Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT

J Exp Med. 2016 Jun 27;213(7):1185-99. doi: 10.1084/jem.20151110.

Baerbel Keller ¹, Irina Zaidman ², O Sascha Yousefi ³, Dov Hershkovitz ⁴, Jerry Stein ⁵, Susanne Unger ¹, Kristina Schachtrup ¹, Mikael Sigvardsson ⁶, Amir A Kuperman ⁷, Avraham Shaag ⁸, Wolfgang W Schamel ⁹, Orly Elpeleg ⁸, Klaus Warnatz ¹⁰, Polina Stepensky ¹¹

Affiliations

1 Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany.
2 Department of Pediatric Hematology Oncology, Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa 3109601, Israel.
3 Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, 79104 Freiburg, Germany.
4 Department of Pathology, Rambam Health Care Campus, Haifa 3109601, Israel.
5 Department of Pediatric Hematology Oncology and Bone Marrow Transplantation Unit, Schneider Children's Medical Center of Israel, Petah-Tikva 49202, Israel.
6 Department of Clinical and Experimental Medicine, Experimental Hematopoiesis Unit, Faculty of Health Sciences, Linköping University, 581 85 Linköping, Sweden.
7 Blood Coagulation Service and Pediatric Hematology Clinic, Galilee Medical Center, Nahariya 22100, Israel Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 5290002, Israel.
8 Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University, Jerusalem 91120, Israel.
9 Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
10 Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, 79106 Freiburg, Germany [email protected] [email protected].
11 Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University, Jerusalem 91120, Israel Department of Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Medical Center, Hebrew University, Jerusalem 91120, Israel [email protected] [email protected].

PMID: 27242165 DOI: 10.1084/jem.20151110

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.