Anti-Lipid IgG Antibodies Are Produced via Germinal Centers in a Murine Model Resembling Human Lupus

Abstract

Anti-lipid IgG antibodies are produced in some mycobacterial infections and in certain autoimmune diseases [such as anti-phospholipid syndrome, systemic lupus erythematosus (SLE)]. However, few studies have addressed the B cell responses underlying the production of these immunoglobulins. Anti-lipid IgG antibodies are consistently found in a murine model resembling human lupus induced by chlorpromazine-stabilized non-bilayer phospholipid arrangements (NPA). NPA are transitory lipid associations found in the membranes of most cells; when NPA are stabilized they can become immunogenic and induce specific IgG antibodies, which appear to be involved in the development of the mouse model of lupus. Of note, anti-NPA antibodies are also detected in patients with SLE and leprosy. We used this model of lupus to investigate in vivo the cellular mechanisms that lead to the production of anti-lipid, class-switched IgG antibodies. In this murine lupus model, we found plasma cells (Gr1−, CD19−, CD138+) producing NPA-specific IgGs in the draining lymph nodes, the spleen, and the bone marrow. We also found a significant number of germinal center B cells (IgD−, CD19+, PNA+) specific for NPA in the draining lymph nodes and the spleen, and we identified in situ the presence of NPA in these germinal centers. By contrast, very few NPA-specific, extrafollicular reaction B cells (B220+, Blimp1+) were found. Moreover, when assessing the anti-NPA IgG antibodies produced during the experimental protocol, we found that the affinity of these antibodies progressively increased over time. Altogether, our data indicate that, in this murine model resembling human lupus, B cells produce anti-NPA IgG antibodies mainly via germinal centers.

Dysregulation of miR-155-5p and miR-200-3p and the Anti-Non-Bilayer Phospholipid Arrangement Antibodies Favor the Development of Lupus in Three Novel Murine Lupus Models

“…This work showed, for the first time, promazine as a drug that can elicit a lupus-like disease in mice, as it had also been demonstrated before in humans [ 31 , 32 ]. Promazine-induced lupus-like disease was similar to that disease already described for chlorpromazine and Mn 2+ , because promazine also induces formation of NPA on liposomes like chlorpromazine or Mn 2+ ; in fact, we have demonstrated that these lipid arrangements, NPA, are responsible for inducing the disease [ 4 , 5 , 25 ].…”

“…It is possible that miR-155-5p underexpression leads to AICDA activation in the three murine lupus-like models, mainly due to the known production of specific IgG-class antibodies against NPA in all of these models. Also, it is highly correlated with the higher gene expression related to exogenous antigen presentation and antibody production, as previously found through RNA arrays and confocal microscopy in the murine lupus-like models [ 7 , 25 ].…”

“…Anti-NPA antibodies are strong biomarkers of the murine lupus-like disease resembling human lupus [ 25 ], and their presence alongside anti-cardiolipin, anti-histone, and lupus anti-coagulant antibodies confirmed that this autoimmune disease was developed by promazine-induced NPA.…”

Delivering natural products and biotherapeutics to improve drug efficacy

“…Financially, the global sales revenue for all monoclonal antibody products was nearly US$75 billion in 2013, and expected to reach $125 billion by 2020. This unprecedented attraction to antibodies originates from the remarkable structural flexibility of these proteins to selectively recognize different antigen classes such as proteins, carbohydrates and lipids and challenging haptens like pharmaceutical small molecules, pesticides and even biomarkers that can contribute to the potential detection of life on other planets like Mars [61,62]. Antibodies not only represent potential therapeutics but can be implemented in diverse bespoke applications such as immunodiagnostics, biosensors, photothermal therapies and nanoparticle conjugation for drug delivery.…”

Rational Design of Antigen Incorporation Into Subunit Vaccine Biomaterials Can Enhance Antigen-Specific Immune Responses

“…To increase the immunogenic response to small proteins and peptides, they are often conjugated to or incorporated into other proteins and/or biomaterials (11). Although there are some biomaterials that can encapsulate or adsorb unmodified proteins and peptides (12)(13)(14), they can also induce immune responses to the material itself (15)(16)(17)(18)(19), or induce tolerance to antigens if a delivery material is used multiple times (20). Therefore, it is beneficial for vaccine formulations to minimize delivery of material that is not the target antigen.…”