Disturbed lipid profile in common variable immunodeficiency – a pathogenic loop of inflammation and metabolic disturbances

Abstract

The relationship between metabolic and inflammatory pathways play a pathogenic role in various cardiometabolic disorders and is potentially also involved in the pathogenesis of other disorders such as cancer, autoimmunity and infectious diseases. Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults, characterized by increased frequency of airway infections with capsulated bacteria. In addition, a large proportion of CVID patients have autoimmune and inflammatory complications associated with systemic inflammation. We summarize the evidence that support a role of a bidirectional pathogenic interaction between inflammation and metabolic disturbances in CVID. This include low levels and function of high-density lipoprotein (HDL), high levels of triglycerides (TG) and its major lipoprotein very low-density lipoprotein (VLDL), and an unfavorable fatty acid (FA) profile. The dysregulation of TG, VLDL and FA were linked to disturbed gut microbiota profile, and TG and VLDL levels were strongly associated with lipopolysaccharides (LPS), a marker of gut leakage in blood. Of note, the disturbed lipid profile in CVID did not include total cholesterol levels or high low-density lipoprotein levels. Furthermore, increased VLDL and TG levels in blood were not associated with diet, high body mass index and liver steatosis, suggesting a different phenotype than in patients with traditional cardiovascular risk such as metabolic syndrome. We hypothesize that these metabolic disturbances are linked to inflammation in a bidirectional manner with disturbed gut microbiota as a potential contributing factor.

Probiotic Limosilactobacillus reuteri DSM 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia and Chronic Hepatitis in Mice

“…We have previously demonstrated significant increases in plasma Th1- and Th2-associated cytokines in SF mice, levels of which were reduced through intragastric administration of DSM 17938 [ 18 ]. Certain lipids have been identified as potential contributors to systemic inflammation in primary autoimmune diseases [ 29 ]. To understand which lipid metabolites were associated with Th1- and Th2-associated inflammation, we conducted a correlation analysis between upregulated lipid metabolites and plasma IFN-γ and IL-4.…”

“…The development of autoimmune disorders is influenced by metabolic disturbances, particularly those related to lipid metabolism. These abnormalities of lipid metabolism are notable in both polygenic autoimmune disorders such as T1DM [ 28 ] and in monogenic primary autoimmune diseases such as common variable immunodeficiency (CVID) [ 29 ]. Lipids are known to play crucial roles in inflammatory processes [ 30 , 31 ].…”

Studying the cellular basis of small bowel enteropathy using high-parameter flow cytometry in mouse models of primary antibody deficiency

“…Disruption to normal lipid metabolism/absorption by gut ISCs could explain this effect. CVID patients have known defects in lipid homeostasis (recently reviewed in ( 46 )), and in two specific studies of CVID patients (that also included the use of antibody-deficient mouse models), bulk RNA sequencing of small intestinal tissues revealed a signature of lipid malabsorption uniquely associated with CVID patients presenting with small bowel enteropathy ( 14 , 15 ). Similar effects were observed in antibody-deficient mouse strains used in these studies.…”

Common variable immunodeficiency—an independent risk factor for atherosclerotic cardiovascular diseases

“…Indeed, CVID patients have higher levels of inflammatory markers such as C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α) and their high-density lipoprotein cholesterol and apoprotein A-I levels are lower than in controls (8). The lipid profile of CVID patients has been proven to be disturbed with low levels and function of high-density lipoprotein (HDL), high levels of triglycerides and very low-density lipoprotein (VLDL) and an unfavorable fatty acid profile (9).…”