* Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan; and Department of Public Health, Toyama Medical and Pharmaceutical University, 930-0194, Japan
Received March 19, 2004; accepted May 18, 2004
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ABSTRACT |
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Key Words: endocrine disruptors; environmental estrogens; autoantibody; B cell; systemic lupus erythematosus; SLE.
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INTRODUCTION |
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At the same time, increasing scientific and social attention had been paid to environmentally dispersed chemicals that can enter the body by ingestion or adsorption and that mimic the actions of estrogens. These chemicals are termed endocrine disruptors (EDs) or environmental estrogens and are found in plastics (bisphenol-A, phthalates), detergents and surfactants (octylphenol, nonylphenol), pesticides (methoxychlor, dichlorodiphenyltrichloroethane or DDT, hexachlorobenzene, and dieldrin), industrial chemicals (polychlorinated biphenyls or PCBs, 2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD), phytoestrogens or natural plant estrogens (genistein, coumesterol), and mycoestrogens or fungal products from Fusarium sp. (zearalenone). Some of these estrogenic chemicals have also been shown to influence the immune system.
The actions of endocrine disruptors are assumed to be mediated through estrogen receptors (ERs), presumably translocate the receptorligand complex from the cytoplasm to the nucleus, and induce the synthesis of estrogen receptorregulated proteins. Binding of these chemicals to novel estrogen receptors other than alpha or beta estrogen receptor is also plausible (Arcaro et al., 1999; Das et al., 1997
). Endocrine disruptors mimic hormones, block or alter hormone binding to receptors, or alter the metabolism of natural estrogens (Soto et al., 1995
).
It has been widely noted that females have stronger immune capabilities (particularly B-cellmediated immunity) than males, as evidenced by their better immune responses to a variety of self-antigens and non-self-antigens. This phenomenon of gender-based immunecapability is largely attributed to the effects of sex hormones (Ahmed, Penhale, and Talal, 1985; Grossman, 1984
; Homo-Delarche et al., 1991
). Estrogens regulate the level of serum and uterine IgM, IgA, and IgG (Wira and Sandoe, 1987
), and they augment antibody production to several non-self-antigens and self-antigens. It is possible that endocrine disruptors that mimic estrogenic activity may be involved in the increased incidence of autoimmune diseases such as SLE (Ahmed, 2000
).
To test this hypothesis, we investigated effects of endocrine disruptors on autoantibody production in a popular murine model for SLE. Female BWF1 mice, a F1 hybrid between New Zealand Black and New Zealand White mouse strains, spontaneously develop a systemic autoimmune disorder resembling SLE in humans (Kotzin, 1996; Theofilopoulos, 1985
). The murine disorder is characterized by high levels of IgG autoantibodies including anti-double-stranded DNA (dsDNA) antibody and massive deposition of immune complexes in glomeruli in the kidney. Although both anti-dsDNA and ssDNA antibody are detected in the serum of SLE patients and murine models for SLE, anti-dsDNA Ab is a better marker for SLE and the disease activity (Eaton, Schneider, and Schur, 1983
). There are other ways to evaluate autoantibody production including plaque-forming cell (PFC) assay for anti-RBC Ab. It has been reported that B1 cells produce autoantibody against phosphatidylcholine expressed on bromelain-treated red blood cells (Br-RBC) using PFC assay (Merucolino et al., 1988
). This method was originally developed by Cunningham and based on sensitive RBC lysis by IgM anti-RBC antibody in the presence of complement at the single-cell level (Cunningham, 1974
). More than 95% of affected mice die of renal failure caused by immune complex deposition in the kidney before 12 months of age. A marked mononuclear cell infiltration in the target organs including the kidney and lung is also observed in aged BWF1 mice.
B1 cells are a specialized cell population that are distinguished from conventional B cells (B2 cells) by their origin, cell surface phenotype, unique tissue distribution, and capacity for self-renewal (Hardy and Hayakawa, 2001; Hayakawa et al., 1983
). The cell surface phenotype of B1 cells is B220intIgMhigh IgDlowCD5+IL-5R+, whereas that of B2 cells is B220high IgMintIgDhighCD5-IL-5R. CD5 expression is usually used for differentiating B1 cells and B2 cells. They have also been considered to be involved in autoantibody production in the development of autoimmune diseases (Murakami et al., 1992
; 1994
).
In the present study we found that 17ß-estradiol (E2), a natural estrogen, and diethylstilbestrol (DES) all enhanced IgG anti-DNA antibody production and IgG immune complex deposition in the kidney. Bisphenol-A (BPA) as well as E2 and DES enhanced anti-Br-RBC autoantibody production by B1 cells in vivo. It was also demonstrated that the three EDs directly enhanced in vitro IgM antibody production, including anti-DNA antibody, by B1 cells. Possible roles of endocrine disruptors in the development of autoimmune diseases are discussed.
