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Cited by 156Cytokine Signaling Pathways and InteractionsImmunodeficiency and Autoimmune DisordersT-cell and B-cell Immunology

Early-onset autoimmunity associated with SOCS1 haploinsufficiency

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Hadjadj, Jérôme, Castro, Carla Noemi, Tusseau, Maud, Stolzenberg, Marie-Claude, Mazerolles, Fabienne, Aladjidi, Nathalie, Armstrong, Martin, Ashrafian, Houman +35 more·2020·Nature Communications
DOI 10.1038/s41467-020-18925-4PMC PMC7578789
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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-γ, 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.

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  • In human macrophages, reduced SUMOylation activates KLF4, which induces SOCS1 and inhibits JAK-STAT and TLR4-MyD88 signaling, thereby reducing NF-κB and MAP kinase activity and promoting restorative polarization.

    “In human macrophages, reduced SUMOylation activates KLF4, which induces suppressor of cytokine signaling 1 (SOCS1) and inhibits JAK–STAT and TLR4–MyD88 signaling, thereby reducing NF-κB and MAP kinase activity and promoting restorative polarization (81–85).”

    From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [83]

    The Introduction (page unavailable) states that SOCS1 directly inhibits JAK activity, and the Results on STAT pathway activation (page unavailable) show increased cytokine-induced STAT activation when SOCS1 function is impaired. The paper does not support the claimed chain from reduced SUMOylation through KLF4 to SOCS1, or the TLR4–MyD88, NF-κB, MAP kinase, and restorative macrophage-polarization effects (searched: SUMOylation/KLF4 and TLR4/MyD88/NF-κB/MAP kinase). (LLM, conf=0.89)

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Sorted by citations

Authors
Hadjadj, J., Castro, C. N., Tusseau, M., Stolzenberg, M.-C., Mazerolles, F., Aladjidi, N., Armstrong, M., Ashrafian, H., Cutcutache, I., Ebetsberger-Dachs, G., Elliott, K. S., Durieu, I., Fabien, N., Fusaro, M., Heeg, M., Schmitt, Y., Bras, M., Knight, J. C., Lega, J.-C., Lesca, G., Mathieu, A.-L., Moreews, M., Moreira, B., Nosbaum, A., Page, M., Picard, C., Ronan Leahy, T., Rouvet, I., Ryan, E., Sanlaville, D., Schwarz, K., Skelton, A., Viallard, J.-F., Viel, S., Villard, M., Callebaut, I., Picard, C., Walzer, T., Ehl, S., Fischer, A., Neven, B., Belot, A., & Rieux-Laucat, F.
Affiliations
  • Inserm (FR)
  • University of Freiburg (DE)
  • Lyon 1 Université (FR)
  • UCB Pharma (Belgium) (BE)
  • University of Oxford (GB)
  • UCB Pharma (United Kingdom) (GB)
  • Centre for Human Genetics (GB)
  • Hospices Civils de Lyon (FR)
  • Hôpital Necker-Enfants Malades (FR)
  • Université Paris Cité (FR)
  • University Hospital Galway (IE)
  • Universität Ulm (DE)
  • Centre National de la Recherche Scientifique (FR)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-10-21
Volume
11
Issue
1
Pages
5341-5341
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-18925-4
PMC
PMC7578789
OpenAlex
W3093864054
Cited by
156
References
2
Citations by year
2026: 18 · 2025: 30 · 2024: 38 · 2023: 24 · 2022: 22 · 2021: 24
FWCI
6.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Institut des maladies génétiques Imagine (ANR-10-IAHU- 01)
  • Deutsche Forschungsgemeinschaft (EXC‐2189, 390939984, FSE2018-041)
  • Agence Nationale de la Recherche (ANR-18-CE17-0001, ANR-14-CE14-0026, CE14-0026-01, ANR-10-IAHU- 01, ANR-18-RHUS-0010, ANR18, ANR-10-IAHU-0001, 10-IAHU-01, ANR-10)
  • Institut National de la Santé et de la Recherche Médicale (ANR‐10‐IAHU‐01)
  • Bundesministerium für Bildung und Forschung (EXC-2189, 390939984, FSE2018-041)
  • Albert-Ludwigs-Universität Freiburg (EXC-2189, 390939984)
  • Fondation ARC pour la Recherche sur le Cancer
  • Ligue Contre le Cancer (ANR-10-IAHU-01)
  • Fondation Bettencourt Schueller
  • Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
  • UCB Pharma
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
SOCS1, haploinsufficiency, autosomal dominant inheritance, JAK/STAT signaling, STAT activation, ruxolitinib, interferon-gamma, interleukin-2, IL-4, self-tolerance
MeSH terms
Suppressor of Cytokine Signaling 1 Protein, Adolescent, Adult, Autoimmune Diseases, Child, Child, Preschool, Female, Humans, Male, Models, Molecular, Mutation, Pedigree, T-Lymphocytes, Signal Transduction, Autoimmunity, Cytokines, Age of Onset, STAT Transcription Factors, Haploinsufficiency

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