In this issue of EJHG, Ge and Concannon [1], combined with results from their previous study [2], report that UBASH3A, which encodes Ubiquitin-associated and SH3 domain-containing protein A and functions as a negative regulator of NF-kB signalling in T cells on stimulation of the antigen T cell receptor [2], is almost certainly a causal gene in the chromosome 21q22.3 region for type 1 diabetes (T1D) and other autoimmune diseases (https://www.immunobase.org). Few genome-wide association study (GWAS) regions have yet converged on a causal gene yet, although as you will see below there are complexities, and there may be additional genes involved in the region.

The presence of the T1D-predisposing non-coding alleles of single nucleotide polymorphisms (SNPs) within the UBASH3 gene, is associated with its increased transcription thereby leading to reduced transcription of the interleukin-2 (IL-2) gene by effector T cells, leading to increased susceptibility to T1D [2]. These results are consistent with a model that T1D results from autoimmune destruction of the pancreatic insulin-producing beta cells in which deficiencies in IL-2 signalling and the functions of the autoimmune disease-protective T regulatory cells, which are wholly dependent IL-2 for their maintenance and function, are recognised as major aetiological pathways of this common multifactorial disorder. The latter consensus is a major justification for the ongoing trials of IL-2 therapy in T1D to improve the regulation of the immune and save some beta cells from autoimmune destruction and reduce or even halt the requirement for multiple daily insulin injections. These results provide further support for this model and the translation of ultra-low dose IL-2 into the T1D clinic [2, 3].

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