Neutrophil and Granulocytic Myeloid-Derived Suppressor Cell–Mediated T Cell Suppression Significantly Contributes to Immune Dysregulation in Common Variable Immunodeficiency Disorders

Abstract

Common variable immunodeficiency disorders (CVID) represent a group of primary immunodeficiency diseases characterized by hypogammaglobulinemia and impaired specific Ab response, resulting in recurrent infections due to dysfunctional immune response. The specific mechanisms mediating immune deficiency in CVID remain to be determined. Previous studies indicated that immune dysregulation in CVID patients is associated with chronic microbial translocation, systemic immune activation, and altered homeostasis of lymphocytic and myeloid lineages. A detailed phenotypic, functional characterization of plasma markers and immune cell populations was performed in 46 CVID patients and 44 healthy donors. CVID patients displayed significantly elevated plasma levels of a marker of neutrophil activation neutrophil gelatinase-associated lipocalin. Neutrophils from CVID patients exhibited elevated surface levels of CD11b and PD-L1 and decreased levels of CD62L, CD16, and CD80, consistent with a phenotype of activated neutrophils with suppressive properties. Neutrophils from CVID patients actively suppressed T cell activation and release of IFN-g via the production of reactive oxygen species. Furthermore, CVID was associated with an increased frequency of low-density neutrophils (LDNs)/granulocytic myeloid-derived suppressor cells. LDN/granulocytic myeloid-derived suppressor cell frequency in CVID patients correlated with reduced T cell responsiveness. Exogenous stimulation of whole blood with bacterial LPS emulated some but not all of the phenotypic changes observed on neutrophils from CVID patients and induced neutrophil population with LDN phenotype. The presented data demonstrate that neutrophils in the blood of CVID patients acquire an activated phenotype and exert potent T cell suppressive activity. Specific targeting of myeloid cellderived suppressor activity represents a novel potential therapeutic strategy for CVID.

Bronchiectasis in common variable immunodeficiency: A systematic review and meta‐analysis

“…2 However, the specific mechanisms mediating immunodeficiency in CVID remain to be unclear. 1,3 In addition to defects in B cell, defects in other components of the immune system are reported in almost onethird of patients with CVID. 4,5 Clinical phenotypes are varying: most of the patients have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias, enteropathy, and/or malignancies.…”

“…Patients with CVID have a marked reduction in serum levels of immunoglobulin G (IgG) with IgA, and/or IgM, and impaired antibody response to vaccine due to impaired B cell differentiation to memory B cell and plasma cell . However, the specific mechanisms mediating immunodeficiency in CVID remain to be unclear . In addition to defects in B cell, defects in other components of the immune system are reported in almost one‐third of patients with CVID .…”

Animal-Free Human Whole Blood Sepsis Model to Study Changes in Innate Immunity

“…The sampling strategy consisted of an initial experiment series with n = 3 for all time points (0 − , 10 min, 60 min, 180 min, 60 min with LPS, 180 min with LPS) focusing on blood gas analysis, whole blood count, and humoral inflammation. Because blood glucose, pH, and lactate level became unphysiological beyond 1 h and previous literature indicated that the neutrophil phenotype as measured by CD11b/CD62l expression reached its final alteration after exposure to LPS for 1 h ( 30 ), cellular immunity was analyzed for this time point from at least five independent specimen. Data analysis was performed with licensed versions of Microsoft Excel 2019 (Microsoft, Redmond, Washington, USA) and GraphPad Prism 8 (GraphPad Software Inc, San Diego, California, USA).…”

Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders

“…Finally, some of the histopathological changes associated with NRH in CVID patients, as T-lymphocyte infiltrates and/or granulomata, may represent a response to microbial translocation. Microbial translocation is the transfer of commensal microbial products from the intestinal lumen into systemic circulation in the absence of overt bacteremia (55). Although the extent of potential damage to intestinal epithelial barrier in CVID is currently unknown, CVID patients may have increased intestinal permeability resulting from the typical CVID-related enteropathy (28).…”