Sex-specific effects of LiCl treatment on preservation of renal function and extended life-span in murine models of SLE: perspective on insights into the potential basis for survivorship in NZB/W female mice.

David A Hart

doi:10.1186/s13293-016-0085-7

Abstract

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.

Highlights

In autoimmune diseases, immune dysfunction can lead to the induction of autoantibodies and/or self-reactive lymphocytes such as T-lymphocytes
Long-term survivorship could be dependent on the constellation of changes observed rather than a single alteration, or the constellation of changes could facilitate the effectiveness of as yet known effects of the Li to account for the percentage of female NZB/W mice exhibiting long-term survivorship while on Li
The impact on females of the NZB/W F1 strain is profound, and treatment protects a large percentage of the treated animals from end-stage renal failure without detectable impact on immune aberrations

Summary

Introduction

Immune dysfunction can lead to the induction of autoantibodies and/or self-reactive lymphocytes such as T-lymphocytes (reviewed in [1, 2]). The above findings with male NZB/NZW mice, and the earlier discussion of the effectiveness of LiCl treatment increasing following onset of puberty, lead to the possibility that androgens are protective against development of renal dysfunction and estrogens contribute to the susceptibility of female NZB/NZW mice to renal dysfunction.

Results

Conclusion