Effects of chronic exposure to DDT and TCDD on disease activity in murine systemic lupus erythematosus.

Oestrogens contribute to the female preponderance of autoimmune diseases such as systemic lupus erythematosus (SLE). Environmental xenoestrogens superimposed upon endogenous pituitary-gonadal axis may affect the development of autoimmunity. This study examined the effects of chronic exposure to xenoestrogens -- o,p'-dichlorodiphenyltrichloroethane (DDT) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on disease activity in the New Zealand Black/New Zealand White F1 hybrid (B/W) mouse model of SLE. Intact female mice had repeatedly received injections of DDT, TCDD or control vehicle since 6 weeks of age. Weight change, albuminuria, mortality, relevant immunological and histological parameters were assessed. DDT exposure markedly increased the incidence of albuminuria and reduced uterine weight but had no measured effects on immunity or mortality in this study. TCDD-exposed mice had significantly lower incidence of albuminuria, serum anti-DNA antibody and total IgG levels, and mortality compared to controls. Also, TCDD group had significantly lower thymic and splenic weights, decreased percentages of CD4(+)CD8(+) thymocytes and splenic CD4(+) T cells, increased percentage of splenic B220(+)sIgM(+) B cells and higher serum interferon gamma concentration. Taken together, DDT exposure appeared to accelerate the development of albuminuria in lupus-prone mice. TCDD was immunosuppressive to murine SLE. Xenoestrogens may have compound- and tissue-specific effects that require further elucidation in future work.

Estrogen and progesterone modulate monocyte cell cycle progression and apoptosis.

PROBLEM: Pregnancy is characterized by dramatic immunologic changes most commonly characterized as suppression of cell-mediated immunity. Mechanisms of this immunosuppression are obscure but may be caused by increases in pregnancy-associated sex steroids such as 17-beta-estradiol or progesterone. METHOD OF STUDY: Using five myelomonocytic cell lines in various stages of differentiation, the effects of 17-beta-estradiol and progesterone on cell cycling, apoptosis, and bcl-2 expression in randomly cycling cells before and after lipopolysaccharide (LPS) activation were examined. RESULTS: Lipopolysaccharide alone inhibited cell cycle progression in THP-1 monocyte-like cells and U-937 histiocyte-like cells. Estrogen alone produced cell cycle arrest in all myelomonocytic cells except HL-60 pro-myelocyte-like cells. Progesterone had effects predominantly on pro-myelocytic-like HL-60 cells, inducing apoptosis. Estrogen and progesterone both decreased levels of bcl-2 in KG-1alpha, HL-60, and THP-1 cells. LPS partially antagonized both estrogen-induced THP-1 apoptosis and its suppression of bcl-2 protein. CONCLUSIONS: Sex steroid-induced effects on cell cycle transition and apoptosis are potential mechanisms by which pregnancy-induced cell-mediated immune suppression may occur. Further investigation should provide a better understanding of pregnancy-induced immune changes and, perhaps, sex-based differences in monocyte function and immunologic responses.

Prolactin in murine systemic lupus erythematosus.

Murine systemic lupus erythematosus (SLE) manifests several autoimmune perturbations that resemble human SLE, including cytokine aberrations, lymphoproliferation, hypergammaglobulinemia, autoantibody formation, and immune complex glomerulonephritis. In multiple studies, elevated serum prolactin concentrations (hyperprolactinemia) stimulated appearance or progression of murine lupus. Autoimmune disease acceleration by prolactin appears to be accentuated by estrogen stimulation of prolactin secretion and independent of immunosuppressive effects of androgens such as testosterone. Conversely, suppression of serum prolactin concentrations by bromocriptine inhibits development of murine SLE. These data clearly support the concept that prolactin is immunostimulatory in autoimmune disease and that the therapeutic goal of lowering serum prolactin concentrations may be beneficial to patients. Further utilization of murine SLE models will facilitate dissection of the actions and interactions of prolactin with estrogen, progesterone and testosterone and lead to a better understanding of hormonal immunomodulation and therapy of autoimmune disease.