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MATERIALS AND METHODS |
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Silastic tube implant with endocrine disruptors. Four-week-old female BWF1 mice were ovariectomized as described previously. Silastic implants (1.5 cm in length, i.d.:o.d.; 1.57:3.18 mm, Kaneka Medix), containing 67 mg of the powdered form of E2, DES, or BPA (all obtained from Sigma, Chemical Co., St. Louis, MO), were surgically placed subcutaneously on the back. Ovariectomized mice that received empty Silastic tubes served as controls. The implants were left in situ for 3 to 4 months and blood samples were collected periodically for ELISA. Mice were killed 4 months after implantation for histological and immunological examinations.
Cell preparation. Peritoneal lavage cells were isolated by flushing the peritoneal cavity with 810 ml of RPMI 1640 supplemented with 10% fetal calf serum (FCS). Cell suspensions prepared from mouse spleen were passed through nylon mesh. Red blood cells in the spleen were lysed by ammonium chloride solution. Peritoneal B1 cells were purified by negative selection with MACS (Miltenyi Biotec, GmbH Bergish Gladbach, Germany) to avoid contamination of B2 cells in the peritoneal cavity. CD5+B220+ cells are usually described as B1 cells and CD5B220+ cells as B2 cells in B cell study. However, in the in vitro antibody production assay, we used Thy-1F4/80CD23 peritoneal cells as B1 cells to avoid contamination of B2 cells in the peritoneal cavity. B2, but not B1 cells express CD23 molecules on the cell surfaces. Using this negative selection, B2 cells (CD23+), macrophages (F4/80+), and T cells (Thy-1+) are effectively removed from peritoneal cells. More than 95% of residual cells are B1 cells (CD5+ B220+). Briefly, T lineage cells, macrophages, and B2 cells were depleted by incubating with a biotinylated mAb cocktail, including anti-Thy1.2, anti-F4/80, and anti-CD23 mAbs. The unwanted cells were then removed magnetically after incubation with streptavidin-conjugated MACS beads. In contrast, B2 cells were purified by positive selection with anti-B220 Ab coupled MACS beads (Miltenyi Biotec) because the percentage of CD5+B220+ cells is very low in the spleen of young BWF1 mice. The cell purity for B1 in each B cell fraction was more than 95% throughout the experiments.
ELISA. Anti-DNA antibody activity in the serum is usually detected using double-stranded DNA (dsDNA), whereas anti-DNA antibody activity in the culture supernatant is detected with single-stranded DNA (ssDNA). Both anti-dsDNA and ssDNA antibody are detected in the serum of SLE patients and murine models, although only anti-ssDNA antibody can be detected in the in vitro system, presumably because of a low concentration of anti-DNA antibody in the culture supernatant, and because of higher sensitivity of the assay for ssDNA. It is generally believed that the level of anti-dsDNA antibody is a better marker for disease activity.
Anti-DNA antibody was measured in ELISA using ssDNA for the culture supernatant and dsDNA for the serum. Double-stranded DNA was obtained by digestion of calf thymus DNA (Sigma) with S1 nuclease (Seikagaku Kogyo, Tokyo, Japan), followed by fractionation on A hydroxyapatite column. Single-stranded DNA was obtained by heat degeneration of dsDNA. Flat-bottomed 96-well plates (Nunc, Roskilde, Denmark) treated with 0.001% protamine sulfate were coated with 50 µl of ssDNA solution (5 µg/ml), and dried overnight at 37°. Nonspecific protein binding was blocked by coating the plate with 50% FCS in PBS. After washing with 0.05% Tween 20 in phosphate-buffered saline (PBS), 50 µl of each sample was incubated for 60 min at room temperature, followed by addition of 50 µl of diluted horseradish peroxidase (HRP)labeled goat anti-mouse IgG or anti-mouse IgM Abs (Bethyl Laboratories, Montgomery, TX). The preparations were then incubated for 60 min at room temperature, washed, and developed with 50 µl of HRP substrate (3,3',5,5'-tetramethyl benzidine) with H2O2. The absorbance was read with a Emax precision microplate reader (Molecular Devices Corporation, Sunnyvale, CA) at 450 nm. Pooled sera of aged BWF1 mice with lupus nephritis were used as positive control at 1,000 U/ml. Serum estrogen was detected by Estradiol EIA Kit (Cayman, Ann Arbor, MI) according to the manufacturer's directions in which estradiol tracer (estradiol linked to acetylcholine esterase) is used as the competitor. The lower limit of the assay is 7.8 pg/ml. Serum BPA was detected by Bisphenol-A (BPA) ELISA Kit (TOYOBO. CO., LTD., Osaka, Japan) according to the manufacturer's directions. The lower limit of the assay is 0.01 ng/ml.
