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Type 1 diabetes results from chronic autoimmune destruction of insulin-producing β-cells within pancreatic islets. Although insulin is a critical self-antigen in animal models of autoimmune diabetes, due to extremely limited access to pancreas samples, little is known about human antigenic targets for islet-infiltrating T cells. Here we show that proinsulin peptides are targeted by islet-infiltrating T cells from patients with type 1 diabetes. We identified hundreds of T cells from inflamed pancreatic islets of three young organ donors with type 1 diabetes with a short disease duration with high-risk HLA genes using a direct T-cell receptor (TCR) sequencing approach without long-term cell culture. Among 85 selected CD4 TCRs tested for reactivity to preproinsulin peptides presented by diabetes-susceptible HLA-DQ and HLA-DR molecules, one T cell recognized C-peptide amino acids 19-35, and two clones from separate donors responded to insulin B-chain amino acids 9-23 (B:9-23), which are known to be a critical self-antigen-driving disease progress in animal models of autoimmune diabetes. These B:9-23-specific T cells from islets responded to whole proinsulin and islets, whereas previously identified B:9-23 responsive clones from peripheral blood did not, highlighting the importance of proinsulin-specific T cells in the islet microenvironment.

Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes (T1D), the DQ8 molecule is common, confers significant disease risk, and is involved in disease pathogenesis. We hypothesized that blocking DQ8 antigen presentation would provide therapeutic benefit by preventing recognition of self-peptides by pathogenic T cells. We used the crystal structure of DQ8 to select drug-like small molecules predicted to bind structural pockets in the MHC antigen-binding cleft. A limited number of the predicted compounds inhibited DQ8 antigen presentation in vitro, with 1 compound preventing insulin autoantibody production and delaying diabetes onset in an animal model of spontaneous autoimmune diabetes. An existing drug with a similar structure, methyldopa, specifically blocked DQ8 in patients with recent-onset T1D and reduced inflammatory T cell responses to insulin, highlighting the relevance of blocking disease-specific MHC class II antigen presentation to treat autoimmunity., Introduction Type 1 diabetes (T1D) results from the chronic autoimmune-mediated destruction of insulin-producing [beta] cells within pancreatic islets (1, 2). There is a wealth of knowledge regarding the disease pathogenesis [...]

The Federal Reserve System (the Fed) is one of the most important financial institutions in the world. As the central bank of the United States, it influences the domestic money supply, credit, and interest rates with the goal of achieving stable prices and full employment for the world's largest economy. It provides a variety of services to foreign central banks and governments, and Federal Reserve monetary policy can affect exchange rates. Yet despite its importance and influence, the functions of the Fed, and how and why it performs these functions, are often widely misunderstood. Confusion and misinformation about the Fed may make it difficult for high school economics teachers to sort through available resources and decide how and what to present to students. The authors have experience teaching about money and the Fed from the high school level through the university master's degree level. They hope to correct what they perceive to be five of the most common and fundamental misunderstandings that lead to difficulties in teaching about money and the Fed. They also propose methods that high school economics teachers may use to help clarify these concepts in their classrooms. The misunderstandings that the authors identify relate to what money is and how it is created, monetary policy tools, and bond buying and selling by the Fed versus the federal government.

A 5 yr old, castrated male, border collie mixed-breed dog was evaluated for cough and subsequently diagnosed with pulmonary coccidioidomycosis. Baseline serum anti-Coccidioides spp. immunoglobulin M and immunoglobulin G antibody titers were negative and 1:8, respectively. Thoracic computed tomography identified marked gravity-dependent pulmonary consolidation of the right middle lung lobe and marked tracheobronchial lymphadenomegaly. First-line antifungals were prescribed without adequate clinical or radiographic improvement, and a right middle lung lobectomy was subsequently performed 5.5 mo after diagnosis. Clinical signs associated with the respiratory tract resolved postoperatively. Fluconazole was discontinued 204 days after surgery because the dog remained subclinical, the thoracic computed tomography revealed near normal imaging with the exception of changes typical following a lung lobectomy, and the serum anti-Coccidioides spp. immunoglobulin G titer was 1:2. The dog remained subclinical >90 days after cessation of fluconazole. This case report describes the successful treatment outcome in a dog with severe Coccidioides spp. pneumonia following lung lobectomy and oral antifungal therapy. Future studies are warranted to determine the utility of adjunctive lung lobectomy in dogs with coccidioidomycosis who have large fungal burdens localized to a single lung lobe and are refractory to standard first-line oral antifungal therapies. [ABSTRACT FROM AUTHOR]

The article offers information on several fundamental misunderstanding related to the Federal Reserve and money students have and how that can be solved. Topics discussed include students perception of similarity between federal government and Federal Reserve System which should be solved by organizing related activity among students, student's view that supply of money consists of currency and changed of monetary tools in post financial crisis.

Context: Type 1 diabetes incidence continues to increase in children, especially among Hispanic Whites (HW)., Objective: We investigated the clinical, immunologic, and genetic characteristics of HW and Non-Hispanic White (NHW) children that presented at type 1 diabetes diagnosis., Methods: In this single-center, observational study, children who were diagnosed with type 1 diabetes (<20 years old) and tested for islet autoantibodies within 1 year of diagnosis were included in the study and divided into two groups by Hispanic ethnicity., Results: Of 1297 children, 398 HW children presented with a younger age at diabetes onset (10.2 ± 3.9 vs. 11.1 ± 4.1 years, p<0.001) and more diabetic ketoacidosis (62.4% vs. 51.9%, p<0.001) compared to NHW children (n=899). There was no difference in sex, A1c levels, or the number and prevalence of islet autoantibodies between the two cohorts. A subset of our cohort was HLA typed as specific alleles confer strong genetic risk for type 1 diabetes (e.g., HLA-DR4 and DQ8). Among 637 HLA-typed children, HW children had a significantly higher prevalence of the DR4-DQ8 haplotype compared to NHW children (79.1% vs. 60.1%, p<0.001), and this frequency was much higher than a reference Hispanic population (OR = 6.5, 95% CI 4.6-9.3)., Conclusions: Hispanic White children developing type 1 diabetes have a high prevalence of HLA DR4-DQ8, which can be utilized to select individuals for immune monitoring with islet autoantibodies to lessen diabetic ketoacidosis and potentially prevent diabetes onset., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)