Sex hormones in the pathogenesis of systemic lupus erythematosus.

Sex hormones--estrogens, progestins, androgens, and prolactin--have well-documented effects on the development, progression, or severity of systemic lupus erythematosus (SLE). These effects are complex and are confounded by in vitro and in vivo considerations that obscure a simple explanation of the sexual dichotomies in SLE. An overview of available experimental and clinical data suggests that low androgens and abnormalities in the prolactin-gonadal axis are the most consistent hormonal aberrations found in human SLE. Additional studies focusing on interactions of gonadal steroids with prolactin and other pituitary hormones should expand our understanding of the role of sex hormones in the pathogenesis of SLE and strengthen the potential of hormonal immunotherapy.

Differential effects of sex steroids on T and B cells: modulation of cell cycle phase distribution, apoptosis and bcl-2 protein levels.

Sex steroids have dramatic and differential effects on classic endocrine organ proliferation and apoptosis. In this investigation we sought to delineate similar effects of sex steroids on proliferation, cell cycle phase and apoptosis in lymphocyte cell lines as models for T and B cells. Estrogen and testosterone inhibited T cell line proliferation, induced accumulation of cells in S/G(2)M phases of the cell cycle, and increased apoptosis in a concentration- and time-dependent manner. There was a more modest effect of estrogen and testosterone on cell cycling and apoptosis in B lymphocyte cell lines, suggesting that estrogen and testosterone are inhibitory to T but not B cell lines. In comparison, progesterone induced cytostasis and modestly increased apoptosis in both T and B cell lines. Estrogen and testosterone were not antagonistic or synergistic to each other in their effects on cell cycle phase distribution, and only minimally synergistic for apoptosis. In contrast, progesterone antagonized cell cycle and apoptotic effects of estrogen in T cells. Estrogen-induced cell cycle and apoptotic effects in T cell lines were associated with suppression of bcl-2 protein levels, which were unaffected in Raji B cells. Progesterone also antagonized the estrogen-induced changes in T cell bcl-2 protein levels. These results suggest that there may be significant and differential sex steroid effects on T and B lymphocytes that may be important to sexual dichotomies in immune and autoimmune responses.

17-beta-estradiol alters Jurkat lymphocyte cell cycling and induces apoptosis through suppression of Bcl-2 and cyclin A.

In this investigation, the effects and potential mechanisms of female sex steroid action on proliferation, cell cycling, and apoptosis in Jurkat CD4 + T lymphocytes were examined. 17-beta-Estradiol (estrogen) inhibited Jurkat T cell proliferation, stimulated accumulation of cells in S and G2/M phases of the cell cycle, and induced apoptosis over 72 h in a dose-dependent manner. 4-Pregnene-3,20-dione (progesterone) did not induce redistribution of the cells in the cell cycle but did induce cytostasis and slightly increased apoptosis. Simultaneous staining with anti-BrDU and propidium iodide indicated that estrogen-treated Jurkat T cells proceeded through S phase prior to apoptosis. Progesterone halted cell cycle progression; cells did not progress through S phase or incorporate BrDU. Both hormones decreased the percentage of cells in S or G2/M expressing cyclin A protein, but did not affect cyclin D protein expression. Cyclin A mRNA was markedly decreased by estrogen. Bcl-2 protein and mRNA were also reduced in estrogen but not progesterone-treated Jurkat T lymphocytes. This data shows that high concentrations of estrogen or progesterone significantly suppress lymphoproliferation in association with suppression of cyclin A. Additionally, bcl-2 protein levels were suppressed in association with estrogen-induced apoptosis. These findings demonstrate direct, hormone-specific effects on lymphocytes that may provide insight into their role in immunomodulation or the development of autoimmunity.

