Abstract
Intravenous immunoglobulin (IVIG) is an effective immunomodulatory treatment for immune dysregulation diseases. However, the mechanisms by which it reduces systemic inflammation are not well understood. NK cell cytotoxicity is decreased by IVIG in women with reduced fertility, but IVIG effects on NK cells in immune dysregulation are less clear. We hypothesized that IVIG modulation of lymphocyte function, especially in NK cells, is important for resolution of inflammation. Our aim was to identify IVIG-induced changes in a cohort of patients with Kawasaki disease (KD) and those that occur broadly in pediatric patients with various immune dysregulatory diseases. Peripheral blood mononuclear cells (PBMCs) of patients with KD or autoimmune/inflammatory diseases were phenotyped pre and post high dose IVIG treatment by flow cytometry. In KD patients, after IVIG infusion Treg cell frequency and the proportion of activated CD25+ immunoregulatory CD56bright NK cells was increased, and multiple lymphocyte subsets showed increased expression of the lymphoid tissue homing receptor CD62L. Importantly, IVIG treatment decreased the frequency of cells expressing the degranulation marker CD107a among cytotoxic CD56dim NK cells, which was reflected in a significant reduction in target cell killing and in decreased production of multiple pro-inflammatory mediators. Interestingly, the activating receptor CD336 was expressed on a higher proportion of CD56bright NK cells after IVIG in both KD and autoimmune/inflammatory patients while other NK receptors were increased differentially in each cohort. In autoimmune/inflammatory patients IVIG induced the proliferation marker CD71 on a higher percentage of CD56dim NK cells, and in contrast to KD patients, CD107a+ cells were increased in this subset. Furthermore, when PBMCs were stimulated ex vivo with IL-2 or Candida antigen in autologous plasma, more of the CD4+ T cells of KD patients expressed CD25 after IVIG therapy but fewer cytotoxic T cells were degranulated based on CD107a expression. In summary, IVIG treatment in patients with immune dysregulation has multiple effects, especially on NK cell subsets and CD4+ T cells, which are compatible with promoting resolution of inflammation. These novel findings provide insight into the immunomodulatory actions of IVIG in autoimmune and inflammatory conditions.
Highlights
Intravenous immunoglobulin (IVIG) is used at low doses as replacement therapy in patients with primary immunodeficiencies, while at high doses it is a potent immunomodulator to reduce morbidity in hyperinflammatory conditions such as Kawasaki disease (KD) and in autoimmune diseases such as immune thrombocytopenia [reviewed in [1]]
To investigate the effects of IVIG on the phenotype and function of natural killer (NK) cells and T cells, Peripheral blood mononuclear cells (PBMCs) isolated pre- and 24-48 hours post-IVIG infusion from patients with KD or autoimmune/ inflammatory diseases were characterized by multiparameter flow cytometry
In KD patients, the frequency of regulatory T cell (Treg) cells was significantly increased in the post-IVIG blood samples (Figure 1A), and IVIG treatment enhanced the activation status of both CD56bright NK cells and CD56+ T cells based on the proportion of CD25+ cells (Figure 1B)
Summary
Intravenous immunoglobulin (IVIG) is used at low doses as replacement therapy in patients with primary immunodeficiencies, while at high doses it is a potent immunomodulator to reduce morbidity in hyperinflammatory conditions such as Kawasaki disease (KD) and in autoimmune diseases such as immune thrombocytopenia [reviewed in [1]]. The mechanism(s) by which IVIG induces its immunomodulatory effects are not completely understood. Many studies have attempted to elucidate the effects of IVIG on inflammatory processes, and possible mechanisms include saturation/modulation of Fcg receptors, inhibition of cytokines, modulation of endothelium phenotype, neutralization of superantigen and/or bacterial components, anti-idiotype inhibition of auto-antibodies, modulation of B cell and natural killer (NK) cell activity, inhibition of the complement cascade, and enhancement of regulatory T (Treg) cell function [reviewed in [5, 6]]. CD56brightCD16− NK cells compose ~10% of peripheral NK cells and are thought to have an immunoregulatory role based on their ability to secrete cytokines, migrate to lymph nodes and tissues, and expand in pregnancy where they mediate immune tolerance [reviewed in [7]]. The major peripheral subset CD56dimCD16+ NK cells are well granulated and are cytotoxic, readily recognizing and killing infected and transformed cells
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