Autoimmune hemolytic anemia (AIHA) leads to accelerated destruction of autologous red blood cells (RBCs) by autoantibodies. AIHA is a severe and sometimes fatal disease. While there are several therapeutic strategies available, there are currently no licensed treatments for AIHA and few therapeutics result in treatment-free durable remission. The etiology of primary AIHA is unknown; however, secondary AIHA occurs concurrently with lymphoproliferative disorders and infections. Additionally, AIHA is the second most common manifestation of primary immunodeficiency disorders and has been described as a side effect of checkpoint inhibitor therapy. Given the severity of AIHA and the lack of treatment options, understanding the initiation of autoimmunity is imperative. Herein, we utilized a well-described model of RBC biology to dissect how RBC-specific autoreactive T cells become educated against RBC autoantigens. We show that, unlike most autoantigens, T cells do not encounter RBC autoantigens in the thymus. Instead, when they leave the thymus as recent thymic emigrants (RTEs), they retain the ability to positively respond to RBC autoantigens; only after several weeks in circulation do RTEs become nonresponsive. Together, these data suggest that any disruption in this process would lead to breakdown of tolerance and initiation of autoimmunity. Thus, RTEs and this developmental process are potential targets to prevent and treat AIHA.

自身免疫性溶血性贫血 (AIHA) 会导致自身抗体加速破坏自体红细胞 (RBC)。AIHA 是一种严重的、有时是致命的疾病。虽然有几种治疗策略可用，但目前没有针对 AIHA 的许可治疗方法，并且很少有治疗方法可以实现无需治疗的持久缓解。原发性 AIHA 的病因不明；然而，继发性 AIHA 与淋巴组织增生性疾病和感染同时发生。此外，AIHA 是原发性免疫缺陷疾病的第二常见表现，并被描述为检查点抑制剂治疗的副作用。鉴于 AIHA 的严重性和缺乏治疗方案，了解自身免疫的启动势在必行。在此处，我们利用一个描述良好的 RBC 生物学模型来剖析 RBC 特异性自身反应性 T 细胞是如何针对 RBC 自身抗原进行训练的。我们表明，与大多数自身抗原不同，T 细胞不会在胸腺中遇到 RBC 自身抗原。相反，当它们作为最近的胸腺移出物 (RTE) 离开胸腺时，它们保留了对红细胞自身抗原做出积极反应的能力；只有在流通数周后，RTE 才会变得无反应。总之，这些数据表明，这一过程中的任何中断都会导致耐受性的破坏和自身免疫的启动。因此，RTE 和这一发展过程是预防和治疗 AIHA 的潜在目标。当它们作为最近的胸腺移出者 (RTE) 离开胸腺时，它们仍保留对红细胞自身抗原做出积极反应的能力；只有在流通数周后，RTE 才会变得无反应。总之，这些数据表明，这一过程中的任何中断都会导致耐受性的破坏和自身免疫的启动。因此，RTE 和这一发展过程是预防和治疗 AIHA 的潜在目标。当它们作为最近的胸腺移出者 (RTE) 离开胸腺时，它们仍保留对红细胞自身抗原做出积极反应的能力；只有在流通数周后，RTE 才会变得无反应。总之，这些数据表明，这一过程中的任何中断都会导致耐受性的破坏和自身免疫的启动。因此，RTE 和这一发展过程是预防和治疗 AIHA 的潜在目标。