Autoantibody Responses to Apolipoprotein A-I Are Not Diet- or Sex-Linked in C57BL/6 Mice

Abstract

Atherosclerosis is responsible for a large percentage of all-cause mortality worldwide, but it is only now beginning to be understood as a complex disease process involving metabolic insult, chronic inflammation, and multiple immune mechanisms. Abs targeting apolipoprotein A-I (ApoA-I) have been found in patients with cardiovascular disease, autoimmune conditions, as well as those with no documented history of either. However, relatively little is known about how these Abs are generated and their relationship to diet and sex. In the current study, we modeled this aspect of autoimmunity using anti-ApoA-I immunization of male and female C57BL/6 mice. Unexpectedly, we found that autoantibodies directed against a single, previously unknown, epitope within the ApoA-I protein developed irrespective of immunization status or dyslipidemia in mice. When total IgG subclasses were analyzed over the course of time, we observed that rather than driving an increase in inflammatory IgG subclasses, consumption of Western diet suppressed agedependent increases in IgG2b and IgG2c in male mice only. The lack of change observed in female mice suggested that diet and sex might play a combined role in Th1/Th2 balance and, ultimately, in immunity to pathogen challenge. This report demonstrates the need for inclusion of both sexes in studies pertaining to diet and aging and suggests that further study of immunogenic epitopes present in ApoA-I is warranted. ImmunoHorizons, 2020, 4: 455-463.

Cyanuric chloride as the basis for compositionally diverse lipids

“…The utility of the divergent route was then explored further by reacting the C18 dichloro-triazine compound (intermediate D) with the N-terminal amine of a protected peptide on rink amide resin, to provide an alternative synthetic route to present lipid-anchored peptides in a liposomal bilayer for vaccination. Using the 44 amino acid sequence from apolipoprotein A-I (ApoA-I) that our group has previously investigated, 22 we achieved 95% lipopeptide purity which is improved as compared to previously described lipopeptide synthetic strategies using cholesteryl hemisuccinate and other lipid anchors. 23 In addition to the improved overall yield, the ease of lipopeptide synthesis using intermediate D provides a convenient platform for continued vaccination studies with minimal downstream purification, as evidenced by the HPLC trace of the lipopeptide (Fig.…”

“…To achieve this we use a lipid anchored 44 amino acid peptide derived from ApoA-I for liposomal immunizations. 22 To determine whether TZ lipids could be used in this setting, formulations were prepared with the respective lipopeptides along with the adjuvant monophosphoryl lipid A (MPLA), which is a toll-like receptor (TLR)-4 agonist. Peptides are formulated in the liposomes (20 mM) at a concentration of 1 mg mL −1 which equates to about 1000 peptides per liposome.…”

Antigen-specific age-related memory CD8 T cells induce and track Alzheimer’s-like neurodegeneration

“…S1A). Females were exclusively used to avoid male-specific autoimmune disease dynamics, some of which are associated with CD8 T cell homeostatic expansion, in related mouse strains (20, 21). Injection results in rapid homeostatic expansion of the donor cells in the circulation, similar to the gradual homeostatic expansion of CD8 T cells that occurs with aging in humans.…”

“…Similarly, the absence of ghost tangles is very likely due to the virtual absence of the ghost tangle-promoting isoforms of MAPT, the gene encoding tau proteins, in adult mice (53) . In addition, the hi T model was analyzed exclusively in female mice due to concerns over male-specific autoimmune dynamics in related strains (20, 21), making it imperative to test its relevance to human males and females with AD.…”

Immune mechanisms associated with cardiovascular disease in systemic lupus erythematosus: A path to potential biomarkers

“…The protective effect of HDL depends largely on the content of apoA-I that mediates the union with macrophages. ApoA-I can become immunogenic, inducing antibodies that modify myeloperoxidase in neutrophils, leading to a destabilization of atheromatous plaques ( 99 ). These antibodies would be generated due to the protein misfolding stimulated by the oxidative microenvironment.…”