Suppression of renal disease and mortality in the female NZB x NZW F1 mouse model of systemic lupus erythematosus (SLE) by chenodeoxycholic acid.

The objective of this study was to examine the effects of ursodeoxycholic (UDCA) and chenodeoxycholic acid (CDCA) on autoimmune disease in the NZB x NZW F1 (B/W) mouse model of systemic lupus erythematosus (SLE). The development of murine lupus was assessed in female B/W mice given UDCA or CDCA. At 6 week intervals mice were examined for weight change, albuminuria, anti-DNA antibody and total IgG levels. Morbidity and mortality were assessed daily. UDCA- and CDCA-treated mice were examined at 24 weeks of age for serum cytokines, lymphocyte phenotype, and in vitro cytokine production after immunization with DNP-KLH. Liver and kidneys were examined histopathologically. The administration of UDCA and CDCA was tolerated without side effects. Weight gain in UDCA- or CDCA-treated and control mice was identical through 24 weeks of age. CDCA, but not UDCA, suppressed the development of renal disease. CDCA-treated B/W mice also had improved survival compared to UDCA-treated or control B/W mice. There were no significant effects of CDCA on anti-DNA antibodies, serum total IgG, or other immunologic parameters. CDCA-treated mice had lower serum IFN-gamma concentrations compared to control and UDCA-treated mice. The bile acid, CDCA, significantly inhibited the development of renal disease and modestly prolonged lifespan in the female B/W mouse model of SLE. Suppression of glomerulonephritis was associated with lower serum IFNgamma concentrations. Further investigation is needed to verify potential mechanisms of action, but these findings suggest that bile acids may alter the development or progression of autoimmunity.

Bromocriptine in rheumatic and autoimmune diseases.

BACKGROUND AND OBJECTIVES: Multiple lines of evidence support the concept that the anterior pituitary hormone prolactin has a pathogenic role in rheumatic and autoimmune diseases including, but not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Reiter's syndrome, psoriatic arthritis, and uveitis. Conversely, the dopaminergic agonist bromocriptine appears to have therapeutic effects through suppression of pituitary prolactin secretion and, perhaps, through actions on peripheral dopamine receptors. This article reviews the experimental and clinical data supporting the therapeutic use of bromocriptine as a nonstandard or adjunctive therapy in rheumatic and autoimmune diseases. METHODS: Data addressing the potential therapeutic role of bromocriptine in rheumatic and autoimmune diseases, as well as frequently associated comorbidities, was accumulated from the author's work, online literature search of the National Library of Medicine, and references from these identified publications. RESULTS: There have been a number of clinical therapeutic trials using 2.5 to 30 mg of bromocriptine per day in a single or divided dose, which have shown efficacy with minimal side effects in the treatment of rheumatic and autoimmune diseases. In RA, bromocriptine administration has induced immunosuppression of several immune parameters and has been associated with improvements in morning stiffness, grip strength, numbers of swollen/painful joints, and the Health Assessment Questionnaire disability index. In two blinded studies, bromocriptine reduced the number of SLE flares and was as effective as hydroxychloroquine in reducing lupus disease activity indices, respectively. In case reports, bromocriptine has been used successfully in the treatment of Reiter's syndrome enthesopathy and psoriatic arthritis. The potential efficacy of bromocriptine in the treatment of uveitis and multiple sclerosis is suggested but remains to be verified. CONCLUSIONS: Double-blind, placebo-controlled studies are limited, but clinical observations and trials support the use of bromocriptine as a nonstandard primary or adjunctive therapy in the treatment of recalcitrant RA, SLE, Reiter's syndrome, and psoriatic arthritis and associated conditions unresponsive to traditional approaches. Additional investigation is needed to verify this conclusion and extend preliminary results. RELEVANCE: In patients with rheumatic and autoimmune diseases, bromocriptine may be a relatively safe and efficacious alternative therapy. Semin Arthritis Rheum 31:21-32.

