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

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

doi:10.1084/jem.20151110

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

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

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

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 Ca²⁺ mobilization, residual T cells were able to induce Ca²⁺ 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.

Original language	English
Pages (from-to)	1185-1199
Number of pages	15
Journal	Journal of Experimental Medicine
Volume	213
Issue number	7
DOIs	https://doi.org/10.1084/jem.20151110
State	Published - 27 Jun 2016

Bibliographical note

Publisher Copyright:
© 2016 Keller et al.

Funding

B. Keller, O.S. Yousefi, S. Unger, W.W. Schamel, and K. Warnatz were supported by the German Federal Ministry of Education and Research (BMBF 01EO1303). P. Stepensky and K. Warnatz received funding from the Deutsche Forschungsgemeinschaft (Discovery and Evaluation of New Combined Immunodeficiency Disease Entities; grant DFG WA 1597/4-1). P. Stepensky was supported by a research grant from the joint fund of the Hebrew University and Hadassah Medical Center. This study was supported in part by the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School).

Funders	Funder number
Excellence Initiative of the German Research Foundation	GSC-4
Hadassah Medical Organization
Deutsche Forschungsgemeinschaft	DFG WA 1597/4-1
Bundesministerium für Bildung und Forschung	01EO1303
Hebrew University of Jerusalem

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10.1084/jem.20151110

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Keller, B., Zaidman, I., Yousefi, O. S., Hershkovitz, D., Stein, J., Unger, S., Schachtrup, K., Sigvardsson, M., Kuperman, A. A., Shaag, A., Schamel, W. W., Elpeleg, O., Warnatz, K., & Stepensky, P. (2016). Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT. Journal of Experimental Medicine, 213(7), 1185-1199. https://doi.org/10.1084/jem.20151110

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title = "Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT",

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 Ca2+ mobilization, residual T cells were able to induce Ca2+ 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.",

author = "Baerbel Keller and Irina Zaidman and Yousefi, {O. Sascha} and Dov Hershkovitz and Jerry Stein and Susanne Unger and Kristina Schachtrup and Mikael Sigvardsson and Kuperman, {Amir A.} and Avraham Shaag and Schamel, {Wolfgang W.} and Orly Elpeleg and Klaus Warnatz and Polina Stepensky",

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Keller, B, Zaidman, I, Yousefi, OS, Hershkovitz, D, Stein, J, Unger, S, Schachtrup, K, Sigvardsson, M, Kuperman, AA, Shaag, A, Schamel, WW, Elpeleg, O, Warnatz, K & Stepensky, P 2016, 'Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT', Journal of Experimental Medicine, vol. 213, no. 7, pp. 1185-1199. https://doi.org/10.1084/jem.20151110

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

Abstract

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