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Front Immunol. 2017 Aug 16;8:964. doi: 10.3389/fimmu.2017.00964. eCollection 2017.

14 Years after Discovery: Clinical Follow-up on 15 Patients with Inducible Co-Stimulator Deficiency.

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Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, United States.
Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.
Royal Manchester Children's Hospital, University of Manchester, Manchester, United Kingdom.
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Great North Children's Hospital, Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Rheumatology Medical Center, Villingen-Schwenningen, Germany.
Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, United Kingdom.



Inducible co-stimulator (ICOS) deficiency was the first monogenic defect reported to cause common variable immunodeficiency (CVID)-like disease in 2003. Since then, 16 patients have been reported worldwide with an increasing range of clinical phenotypes.


We sought to compare the clinical and immunological phenotype and provide clinical follow-up and therapeutic approaches for treating ICOS-deficient patients.


We describe the clinical and laboratory data of 15 patients with available clinical data. Previous publications and clinical assessment were used as data sources.


The observed ICOS gene mutations were all deletions leading to undetectable protein expression. The clinical phenotype of ICOS deficiency is much broader than initially anticipated and includes not only CVID-like disease but an increased susceptibility to viral and opportunistic infections, as well as cancer. Impaired B-cell development led to decreased memory B-cells in all patients, and hypogammaglobulinemia in all but one patient. Circulating CXCR5+ CD4+ follicular T-helper-cell numbers were also reduced in all patients. Treatment included immunoglobulin replacement, regular antibiotic prophylaxis, corticosteroids, and steroid-sparing agents. Three patients underwent hematopoietic stem cell transplantation; one of them died due to capillary leak syndrome on day 5 posttransplantation.


The disease spectrum of ICOS deficiency is expanding from solely B-cell to combined B- and T-cell immunodeficiency, suggesting genetic and environmental modifiers. Genetic diagnosis is the only tool to distinguish ICOS deficiency from other immunological defects. Patients with antibody deficiency, autoimmunity, and combined immunodeficiency should be screened for ICOS mutations.


ICOS deficiency; autoimmunity; combined immunodeficiency; common variable immunodeficiency; hypogammaglobulinemia; immune dysregulation; opportunistic infections

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