Phospholipid Membranes Form Specific Nonbilayer Molecular Arrangements That Are Antigenic

Abstract

Hexagonal phase (H II )-preferring lipids such as phosphatidate, cardiolipin, and phosphatidylserine form nonbilayer molecular arrangements in lipid bilayers. While their presence in biological membranes has not been established, in vitro studies suggest that alterations in membrane properties modify their function. In this study, antiphospholipid monoclonal antibodies were developed against nonbilayer structures. One of the monoclonal antibodies identifies nonplanar surfaces in liposomes and in membranes of cultured cells. These results are the first evidence that natural membranes maintain a fragile balance between bilayer and nonbilayer lipid arrangements. Therefore, these antibodies can be used to evaluate the role of H II -preferring lipids in the modulation of membrane activities. Our studies demonstrated that nonplanar surfaces are highly immunogenic. Although these structures are normally transient, their formation can be stabilized by temperature variations, drugs, antibiotics, apolar peptides, and divalent cations. Our studies demonstrated that abnormal exposure of nonbilayer arrangements may induce autoimmune responses as found in the antiphospholipid syndrome.

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

“…We have shown that these lipid structures are highly immunogenic since both poly-and monoclonal antibodies against them are easily attained [3,4]. These antibodies identify lipids associated in NPA both in liposomes and in cell membranes, confirming the presence of NPA in intact mammalian cells.…”

“…Rauch et al [13] demonstrated that human hybridomas and lupus anticoagulant antibodies from SLE patients recognize tubular H H H associations but not bilayer arrangements of PE. Since it is difficult to relate cell membrane activities to extensive areas of H H H lipid tubular associations, we have shown that NPA in the bilayer matrices of liposomes and cell membranes are more compatible with the structure and modulation of physiological and pathological membrane activities [4].…”

“…NPA are found transiently in intact cell membranes [4] participating in functions such as membrane fissionfusion processes [5,6], organization of tight junctions between mammalian cells [7], and in activating membrane enzymes [8]; they are essential for the viability of Escherichia coli [9]. We have shown that these lipid structures are highly immunogenic since both poly-and monoclonal antibodies against them are easily attained [3,4].…”

“…Trying to test this hypothesis, we injected both syngenic BALB/c strain and non-syngenic NIH mice with the murine IgM H308-AP mAb, specific to membrane NPA [4]. We also passively transferred sera attained from animals, which already had a well-established induced autoimmune-like disease, into naïve mice.…”

Cardiolipin: Setting the beat of apoptosis

“…The exposure of CL on the outer leaflet of the mitochondrial inner membrane was observed after death receptor stimulation before mitochondria depolarization and PS exposure on the plasma membrane, and at the same time as ROS generation [86]. Peroxidation of CL may account for their redistribution by altering their molecular organization and favouring formation of a non-bilayer hexagonal structure [87]. This could increase exposure of CL on the contact sites of mitochondrial membranes and provide access for tBid.…”