Chronic immune activation in common variable immunodeficiency (CVID) is associated with elevated serum levels of soluble CD14 and CD25 but not endotoxaemia

Common variable immunodeficiency is the most common form of symptomatic primary antibody failure in adults and children. Replacement immunoglobulin is the standard treatment of these patients. By using a differential proteomic approach based on 2D-DIGE, we examined serum samples from normal donors and from matched, naive, and immunoglobulin-treated patients. The results highlighted regulated expression of serum proteins in naive patients. Among the identified proteins, clusterin/ApoJ serum levels were lower in naive patients, compared to normal subjects. This finding was validated in a wider collection of samples from newly enrolled patients. The establishment of a cellular system, based on a human hepatocyte cell line HuH7, allowed to ascertain a potential role in the regulation ofCLUgene expression by immunoglobulins.

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Serum B cell activating factor and interleukin 10 levels in common variable immunodeficiency: Relationship with clinical findings

Vojnosanitetski pregled ◽

10.2298/vsp161115068m ◽

2019 ◽

Vol 76 (1) ◽

pp. 42-49

Author(s):

Radovan Mijanovic ◽

Sladjana Andrejevic ◽

Vladimir Jurisic ◽

Branka Bonaci-Nikolic

Keyword(s):

Autoimmune Diseases ◽

B Cell ◽

Common Variable Immunodeficiency ◽

Healthy Subjects ◽

Serum Levels ◽

Pulmonary Diseases ◽

Recurrent Infections ◽

B Cell Activating Factor ◽

Chronic Pulmonary Diseases ◽

Common Variable

Background/Aim. Common variable immunodeficiency (CVID) is an immunologically and clinically heterogeneous disorder. Disturbed cytokine production is implicated in dysfunctional immune response. The aim of this study was to investigated B-cell activating factor (BAFF) and interleukin (IL)- 10 levels in CVID patients. Methods. The study included 28 CVID patients diagnosed and followed during a 20-year period (mean follow-up 14.5 years). Control groups consisted of 4 patients with X-linked agammaglobulinemia (XLA) and 21 healthy subjects. According to clinical characteristics, the CVID patients were divided into four groups which partly overlap: chronic pulmonary diseases (n = 21), splenomegaly (n = 13), autoimmune diseases (n = 9) and patients with recurrent infections despite regular intravenous immunoglobulin (IVIg) substitution (n = 4). The serum levels of BAFF and IL-10 were measured by commercial ELISA. Results. The BAFF levels were found to be higher in all CVID patients compared to the healthy controls (p < 0.01). The most significant differences were observed in the patients with pulmonary diseases and splenomegaly (p < 0.0001). Also, concentrations of IL-10 were higher in all CVID patients in comparison with the XLA patients (p < 0.05) and healthy subjects (p < 0.01). A statistically significant positive correlation (r = 0.86; p < 0.01) was found between the levels of BAFF and IL-10 in the CVID patients with autoimmune diseases. We demonstrated that the CVID patients with chronic pulmonary diseases had higher levels of IL-10, while the CVID patients with recurrent infections had higher BAFF concentrations in comparison to the patients without these features (p < 0.05). Conclusion. In spite of the limited number of patients, this is the first report from Serbia, examining the serum levels of BAFF and IL-10 in the CVID patients. Our study showed significantly increased concentrations of serum BAFF and IL-10 in the patients with CVID compared to the healthy subjects. Further studies are needed to confirm our findings that the BAFF levels are more pronounced in patients with recurrent infections while IL-10 levels are higher in patients with chronic pulmonary diseases.

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Chronically Activated T-cells Retain Their Inflammatory Properties in Common Variable Immunodeficiency

Journal of Clinical Immunology ◽

10.1007/s10875-021-01084-6 ◽

2021 ◽

Author(s):

Roos-Marijn Berbers ◽

M. Marlot van der Wal ◽

Joris M. van Montfrans ◽

Pauline M. Ellerbroek ◽

Virgil A. S. H. Dalm ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Common Variable Immunodeficiency ◽

Immune Activation ◽

Cell Activation ◽

Immune Dysregulation ◽

Negative Regulators ◽

Migratory Capacity ◽

Common Variable

Abstract Purpose Immune 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). Methods Flow 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. Results Both 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. Conclusion CVIDid 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.

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Circulating bioactive bacterial DNA is associated with immune activation and complications in common variable immunodeficiency

JCI Insight ◽

10.1172/jci.insight.144777 ◽

2021 ◽

Vol 6 (19) ◽

Author(s):

Hsi-en Ho ◽

Lin Radigan ◽

Gerold Bongers ◽

Ahmed El-Shamy ◽

Charlotte Cunningham-Rundles

Keyword(s):

Common Variable Immunodeficiency ◽

Immune Activation ◽

Bacterial Dna ◽

Common Variable

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Features of the cytokine profile in humoral primary immunodeficiency patients

Rossiiskii Allergologicheskii ZHurnal ◽

10.36691/rja476 ◽

2015 ◽

Vol 12 (1) ◽

pp. 34-37

Author(s):

L P Sizyakina ◽

I I Andreeva ◽

E A Antonova

Keyword(s):

Primary Immunodeficiency ◽

Common Variable Immunodeficiency ◽

Serum Levels ◽

Cytokine Profile ◽

Common Variable

The results of cytokines serum levels in patients with infectious and autoimmune phenotypes of X-linked agammaglobulinemia (X-AGG) and common variable immunodeficiency (CVID) are presented. In patients with varying nature of the primary agammaglobulinemia similar cytokine changes were estimated.

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Gut Microbiome and Common Variable Immunodeficiency: Few Certainties and Many Outstanding Questions

Frontiers in Immunology ◽

10.3389/fimmu.2021.712915 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gilda Varricchi ◽

Remo Poto ◽

Gianluca Ianiro ◽

Alessandra Punziano ◽

Gianni Marone ◽

...

Keyword(s):

Gut Microbiota ◽

Common Variable Immunodeficiency ◽

Cell Activation ◽

Immune Cell ◽

Serum Levels ◽

Therapeutic Interventions ◽

Polygenic Inheritance ◽

Alpha And Beta Diversity ◽

Inflammatory Conditions ◽

Common Variable

Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody immunodeficiency, characterized by reduced serum levels of IgG, IgA, and/or IgM. The vast majority of CVID patients have polygenic inheritance. Immune dysfunction in CVID can frequently involve the gastrointestinal tract and lung. Few studies have started to investigate the gut microbiota profile in CVID patients. Overall, the results suggest that in CVID patients there is a reduction of alpha and beta diversity compared to controls. In addition, these patients can exhibit increased plasma levels of lipopolysaccharide (LPS) and markers (sCD14 and sCD25) of systemic immune cell activation. CVID patients with enteropathy exhibit decreased IgA expression in duodenal tissue. Mouse models for CVID unsatisfactorily recapitulate the polygenic causes of human CVID. The molecular pathways by which gut microbiota contribute to systemic inflammation and possibly tumorigenesis in CVID patients remain poorly understood. Several fundamental questions concerning the relationships between gut microbiota and the development of chronic inflammatory conditions, autoimmune disorders or cancer in CVID patients remain unanswered. Moreover, it is unknown whether it is possible to modify the microbiome and the outcome of CVID patients through specific therapeutic interventions.

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