Immunofluorescence study. The kidney was embedded in Tissue-Teck OCT compound (Miles Inc., Elkhart, IN) and frozen in liquid nitrogen. Six-micron cryostat sections were incubated in fluorescein (FITC)-conjugated anti-mouse IgG Ab (R19-15, PharMingen) and observed under a fluorescent microscope (Olympus Optical Co., Ltd., Tokyo, Japan). Normal IgG was used as control.
Plaque-forming assay. Plaque-forming cells to autologous bromelain-treated erythrocytes (Br-RBC) were enumerated in a modified Cunningham plaque assay (Cunningham, 1974).This method is based on sensitive RBC lysis by IgM anti-RBC antibody in the presence of complement at a single-cell level. It was previously reported that B1 cells produce autoantibody against phosphatidylcholine expressed on Br-RBC using the PFC assay (Merucolino et al., 1988
). The erythrocytes were first treated with the proteolytic enzyme bromelain (Sigma) (50% erythrocyte suspension in 20 mg/ml bromelain/PBS for 60 min at 37°), then 20 µl of a 30% (v/v) suspension of the Br-RBC was mixed with 106 spleen cells and rabbit complement (Cedarlane Laboratories Ltd., Ontario, CA), loaded into Cunningham chambers, and incubated for 1 to 2 h in a CO2 incubator at 37°. The plaques were counted under a phase-contrast microscope.
Flow cytometry. Flow cytometric analysis on splenic and peritoneal cells was performed with the use of an Epics Elite cell sorter (Coulter Electronics, Hialeah, FL). After Fc block with anti-CD16/32 Ab (PharMingen, San Diego, CA) for 10 min, cells were stained with FITC-conjugated anti-CD4 (GK1.5, PharMingen), phycoerythrin (PE)-conjugated anti-CD8 (536.7, PharMingen) and allophycocyanin (APC)-conjugated anti-B220 (RA3-6B2, PharMingen). Cells were also stained with FITC-conjugated anti-CD5 (537.3RRH) and APC-conjugated anti-B220 Abs. CD5+B220+ cells were detected as B1 cells, and CD5-B220+ cells were detected as B2 cells (shown in Figure 1 of the Supplementary Material online). As reported by Hayakawa et al. (1983)
, B1 cells express a lower level of B220 than B2 cells do. The expression level of CD5 molecules is also lower than on T cells. Twenty thousand cells were analyzed on live cells.
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Reverse transcription and real-time quantitative polymerase chain reaction (PCR) analysis. Total cellular RNA was prepared from purified B1 and B2 cells using RNeasy Mini Kit (Qiagen, Hilden, Germany). Five µg total cellular RNA was reversely transcribed into cDNA using Superscript preamplification kit (Life Technologies, Gaithersburg, MD) and amplified with specific oligonucleotide primers. The sense primer for ER- was 5'-GGCCTGACTCTGCAGCAGCAG-3', and the antisense primer was 5'-GTTGGGGAAGCCCTCTGCTTC-3'. The sense primer for ER-ß was 5'-GGCATTCTACAGTCCTGCTG-3', and the antisense primer was 5'-TCTGCATAGAGAAGCGATGA-3'. The PCR was performed by thermal cycle for 36 cycles of 95° for 60 s, 60° for 60 s, and 72° for 120 s, and the final extension was done at 72° for 10 min. The PCR products of ß-actin, ER
, and ERß were examined by 1.5% agarose gel electrophoresis. After ethidium bromide staining, bands were visible only at the expected size for each mRNA product. Real-time quantitative PCR analysis was performed by means of the ABI7700 sequence detector system (PE Applied Biosystems, Foster City, CA). FAM (6-carboxylfluorescein)-labeled primers were used as target hybridization probes for ER-
and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (ER-
; 5'-GCATGATGAAAGGCGGCATACGGAA-3', GAPDH; 5'-AAGGGACACAGTCAAGGCCGAGAAT-3'). The thermal cycling condition included 50° for 2 min and 95° for 10 min, followed by 45 cycles of amplification at 95° for 15 s and 55° for 1.5 min for denaturing and annealing, respectively. The PCR reactions were run in duplicate; ER-
quantity was normalized by the level of GAPDH.
Statistics. Comparisons between two groups were performed using the Student's t-test. Results are presented as mean ± SD. Values of p < 0.05 were considered statistically significant.
