Abstract
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency, characterized by inadequate antibody responses and recurrent bacterial infections. Paradoxically, a majority of CVID patients have non-infectious inflammatory and autoimmune complications, associated with systemic immune activation. Our aim was to explore if HDL, known to have anti-inflammatory properties, had impaired function in CVID patients and thereby contributed to their inflammatory phenotype. We found reduced HDL cholesterol levels in plasma of CVID patients compared to healthy controls, particularly in patients with inflammatory and autoimmune complications, correlating negatively with inflammatory markers CRP and sCD25. Reverse cholesterol transport capacity testing showed reduced serum acceptance capacity for cholesterol in CVID patients with inflammatory and autoimmune complications. They also had reduced cholesterol efflux capacity from macrophages to serum and decreased expression of ATP-binding cassette transporter ABCA1. Human HDL suppressed TLR2-induced TNF release less in blood mononuclear cells from CVID patients, associated with decreased expression of transcriptional factor ATF3. Our data suggest a link between impaired HDL function and systemic inflammation in CVID patients, particularly in those with autoimmune and inflammatory complications. This identifies HDL as a novel therapeutic target in CVID as well as other more common conditions characterized by sterile inflammation or autoimmunity.
Highlights
In view of the wide variety of phenotypes in Common variable immunodeficiency (CVID), it is useful to subdivide the patient group into two main categories: those with infections only and those who display non-infectious complications
Not all sub analyses and in vitro experiments were performed in all patients and so clinical characteristics of the 40 patients making up the smaller cohort, used for high-density lipoprotein (HDL) subclass analyses and Peripheral blood mononuclear cells (PBMC) gene expression studies, and the cohorts used for functional studies are shown in Supplemental Table S2
When dividing the CVID cohort into subgroups by phenotype, we found significantly lower HDL levels in CVID patients with non-infectious complications (n = 76) than in CVID patients with infections only (n = 26) (1.1 [0.9, 1.5] vs 1.4 [1.1, 1.9] respectively, p < 0.01, HDL results given as median [25th, 75th percentile] mmol/L) (Fig. 1)
Summary
In view of the wide variety of phenotypes in CVID, it is useful to subdivide the patient group into two main categories: those with infections only and those who display non-infectious complications. CVID patients with one or more of these non-infectious complications have an 11-fold increase in mortality[7]. We hypothesized HDL levels and functional activity to be altered in CVID, possibly contributing to systemic immune activation and inflammation as well as development of autoimmunity. We explored this hypothesis both by conducting analyses of lipid profiles in a large CVID population and by running experimental studies of HDL function in relation to cholesterol efflux capacity and anti-inflammatory effects in CVID patients and controls. We present novel insights into the role of HDL in systemic inflammation of CVID, findings that can be of relevance to other autoimmune and inflammatory disorders as well
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