T Lymphocyte Dysfunction in Lupus Erythematosus

描述(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，其特征是T细胞效应器功能受损。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催化的蛋白质磷酸化作用受损。同工酶活性的缺陷主要反映I型调节性β亚基蛋白(RIbeta)的显著减少或缺失。这一应用将探讨PKA-I同工酶活性缺陷是一种完整的信号紊乱，导致CD8、CD45RA/RO-和CD8、CD45RA/RO介导的辅助功能和细胞毒功能受损的假说，这些功能可以通过恢复生理PKA-I活性来部分重建。我们的具体目标是：(1)研究蛋白降解/泛素化和翻译沉默作为调节T细胞系和正常T细胞RIbeta蛋白周转的机制，并探讨异常蛋白分解/泛素化和/或翻译沉默在SLE T细胞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)研究RIbeta2C2全酶在SLE和正常T细胞T细胞效应功能中的作用。(4)进行SLE多基因家系研究，以确定(4a)RIbeta蛋白缺乏症的患病率。(4A)RIbeta蛋白减少/缺失所致的PKA-I活性降低是否为狼疮先证者家族的遗传性疾病。因此，这项研究的意义在于它可能解释T细胞内的信号通路缺陷如何导致T细胞效应器功能异常，从而导致狼疮的免疫发病。

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.