Title |
Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT
|
---|---|
Published in |
The Journal of Experimental Medicine, May 2016
|
DOI | 10.1084/jem.20151110 |
Pubmed ID | |
Authors |
Baerbel Keller, Irina Zaidman, O. Sascha Yousefi, Dov Hershkovitz, Jerry Stein, Susanne Unger, Kristina Schachtrup, Mikael Sigvardsson, Amir A. Kuperman, Avraham Shaag, Wolfgang W. Schamel, Orly Elpeleg, Klaus Warnatz, Polina Stepensky |
Abstract |
The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca(2+) mobilization, residual T cells were able to induce Ca(2+) influx and nuclear factor (NF) κB signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease. |
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