Costimulatory Molecules and Cytokine Production by T Lymphocytes in Common Variable Immunodeficiency Disease

Abstract

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by hypogammaglobulinaemia and recurrent infections. Although early works pointed to a primary B-lymphocyte defect as a cause of the disease, a failure in T-lymphocyte cooperation has also been suggested. T cells exert their costimulatory function through either membrane costimulatory molecules or secreted cytokines, both having an influence in the development of the humoral response. The aim of our study was to evaluate whether an abnormal expression and induction of costimulatory molecules or alterations in the production of cytokines by T cells cause deficient T/B cooperation in CVID patients. We studied the expression and upregulation of costimulatory molecules (CD28, CD40L/CD154 and CTLA-4/CD152) and production of cytokines (IL-2, IL-4, IL-6, IL-10, IFN-gamma and TNF-alpha) in purified T lymphocytes from CVID patients stimulated with optimal doses of anti-CD3 or suboptimal doses of anti-CD3 and anti-CD28. Stimulated T cells from CVID patients expressed normal levels of CD28, CD40L/CD154 and CTLA-4/CD152 when compared with controls. Except for higher production of IL-4 after stimulation with anti-CD3, T cells of CVID patients produced similar amounts of cytokines compared with controls. An imbalance between costimulatory molecules expression (CD28, CD40L/CD154 and CTLA-4/CD152) and cytokine production by T cells does not explain a deficient cooperation between T and B cells in this group of CVID patients.

Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency

“…Recent evidence confirms that IL-4 and IL-10 production and the frequencies of polymorphisms in these genes are comparable with healthy controls, suggesting a minor, if any, role in the pathogenesis of these diseases. 30,[44][45][46][47] Furthermore, CD40 ligand (CD40L/CD154), acting as an important component of the mechanism of Ig production, is normally expressed on stimulated T lymphocytes in a predominant proportion of CVID patients. 45,46,48 Taken together, it appears that the present abnormalities of B-cell differentiation and failure to produce normal amounts of switched immunoglobulin in CVID and IgAD are not due to defect signaling through IL-4, IL-10, or IL-21 and CD40.…”

“…30,[44][45][46][47] Furthermore, CD40 ligand (CD40L/CD154), acting as an important component of the mechanism of Ig production, is normally expressed on stimulated T lymphocytes in a predominant proportion of CVID patients. 45,46,48 Taken together, it appears that the present abnormalities of B-cell differentiation and failure to produce normal amounts of switched immunoglobulin in CVID and IgAD are not due to defect signaling through IL-4, IL-10, or IL-21 and CD40. Furthermore, the ability to undergo CSR and plasma cell differentiation when stimulated with IL-21, IL-4, and anti-CD40 mAb implies that B cells from patients with CVID or IgAD are not lacking the molecular machinery necessary for such processes.…”

Cytokine Gene Polymorphisms in Common Variable Immunodeficiency

“…The allele and genotype frequencies of IFN-γ at position UTR +5644 were similar in the patients and controls. Although a recent study by Pons et al [23] showed a insignificantly higher production of IL-2 and IFN-γ after T-cell stimulation, in our recent study and also in the study by Inoue et al [39], there was no significant difference in the production of these cytokines between patient and control groups. A granulomatous condition, which could lead to a trend to Th1 response, was not detected in our patient group.…”

“…There are several studies indicating cytokine production abnormalities in CVID [21,22,23,24]. While cytokine production could be affected by cytokine gene polymorphism, we have genotyped a sample of CVID patients for a number of these cytokines.…”

“…Although the cytokine production in CVID has been evaluated in several studies, conflicting results were found [21,22,23,24]. The expression and secretion of cytokines could be affected, at least in part, by genetic polymorphisms within coding and promoter regions of cytokine genes [25, 26].…”