Physiologic apoptosis, β2-glycoprotein I, and antiphospholipid autoantibodies

We wish to add to the comments of Silver et al. (Silver RM, Pierangeli SS, Gharavi AE, Harris EN, Edwin SS, Salafia CM, et al. Induction of high levels of anticardiolipin antibodies in mice by immunization with β2-glycoprotein I does not cause fetal death. Am J Obstet Gynecol 1995;173:1410-5) on their failure to observe fetal deaths in female BALB/c mice after immunization with β2-glycoprotein I, the antiphospholipid antibody cofactor. The induction, by β2-glycoprotein injections, of high titers of serum antiphospholipid antibody without consequent fetal deaths may not be unexpected in view of the in vivo studies of Chonn et al.1Chonn A Semple SC Cullis PR. β2-Glycoprotein I is a major protein associated with very rapidly cleared liposomes in vivo, suggesting a significant role in the immune clearance of non-self particles.J Biol Chem. 1995; 270: 25845-25849Crossref PubMed Scopus (173) Google Scholar in mice. The group used anionic phospholipid-containing liposomes that are rapidly cleared from the circulation. Besides albumin, β2-glycoprotein was found to be a major protein associated with the liposomes, although the serum concentration of albumin is 200-fold greater than that of β2-glycoprotein. Moreover, the half-life of cardiolipin-containing liposomes in the blood was extended when the mice were pretreated with anti - β2-glycoprotein antibodies. These data from liposomes used as models of cell membranes strongly indicate, by extension, that β2-glycoprotein plays an essential role in mediating the clearance of cells undergoing apoptosis because senescent cells during programmed cell death, but not normal cells, expressed anionic phospholipids such as phosphatidylserine on the cell surface.1Chonn A Semple SC Cullis PR. β2-Glycoprotein I is a major protein associated with very rapidly cleared liposomes in vivo, suggesting a significant role in the immune clearance of non-self particles.J Biol Chem. 1995; 270: 25845-25849Crossref PubMed Scopus (173) Google Scholar This being the case, β2-glycoprotein - assisted scavenging of aged cells would be a regular event in the physiologic turnover of cells in the normal individual. The complex of β2-glycoprotein with anionic phospholipids on apoptotic membranes would present immunogenic epitopes that could then stimulate the generation of serum antiphospholipid antibody. This synthesis would constitute the immunogenesis of naturally occurring antiphospholipid antibody that is ubiquitous in both human and animal sera.2Cheng HM Cryptic antiphospholipid antibodies and serum coinhibitors.Autoimmunology. 1994; 19: 127-133Crossref PubMed Scopus (5) Google Scholar Natural antiphospholipid antibody would not be expected to be intrinsically pathogenic. However, as discussed by Silver et al., other laboratories have achieved resultant fetal deaths in mice, concurrent with elevated antiphospholipid antibody titers, after β2-glycoprotein immunization. This could perhaps be due to differences in immunization protocols or quality of the β2-glycoprotein immunogen preparations. We have nevertheless found that a subpopulation of natural antiphospholipid antibody activity may also be modulated by serum cofactors, implicating a masking of their immunoreactivity.2Cheng HM Cryptic antiphospholipid antibodies and serum coinhibitors.Autoimmunology. 1994; 19: 127-133Crossref PubMed Scopus (5) Google Scholar An enlarged view of autoimmunity now includes mechanisms involving abnormal apoptosis.3Mountz JD Wu J Cheng J Zhou T Autoimmune disease - a problem of defective apoptosis.Arthritis Rheum. 1994; 37: 1415-1420Crossref PubMed Scopus (232) Google Scholar Accelerated apoptosis of lymphocytes in patients with systemic lupus erythematosus have been described. Enhanced apoptosis may progress ahead of β2-glycoprotein housekeeping function and release nucleosomal and cytoplasmic antigens, including secluded acidic phospholipids that activate the production of autoantibodies. The physiologic and pathologic cofactor roles of β2-glycoprotein for natural and autoimmune antiphospholipid antibody certainly needs to be better defined. 6/8/76008 .