17-beta-estradiol suppresses IL-2 and IL-2 receptor.

Interleukin-2 (IL-2) plays an important role in adaptive immune responses. These responses differ between females and males and may be due to the sex steroid estrogen. In this investigation we show that estrogen suppresses IL-2 production from activated peripheral blood T cells and CD4+ T cell lines at the transcriptional level. Suppression of IL-2 occurred at short term, high 17-beta-estradiol concentrations as well as longer term lower 17-beta-estradiol concentrations. In CD4+ Jurkat T cells, suppression of IL-2 was associated with decreased nuclear binding of two important IL-2 promoter transcription factors: NFkappaB and AP-1. The decreased nuclear binding of NFkappaB occurred in the setting of estrogen-induced increases in IkappaBalpha protein levels, an important inhibitor of NFkappaB nuclear translocation. 17-beta-Estradiol was also shown to inhibit IL-2 receptor (IL-2R) expression in activated peripheral blood T cells. Estrogen-induced suppression of IL-2 and its receptor may have many ramifications for our understanding of immune and autoimmune sexual dichotomies, immune responses during pregnancy, and potential therapeutic intervention with hormone agonists and antagonists.

Estrogen, prolactin, and autoimmunity: actions and interactions.

Estrogen and prolactin have a reciprocal endocrinologic relationship and both hormones have pleiotropic effects on the immune system. Despite the presence of a number of confounding variables, these hormones modulate autoimmunity; however, mechanisms by which this modulation occurs remain obscure. Estrogen appears to suppress cell-mediated and augment humoral-based immunity. Prolactin appears to stimulate both cell and humoral-based immunity. Both hormones have been shown to modulate IFN gamma secretion. Similar evidence in experimental models, human autoimmune disease, and during pregnancy in autoimmune disease patients suggests disparate effects of estrogen and prolactin on autoimmune responses and disease pathogenesis. In the NZB x NZW F1 mouse model of lupus, prolactin accelerates disease expression, whereas estrogen, devoid of its prolactin stimulating properties, is immunosuppressive and inhibits IL-2 production. Estrogen, because of its endocrinologic and immune effects, may directly or indirectly stimulate or inhibit immune responses. These dichotomous effects have limited its successful pharmacologic manipulation in human autoimmune disease with estrogen compounds, tamoxifen, oral contraceptives, antigonadotropic agents, or ovulation induction regimens. In contrast, reduction of immunostimulatory concentrations of prolactin with bromocriptine has successfully suppressed development or expression of murine and human autoimmune disease. Further investigation into actions and interactions of estrogen and prolactin with autoimmunity will provide a better understanding of the female preponderance of autoimmunity and facilitate a more rational approach to hormonal immunotherapy.

Antioxidants suppress mortality in the female NZB x NZW F1 mouse model of systemic lupus erythematosus (SLE).

