Antibodies to non‐bilayer phospholipid arrangements induce a murine autoimmune disease resembling human lupus

Abstract

Antibodies recognizing non-bilayer phospholipid arrangements (NPA) in membrane models and in cell membranes in vivo, triggered an autoimmune-like disease in mice. This exhibited features similar to human lupus and was induced by injecting mice either with the H308 monoclonal antibody specific to NPA, with sera from mice which already had developed the autoimmune disease, or with liposomes treated with the NPA inductors chlorpromazine or procainamide; or with these NPA inductors alone. All these procedures revealed the involvement of antibodies to non-bilayer phospholipids in inducing this autoimmune-like disease. Unraveling the mechanisms of these antibodies might contribute to a better understanding of the molecular and immunological basis of autoimmune diseases like lupus and, hopefully, towards the development of better therapeutic strategies.

Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus

“…The detection of nonbilayer phospholipid arrangements by flow cytometry was previously validated by freeze-fracture electron microscopy and 31 P-NMR spectroscopy [ 10 , 14 , 15 ]. Therefore, in this study we only used flow cytometry to demonstrate the formation of these arrangements on liposomes.…”

“…The most commonly used lupus-prone mice are the F 1 hybrids of New Zealand black (NZB) and NZ white (NZB/NZW F 1 ) mice, the Murphy-Roths large/lymphoproliferative locus (MLR/lpr) mice, and the recombinant C57BL/6 female and SB/Le male strain/Y-linked autoimmune accelerator (BXSB/Yaa) mice [ 3 , 8 , 9 ]. Our group has also developed a mouse model of autoimmune disease resembling human lupus that can be induced in normal mice [ 10 ]. In this model, the disease is triggered by liposomes with nonbilayer phospholipid arrangements.…”

“…Liposomes are model membranes made of cylindrical phospholipids, such as phosphatidylcholine, and H II -preferring (conical shaped) phospholipids, such as phosphatidic acid, phosphatidylserine, or cardiolipin [ 11 ]. Conical phospholipids can form molecular associations distinct to lipid bilayers, known as nonbilayer phospholipid arrangements, in the presence of inducers such as Mn 2+ [ 12 , 13 ] or the drugs chlorpromazine and procainamide, which can trigger DILE in humans [ 10 ]. Nonbilayer phospholipid arrangements are formed by an inverted micelle (made of conical phospholipids with their polar heads towards the center of the micelle, where the inducer is also located) inserted into and distorting the shape of the phospholipid bilayer ( Figure 1(a) ).…”

“…We demonstrated that liposomes with nonbilayer phospholipid arrangements induced by Mn 2+ , chlorpromazine, or procainamide cause an autoimmune disease resembling human lupus in mice. A similar disease is produced by treating mice directly with Mn 2+ , chlorpromazine, or procainamide (which induce nonbilayer phospholipid arrangements on mouse cells) or by injecting the monoclonal antibody H308 (which binds specifically to nonbilayer phospholipid arrangements and stabilizes these arrangements on mouse cells) [ 10 , 14 ].…”

“…IgM and IgG antibodies against nonbilayer phospholipid arrangements are found in the sera of mice with the autoimmune disease resembling human lupus, and also in the sera of patients with lupus [ 10 , 15 ]. Usually, the efficient production of IgG antibodies requires an activation of the innate immune response.…”