Kewalramani Reshma, Singh Ajay K
Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Curr Opin Nephrol Hypertens. 2002 May;11(3):273-7. doi: 10.1097/00041552-200205000-00002.
Systemic lupus erythematosus is a multisystemic autoimmune disease. The immunopathogenesis is characterized by the loss of tolerance to self. While many abnormalities in the immune system have been detected, genetic factors play a central role in the pathogenesis. The event proximate to target organ involvement appears to be autoantigen-driven, T cell-mediated, B cell activation. High levels of autoantibodies are produced. However, not all autoantibodies are pathogenic to the kidney (i.e. 'nephritogenic'). These nephritogenic autoantibodies appear to share specific physiochemical features that correlate well with patterns of renal injury. While DNA was initially regarded as the inciting autoantigen, this view does not appear to be supported by the prevailing evidence. Nucleosomes, which are structures comprising histones and DNA, have emerged as the more likely candidate autoantigen. Autoantibodies directed against nucleosomes that cross-react with nucleosomal epitopes have been identified. Furthermore, evidence suggests that immunoglobulin-nucleosomal complexes may be important in target organ immune deposition. In-vivo generation of nucleosomes requires apoptosis; in fact, there are several examples of aberrant apoptotic processes that present with autoimmunity. Aberrant apoptosis may also be critical in lupus immunopathogenesis. Indeed, studies on Fas/FasL and Bcl-2 in animal models and in humans have underscored the importance of apoptosis as an etiological factor in lupus. Cytokines, hormonal, infectious and environmental factors have also been found to be important in the pathogenesis of systemic lupus erythematosus. Overall, much progress has been made in elucidating the etiological agents and pathogenic mechanisms by which lupus develops. However, there is still some way to go before arriving at a unifying hypothesis. The reward for a better understanding of lupus immunopathogenesis will be the development of more specific targets for treatment, and the introduction of better and safer treatment modalities.
系统性红斑狼疮是一种多系统自身免疫性疾病。其免疫发病机制的特征是对自身失去耐受性。虽然已检测到免疫系统存在许多异常，但遗传因素在发病机制中起核心作用。与靶器官受累最直接相关的事件似乎是自身抗原驱动的、T细胞介导的B细胞活化。会产生高水平的自身抗体。然而，并非所有自身抗体都对肾脏具有致病性（即“致肾炎性”）。这些致肾炎性自身抗体似乎具有特定的物理化学特征，与肾损伤模式密切相关。虽然DNA最初被认为是引发自身抗原，但现有证据似乎并不支持这一观点。核小体是由组蛋白和DNA组成的结构，已成为更有可能的自身抗原候选物。已鉴定出针对与核小体表位发生交叉反应的核小体的自身抗体。此外，有证据表明免疫球蛋白 - 核小体复合物可能在靶器官免疫沉积中起重要作用。核小体的体内生成需要细胞凋亡；事实上，有几个异常凋亡过程的例子与自身免疫有关。异常凋亡在狼疮免疫发病机制中也可能至关重要。确实，对动物模型和人类中Fas/FasL和Bcl-2的研究强调了细胞凋亡作为狼疮病因的重要性。细胞因子、激素、感染和环境因素在系统性红斑狼疮的发病机制中也被发现很重要。总体而言，在阐明狼疮发病的病因和致病机制方面已取得了很大进展。然而，在得出一个统一的假说之前仍有一段路要走。更好地理解狼疮免疫发病机制的回报将是开发更具特异性的治疗靶点，并引入更好、更安全的治疗方式。
