Abstract
PurposeImmune dysregulation complications cause significant morbidity and mortality in common variable immunodeficiency (CVID), but the underlying pathophysiology is poorly understood. While CVID is primarily considered a B-cell defect, resulting in the characteristic hypogammaglobulinemia, T-cells may also contribute to immune dysregulation complications. Here, we aim to further characterize T-cell activation and regulation in CVID with immune dysregulation (CVIDid).MethodsFlow cytometry was performed to investigate T-cell differentiation, activation and intracellular cytokine production, negative regulators of immune activation, regulatory T-cells (Treg), and homing markers in 12 healthy controls, 12 CVID patients with infections only (CVIDio), and 20 CVIDid patients.ResultsBoth CD4 + and CD8 + T-cells in CVIDid showed an increased activation profile (HLA-DR + , Ki67 + , IFNγ +) when compared to CVIDio, with concomitant upregulation of negative regulators of immune activation PD1, LAG3, CTLA4, and TIGIT. PD1 + and LAG3 + subpopulations contained equal or increased frequencies of cells with the capacity to produce IFNγ, Ki67, and/or GzmB. The expression of PD1 correlated with serum levels of CXCL9, 10, and 11. Treg frequencies were normal to high in CVIDid, but CVIDid Tregs had reduced CTLA-4 expression, especially on CD27 + effector Tregs. Increased migratory capacity to inflamed and mucosal tissue was also observed in CVIDid T-cells.ConclusionCVIDid was characterized by chronic activation of peripheral T-cells with preserved inflammatory potential rather than functional exhaustion, and increased tissue migratory capacity. While Treg numbers were normal in CVIDid Tregs, low levels of CTLA-4 indicate possible Treg dysfunction. Combined studies of T-cell dysfunction and circulating inflammatory proteins may direct future treatment strategies.
Highlights
Common variable immunodeficiency (CVID) is characterized by recurrent infections caused by low IgG, and IgA or IgM [1], for which patients are treated with immunoglobulin G replacement therapy (IgRT) [2]
To investigate immune activation and regulation in CVID, Peripheral blood mononuclear cells (PBMC) were isolated from 12 healthy controls (HC), 12 CVID patients with infections only (CVIDio), and 20 patients with CVID with immune dysregulation (CVIDid) (Table 1)
CVIDio and HC clustered closely together and were distinct from most CVIDid samples. This suggests that most variation in the flow cytometric T-cell data related to immune dysregulation and not to the hypogammaglobulinemia shared by CVID patients
Summary
Common variable immunodeficiency (CVID) is characterized by recurrent infections caused by low IgG, and IgA or IgM [1], for which patients are treated with immunoglobulin G replacement therapy (IgRT) [2]. IgRT has significantly decreased the risk of infectious complications in CVID, but over a third of patients develop immune dysregulation complications [3, 4], resulting in significant morbidity and mortality [5, 6]. While the defining hypogammaglobinemia in CVID is considered to be primarily the result of B-cell dysfunction, several lines of evidence suggest an additional role for T-cells in CVID with immune dysregulation (CVIDid). In peripheral blood of patients with CVIDid, a decreased CD4/CD8 ratio was observed with decrease of naïve T-cells [12], Tregs, Th17 cells, and follicular helper T (Tfh) cells [13, 14]. Monogenic primary immunodeficiencies caused by mutations in immune regulation genes such as CTLA4 [19] and ICOS [20] often result in a CVIDid phenotype. How the interplay between immune regulation and immune activation results in CVIDid remains poorly understood
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