T Lymphocyte Dysfunction in Lupus Erythematosus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种病因不明的自身免疫性疾病，以T细胞效应功能受损为特征。我们已经证明，由于I型蛋白激酶A （PKA-I）同工酶活性不足，蛋白激酶A催化的蛋白磷酸化受损。同工酶活性不足主要反映I型调节β亚基蛋白（RIbeta）显著减少或缺失。本应用程序将研究PKA-I同工酶活性缺陷是一种整体信号失调的假设，该失调分别导致CD4+，CD45RA/RO+-和CD8+，CD45RA/RO+-介导的辅助和细胞毒性功能受损，这些功能可以通过恢复生理性PKA-I活性部分重建。我们的具体目标是：(1)研究蛋白水解/泛素化和翻译沉默作为调节T细胞系和正常T细胞中RIbeta蛋白转换的机制，以及研究异常蛋白水解/泛素化和/或翻译沉默在SLE T细胞中RIbeta蛋白表达减少/缺失中的作用。(2)确定PKA-I活性缺陷是否影响所有T细胞或特定T细胞亚群及其与cd59v表达的关系。(3)探讨RIbeta2C2全酶在SLE和正常T细胞中T细胞效应功能中的作用。(4)开展SLE多重家族研究，以确定（4a） RIbeta蛋白缺乏的患病率。（4a）在狼疮先发家族中，由于RIbeta蛋白减少/缺失而导致的PKA-I活性不足是否是一种遗传性疾病。因此，这项研究的意义在于它有可能解释T细胞内有缺陷的信号通路如何导致导致狼疮免疫发病的异常T细胞效应功能。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by impaired T cell effector functions. We have demonstrated impaired protein kinase A-catalyzed protein phosphorylation due to deficient type I protein kinase A (PKA-I) isozyme activity. Deficient isozyme activity predominantly reflects markedly reduced or absent type I regulatory beta subunit protein (RIbeta). This application will investigate the hypothesis that deficient PKA-I isozyme activity is an integral signaling disorder that results in impaired CD4+,CD45RA/RO+- and CD8+,CD45RA/RO+-mediated helper and cytotoxic functions, respectively, which can be partially reconstituted by restoring physiologic PKA-I activity. Our specific aims are: (1) To investigate the role proteolysis/ubiquitination and translational silencing as mechanisms regulating RIbeta protein turnover in T cell lines and normal T cells and to investigate the role of abnormal proteolysis/ubiquitination and/or translational silencing in reduced/absent RIbeta protein expression in SLE T cells. (2) To determine whether deficient PKA-I activity affects all T cells or a specific T cell subset and its relationship to CD59 v expression. (3) To examine the role of the RIbeta2C2 holoenzyme in T cell effector functions in SLE and normal T cells. (4) To perform SLE multiplex family studies to determine (4a) The prevalence of RIbeta protein deficiency. (4a) Whether deficient PKA-I activity due to reduced/absent RIbeta protein is a heritable disorder in families of lupus probands. Thus, the significance of this research is its potential to explain how defective signaling circuitry within the T cell can lead to the aberrant T cell effector functions that result in lupus immunopathogenesis.