Androgenic Hormones Modulate Autoantibody Responses and Improve Survival in Murine Lupus

Roubinian, Jirayr R.; Papoian, Ruben; Talal, Norman

doi:10.1172/jci108729

Cited by 273 publications

(119 citation statements)

References 9 publications

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“…Effect of gender on lupus-like disease traits and splenic immune cell phenotypes of BWF1 male and female mice To extend previously reported gender-specific differences in lupus susceptibility and the potential protective effect of androgens in BWF1 mice, [7][8][9] we characterized proteinuria and autoantibody production in intact male and female mice as well as in orchiectomized and shamorchiectomized male animals ( Figure 1). While intact and sham-orchiectomized male mice showed a delay in the development of proteinuria, the percentages of orchiectomized male and intact female mice with severe proteinuria progressively increased at 6 months of age and reached 100% at 12 months of age (female versus male, P ¼ 0.0001 and orchiectomized versus shamorchiectomized, P ¼ 0.0005) (Figure 1a).…”

Section: Resultsmentioning

confidence: 97%

“…[7][8][9][10][11][12][13] One group reported that prepubescent orchiectomy of BWF1 male mice increased the incidence of proteinuria and mortality and accelerated the appearance of ANAs as compared to intact males. 7 In addition, administration of dihydrotestosterone (DHT), a nonaromatizable form of testosterone, to neutered mice was sufficient to reduce disease development compared to that observed in intact male mice, while administration of estradiol-17b (E2) to neutered mice accelerated disease. 8 Studies examining the effects of chemical manipulation of sex hormones in BWF1 mice have also generally supported the hypothesis that androgens inhibit and estrogens intensify lupus.…”

Section: Introductionmentioning

confidence: 99%

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Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus

2007

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Ninety percent of systemic lupus erythematosus patients are female, and gender differences in lupus susceptibility are also observed in (New Zealand Black Â New Zealand White)F1 (BWF1) lupus-prone mice. We followed orchiectomized, intact male and female BWF1 mice for lupus-like disease for 1 year. A comparative gene expression analysis was then used to identify candidate genes potentially responsible for gender-dependent differences in lupus susceptibility. Seven genes encoded on the sex chromosomes and 77 probe sets, including 14 immunoglobulin genes, encoded on the autosomal chromosomes were identified as differentially expressed in male versus female BWF1 splenocytes prior to disease onset. Five genes were determined to be regulated by either estradiol or dihydrotestosterone in an in vivo system and most of them were preferentially expressed in antigen-presenting cells. Gender differences in the expression of Csf3-r, Histh1c, Serpinb2, Slc6a4 and Cd22 in BWF1 mice are the result of transcriptional modification by sex hormones and warrant further investigation. The identification of candidate genes and their expression patterns in splenocyte sub-populations provide new information regarding the mechanisms by which sex hormones influence the development of mouse lupus.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus

2007

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“…Past studies conducted using animal autoimmune models have shown that an increased but non-toxic load of sex hormone [2][3][4], treatment with agonistic or antagonistic agent related to a sex hormone receptor [2,[4][5][6], or removal of sex glands [7,8] affects the incidence or severity of autoimmune phenotypes. In humans, polymorphisms of genes encoding sex hormone receptors were shown to be associated with the onset of SLE [9] and RA [10,11].…”

Section: Introductionmentioning

confidence: 99%

Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

et al. 2007

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Sex-related differences (SrD) are a general characteristic of human autoimmune diseases. There is an increasing body of evidence that suggests a link between sexrelated hormones and autoimmune onsets. Here, through a genetic approach using a lupus mouse model, we attempted to show the involvement of genetic factors in the development of SrD in autoimmune diseases. Using MRL/lpr Â (MRL/lpr Â C57BL/ 6.Fas lpr )F1 (MBN2) mice, the whole genome was searched to identify linkage loci to autoimmune phenotypes inherited from a lupus MRL/Mp.Fas lpr (MRL/lpr) strain of mice, which exhibits glomerulonephritis, splenomegaly and antinuclear autoantibody. The genome-wide association study confirmed four linkage loci on chromosomes 4, 7, 13, and 17. Furthermore, differential analyses performed using male and female groups of MBN2 mice revealed that two loci located on chromosomes 4 (41-72 cM, MRL/lpr allele) and 7 (4-21 cM, B6/lpr allele) were male specific and suppressed autoimmune phenotypes. Notably, the sum effect of the two loci adequately explained a range of SrD developed in the MBN2 mice. Our present findings suggest the presence of a malepredominant mechanism underlying the development of SrD in autoimmunity, depending on the effects of autosomal loci under an undefined male-specific condition.

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“…Prepubertal castration of males, but not females, led to a marked acceleration of anti-DNA production, proteinuria, and death (16,18,2 1). Administration of testosterone to castrated and even intact females significantly inhibited the disease (16)(17)(18)20). In a recent study (24) castrated NZB/NZW mice treated from 6 months of age had significant improvement in the autoimmune process.…”

Section: Discussionmentioning

confidence: 97%

“…One half of the females die by 10 months of age, a time when all males are still alive (16). Earlier studies demonstrated the role of sex hormones in modulating the immune response and the disease in NZB/NZW F, mice (16)(17)(18)(19)(20)(21). Male sex hormones inhib- ited and female sex hormones accelerated the development of autoimmunity.…”

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confidence: 99%

Therapeutic studies in new zealand mice

Melez

Boegel

Steinberg

1980

Arthritis & Rheumatism

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In view of the known inhibitory effects of androgens on the spontaneous production of autoantibodies in hybrids of NZB mice, as well as the dramatic effects of sex hormones on the modulation of autoimmunity in NZB/NZW F1 mice, we undertook a systematic study of treatment of female NZB/NZW mice with androgens. We initiated treatment at 0.5, 3, 5, 6, 7, or 8 months of life in castrated or intact mice by use of one of three steroid preparations at different doses. We found that danazol was not effective in suppressing proteinuria, reducing antibodies to ssDNA, or in prolonging survival. In contrast, both testosterone and 5 α‐dihydrotestosterone were capable of prolonging survival, suppressing proteinuria, and reducing anti‐ssDNA in both intact and castrated mice. Testosterone was effective at lower doses than was the 5 α hormone. Testosterone significantly prolonged survival even when started after the onset of clinical illness at 5, 7, and 8 months of age. Mice treated from 5 months of life with testosterone had a much more marked reduction in antibodies to ssDNA than to native DNA. However, treatment from 7 months of age significantly prolonged survival without altering the serum levels of either autoantibody, suggesting that some other mechanism of testosterone action may be contributing to therapeutic efficacy. These studies indicate that androgen therapy may be beneficial even after the development of clinical illness, that castration is not necessary for benefit, and that the effectiveness of a therapeutic regimen is dependent upon both the dose and the particular preparation of hormone.

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Androgenic Hormones Modulate Autoantibody Responses and Improve Survival in Murine Lupus

Cited by 273 publications

References 9 publications

Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus

Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus

Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

Therapeutic studies in new zealand mice

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