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RESULTS |
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DISCUSSION |
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Diethylstilbestrol, a synthetic estrogen with strong estrogenic activity, once had been prescribed to pregnant women to ameliorate problems during pregnancy for a certain period of time. It caused adverse effects on the female offspring known as "DES daughter syndrome" (Wingard and Turiel, 1988). Limited studies in humans have suggested that DES-exposed women developed a variety of autoimmune diseases (Noller et al., 1988
). Animal studies have confirmed that DES has profound immunomodulatory effects, including the induction of autoantibodies to cardiolipin (Forsberg, 2000
). These results are consistent with our findings that a DES implant resulted in increased plaque-forming cells (PFC) producing anti-Br-RBC autoantibody, IgG anti-DNA antibody production, and immune complex deposition in castrated BWF1 mice. Diethystilbestrol also directly enhanced IgM production by purified B1 cells in vitro as effectively as E2. It should be noted that BPA also showed a significant enhancement of anti-Br-RBC autoantibody production in vivo and increased IgM antibody production by B1 cells in vitro, in spite of weak estrogenic activity. These findings suggest a possibility that B1 cells are sensitive target cells for endocrine disruptors with weak estrogenic activity. In contrast, BPA failed to enhance IgG anti-DNA production, whereas it promoted IgM autoantibody production by B1 cells both in vivo and in vitro. This is presumably due to weak estrogenic activity of BPA (10,000-fold weaker than E2) level in mice implanted with BPA, as shown in Figure 1. It has been reported that BPA and NP express their activity at concentrations of 106 to 107 M in the human breast cancer cell line MCF-7, whereas 17ß-estradiol is still effective at 107 to 1011 M (Inadera et al., 2000
). It is well established that IgG, but not IgM, anti-DNA antibody production and subsequent IgG immune complex deposition in the kidney are well correlated with the development of lupus nephritis, as reviewed by Shirai et al. (1991)
. Because IgG anti-DNA antibody production needs T cell help, including cytokine production, it is possible that the serum level of BPA is enough to activate anti-Br-RBC autoantibody by B1 cells, but not enough to activate helper T cells to provide T cell help essential for IgG class switching. It has been reported that E2 can modulate both pro-inflammatory and anti-inflammatory cytokine syntheses by CD4 T cells depending the dose of hormone (Gilmore, Weiner, and Correale, 1997
). Nevertheless, many other articles describing the effect of estrogens on T cells indicate that the effect varies depending on the experimental systems employed, and therefore the precise mechanism of action remains largely unknown (Ahmed, 2000
). It remains to be elucidated whether Ig class-switching from IgM to IgG occurs in B1 cells in the development of autoimmune diseases. Preliminary data suggest that B1 cells produce IgG antibody in the presence of CD4 T cells obtained from aged, but not young BWF1 mice (unpublished data). It is possible that T cells as well as B2 cells have a higher threshold for endocrine disruptors than B1 cells do. In other words, B1 cells are immunocompetent cells highly sensitive to endocrine disruptors in the immune system. In the present study, mice were implanted with 300350 mg/kg of BPA; yet the safe daily intake for BPA is 50 mg/kg/day. On the other hand, the permissible elution limit of BPA from polycarbonate tableware is 2.5 ppm, whereas actual elution from tableware is at most several parts per billion. It is, therefore, very unlikely that people are exposed to the high dose of BPA used in the present study. However, because B1 cells appeared to be more sensitive to EDs in the immune system, the effect of lower doses and longer exposures of BPA should be investigated in the future.
Many EDs bind to ERs, and then the estrogenER complex recognizes the estrogen response element (ERE) located in the 5'-flanking region of a particular gene to be expressed (Nishikawa et al., 1999). However, it remains unknown which genes in B1 cells are activated or suppressed by stimulation with EDs. Comprehensive gene expression analysis on B1 cells by SAGE (serial analysis of gene expression) or by DNA microarray will be useful to identify the responsible genes for enhanced autoantibody production by B1 cells. It should be noted that ER
mRNA in B1 cells was increased in aged BWF1 mice, whereas that in B2 cells was rather decreased. Erlandsson et al. (2003)
reported that ER-
, but not ER-ß, is necessary for the E2-mediated elevation of immunoglobulin production by B cells in young mice. It was also demonstrated that E2 treatment suppresses B-cell development in the bone marrow (Medina, Stasser, and Kincade, 2000
) and stimulates antibody production (Carlsten et al., 1989
). Enhanced expression of ER-
gene in B1 cells in aged BWF1 mice may possibly facilitate autoantibody production by B1 cells by EDs during the development of lupus nephritis.
In conclusion, we demonstrated that endocrine disruptors directly enhanced autoantibody production by B1 cells. The increased incidence of autoimmune diseases such as SLE and ITP for several decades may possibly be attributed to accumulated endocrine disruptors. B1 cells, because of their high sensitivity, may also provide a good tool for evaluating biological significance of endocrine disruptors for the development of autoimmune diseases.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Fax: 81-3-5841-3393; E-mail: koujim{at}m.u-tokyo.ac.jp
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