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.

Immune reactivity is greater in females than in males. In both experimental animals and in man there is a greater preponderance of autoimmune diseases in females, compared with males. Studies in many experimental models have established that the underlying basis for this sex-related susceptibility is the marked effects of sex hormones. Sex hormones influence the onset and severity of immune-mediated pathologic conditions by modulating lymphocytes at all stages of life, prenatal, prepubertal, and postpubertal. However, despite extensive studies, the mechanisms of sex hormone action are not precisely understood. Earlier evidence suggested that the sex hormones acted via the thymus gland. In recent years it has become apparent that sex hormones can also influence the immune system by acting on several nonclassic target sites such as the immune system itself (nonthymic lymphoid organs), the central nervous system, the macrophage-macrocyte system, and the skeletal system. Immunoregulatory T cells appear to be most sensitive to sex hormone action among lymphoid cells. Several mechanisms of action of sex hormones are discussed in this review. The possibility of using sex hormone modulation of immune responses for the treatment of autoimmune disorders is a promising area for future investigation.

Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action

This review covers major advances in clinical issues related to systemic lupus erythematosus (SLE) published between 1995 and 2000. The classification criteria for both SLE and antiphospholipid syndrome (APS) have been updated, and up to 19 different subsets of neuropsychiatric lupus have been defined. New epidemiological data show that the incidence of new cases and the survival of patients with SLE are both increasing. Several randomised controlled trials have defined the role of cyclophosphamide, methotrexate, antimalarials, and hormonal treatment in the management of SLE. New data are available for drugs such as ciclosporin and thalidomide. Finally, several new treatments for severe refractory cases, such as mycophenolate mofetil and stem-cell transplantation, are being increasingly used. New data also refer to management of thrombosis in APS and high-risk pregnancies in women with SLE or APS.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)60279-7.pdf

Systemic Lupus Erythematosus

Gender differences in autoimmune disease.

Introduction IN THE PAST 10 years there has been a significant increase in studies relating to the function of the immune system. The recent popularity of research in this area is due in part to the awareness by the medical and scientific community of the importance of immune function in the maintenance of a disease-free homeostasis, to technological advances in the field of immunological research, and to the increased availability of funds for investigation in this area. From the rapidly expanding literature in this field it has become increasingly apparent that the immune system interacts with most, if not all, of the body systems. One of the most intriguing of these interrelationships is that which occurs between the immune and reproductive systems and involves interactions of pituitary hormones, gonadal steroid hormones and thymic hormones. Because of the complexity of this area the present review will concentrate on only one aspect of the interaction between the two systems, namely the effects of gon...

Regulation of the Immune System by Sex Steroids

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.

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Androgenic Hormones Modulate Autoantibody Responses and Improve Survival in Murine Lupus

NZW F1 (B/W) mice were subjected to sham surgery or neonatal thymectomy and/or splenectomy and studied for immunoglobulin class of antibodies to double-stranded DNA and polyadenylic acid (Poly A) at 4 to 13 months of age. These antibodies occur spontaneously during the course of autoimmune disease in B/W mice. Sera were fractionated by sucrose density gradient ultracentrifugation and assayed for antibodies by a filter radioimmunoassay method. IgM was recovered in the 19S region and IgG in the 7S region as demonstrated by immunodiffusion. In sham-operated controls, at all ages studied, anti-DNA antibodies were both IgM and IgG, with the former predominating in males, and the latter in females. In both sexes, anti-Poly A antibodies were primarily IgM in young mice. There was a sequential switch from IgM to either enhanced or new IgG production in the following sequence: female anti-DNA and anti-Poly A (6 months), male anti-DNA (9 months), and male anti-Poly A (11 months). Both thymectomy and splenectomy caused earlier death in male mice, whereas females lived significantly longer after thymectomy. Neonatal thymectomy in males caused a premature switch from IgM to IgG antibodies to DNA, but it had a transient effect in females. Thymectomy almost completely prevented the late switch to IgG antibodies to Poly A in both sexes. By contrast, splenectomy promoted the formation of IgG antibodies to Poly A in male mice. These results suggest that the newborn B/W thymus and spleen contain regulatory cells and/or factors exerting different controlling influences on spontaneous antibodies to DNA and Poly A. Male B/W mice appear to be under the regulatory influence of suppressor cells, whereas the predominant regulation in female B/W mice appears to be a helper effect.

Ruben Papoian

Papers

Androgenic Hormones Modulate Autoantibody Responses and Improve Survival in Murine Lupus

Effects of neonatal thymectomy and splenectomy on survival and regulation of autoantibody formation in NZB/NZW F1 mice.