricans may be an independent risk factor for this disease. Detection of acanthosis nigricans may help clinicians more rapidly identify high-risk individuals for diabetes counseling.