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

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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