MRL/1 and BXSB male mice have a systemic lupus erythematosus (SLE)-like disease similar to but more acute than that occurring in NZB X W mice. The common elements of lymphoid hyperplasia, B-cell hyperactivity, autoantibodies, circulating immune complex (IC), complement consumption, IC glomerulonephritis with gp70 deposition, and thymic atrophy were found in all three kinds of SLE mice. On the basis of these common elements, SLE seen in these mice can be considered a single disease in the same sense that human SLE is one disease. The differences in the SLE expressed in the different mice are no greater than those found in an unselected series of humans with SLE. However, the significant quantitative and qualitative variations in abnormal immunologic expression suggest that different constellations of factors, genetic and/or pathophysiologic, may operate in the three murine strains and that each constellation is capable of leading, via its particular abnormal immunologic consequences, to the activation of common immunopathologic effector mechanisms that cause quite similar SLE-like syndromes. From an experimental point of view, the availability of several inbred murine strains of commonplace histocompatibility types that express an SLE-like syndrome makes possible innumerable manipulations which should help to elucidate the nature and cause(s) of this disorder.

https://rupress.org/jem/article-pdf/148/5/1198/1089624/1198.pdf

Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains.

Publisher Summary This chapter reviews the histopathologic, serologic, lymphocytic, virological, hormonal, and genetic characteristics of murine models of systemic lupus erythematosus (SLE). The pathogenetic mechanisms underlying murine SLE are highly complex, apparently well-programmed genetically, but still diverse and their bases not as yet well defined. Significant serologic and cellular experimental data support the statement that the final immunopathologic perturbation in murine (and human) SLE is a B lymphocyte hyperactivity with corresponding enhancement of serum antibodies and autoantibodies, particularly IgG, and consequent formation of pathogenic antigen–antibody ICs. On the basis of the available data, it appears that this B cell hyperactivity is polyclonal but not necessarily panclonal in nature, because not only antibodies against a wide array of autoantigens but also antibodies against incidental antigens, such as haptens, can be detected. The presence of autoantibodies and of their idiotypes in some recombinant lupus x normal murine lines expressing the normal partner's V genes, normal mice in which an exogenous or endogenous (Ipr gene) immunostimulator has been introduced, and unmanipulated normal mice indicate that lupus mice are not unique in their structural genetic Ig elements, whose presence determines the development of their autoimmune disease. The cause of B cell hyperactivity in lupus has not yet been fully elucidated. Autonomous B cell maturation does not appear likely, because B cell proliferation and differentiation in lupus mice was found to be dependent on the same number of accessory signals as in normal mice.

Murine models of systemic lupus erythematosus.

The immune system is regulated by the gonadal steroids estrogen, androgen, and progesterone, but the circulating levels of these steroids can also be affected by immune system function. Such interactions appear to be mediated through the hypothalamic-pituitary-gonadal-thymic axis and depend on pituitary luteinizing hormone released by thymic factors under the control of the gonadal steroids.

https://science.sciencemag.org/content/sci/227/4684/257.full.pdf

Interactions between the gonadal steroids and the immune system

Publisher Summary The recognition of the existence of natural cell-mediated immunity, particularly natural cell-mediated cytotoxicity, has significantly altered the concepts concerning the potential mechanisms for in vivo resistance against tumor growth and for in vitro cell-mediated immune reactions. When cytotoxic reactions are measured, the evaluation of the role of natural killer (NK) cells and other more well-known mechanisms of cytotoxicity must be done carefully. This chapter focuses on natural cell-mediated cytotoxicity. It summarizes the known information on the expression of natural cytotoxicity in rodents and in man, its specificity, the nature of the effector cells and their relationship to other immune mechanisms, and the possible in vivo relevance of natural cytotoxicity, particularly in regard to resistance against tumor growth. The basic observation that initiated the studies of natural cell mediated cytotoxicity includes that lymphoid cells from some normal mice, rats, and human donors, which are not inoculated with tumor cells or other sources of antigen, exhibit significant levels of cytotoxic reactivity against certain syngeneic or allogeneic tumor cells.

Natural Cell-Mediated Immunity

background Oral contraceptives are rarely prescribed for women with systemic lupus erythematosus, because of concern about potential negative side effects. In this double-blind, randomized, noninferiority trial, we prospectively evaluated the effect of oral contraceptives on lupus activity in premenopausal women with systemic lupus erythematosus. methods A total of 183 women with inactive (76 percent) or stable active (24 percent) systemic lupus erythematosus at 15 U.S. sites were randomly assigned to receive either oral contraceptives (triphasic ethinyl estradiol at a dose of 35 µg plus norethindrone at a dose of 0.5 to 1 mg for 12 cycles of 28 days each; 91 women) or placebo (92 women) and were evaluated at months 1, 2, 3, 6, 9, and 12. Subjects were excluded if they had moderate or high levels of anticardiolipin antibodies, lupus anticoagulant, or a history of thrombosis. results The primary end point, a severe lupus flare, occurred in 7 of 91 subjects receiving oral contraceptives (7.7 percent) as compared with 7 of 92 subjects receiving placebo (7.6 percent). The 12-month rates of severe flare were similar: 0.084 for the group receiving oral contraceptives and 0.087 for the placebo group (P=0.95; upper limit of the one-sided 95 percent confidence interval for this difference, 0.069, which is within the prespecified 9 percent margin for noninferiority). Rates of mild or moderate flares were 1.40 flares per person-year for subjects receiving oral contraceptives and 1.44 flares per person-year for subjects receiving placebo (relative risk, 0.98; P=0.86). In the group that was randomized to receive oral contraceptives, there was one deep venous thrombosis and one clotted graft; in the placebo group, there was one deep venous thrombosis, one ocular thrombosis, one superficial thrombophlebitis, and one death (after cessation of the trial). conclusions Our study indicates that oral contraceptives do not increase the risk of flare among women with systemic lupus erythematosus whose disease is stable.

