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Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency

Lookup NU author(s): Professor Sophie HambletonORCiD

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Abstract

© 2019, The Author(s). Background: Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)–like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte–associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition. Methods: A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA. Results: Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ stimulation. This was associated with skewing of CD4+ T cells towards Th1 phenotype and increased expression of ICOSL on monocytes. Lastly, reduced CTLA4 expression was found in 2 patients. One patient treated with ustekinumab for pancytopenia due to granulomatous bone marrow infiltration failed to respond to this targeted therapy. Conclusions: ICOS deficiency is associated with defective T cell activation, with simultaneously enhanced stimulation of monocytes. The latter is likely to result from a lack of ICOS/ICOSL interaction which might be necessary to provide negative feedback which limits monocytes activation.

Publication metadata

Author(s): Abolhassani H, El-Sherbiny YM, Arumugakani G, Carter C, Richards S, Lawless D, Wood P, Buckland M, Heydarzadeh M, Aghamohammadi A, Hambleton S, Hammarstrom L, Burns SO, Doffinger R, Savic S

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Immunology

Year: 2020

Volume: 40

Pages: 277-288

Print publication date: 01/02/2020

Online publication date: 20/12/2019

Acceptance date: 13/12/2019

Date deposited: 10/01/2020

ISSN (print): 0271-9142

ISSN (electronic): 1573-2592

Publisher: Springer Nature

URL: https://doi.org/10.1007/s10875-019-00735-z

DOI: 10.1007/s10875-019-00735-z

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