Hypomorphic RAG2 Deficiency Promotes Selection of Self-Reactive B Cells.

Reduced function or hypomorphic variants in recombination-activating genes (RAG) 1 or 2 result in a broad clinical phenotype including common variable immunodeficiency (CVID) and even adult-onset disease. Milder RAG variants are less characterized. Here we describe the longitudinal course of a milder combined RAG deficiency in 3 of 7 siblings sharing the same RAG2 mutations over a 50-year study.

Reduced function of the adaptor SH2B3 promotes T1D via altered gc cytokine-regulated, T cell intrinsic immune tolerance.

Unlabelled: Genome-wide association studies have identified as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single haplotype significantly associated with increased risk for human T1D, and this haplotype carries the single nucleotide variant rs3184504*T in To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T cell-intrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling.

Combination of Standard Addition and Isotope Dilution Mass Spectrometry for the Accurate Determination of Melamine and Cyanuric Acid in Infant Formula.

In the melamine scandals of the early 2000s, different companies of the dairy industry cheated their products by applying chemical substances to feign a higher content of nitrogen. However, this had a severe toxic impact on the kidney health of consumers. As a result, tremendous effort was put into the prevention of further harm to the public.

Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.

Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen.

The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner.

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet β-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 () and confers an increased risk for several autoimmune diseases, including T1D.