Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Department of Allergy and Rheumatology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
Front Immunol. 2018 Dec 10;9:2836. doi: 10.3389/fimmu.2018.02836. eCollection 2018.
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.
抗磷脂综合征（APS）和系统性红斑狼疮（SLE）是自身免疫性疾病，其特征为自身抗体的产生和与自身抗体相关的病理学。抗磷脂抗体（aPL）存在于所有 APS 患者和 20-30%的 SLE 患者中。aPL 识别许多自身抗原，但 APS 和 SLE 中的主要靶标均为β2-糖蛋白 I（β2GPI）。APS 和 SLE 中 IgG aPL 的产生以及 aPL 与某些 MHC Ⅱ类分子的关联，促使人们研究β2GPI 反应性辅助性 T（Th）细胞的作用。β2GPI 反应性 CD4 Th 细胞与原发性 APS 和与 SLE 相关的继发性 APS 中 aPL 的存在以及 SLE 患者和缺乏 aPL 的健康对照者有关。在大多数情况下，APS 和 SLE 中与β2GPI 反应的自身反应性 CD4 T 细胞靶向的表位似乎是由于β2GPI 的抗原加工而产生的，该加工与可溶性天然形式的β2GPI 在结构上不同。这可能是由于分子相互作用（例如，与磷脂）、翻译后修饰（例如，氧化或糖化）、遗传改变（例如，β2GPI 变体）或分子模拟（例如，微生物组）所致。已经描述了许多 T 细胞表位，特别是在β2GPI 的脂质结合域，即结构域 V 中。与β2GPI 结合的带负电荷的脂质的可能来源包括氧化的 LDL、活化的血小板、微生物组（例如肠道共生菌）和死亡（例如凋亡）细胞。凋亡细胞不仅结合β2GPI，还表达在 APS 和 SLE 中靶向的多种其他细胞自身抗原。因此，结合了β2GPI 的凋亡细胞提供了丰富的自身抗原来源，这些自身抗原可以被具有广泛自身抗原特异性的 B 细胞识别。β2GPI 反应性 T 细胞可能为已经摄取和处理凋亡（或其他死亡）细胞并随后在主要组织相容性复合物（MHC）Ⅱ类分子背景下将β2GPI 呈递在表面上的自身抗原特异性 B 细胞提供 T 细胞帮助。在这里，我们综述了有关β2GPI 反应性 T 细胞的文献，并强调了支持这些 T 细胞在 APS 和 SLE 中驱动自身抗体产生的假说的发现。