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Combined Oral Contraceptives in Women with Systemic Lupus Erythematosus

NZB/NZW F1 mice of both sexes were castrated at 2 wk of age and implanted subcutaneously with silastic tubes containing either 5-alpha-dihydrotestosterone or estradiol-17-beta. Mice receiving androgen showed improved survival, reduced anti-nucleic acid antibodies, or less evidence of glomerulonephritis as determined by light, immunofluorescent, and electron microscopy. By contrast, opposite effects were observed in castrated mice receiving estrogen. Intact male NZB/NZW F1 mice received androgen implants at 8 mo, an age when they develop an accelerated autoimmune disease associated with a decline in serum testosterone concentration. Such treated mice had improved survival and reduced concentrations of antibodies to DNA and to polyadenylic acid (Poly A). Prepubertal castration of male NZB/NZW F1 mice results in an earlier appearance of IgG antibodies to Poly A. This effect of castration was prevented if neonatal thymectomy was also performed.

/pdf/effect-of-castration-and-sex-hormone-treatment-on-survival-56shoxf5nq.pdf

Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in nzb/nzw f1 mice.

Evidence that andogenic hormones modulate autoantibody responses and improve survival in murine lupus is reported. Hybrid mice were either castrated or subjected to sham surgery at 2 weeks of age and studied for immunoglobulin class of antibodies to nucleic acids at 4 6 and 7 months postsurgery. Prepubertal male castation caused premature death in 60% of the mice. Castrated males had a marked decline in serum testosterone concentration. An increase in deoxyribonucleic acid and polyadenylic A (Poly A) binding and an accelerated switch from 19S to 7S antibodies to nucleic acids. Castrated females revealed no change in mortality however castrated females given maintained androgen treatment had a decreased mortality compared with castrasted females receiving estrogens (14 vs. 94%). The anticipated switch to 7S antibodies to Poly A was nearly eliminated in castrated females. These data suggest that sex hormones modulate immunologic regulation and that androgenic hormones are protective in murine lupus.

/pdf/androgenic-hormones-modulate-autoantibody-responses-and-4kj2s9oexl.pdf

Androgenic Hormones Modulate Autoantibody Responses and Improve Survival in Murine Lupus

Sex hormone modulation of autoimmunity in NZB/NZW mice.

beta-estradiol was administered to mice continuously by diffusion from a silastic tube that was implanted subcutaneously at 4 weeks of age. Four to 6 weeks of estrogen administration caused a substantial reduction in natural killer cell activity in the spleens from mice of either sex. Androgen (5alpha-dihydrotestosterone) did not. Castration of male or female mice did not affect natural killing and did not alter the effect of beta-estradiol. Estradiol did not affect natural killing in vitro and the loss of natural killing was not due to a soluble or a cellular suppressor of natural killing. The effects of estradiol were not dependent on the thymus, since estradiol reduced natural killing in mice that had been neonatally thymectomized. After removal of the estrogen implant, natural killing recovered over a period of 8 weeks. The loss of natural killing may reflect a loss of bone marrow secondary to estrogen-induced osteosclerosis.

Beta-estradiol reduces natural killer cells in mice.

Female NZB/NZW F1 mice were treated as adults with 5-alpha-dihydrotestosterone powder packed into subcutaneous implants. Two treatment protocols were followed: (a) 3-mo-old mice received 6 mg of androgen, and (b) 6-mo-old mice were castrated and given 12 mg of androgen. Sham females received empty implants. Mice were followed monthly for surival, for antibodies to DNA and polyadenylic acid, and for renal histopathology. The percent survival at 11 mo was 74% for mice treated at 3 mo, compared to 11% for the sham controls, and 100% for mice treated at 6 mo, compared to 20% for their sham controls. Androgen-treated mice had less immune complex glomerulonephritis as determined by immunofluorescent and electron microscopy. Surprisingly, treated mice had no significant sustained reduction in antibodies to DNA although they had reduced antibodies to polyadenylic acid. These results suggest that androgens can still prolong survival and reduce immune complex deposition even when treatment is delayed to an age when disease is relatively established. After delayed androgen treatment, mice survive despite the presence of high levels of IgG antibodies to DNA.

/pdf/delayed-androgen-treatment-prolongs-survival-in-murine-lupus-27s2pn3sez.pdf

Jirayr R. Roubinian

Papers

Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in nzb/nzw f1 mice.

Androgenic Hormones Modulate Autoantibody Responses and Improve Survival in Murine Lupus

Sex hormone modulation of autoimmunity in NZB/NZW mice.

Beta-estradiol reduces natural killer cells in mice.

Delayed androgen treatment prolongs survival in murine lupus.