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Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency.

ABSTRACT: The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

SUBMITTER: Boland BS

PROVIDER: S-EPMC4355235 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency.

Boland Brigid S BS Widjaja Christella E CE Banno Asoka A Zhang Bing B Kim Stephanie H SH Stoven Samantha S Peterson Michael R MR Jones Marilyn C MC Su H Irene HI Crowe Sheila E SE Bui Jack D JD Ho Samuel B SB Okugawa Yoshinaga Y Goel Ajay A Marietta Eric V EV Khosroheidari Mahdieh M Jepsen Kristen K Aramburu Jose J López-Rodríguez Cristina C Sandborn William J WJ Murray Joseph A JA Harismendy Olivier O Chang John T JT

Journal of immunology (Baltimore, Md. : 1950) 20150209 6

The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor re ...[more]

PMID: 25667416

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Project description:BackgroundBiallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step.ObjectivesThis study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance.MethodsExtensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed.ResultsA novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4+ T cells and low TCR-Vα7.2+ T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient.ConclusionsThis study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.

Dataset Information

Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency.

Publications

Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency.

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