β2-Glycoprotein I-Reactive T Cells in Autoimmune Disease

Abstract

Anti-phospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are autoimmune diseases characterized by autoantibody production and autoantibody-related pathology. Anti-phospholipid antibodies (aPL) are found in all patients with APS and in 20-30% of individuals with SLE. aPL recognize a number of autoantigens, but the primary target in both APS and SLE is β2-glycoprotein I (β2GPI). The production of IgG aPL in APS and SLE, as well as the association of aPL with certain MHC class II molecules, has led to investigation of the role of β2GPI-reactive T helper (Th). β2GPI-reactive CD4 Th cells have been associated with the presence of aPL and/or APS in both primary APS and secondary APS associated with SLE, as well as in SLE patients and healthy controls lacking aPL. CD4 T cells reactive with β2GPI have also been associated with atherosclerosis and found within atherosclerotic plaques. In most cases, the epitopes targeted by autoreactive β2GPI-reactive CD4 T cells in APS and SLE appear to arise as a consequence of antigenic processing of β2GPI that is structurally different from the soluble native form. This may arise from molecular interactions (e.g., with phospholipids), post-translational modification (e.g., oxidation or glycation), genetic alteration (e.g., β2GPI variants), or molecular mimicry (e.g., microbiota). A number of T cell epitopes have been characterized, particularly in Domain V, the lipid-binding domain of β2GPI. Possible sources of negatively charged lipid that bind β2GPI include oxidized LDL, activated platelets, microbiota (e.g., gut commensals), and dying (e.g., apoptotic) cells. Apoptotic cells not only bind β2GPI, but also express multiple other cellular autoantigens targeted in both APS and SLE. Dying cells that have bound β2GPI thus provide a rich source of autoantigens that can be recognized by B cells across a wide range of autoantigen specificities. β2GPI-reactive T cells could potentially provide T cell help to autoantigen-specific B cells that have taken up and processed apoptotic (or other dying) cells, and subsequently present β2GPI on their surface in the context of major histocompatibility complex (MHC) class II molecules. Here, we review the literature on β2GPI-reactive T cells, and highlight findings supporting the hypothesis that these T cells drive autoantibody production in both APS and SLE.

Keywords: MHC class II haplotypes; T cells; anti-phospholipid syndrome; autoantibodies; systemic lupus erythematosus; β2-glycoprotein I.

Figure 1

β2GPI-reactive T cells promote autoantibody production and pathology in APS and SLE. This simplified schematic diagram illustrates a possible mechanism by which β2GPI-reactive T cells may promote the development of multiple serological and clinical outcomes. Immunization of mice with β2GPI and lipopolysaccharide (LPS) results in the presentation of β2GPI-derived peptides (green circles) to T cells by dendritic cells and activation and proliferation of β2GPI-reactive CD4 T cells. In the second phase of the response, β2GPI-reactive CD4 T cells could provide help not only to B cells specific for β2GPI, but also to other autoantigen-specific B cells. We propose that autoantigen-specific B cells can recognize their cognate antigen on dying cells and ingest dying cells that have β2GPI bound to their surface. This would result in the presentation of β2GPI peptides in the context of MHC class II on the B cell surface, and allow T cell help from a β2GPI-reactive CD4 T cell. The examples shown here are a B cell specific for the SLE autoantigen dsDNA, and a B cell specific for β2GPI, with β2GPI-reactive T cell help resulting in anti-dsDNA and anti-β2GPI (and/or anti-CL), respectively. In addition, pro-inflammatory cytokines (e.g., IFN-γ and TNF-α) produced by the β2GPI-reactive T cells can impact other cells and tissues, either locally in a paracrine manner or at a distance in an endocrine manner. Depending on the autoantibodies and cytokines produced, different pathologies would arise (e.g., thrombosis or atherosclerosis with aPL, and glomerulonephritis with anti-dsDNA). In this way, β2GPI-reactive T cells could be a driving force for autoantibody production and pathology in both APS and SLE.