Inflammation produces reactive oxygen intermediates (ROI) that cause vascular damage and activate T lymphocytes. Conversely, antioxidants not only protect tissue from oxidative damage but also suppress immune reactivity. The objective of this study was to examine immunomodulatory effects of the non-enzymatic antioxidants, N-acetylcysteine (NAC) and cysteamine (CYST), on autoimmune disease, glomerulonephritis, and mortality in the female B/W mouse model of human systemic lupus erythematosus (SLE). The development of murine lupus was assessed during the lifespan of female B/W mice given NAC or CYST. Morbidity and mortality were assessed daily. At 6 week intervals mice were examined for weight change, albuminuria, serum BUN, antibodies to DNA, and IgG immunoglobulin levels. Serum prolactin, estrogen and progesterone were measured at 18 weeks of age. In a parallel study, NAC- and CYST-treated and control B/W mice were examined at 24 weeks of age for interval renal histopathology, lymphocyte adhesion molecule expression, and antibody titers and in vitro cytokine production in response to immunization with DNP-KLH. CYST significantly suppressed development of albuminuria and azotemia at 36 and 42 weeks of age compared to control and NAC-treated mice. NAC significantly suppressed anti-DNA antibody levels at 24 weeks. In contrast CYST significantly increased anti-DNA antibody levels at 18 weeks of age (P < 0.001 CYST vs control and NAC-treated mice). Kidneys of CYST-treated mice also had accelerated inflammatory histologic changes despite their lower incidence of albuminuria and azotemia. Mean (+/- s.e.m.) survival of control mice was 33 +/- 2 weeks compared to 38 +/- 2 weeks in NAC-treated mice (P < 0.05 vs control), and 48 +/- 2 weeks in the CYST-treated group (P < 0.01 vs control mice). The antioxidants, NAC and CYST, significantly improved mortality in the female B/W mouse model of SLE. NAC suppressed autoantibody formation and modestly prolonged survival. CYST, despite its augmentation of anti-DNA levels and renal inflammatory changes, inhibited the development of renal insufficiency and markedly improved survival. These findings suggest that ROIs play a role in the pathogenesis of lupus nephritis and that antioxidants reduce the damage causing renal insufficiency. Antioxidants may be a beneficial adjunctive therapy in the treatment of human SLE.

Lues and lupus: syphilis mimicking systemic lupus erythematosus (SLE).

Malar rash and photosensitivity are common findings in systemic lupus erythematosus (SLE). However, a number of inflammatory, dermatologic, infectious or drug-induced conditions may mimic cutaneous findings of SLE. These typically include seborrheic dermatitis, contact dermatitis, rosacea, polymorphous light eruption, syphilis and dermatomyositis sine myositis. Herein we describe a patient with fever, malar rash, alopecia, photosensitivity, arthralgias and lymphadenopathy who was subsequently diagnosed with secondary syphilis. In this case report we review clinical and histopathological findings in the differential diagnosis of malar rash and photosensitivity and discuss the overlapping features of syphilis and SLE.

Primary non-Hodgkin's lymphoma of bone.

We describe a patient with hip pain who had a painful solitary pelvic bone lesion with a lytic, permeative appearance and minimal periosteal reaction, despite a relatively large soft tissue mass. Histologic examination and thorough evaluation revealed this solitary tumor to be a primary non-Hodgkin's lymphoma of the bone.

Progesterone inhibits glucocorticoid-induced murine thymocyte apoptosis.

Sex and sex hormones modulate immune development and responses. A primary target of their effects is the structure and cellularity of the thymus; therefore, we examined the effects of sex and sex steroids on thymocyte apoptosis. We demonstrate initially that male DBA mice have a significantly higher percentage of glucocorticoid-induced apoptotic thymocytes (46.1+/-3.8%) than their female counterparts (31.6+/-3.1%; P=0.012). We postulated that this gender difference was due to differential modulation of glucocorticoid-induced apoptosis by sex hormones such as estrogen, testosterone or progesterone. Both estrogen and testosterone increased in vitro thymocyte apoptosis. In contrast, progesterone not only inhibited spontaneous in vitro thymocyte apoptosis, but also prevented in vitro glucocorticoid-induced apoptosis. Progesterone administration also suppressed glucocorticoid-induced in vivo thymocyte apoptosis. These results suggest that anti-apoptotic effects of progesterone may influence T cell development and subsequent immune responses.

Mood states and disease activity in patients with systemic lupus erythematosus treated with bromocriptine.

