High Dose Intravenous IgG Therapy Modulates Multiple NK Cell and T Cell Functions in Patients With Immune Dysregulation

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.

Human Transcriptome Array Analysis Identifies CDR2 as a Novel Suppressed Gene for Kawasaki Disease

“…Balamurugan et al indicated that the overexpression of the CDR2 gene plays an important role in repressing HIF-1 transactivation activity by interfering with p300 recruitment in their study on solid tumors [ 35 ]. Buenafe et al also showed that T-cell receptor CDR2 peptide immunotherapy was effective in regulating pathogenic T-cells via the activity of the Foxp3(+) regulatory T-cells [ 33 ], which is consistent with our previous findings that IVIG therapy for KD results in increased expression of Treg-related FoxP3 [ 17 ]. Herein, we showed that the suppression of the CDR2 gene of leukocytes and its increase after IVIG administration may play a role in the pathogenesis of KD.…”

“…Growing evidence has revealed several possible mechanisms by which IVIG might induce such a rapid resolution of inflammation in KD [ 16 ]. Antibodies in IVIG may neutralize the antigen or immune complex that modulates multiple NK cell and T-cell functions of KD [ 17 ] and affects Treg activation via the secretion of such anti-inflammatory cytokines as Treg-related IL-10 and FoxP3 [ 15 , 16 , 17 ]. Genome-wide association studies have revealed a functional single nucleotide polymorphism (SNP) in the ITPKC gene, encoding inositol 1,4,5-trisphosphate 3-kinase C, whose role is to negatively regulate T-cell activation through the calcium signaling pathway, which is associated with susceptibility to KD [ 18 , 19 ] and coronary artery aneurysms [ 20 ].…”

Case Report: Susceptibility to viral infections and secondary hemophagocytic lymphohistiocytosis responsive to intravenous immunoglobulin as primary manifestations of adenosine deaminase 2 deficiency

“…The immunomodulatory action of IVIG, able to reduce the level of pro-inflammatory cytokines (such as TNFa) (27) and to inhibit the endothelial activation (28), can partially explain the role of this treatment in the prevention of the inflammatory and vascular manifestation of the disease. Interestingly, another role that IVIG might have played in this patient is shown by the induction of multiple phenotypic and functional changes in NK cells, mainly promoting resolution of inflammation (29).…”

Systems biology and artificial intelligence analysis highlights the pleiotropic effect of IVIg therapy in autoimmune diseases with a predominant role on B cells and complement system

“…Overall, the presence of Tregitopes might in part explain the success of IVIg therapy in treating autoimmune diseases (122,126). IVIg treatment has been reported to affect natural killer cells and subsequently regulate Treg function in KD patients (127). IVIg has been shown to affect T cells chemokine production, as observed by Pigard and colleagues, thus affecting their function and compartmentalization (128).…”