Expanding clinical phenotype and novel insights into the pathogenesis of ICOS deficiency

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Abolhassani, H., El-Sherbiny, Y.M. ORCID: 0000-0003-4791-3475, Arumugakani, G., Carter, C., Richards, S., Lawless, D., Wood, P., Buckland, M., Heydarzadeh, M., Aghamohammadi, A., Hambleton, S., Hammarström, L., Burns, S.O., Doffinger, R. and Savic, S., 2019. Expanding clinical phenotype and novel insights into the pathogenesis of ICOS deficiency. Journal of Clinical Immunology. ISSN 0271-9142

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

Abstract

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.

Item Type:

Journal article

Publication Title:

Journal of Clinical Immunology

Creators:

Abolhassani, H., El-Sherbiny, Y.M., Arumugakani, G., Carter, C., Richards, S., Lawless, D., Wood, P., Buckland, M., Heydarzadeh, M., Aghamohammadi, A., Hambleton, S., Hammarström, L., Burns, S.O., Doffinger, R. and Savic, S.

Publisher:

Springer

Date:

20 December 2019

ISSN:

0271-9142

Identifiers: