Patient-derived anti-β2GP1 antibodies recognize a peptide motif pattern and not a specific sequence of residues

Moerloose, Philippe de; Fickentscher, Céline; Boehlen, Françoise; Tiercy, Jean‐Marie; Kruithof, Egbert K. O.; Brandt, Karim J.

doi:10.3324/haematol.2017.170381

Cited by 14 publications

(27 citation statements)

References 35 publications

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“…A second group (42) also demonstrated an immunodominant T cell epitope within Domain I of β2GPI, in this case in PBMCs of 9 patients with APS (primary or secondary not specified). Five of the 9 patients had a thrombotic event, while the remaining 4 had fetal loss.…”

Section: β2gpi-reactive T Cells In Aps and Slementioning

confidence: 75%

“…APS, anti-phospholipid syndrome; SAPS, secondary APS; SLE, systemic lupus erythematosus. The numbering of amino acids in the studies by Salem et al (40, 41) and de Moerloose et al (42) includes the 19-amino acid leader sequence. In studies by Salem et al (40, 20), murine T cells were derived from spleen.† Prominent HLA restrictions are noted here, but additional restrictions were found; , HLA restriction was not defined .…”

Section: β2gpi-reactive T Cells In Aps and Slementioning

confidence: 99%

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β2-Glycoprotein I-Reactive T Cells in Autoimmune Disease

et al. 2018

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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.

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Section: β2gpi-reactive T Cells In Aps and Slementioning

confidence: 75%

Section: β2gpi-reactive T Cells In Aps and Slementioning

confidence: 99%

β2-Glycoprotein I-Reactive T Cells in Autoimmune Disease

et al. 2018

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“…The mechanism responsible for generating a β2GPI T cell epitope that is shared not only between spontaneous and induced SLE, but also across MHC class II haplotypes remains to be determined. In APS, de Moerloose et al 26 demonstrated an immunodominant T cell epitope in domain I of β2GPI and related it to anti-β2GPI antibody-binding motifs that could be shared among individuals with different MHC class II haplotypes. Currently, there is a paucity of knowledge about common T cell epitopes shared across MHC class II haplotypes in SLE.…”

Section: Discussionmentioning

confidence: 99%

T cells from induced and spontaneous models of SLE recognize a common T cell epitope on β2-glycoprotein I

et al. 2018

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Systemic lupus erythematosus is a prototypic model for B-cell epitope spread in autoimmunity. Autoantibodies to numerous molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting phospholipid-binding proteins, particularly β2-glycoprotein I. Notably, mice immunized with β2-glycoprotein I and lipopolysaccharide develop a strong T cell response to β2-glycoprotein I that is associated with autoantibody production and renal disease, similar to that seen in human SLE. Here we hypothesized that mice with murine systemic lupus erythematosus, whether induced or spontaneous, should have T cells that recognize β2-glycoprotein I. We evaluated the response of splenic T cells from mice with induced (C57BL/6 and C3H/HeN) and spontaneous (MRL/lpr) systemic lupus erythematosus to peptides spanning the entire sequence of human β2GPI. We found that mice with induced and spontaneous systemic lupus erythematosus recognize a common T cell epitope (peptide 31; LYRDTAVFECLPQHAMFG) in domain III of β2-glycoprotein I. β2GPI-reactive CD4 T cells from the two models differed primarily in cytokine production: T cells from mice with induced SLE expressed IFN-γ, while T cells from MRL/lpr mice expressed both IL-17 and IFN-γ, indicating that IL-17-expressing T cells are not necessary for generating a β2GPI-reactive T cell response. These data suggest that the generation of a β2-glycoprotein I-reactive T cell response is shared by both induced and spontaneous models of systemic lupus erythematosus and that this T cell response may mediate epitope spread to autoantibodies in both models.

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“…However, in the light of recent work by de Moerloose et al . , specific amino acid sequences might be less important than structural motifs in the molecule. Furthermore, we cannot exclude the possibility that there might be minor differences between domain‐1 antibodies and anti‐β 2 GPI binding to other domains that we may have overlooked.…”

Section: Discussionmentioning

confidence: 99%

Antiphospholipid antibody‐induced cellular responses depend on epitope specificity : implications for treatment of antiphospholipid syndrome

Müller‐Calleja

Hollerbach

Häuser

et al. 2017

Journal of Thrombosis and Haemostasis

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Background Antiphospholipid antibodies (aPLs) contribute to the pathogenesis of the antiphospholipid syndrome (APS) by induction of an inflammatory and procoagulant state in different cell types, and several signaling pathways have been described. Objectives To investigate whether signaling depends on the epitope specificity of aPLs. Methods Cellular effects of three human monoclonal aPLs with distinctly different epitope specificities were analyzed in vitro. Expression of tumor necrosis factor-α mRNA by mouse and human monocytes was the major readout. Analysis included cells from genetically modified mice, and the use of specific inhibitors in human monocytes. Data were validated with IgG isolated from 20 APS patients. Results Cofactor-independent anticardiolipin aPLs activated monocytes by induction of endosomal NADPH oxidase. Activation could be blocked by hydroxychloroquine (HCQ). Anti-β -glycoprotein I aPL activated monocytes by interacting with LDL receptor-related protein 8 (LRP8). This could be blocked by rapamycin. Analysis of 20 APS patients' IgG showed that all IgG fractions activated the same two pathways as the monoclonal aPL, depending on their epitope patterns as determined by ELISA. Monocyte activation by APS IgG could be blocked completely by HCQ and/or rapamycin, suggesting that in most, if not all, APS patients there is no other relevant signaling pathway. Conclusions aPLs activate two major proinflammatory signal transduction pathways, depending on their epitope specificity. HCQ and rapamycin, either alone or in combination, completely suppress signaling by APS IgG. These observations may provide a rationale for specific treatment of APS patients according to their aPL profile.

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Patient-derived anti-β2GP1 antibodies recognize a peptide motif pattern and not a specific sequence of residues

Cited by 14 publications

References 35 publications

β2-Glycoprotein I-Reactive T Cells in Autoimmune Disease

β2-Glycoprotein I-Reactive T Cells in Autoimmune Disease

T cells from induced and spontaneous models of SLE recognize a common T cell epitope on β2-glycoprotein I

Antiphospholipid antibody‐induced cellular responses depend on epitope specificity : implications for treatment of antiphospholipid syndrome

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