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

Abstract

BackgroundInducible 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.ObjectiveWe sought to compare the clinical and immunological phenotype and provide clinical follow-up and therapeutic approaches for treating ICOS-deficient patients.MethodsWe describe the clinical and laboratory data of 15 patients with available clinical data. Previous publications and clinical assessment were used as data sources.ResultsThe 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.ConclusionThe 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.

Advances in Evaluation of Chronic Diarrhea in Infants

“…Recent genetics studies have rapidly increased the number of monogenic disorders, including FOXP3, 70,71 ICOS, 72 IL10R, 73 TRIM22, 74 and ARPC1B, 38 which cause dysregulation of the immune system and subsequently inflammation and enteropathy in the intestine. Immune-mediated intestinal disorders present with a wide variety of manifestations, but all have bloody or watery diarrhea, and are frequently associated with systemic disease and multi-organ involvement.…”

“…70,71 The intestinal pathologic features vary from complete villus atrophy with apoptosis in a graft-vs-host appearance, to loss of goblet and Paneth cells, with mild inflammation. Similarly, mutations in the gene encoding ICOS, 72 a T-cell co-stimulatory protein, presents with watery predominantly diet-induced diarrhea starting after a few months of life with biopsy findings of villus atrophy, crypt apoptosis, and an inflammatory infiltrate (Figure 3A-C). …”

Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders

“…The spectrum of disease extended to include liver involvement in 2015, when two patients presenting in early childhood with raised liver enzymes, diarrhea, colitis, and defective clearance of human herpesvirus 6 were described (90). Hepatomegaly and non-infectious hepatitis were found in 20% of a 15-patient ICOS deficiency cohort (91). Histological analysis revealed alcoholic steato-hepatitis in one case of non-infectious hepatitis, while pathogenesis remained unclear in the remaining cases, possibly involving drug-induced toxicity.…”

The utility of flow cytometry for the diagnosis of primary immunodeficiencies

“…Mutations in genes encoding CD19, BAFF‐R, and ICOS have been implicated in subgroup of CVID patients. Mutations in CD19 and BAFF‐R may result in decreased expression of these molecules on the surface of B cells, and mutations in ICOS may result in decreased expression on activated T cells …”