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.

Keywords: CVID - common variable immunodeficiency; HDL - cholesterol; antibody deficiencies; fatty acids; inflammation; metabolism; triglycerid.

Figure 1

Simplified schematic illustration of cholesterol and fatty acid metabolism. 1. Intestinal absorption of dietary lipids. Cholesteryl esters, free fatty acids (FA) and triglycerides (TG) from the diet are absorbed in the intestinal lumen. In the enterocytes, chylomicrons are formed, which enters the circulation via the lymphatic system. In addition, ApoA1, the major protein component of HDL, is endogenous synthetized in enterocytes (and liver). 2. Chylomicrons deliver lipids to peripheral organs. Within the Chylomicrons, TGs are hydrolyzed by lipoprotein lipase (LPL) in peripheral organs, releasing FAs for storage. 3. The assembly of VLDL in the liver. The chylomicron remnants containing cholesterol are taken up by the liver. The liver delivers both endogenously synthesized and exogenously acquired FAs. FAs are re-esterified to form triglyceride and together with cholesterol form VLDL. VLDL enters the bloodstream as triglyceride rich lipoprotein VLDL. The liver also eliminate cholesterol via bile/intestine. 4. VLDLs transport triglycerides to peripheral tissues. Via the blood stream, VLDL can transport TGs to peripheral cells e.g. adipose tissue and muscle, where it is hydrolyzed by LPL to FAs for energy production or storage. VLDL can also generate circulating LDL which can either return to the liver or it can be oxidized and taken up by macrophages in peripheral organs. Macrophages loaded with excess cholesterol become foam cells. 5. Cholesterol is recycled or eliminated through reverse cholesterol transport. HDL cholesterol is transported from peripheral cells/tissues back to the liver and intestine, where cholesterol is recycled or eliminated. HDL cholesterol can reach the liver either directly through binding to SR-B1, or indirectly after a lipid exchange with VLDL/LDL, which are cleared by hepatic LDL receptor. Red arrows indicate exogenous pathways, black arrows indicate endogenous pathways and blue arrows indicate reverse cholesterol transport. ApoA-I, apolipoprotein A-I; FA, fatty acid; HDL, high-density lipoprotein, LDLr, low-density lipoprotein receptor; LPL, lipoprotein lipase; oxLDL, oxidized low-density lipoprotein; SR, scavenger receptor; TG, triglycerides; VLDL, very low-density lipoprotein. Created with BioRender.com.

Figure 2

Decreased HDL levels and function in CVID may facilitate inflammatory responses in macrophages. Panel (A) HDL exert anti-inflammatory effects in macrophages by the induction of ATF3. CVID patients with systemic inflammation autoimmunity and inflammation have impaired HDL levels and function along with decreased AFT3 expression resulting in enhanced TLR2/4 signaling and increased production of inflammatory cytokines. Panel (B) CVID patients with autoimmunity and systemic inflammation had impaired cholesterol efflux capacity along with decreased expression of ABCA1 (PBMC) an ApoA-1 (serum), suggesting impaired RCT. This may result in (i) less inhibition of TLR4 and type I IFN signaling caused by attenuated RCT, (ii) less inhibition of TLR4 mediated release of inflammatory cytokines caused by down-regulation of ApoA-I and ABCA1. ABCA1, ATP-binding cassette transporter A1; ApoA-I, apolipoprotein A1; PBMC, peripheral blood mononuclear cells; RCT, reverse cholesterol transport; TLR, toll-like receptor. Created with BioRender.com.

Figure 3

Theoretical figure showing how reduced HDL levels/function may explain reduce number/function of regulatory T cells (Treg) in CVID. In contrast to LDL, HDL is taken up in Tregs through the scavenger receptor SR-BI/BII, increasing the survival of this important T cell subset. Treg may attenuate dendritic cell response as well as proliferation of effector T cells to ensure a balanced immune response. This regulatory function of Tregs may be weakened in a situation with impaired HDL levels and function, as in CVID. We hypothesized that reduced HDL levels and function are associated with reduced Treg in CVID, which in turn decrease suppression of co-stimulatory molecules and increase effector T cell proliferation as well as inflammatory cytokines. Created with BioRender.com.

Figure 4

A bidirectional interaction between inflammation and triglycerides and very low-density lipoprotein. The left part of the Figure illustrates the complex effect of TG/VLDL on inflammation, inducing upregulation of TLR2/TLR4 in macrophages as well as promoting enhanced production of reactive oxygen species, activation of NFkB signaling pathways and activation of NLRP inflammasomes in both endothelial (NLRP1) and macrophages (NLRP3). The latter involves ApoC-III related mechanisms. The activation of endothelial cells facilitates leukocyte migration into inflamed tissue. The right part of the Figure illustrates that inflammation increases TG/VLDL levels by downregulating levels and attenuating the lipolytic activity of the enzymes, hepatic and lipoprotein lipase. Apoliprotein C-III, a major component of VLDL, could also attenuate the lipolytic activity of lipoprotein lipase. ApoC-III, apolipoprotein C-III; HL, hepatic lipase; LPL, lipoprotein lipase; ROS, reactive oxygen species, TG, triglycerides; VLDL, very low-density lipoprotein. Created with BioRender.com.

Figure 5

Comparing the metabolic phenotype of CVID patients to patients with classical metabolic syndrome. Differences are highlighted in blue and similarities in black. NRH, nodular regenerative hyperplasia. Created with BioRender.com.

Figure 6

A pathogenic loop between persistent low-grade systemic inflammation, metabolic disturbances and gut microbiota in CVID. We hypothesize that in CVID patients with autoimmunity and inflammatory complications there is a pathogenic loop between persistent low-grade systemic inflammation and metabolic disturbances with altered gut microbiota as a contributing factor.