Hart David A
Department of Surgery, Wound Healing Initiative, McCaig Institute for Bone and Joint Health, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1 Canada ; Faculty of Kinesiology, University of Calgary, Calgary, Alberta Canada ; Centre for Hip Health and Mobility, University of British Columbia, Vancouver, British Columbia Canada.
Biol Sex Differ. 2016 Jun 27;7:31. doi: 10.1186/s13293-016-0085-7. eCollection 2016.
Considerable research effort has been invested in attempting to understand immune dysregulation leading to autoimmunity and target organ damage. In systemic lupus erythematosus (SLE), patients can develop a systemic disease with a number of organs involved. One of the major target organs is the kidney, but patients vary in the progression of the end-organ targeting of this organ. Some patients develop glomerulonephritis only, while others develop rapidly progressive end organ failure. In murine models of SLE, renal involvement can also occur. Studies performed over the past several years have indicated that treatment with LiCl of females, but not males of the NZB/W model, at an early age during the onset of disease, can prevent development of end-stage renal disease in a significant percentage of the animals. While on Li treatment, up to 80 % of the females can exhibit long-term survival with evidence of mild glomerulonephritis which does not progress to renal failure in spite of on-going autoimmunity. Stopping the treatment led to a reactivation of the disease and renal failure. Li treatment of other murine models of SLE was less effective and decreased survivorship in male BxSB mice, exhibited little effect on male MRL-lpr mice, and only modestly improved survivorship in female MRL-lpr mice. This perspective piece discusses the findings of several related studies which support the concept that protecting target organs such as the kidney, even in the face of continued immune insults and some inflammation, can lead to prolonged survival with retention of organ function. Some possible mechanisms for the effectiveness of Li treatment in this context are also discussed. However, the detailed mechanistic basis for the sex-specific effects of LiCl treatment particularly in the NZB/W model remains to be elucidated. Elucidating such details may provide important clues for development of effective treatment for patients with SLE, ~90 % of which are females.
为了理解导致自身免疫和靶器官损伤的免疫失调，人们投入了大量的研究精力。在系统性红斑狼疮（SLE）中，患者会患上累及多个器官的全身性疾病。主要靶器官之一是肾脏，但患者在该器官终末器官靶向的进展方面存在差异。一些患者仅发展为肾小球肾炎，而另一些患者则迅速发展为进行性终末器官衰竭。在SLE的小鼠模型中，也会出现肾脏受累情况。过去几年进行的研究表明，在疾病发病初期对NZB/W模型的雌性而非雄性小鼠用LiCl治疗，可在相当比例的动物中预防终末期肾病的发展。在锂治疗期间，高达80%的雌性小鼠可表现出长期存活，有轻度肾小球肾炎的迹象，尽管存在持续的自身免疫，但并未进展为肾衰竭。停止治疗会导致疾病重新激活和肾衰竭。对其他SLE小鼠模型进行锂治疗效果较差，在雄性BxSB小鼠中会降低存活率，对雄性MRL-lpr小鼠几乎没有影响，而在雌性MRL-lpr小鼠中仅适度提高存活率。这篇观点文章讨论了几项相关研究的结果，这些结果支持这样一种观点，即即使面对持续的免疫攻击和一些炎症，保护诸如肾脏等靶器官也可导致延长存活并保留器官功能。文中还讨论了锂治疗在这种情况下有效的一些可能机制。然而，LiCl治疗的性别特异性效应，特别是在NZB/W模型中的详细机制基础仍有待阐明。阐明这些细节可能为开发针对SLE患者（其中约90%为女性）的有效治疗方法提供重要线索。
