Novel molecular pathogenesis of autoimmune diseases : Self attack as a result of breakdown of central tolerance

区分自身和非自身抗原的能力对于免疫系统防御身体特异性入侵微生物至关重要。耐受性自身抗原的机制的崩溃可导致病理性自身免疫，伴随着免疫系统对身体自身组织的破坏或破坏。我们证明，干燥综合征的动物模型IQI/Jic小鼠在年老时不仅在泪腺和唾液腺，而且在包括肺、胰腺和肾脏在内的多个器官中自发地产生主要由CD 4 ^+ T细胞和B细胞浸润的炎性病变。我们接下来鉴定了激肽释放酶-13是与IQI/Jic小鼠中的全身性自身免疫相关的自身抗原。此外，我们发现，IL-2的产生的T细胞在转录水平受损IQI/Jic小鼠。提示T细胞活化不良导致的IL-2产生缺陷可消除自身耐受机制， ...更多信息 h IL-2，并在IQI/Jic小鼠中产生自身免疫性疾病的基础。最后，我们在IQI/Jic小鼠中出生后第3天（D3 Tx）进行胸腺切除术，已知其消除调节性T细胞（Treg）以解决是否存在通过Treg的耐受机制的丧失，并且其有助于IQI/Jic小鼠中自身免疫性病变的早期发展。提示IQI/Jic小鼠中的自发性自身免疫性病变的发展独立于通过Treg的自我耐受机制。总之，在IQI/Jic小鼠中，活化的T细胞产生最佳水平的IL-2的功能障碍可以废除不通过Treg的自我耐受机制，并导致与自身抗原反应的T细胞的持续活化。此外，针对自身抗原（包括Klk-13）的自身免疫可能在疾病从唾液腺特异性疾病进展为全身性疾病的病因学中至关重要。从这项工作中获得的这些发现可能有助于更好地了解干燥综合征在人类和其他自身免疫性疾病的发病机制。少

The ability to discriminate between self and non-self antigens is pivotal for the immune system to defense the body specifically invading microorganisms. The breakdown of mechanisms to tolerance self-antigens can result in the pathological autoimmunity with the destruction or disruption of the body's own tissues by the immune system. We demonstrated that IQI/Jic mice, an animal model for Sjogren's syndrome, spontaneously develop inflammatory lesions mainly infiltrated with CD4^+ T cells and B cells not only in the lacrimal and salivary glands but also in multiple organs including the lung, pancreas, and kidney at advanced ages. We next identified Kallikrein-13 was an autoantigen associated with systemic autoimmunity in IQI/Jic mice. In addition, we found that IL-2 production of T cells was impaired at the transcriptional level in IQI/Jic mice. It was suggested that defective production of IL-2 resulting from poor activation of T cells could abrogate the self-toleration mechanism throug … More h IL-2 and create the basis of autoimmune disease in IQI/Jic mice. Finally, we performed thymectomy on day 3 after birth (D3Tx) in IQI/Jic mice, which is known to eliminate regulatory T cells (Treg) to address whether there is a loss of toleration mechanism through Treg and it contributes to the early development of autoimmune lesions in IQI/Jic mice. It was suggested that spontaneous autoimmune lesions in IQI/Jic mice develop independently of the self-toleration mechanism through Treg. In conclusion, in IQI/Jic mice, dysfunction of activated T cells to produce optimal levels of IL-2 could abrogate the self-toleration mechanisms not through Treg and cause persistent activation of T cells reactive with autoantigens. Moreover, autoimmunity against autoantigens including Klk-13, might be crucial in the etiology of disease progression from salivary gland-specific to systemic disorder. These findings obtained from this work could contribute to a better understanding of the pathogenesis of Sjogren's syndrome in humans and other autoimmune diseases. Less