Immunization with an Apoptotic Cell-Binding Protein Recapitulates the Nephritis and Sequential Autoantibody Emergence of Systemic Lupus Erythematosus

Abstract

The initial events predisposing to loss of tolerance in patients with systemic lupus erythematosus (SLE) are largely unknown, as are the events that precipitate the transition from preclinical to overt disease. We hypothesized that induction of murine SLE would require tipping the balance between tolerance and immunity in two ways: 1) an immunogen that could take advantage of apoptotic cells as a scaffold for epitope spread, and 2) an immune activator that would generate a strong and persistent T cell response to the inciting immunogen. We show that immunization of C57BL/6 and BALB/c mice with human β2-glycoprotein I, an apoptotic cell-binding protein, in the presence of LPS induces a long-lived, potent response to β2-glycoprotein I that results in epitope spread to multiple SLE autoantigens. SLE-specific autoantibodies emerged in a sequential manner that recapitulated the order seen in human SLE. Moreover, immunized mice developed overt glomerulonephritis closely resembling human lupus nephritis.

Ro 60 functions as a receptor for β2‐glycoprotein I on apoptotic cells

“…An earlier study has shown that anti-␤ 2 GPI responses spread rapidly to Ro 60 in mice immunized with ␤ 2 GPI, providing a clue that these autoantigens may be present as a complex on the apoptotic cell surface (15). In this study, we demonstrate that ␤ 2 GPI binds to an exposed region of Ro 60 on apoptotic cells and masks the Ro 60 apotope, thereby preventing the formation of IgG-apoptotic cell complexes.…”

“…Previous studies using soluble MaBP fusion proteins expressing fragments of Ro 60 have identified an apotope within the aa 82-244 region (19). Given the relationship between Ro 60 and ␤ 2 GPI in experimental autoimmunity (15) and the ability of these lupus autoantigens to bind cognate autoantibodies on the surface of apoptotic cells (4,11), we investigated whether MaBP-Ro 60 aa 82-244 interacts with ␤ 2 GPI in direct binding experiments. MaBP-Ro 60 aa 82-244 bound to immobilized ␤ 2 GPI in a dose-dependent manner, while no significant binding was observed with an MaBP control ( Figure 1A).…”

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

“…It is reported that the prevalence of aPL in SLE cohorts varies from 20 to 50%, and patients with primary APS may subsequently evolve towards SLE, implying a strong interplay between APS and SLE (Tincani et al, 2009). Levine et al (2006) proposed a murine model of SLE involving TLR4 in the origin of aPL antibodies, which is somewhat analogous to Buttari' hypothesis. They showed that in C57BL/6 and BALB/c mice immunized with human b2GPI, which is not only a phospholipid-binding protein in APS but also an apoptotic cell-binding protein and one of the first autoantigens targeted in SLE, LPS induced a long-lived, potent immune response to b2GPI in the presence of TLR4 ligand that resulted in epitope spread to multiple SLE autoantigens, and the development of lupus-like glomerulonephritis (Levine et al, 2006).…”

“…Levine et al (2006) proposed a murine model of SLE involving TLR4 in the origin of aPL antibodies, which is somewhat analogous to Buttari' hypothesis. They showed that in C57BL/6 and BALB/c mice immunized with human b2GPI, which is not only a phospholipid-binding protein in APS but also an apoptotic cell-binding protein and one of the first autoantigens targeted in SLE, LPS induced a long-lived, potent immune response to b2GPI in the presence of TLR4 ligand that resulted in epitope spread to multiple SLE autoantigens, and the development of lupus-like glomerulonephritis (Levine et al, 2006). Based on these observations, they hypothesized that antigen-presenting cells (APCs) interact with LPS via TLR4, leading to APC activation and the generation of multiple proteins that contribute to inflammation and enhance adaptive immunity.…”

“…In this autoimmune spiral, the human b2GPI-specific T cell can provide help to any B cell that internalizes an apoptotic cell binding human b2GPI on its surface. In this way, multiple autoreactive B cells can be activated by a single human b2GPI-specific T-cell and produce high titres of aPL and other SLE autoantibodies (Levine et al, 2006;Rauch et al, 2010).…”