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

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 Hassan Abolhassani and Yasser M. El-Sherbiny contributed equally to this work.

A rare case report: ICOS and WIPF1 mutation together in a patient

“…5 Disease severity varied in two patients who shared the same homozygous-missense mutation, suggesting that this wide variety of clinical presentations was the result of other modifying factors. 5 One female patient, although she had a homozygous mutation, was reported asymptomatic, but intravenous immunoglobulin treatment was applied to this patient. 3 Among the two siblings of our patient with homozygous mutation, her 8-year-old brother had no symptoms other than joint pain, while her 7-year-old brother was asymptomatic.…”

“…Therefore, patients often have cellular and humoral immunode ciencies that result in increased susceptibility to bacterial, viral, and opportunistic infections such as Pneumocystisjirovecii. 3,5 ICOS-de cient T cells fail to express CXCR5, demonstrating the essential role of ICOS in the differentiation of CXCR5 + CD4 + T cells, which initiates germinal center formation and signals for maturation, differentiation, and survival of B cells. 3 Therefore, patients with ICOS de ciency generally exhibited low B cells with a low memory component, as in our patient.…”

“…Most of the patients with enteropathy exhibited mild symptoms without growth retardation. 3,5 However, a male patient with severe enteropathy who was dependent on total parenteral nutrition and required HSCT (Hematopoietic stem-cell transplantation) to relieve symptoms was reported. 9 Our patient's height and weight were also < 3 percentile.…”

“…3,4 Furthermore, ICOS mediates the interaction of T and B cells resulting in the formation of germinal centers and thus differentiates B cells into memory and long lasting plasma cells. 3,5 Autosomal recessive inherited ICOS de ciency is classi ed as combined immunode ciency (CID) and has a wide clinical spectrum including hypogammaglobulinemia, recurrent infections, enteropathies, autoimmunity, lymphoproliferation and malignancy. 6 Wiskott-Aldrich syndrome-2 (WAS2) is an autosomal recessive immunological disease characterized by recurrent infections starting in infancy.…”

Specific Immune Response and Cytokine Production in CD70 Deficiency

“…Approximately 5-10% of patients harbor mutations in the TNFRSF13B gene (TACI) (6). Disease-causing mutations in TNFRSF13C (BAFFR), encoding one of the ligands for TACI (7); T-cell co-stimulation gene encoding inducible co-stimulator (ICOS) (8); B-cell co-receptor complex genes including CD19, CD81, CD20, and CD21 (9-12); genes encoding the lipopolysaccharide-responsive vesicle trafficking beach and anchor containing protein (LRBA) (13); cytotoxic Tlymphocyte-associated protein 4 (CTLA4) (14); Ras-related C3 botulinum toxin substrate 2 (RAC2) (15); phosphatidylinositol 3kinase (PI3K) receptor 1 (PIK3R1) (16); PI3K catalytic subunit delta (PIK3CD); phosphatase and tensin homolog (PTEN); protein kinase C delta (PRKCD) (17); tumor necrosis factorlike weak inducer of apoptosis (TWEAK/TNFSF12) (18); nuclear factor-kappa B1 (NFKB1) (19); NFKB2; and interleukin 21 (IL21) (14) and its receptor IL21R (20) have also been described in a few patients presenting with features of CVID. Furthermore, mutations in tRNA nucleotidyltransferase 1 (TRNT1), IKAROS Family Zinc Finger 1 (IKZF1), interferon regulatory factor 2 binding protein 2 (IRF2BP2), ATPase proton transporting accessory protein 1 (ATP6AP1), Rho guanine nucleotide exchange factor 1 (ARHGEF1), SH3 domain-containing kinasebinding protein 1 (SH3KBP1), SEC61 translocon Subunit alpha 1 (SEC61A1), and mannosyl-oligosaccharide glucosidase (MOGS) have been shown to be associated with the development of the disease (2).…”