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Sic H, Speletas M, Cornacchione V, et al. An Activating Janus Kinase-3 Mutation Is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome. Front Immunol. 2017;8:1824doi: 10.3389/fimmu.2017.01824.
Sic, H., Speletas, M., Cornacchione, V., Seidl, M., Beibel, M., Linghu, B., Yang, F., Sevdali, E., Germenis, A. E., Oakeley, E. J., Vangrevelinghe, E., Sailer, A. W., Traggiai, E., Gram, H., & Eibel, H. (2017). An Activating Janus Kinase-3 Mutation Is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome. Frontiers in immunology, 81824. https://doi.org/10.3389/fimmu.2017.01824
Sic, Heiko, et al. "An Activating Janus Kinase-3 Mutation Is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome." Frontiers in immunology vol. 8 (2017): 1824. doi: https://doi.org/10.3389/fimmu.2017.01824
Sic H, Speletas M, Cornacchione V, Seidl M, Beibel M, Linghu B, Yang F, Sevdali E, Germenis AE, Oakeley EJ, Vangrevelinghe E, Sailer AW, Traggiai E, Gram H, Eibel H. An Activating Janus Kinase-3 Mutation Is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome. Front Immunol. 2017 Dec 15;8:1824. doi: 10.3389/fimmu.2017.01824. eCollection 2017. PMID: 29375547; PMCID: PMC5770691.
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Front Immunol. 2017 Dec 15;8:1824. doi: 10.3389/fimmu.2017.01824. eCollection 2017.

An Activating Janus Kinase-3 Mutation Is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome.

Frontiers in immunology

Heiko Sic, Matthaios Speletas, Vanessa Cornacchione, Maximillian Seidl, Martin Beibel, Bolan Linghu, Fan Yang, Eirini Sevdali, Anastasios E Germenis, Edward J Oakeley, Eric Vangrevelinghe, Andreas W Sailer, Elisabetta Traggiai, Hermann Gram, Hermann Eibel

Affiliations

  1. Novartis Institute for Biomedical Research, Basel, Switzerland.
  2. Department of Immunology and Histocompatibility, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa, Greece.
  3. Institute for Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany.
  4. Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
  5. Novartis Institutes for Biomedical Research, Cambridge, MA, United States.

PMID: 29375547 PMCID: PMC5770691 DOI: 10.3389/fimmu.2017.01824

Abstract

Heterozygous mutations in the cytotoxic T lymphocyte antigen-4 (CTLA-4) are associated with lymphadenopathy, autoimmunity, immune dysregulation, and hypogammaglobulinemia in about 70% of the carriers. So far, the incomplete penetrance of CTLA-4 haploinsufficiency has been attributed to unknown genetic modifiers, epigenetic changes, or environmental effects. We sought to identify potential genetic modifiers in a family with differential clinical penetrance of CTLA-4 haploinsufficiency. Here, we report on a rare heterozygous gain-of-function mutation in Janus kinase-3 (JAK3) (p.R840C), which is associated with the clinical manifestation of CTLA-4 haploinsufficiency in a patient carrying a novel loss-of-function mutation in CTLA-4 (p.Y139C). While the asymptomatic parents carry either the CTLA-4 mutation or the JAK3 variant, their son has inherited both heterozygous mutations and suffers from hypogammaglobulinemia combined with autoimmunity and lymphoid hyperplasia. Although the patient's lymph node and spleen contained many hyperplastic germinal centers with follicular helper T (T

Keywords: T follicular helper cell; T regulatory cell; common variable immunodeficiency; cytotoxic T lymphocyte antigen-4; haploinsufficiency; immune checkpoint; immune dysregulation syndrome; janus kinase-3

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