We tested mood states in patients with systemic lupus erythematosus (SLE) treated with the prolactin-lowering drug, bromocriptine. Bromocriptine was given to seven patients in an open-label study to test its effects on active SLE. Two independent measures of SLE activity, the SLE Activity Measure (SLAM) and the SLE Disease Activity Index (SLEDAI), were scored and the Symptom Questionnaire (SQ) mood survey was administered at entry and at 6 monthly follow-up visits. The SLAM and SLEDAI scores improved significantly during treatment. Two of the four mood scales in the SQ (Anxiety Scale and Anger-Hostility Scale) showed significant improvement compared to the entry value at least once during treatment. Significant improvement was also observed in the Total Distress Score, which is the sum of the four scales and is a more sensitive measure of distress than the score of an individual scale. Depression, anxiety, somatic complaints, and total distress correlated positively with SLAM and/or SLEDAI scores. The Anxiety Scale and the Total Distress Score improved with treatment and did correlate positively with SLE activity. In contrast, the Anger-Hostility Scale improved with treatment but did not correlate with SLE activity.

Osteoarthritis of the sternoclavicular joint.

Primary osteoarthritis of the sternoclavicular joint (SCJ) is relatively common, occurring in 90% of people over age 60, and must be considered in the differential of chest wall pain. Lesions typically appear after age 40 years and are either bilateral or slightly more common in the SCJ of the dominant hand. Diagnosis by plain x-rays is confounded by overlapping structures; therefore SCJ osteoarthritis is most easily diagnosed by classic radiographic findings on computed tomography of the sternoclavicular joint. Treatment consists of rest, physical therapy, non-steroidal anti-inflammatory drugs, or local corticosteroid injection, with surgery for those with intractable pain.

Systemic lupus erythematosus and Castleman's disease.

Lymphadenopathy is a common finding in systemic lupus erythematosus (SLE), yet lymphoid malignancy is rare. Typically, adenopathy associated with SLE responds to glucocorticoid therapy. We evaluated a patient with a diagnosis of SLE who had progressive lymphadenopathy despite receiving aggressive corticosteroid therapy for SLE associated thrombocytopenia. Histopathology initially revealed an aggressive plasmacytosis characteristic of Castleman's disease (CD). CD, or angiofollicular hyperplasia, is a rare lymphoproliferative neoplasm that has features overlapping many autoimmune diseases. This disorder should be considered in autoimmune diseases with unremitting or progressive adenopathy.

Mycophenolate mofetil suppresses autoimmunity and mortality in the female NZB x NZW F1 mouse model of systemic lupus erythematosus.

OBJECTIVE: To examine the effects of the immunosuppressant, mycophenolate mofetil (MM), on autoimmunity, glomerulonephritis, and mortality in the female NZB x NZW F1 (B/W) mouse model of systemic lupus erythematosus (SLE). METHODS: The development of murine lupus was assessed during the lifespan of 10 female B/W mice given 200 mg/kg/day of MM compared to 10 female B/W mice given vehicle. At 6 week intervals, mice were examined for weight change, albuminuria, antibodies to DNA, and IgG immunoglobulin levels. Morbidity and mortality were assessed daily. In a parallel study, MM treated and control B/W mice were examined at 18 weeks of age for splenocyte phenotype and adhesion molecule expression, as well as antibody titers and in vitro cytokine production in response to immunization with dinitrophenyl-keyhole limpet hemocyanin (DNP-KLH). RESULTS: The administration of MM was well tolerated without apparent side effects. Weight gain in MM treated and control mice was identical through 36 weeks of age. In the treatment group, MM suppressed the development of albuminuria and anti-DNA antibodies compared to the control animals. There were no significant differences between groups in serum concentrations of total IgG. At 60 weeks of age survival in the MM treated group was 100% compared to 10% in the control group. MM did not alter the percentages of CD4, CD8, or IgM positive splenocytes; however, the percentage of CD4+ T lymphocytes expressing very late antigen 4 and intercellular adhesion molecule 1 was reduced. MM inhibited the antibody response to DNP-KLH immunization in vivo; however, in vitro cytokine production in response to KLH was not suppressed. CONCLUSION: MM suppressed the development of autoimmunity and prolonged lifespan in the female B/W mouse model of SLE. Suppression of autoimmunity was achieved without obvious side effects or altered CD4:CD8 T cell ratios. MM may be a useful primary or adjunctive therapy in human SLE.