Plasma Levels of mir-34a-5p Correlate with Systemic Inflammation and Low Naïve CD4 T Cells in Common Variable Immunodeficiency.

PURPOSE: Common variable immunodeficiency (CVID) is a primary antibody deficiency that commonly manifests as recurrent infections. Many CVID patients also suffer from immune dysregulation, an inflammatory condition characterized by polyclonal lymphocytic tissue infiltration and associated with increased morbidity and mortality. The genetic cause is unknown in most CVID patients and epigenetic alterations may contribute to the broad range of clinical manifestations. MicroRNAs are small non-coding RNAs that are involved in epigenetic modulation and may contribute to the clinical phenotype in CVID. METHODS: Here, we determined the circulating microRNAome and plasma inflammatory proteins of a cohort of CVID patients with various levels of immune dysregulation and compared them to healthy controls. A set of deregulated microRNAs was validated by qPCR and correlated to inflammatory proteins and clinical findings. RESULTS: Levels of microRNA-34a correlated with 11 proteins such as CXCL9, TNF, and IL10, which were predicted to be biologically connected. Moreover, there was a negative correlation between mir-34 levels and the number of naïve CD4 T cells in CVID. CONCLUSION: Collectively, our data show that microRNAs correlate with the inflammatory response in CVID. Further investigations are needed to elucidate the role of miRNAs in the development of CVID-related immune dysregulation.

In-depth immune profiling reveals advanced B- and T-cell differentiation to be associated with Th1-driven immune dysregulation in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by low levels of antibodies. In addition to infections, many patients also suffer from T-helper 1-driven immune dysregulation, which is associated with increased mortality. The aim of this study was to perform in-depth characterization of the T and the B cell compartments in a well-defined cohort of patients affected by CVID and correlate the findings to the level of clinical immune dysregulation. We used mass cytometry, targeted proteomics, flow cytometry and functional assays to delineate the immunological phenotype of 15 CVID-affected patients with different levels of immune dysregulation. Unbiased clustering of T cell mass cytometry data correlated with CVID-related immune dysregulation and plasma protein profiles. Expanded CXCR3+ T-bet-expressing B cells correlated with effector memory CD4+ T cell clusters, and increased plasma levels of CXCR3-ligands. Our findings indicate an interplay between B cells and T cells in CVID-related immune dysregulation and provide a better understanding of the underlying pathological mechanisms.

Plasma protein profiling reflects TH1-driven immune dysregulation in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is a disorder characterized by antibody deficiency. A significant fraction of the patients suffer from immune dysregulation, which leads to increased morbidity and mortality. The pathogenesis of this condition is poorly understood. OBJECTIVE: Our aim was to find out whether the plasma protein signature in CVID is associated with clinical characteristics and lymphocyte aberrations. METHODS: A highly sensitive proximity extension assay was used for targeted profiling of 145 plasma proteins in 29 patients with CVID. Phenotyping of peripheral lymphocytes was done by flow cytometry. The findings were correlated with the burden of immune dysregulation. RESULTS: Unsupervised clustering of plasma protein profiles identified 2 distinct groups of patients with CVID that differed significantly in terms of the degree of complications due to immune dysregulation and in terms of the frequency of activated B- and T-cell subpopulations. Pathway analysis identified IFN-γ and IL-1ß as the top enriched upstream regulators associated with higher grade of immune dysregulation. In addition, CVID was found to be associated with increased plasma levels of the B-cell-attracting chemokine CXCL13. CONCLUSION: Clustering based on plasma protein profiles delineated a subgroup of patients with CVID with activated T cells and clinical complications due to immune dysregulation. Thus, data indicate that CVID-associated immune dysregulation is a TH1-mediated inflammatory process driven by the IFN-γ pathway.

Inorganic carbonate composites as potential high temperature CO2 sorbents with enhanced cycle stability.

A calcium magnesium carbonate composite (CMC) material containing highly porous amorphous calcium carbonate (HPACC) and mesoporous magnesium carbonate (MMC) was synthesized. CMCs with varying HPACC : MMC mol ratios and high BET surface area (over 490 m2 g-1) were produced. The CMCs retained the morphology shared by HPACC and MMC. All these materials were built up of aggregated nanometer-sized particles. We tested the CO2 uptake properties of the synthesized materials. The CMCs were calcined at 850 °C to obtain the corresponding calcium magnesium oxide composites (CMOs) that contained CaO : MgO at different mol ratios. CMO with CaO : MgO = 3 : 1 (CMO-3) showed comparable CO2 uptake at 650 °C (0.586 g g-1) to CaO sorbents obtained from pure HPACC (0.658 g g-1) and the commercial CaCO3 (0.562 g g-1). Over 23 adsorption-desorption cycles CMOs also showed a lower CO2 uptake capacity loss (35.7%) than CaO from HPACC (51.3%) and commercial CaCO3 (79.7%). Al was introduced to CMO by the addition of Al(NO3)3 in the synthesis of CMC-3 to give ACMO after calcination. The presence of ∼19 mol% of Al(NO3)3 in ACMO-4 significantly enhanced its stability over 23 cycles (capacity loss of 5.2%) when compared with CMO-3 (calcined CMC-3) without adversely affecting the CO2 uptake. After 100 cycles, ACMO-4 still had a CO2 uptake of 0.219 g g-1. Scanning electron microscope images clearly showed that the presence of Mg and Al in CMO hindered the sintering of CaCO3 at high temperatures and therefore, enhanced the cycle stability of the CMO sorbents. We tested the CO2 uptake properties of CMO and ACMO only under ideal laboratory testing environment, but our results indicated that these materials can be further optimized as good CO2 sorbents for various applications.