Cytokines in Common Variable Immunodeficiency as Signs of Immune Dysregulation and Potential Therapeutic Targets – A Review of the Current Knowledge

Abstract

Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins and compromised specific antibody response leading to frequent infections. Cytokines play an important role in the orchestration of the antibody response. Several previous studies have attempted to identify distinct cytokines responsible for the inflammatory changes and different manifestations of CVID, but there are conflicting results regarding the cytokine profiles in CVID patients. In light of this, an extensive review regarding the level of various cytokines and their potential therapeutic role in CVID patients was performed. This review delineates the contribution of interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-21, interferons, tumor necrosis factor (TNF)-α, IL-17, APRIL (a proliferation inducing ligand) and BAFF (B cell activating factor) in CVID disease and outline their potential therapeutic implications in these patients.

T-Cell Abnormalities in Common Variable Immunodeficiency

“…CVID patients with hepatomegaly had higher IL-2 and IFN-γ levels in stimulated CD4 + T cells, and patients with granuloma were found to have higher CCR5 expression in CD4 + T cells, suggesting that T H 1 cells may play a role in granuloma formation in CVID patients [14]. Overall, increased production of some chemokines [56] and cytokines, including IFN-γ [57], TNF-α [12], IL-12 [57], IL-9 [49], IL-4, and IL-10 [58] by T H subsets has been reported in CVID patients [59]. Some of these cytokines play a pivotal role in antibody synthesis.…”

Autoimmunity in Primary Antibody Deficiencies

“…The cellular alterations in CVID comprise a spectrum of B- and T-cell abnormalities, including defects in B-cell differentiation into plasma cell and memory B cells, defects in Treg and Breg cells, accelerated T-cell apoptosis, and abnormality in cytokine production secondary to gene polymorphisms [6,65,66,67,68]. The influence of these defects on the interaction between T and B cells not only could explain the immunodeficiency, but also the development of autoimmunity in CVID patients [6].…”

Regulatory B cells in CVID patients fail to suppress multifunctional IFN-γ+TNF-α+CD4+ T cells differentiation

“…The increase in activation of CD4 + T cells is also reflected by the increase in production of interferon (IFN)-γ by CD4 + T cells in CVID patients upon CD3 or PMA/PMH stimulation after 24 h and upon phorbol myristate acetate (PMA)/Ionomycine stimulation after 12 h [11,12]. Increased levels of (tumor necrosing factor) TNF-α and also IFN-γ after stimulation of T-cells were reported in several studies in CVID patients [13]. IFN-γ and TNF-α are both considered crucial Th1 cytokines (10).…”