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

Hassan Abolhassani,Matthew Buckland,Rainer Doffinger,Clive Carter,Gururaj Arumugakani,Sophie Hambleton,Yasser M El-Sherbiny,Sinisa Savic,Lennart Hammarström,Stephen Richards,Philip Wood,Siobhan O Burns,Asghar Aghamohammadi,Dylan Lawless,Marzieh Heydarzadeh

doi:10.1007/s10875-019-00735-z

Abstract

BackgroundInducible 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.MethodsA 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.ResultsFour 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.ConclusionsICOS 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.

Highlights

Inducible T cell co-stimulator (ICOS) is a member of the CD28/cytotoxic T lymphocyte–associated protein 4 (CTLA4) family, which plays an important role in regulating T cell–mediated immune responses as a secondary costimulatory signal delivered in concert with T cell receptor stimulation [1, 2]
We report 7 new patients presenting with four novel ICOS mutations resulting in a common variable immunodeficiency (CVID) phenotype, including the first 2 cases ever reported of ICOS deficiency due to a missense mutation located within the helical domain of the protein, and another 2 patients with a compound heterozygous mutations, one of which is located at a splice site
We show that inflammatory complications associated with ICOS deficiency might be due to a skewed Th1 response, resulting from excessive IL-12 production caused by the failure to downregulate ICOSL expression on antigen presenting cells, including dendritic cells and monocytes

Summary

Results

We combined the information from previously published cases (P1–P15) [12,13,14,15,16,17] and our new patients (P16–P22) to provide an up to date clinical overview of ICOS deficiency. Neither P16 nor P17 (with homozygous deletion mutations) had any expression of ICOS on CD4+ T cells following stimulations with anti-CD3 and PHA (Supplementary Fig. E4). The clinical features observed in all patients with ICOS deficiency (Table 1, Supplementary Tables E3–7, and Fig. 2) are heterogeneous with the age of presentation ranging from early infancy to 39 years. ICOS-deficient patients showed significantly higher IL-6 production following LPS or combined. Disease severity varied in a similar fashion between P21 and P22, despite them sharing the same novel homozygous missense mutation This suggests that a wide range of clinical presentations is probably the result of other modifying factors. Despite receiving 6 months of treatment, no significant improvement in the platelet count, neutrophil count, or hemoglobin levels was observed

Introduction

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