A reply to "TCR+/BCR+ dual-expressing cells and their associated public BCR clonotype are not enriched in type 1 diabetes".

We have recently identified a novel lymphocyte that is a dual expresser (DE) of TCRαß and BCR. DEs in T1D patients are predominated by a public BCR clonotype (clone-x) that encodes a potent autoantigen that cross-activates insulin-reactive T cells. Betts and colleagues were able to detect DEs but alleged to not detect high DE frequency, clone-x, or similar clones in T1D patients. Unfortunately, the authors did not follow our methods and when they did, their flow cytometric data at two sites were conflicting. Moreover, contrary to their claim, we identified clones similar to clone-x in their data along with clones bearing the core motif (DTAMVYYFDYW). Additionally, their report of no increased usage of clone-x VH/DH genes by bulk B cells confirms rather than challenges our results. Finally, the authors failed to provide data verifying purity of their sorted DEs, making it difficult to draw reliable conclusion of their repertoire analysis. This Matters Arising Response paper addresses the Japp et al. (2021) Matters Arising paper, published concurrently in Cell.

A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen.

T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.

IL-17 and limits of success.

Interleukin-17 (IL-17) is a potent proinflammatory cytokine that protects a host against fungal and extracellular bacterial infections. On the other hand, excessive or dysregulated production of IL-17 underlines susceptibility to autoimmune disease. Consequently, blocking IL-17 has become an effective strategy for modulating several autoimmune diseases, including multiple sclerosis (MS), psoriasis, and rheumatoid arthritis (RA). Notably, however, IL-17 blockade remains ineffective or even pathogenic against important autoimmune diseases such as inflammatory bowel disease (IBD). Furthermore, the efficacy of IL-17 blockade against other autoimmune diseases, including type 1 diabetes (T1D) is currently unknown and waiting results of ongoing clinical trials. Coming years will determine whether the efficacy of IL-17 blockade is limited to certain autoimmune diseases or can be expanded to other autoimmune diseases. These efforts include new clinical trials aimed at testing second-generation agents with the goal of increasing the efficiency, spectrum, and ameliorating side effects of IL-17 blockade. Here we briefly review the roles of IL-17 in the pathogenesis of selected autoimmune diseases and provide updates on ongoing and recently completed trials of IL-17 based immunotherapies.

Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial.

Background: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia. Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 µg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22). Findings: Forty-two participants received TransCon CNP at doses of 6 µg (n = 10; 7 female), 20 µg (n = 11; 3 female), 50 µg (n = 10; 3 female), or 100 µg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 µg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 µg CNP/kg/week. Interpretation: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 µg CNP/kg/week in the ongoing pivotal trial. Funding: Ascendis Pharma, A/S.

Current understandings of the pathogenesis of type 1 diabetes: Genetics to environment.

Type 1 diabetes (T1D) is an autoimmune disease that usually strikes early in life, but can affect individuals at almost any age. It is caused by autoreactive T cells that destroy insulin-producing beta cells in the pancreas. Epidemiological studies estimate a prevalence of 1 in 300 children in the United States with an increasing incidence of 2%-5% annually worldwide. The daily responsibility, clinical management, and vigilance required to maintain blood sugar levels within normal range and avoid acute complications (hypoglycemic episodes and diabetic ketoacidosis) and long term micro- and macro-vascular complications significantly affects quality of life and public health care costs. Given the expansive impact of T1D, research work has accelerated and T1D has been intensively investigated with the focus to better understand, manage and cure this condition. Many advances have been made in the past decades in this regard, but key questions remain as to why certain people develop T1D, but not others, with the glaring example of discordant disease incidence among monozygotic twins. In this review, we discuss the field's current understanding of its pathophysiology and the role of genetics and environment on the development of T1D. We examine the potential implications of these findings with an emphasis on T1D inheritance patterns, twin studies, and disease prevention. Through a better understanding of this process, interventions can be developed to prevent or halt it at early stages.