IVIg Immune Reconstitution Treatment Alleviates the State of Persistent Immune Activation and Suppressed CD4 T Cell Counts in CVID

Abstract

Common variable immunodeficiency (CVID) is characterized by defective B cell function, impaired antibody production, and increased susceptibility to bacterial infections. Here, we addressed the hypothesis that poor antibody-mediated immune control of infections may result in substantial perturbations in the T cell compartment. Newly diagnosed CVID patients were sampled before, and 6–12 months after, initiation of intravenous immunoglobulin (IVIg) therapy. Treatment-naïve CVID patients displayed suppressed CD4 T cell counts and myeloid dendritic cell (mDC) levels, as well as high levels of immune activation in CD8 T cells, CD4 T cells, and invariant natural killer T (iNKT) cells. Expression of co-stimulatory receptors CD80 and CD83 was elevated in mDCs and correlated with T cell activation. Levels of both FoxP3+ T regulatory (Treg) cells and iNKT cells were low, whereas soluble CD14 (sCD14), indicative of monocyte activation, was elevated. Importantly, immune reconstitution treatment with IVIg partially restored the CD4 T cell and mDC compartments. Treatment furthermore reduced the levels of CD8 T cell activation and mDC activation, whereas levels of Treg cells and iNKT cells remained low. Thus, primary deficiency in humoral immunity with impaired control of microbial infections is associated with significant pathological changes in cell-mediated immunity. Furthermore, therapeutic enhancement of humoral immunity with IVIg infusions alleviates several of these defects, indicating a relationship between poor antibody-mediated immune control of infections and the occurrence of abnormalities in the T cell and mDC compartments. These findings help our understanding of the immunopathogenesis of primary immunodeficiency, as well as acquired immunodeficiency caused by HIV-1 infection.

T-Cell Abnormalities in Common Variable Immunodeficiency

“…On the other hand, the frequency of iNKT cells as another subset of T cells with suppressor function is not restored, and HLA-DR remains elevated following IVIG therapy. However, expression of PD-1 and CD161 is reduced when CVID patients receive treatment with IVIG [94]. These data indicate that IVIG can attenuate iNKT cell activation and exhaustion in CVID patients.…”

“…This elevation seems to be transient, because no sustained effect of IVIG on Treg cell counts was observed between samples obtained at baseline and up to 1 year after the infusion [94]. On the other hand, the frequency of iNKT cells as another subset of T cells with suppressor function is not restored, and HLA-DR remains elevated following IVIG therapy.…”

“…IVIG resulted in elevation of CD4 + T-cell percentages [92], correction of the inverted CD4/CD8 ratio, and improvement in T-cell function [93]. Paquin-Proulx et al [94] showed that immunotherapy with IVIG in CVID patients alleviates the state of persistent immune activation and suppressed CD4…”

“…+ T-cell counts [94]. CD4 + T cells in CVID patients have elevated levels of Ki67, CD38, and HLA-DR as the activation markers and of PD-1 and CTLA-4 as exhaustion markers.…”

“…CD4 + T cells in CVID patients have elevated levels of Ki67, CD38, and HLA-DR as the activation markers and of PD-1 and CTLA-4 as exhaustion markers. Expression levels of activation and exhaustion markers remained elevated for up to 1 year in patients receiving IVIG [94]. Paradoxically, one study showed that treatment with IVIG could reduce expression of [37].…”