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Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

ABSTRACT: Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-?, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.

SUBMITTER: Hadjadj J

PROVIDER: S-EPMC7578789 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

Hadjadj Jérôme J Castro Carla Noemi CN Tusseau Maud M Stolzenberg Marie-Claude MC Mazerolles Fabienne F Aladjidi Nathalie N Armstrong Martin M Ashrafian Houman H Cutcutache Ioana I Ebetsberger-Dachs Georg G Elliott Katherine S KS Durieu Isabelle I Fabien Nicole N Fusaro Mathieu M Heeg Maximilian M Schmitt Yohan Y Bras Marc M Knight Julian C JC Lega Jean-Christophe JC Lesca Gaetan G Mathieu Anne-Laure AL Moreews Marion M Moreira Baptiste B Nosbaum Audrey A Page Matthew M Picard Cécile C Ronan Leahy T T Rouvet Isabelle I Ryan Ethel E Sanlaville Damien D Schwarz Klaus K Skelton Andrew A Viallard Jean-Francois JF Viel Sebastien S Villard Marine M Callebaut Isabelle I Picard Capucine C Walzer Thierry T Ehl Stephan S Fischer Alain A Neven Bénédicte B Belot Alexandre A Rieux-Laucat Frédéric F

Nature communications 20201021 1

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by ...[more]

PMID: 33087723

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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.

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Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

Publications

Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

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