This article is based on a presentation at the Workshop on Linking Environmental Agents and Autoimmune Diseases held 1-3 September 1998 in Research Triangle Park, North Carolina.
Address correspondence to W.H. Reeves, Division of Rheumatology and Immunology, University of North Carolina at Chapel Hill, 3330 Thurston Bldg, CB #7280, Chapel Hill, NC 27599-7280. Telephone: (919) 966-4191. Fax: (919) 966-1739. E-mail: westley_reeves@unc.edu
This work was supported by research grants from the U.S. Public Health Service (R01-AR44731, R01-AR40391, and T32-AR7416). H.B. Richards is an Arthritis Foundation Postdoctoral Fellow.
Received 28 December 1998; accepted 23 April 1999.
Systemic lupus erythematosus (SLE) is an idiopathic autoimmune syndrome influenced by both genetic and environmental factors and characterized immunologically by the development of autoantibodies directed against self-nuclear, nucleolar, and cytoplasmic antigens (
1). Autoantibodies produced in SLE that serve as subset-specific disease markers include anti-Smith antigen (Sm), antiribosomal P, and anti-double-stranded DNA (anti-dsDNA). Other antibodies associated with SLE, such as anti-nuclear ribonucleoprotein (nRNP), anti-single stranded DNA (anti-ssDNA), antichromatin, antihistone, and anti-Su are less subset specific. SLE is defined clinically by a spectrum of abnormalities such as skin rashes (malar rash, photosensitivity, discoid lesions), nonerosive arthritis, serositis, central nervous system involvement (seizures, psychosis, and other manifestations), and immune complex-mediated glomerulonephritis (
2). A similar syndrome develops spontaneously in (NZB
NZW)F
1 mice (
3). Although a useful model for SLE, the lupuslike disease in these mice is not associated with arthritis, serositis, rashes, or some of the characteristic serological abnormalities (anti-Sm and antiribosomal P autoantibodies) (Table 1).
Certain medications, notably procainamide, quinidine, hydralazine, methyldopa, and isoniazid, induce a syndrome in humans that resembles idiopathic lupus (4). Drug-induced lupus is associated with arthritis, serositis, and other manifestations of SLE but not with glomerulonephritis (5) (Table 1). Autoantibodies to a subset of antigens (anti-ssDNA, -chromatin, -histone) also are produced (6), whereas the marker autoantibodies anti-dsDNA, anti-Sm, and antiribosomal P are not. Thus, although similar in some respects to idiopathic lupus, both the lupuslike syndrome in (NZB NZW)F1 mice and drug-induced lupus differ from SLE in key respects (Table 1).
Our laboratory has established a mouse model in which a lupuslike syndrome is induced by a single intraperitoneal (ip) injection of pristane (2,6,10,14-tetramethylpentadecane) (7,8). All inbred strains of mice tested so far are susceptible. As indicated in Table 1, the lupuslike syndrome developing in pristane-treated mice closely resembles idiopathic SLE. Pristane-treated mice develop a strikingly similar immune complex disease with severe glomerulonephritis (8). Although arthritis develops in some strains, it is erosive and therefore more reminiscent of rheumatoid arthritis than SLE (9,10). In addition, pristane treatment induces the marker autoantibodies characteristic of SLE, including anti-dsDNA, anti-Sm, and antiribosomal P along with a variety of other lupus-associated autoantibodies that includes antihistone, antichromatin, and anti-Su (7,11,12). Thus, pristane-induced lupus appears to mimic the human idiopathic lupus syndrome more closely than either drug-induced lupus or the lupuslike syndrome of (NZB NZW)F1 mice. Significantly, pristane is the first chemical to induce a true SLE syndrome with both characteristic autoantibodies and immune complex disease. Moreover, human exposure to pristane and related hydrocarbons is widespread (13-17), making pristane-induced lupus a useful model for understanding how chemicals in the environment may trigger lupus.
Mice
Female SJL/J and BALB/c mice 4 weeks of age were purchased from Jackson Laboratory (Bar Harbor, ME) and housed in a conventional animal facility. At 10 weeks of age, SJL/J and BALB/cByJ mice received a single injection (0.5 mL, ip) of pristane or sterile phosphate-buffered saline (PBS). Sera were collected from the tail vein before injection at 1, 2, and 4 weeks afterward and at 1-month intervals thereafter. Urine samples were tested monthly for protein concentration using Albustix reagent strips (Miles Laboratories, Elkhart, IN). Additional SJL and BALB/c ByJ mice were injected with HgCl
2 (1.6 mg/kg subcutaneously twice weekly) or with sterile PBS for 8 weeks (
18). The care and treatment of animals in this study were in compliance with all applicable federal and state regulations. The University of North Carolina at Chapel Hill is an Association for the Assessment and Accreditation of Laboratory Care (AAALAC)-accredited institution.
Immunoprecipitation
K562 (human erythroleukemia) cells (American Type Culture Collection, Rockville, MD) were radiolabeled with [35S]methionine, and cell extracts were immunoprecipitated using murine sera as described (7). Human prototype sera specific for nRNP, Sm, or Su antigens were obtained with informed consent and used as standards. Immunoprecipitated proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography.
Fluorescence Assay for Autoantibodies
Indirect immunofluorescence of autoantibodies to nuclear and cytoplasmic antigens was performed using methanol-fixed HeLa cells (11). Cells were incubated for 30 min with 1:40 murine serum in blocking buffer (10% calf serum in PBS), washed 3 times with PBS, then incubated for 30 min with 1:40 fluorocein isothiocyanate-conjugated goat anti-mouse IgG (
-chain-specific; Southern Biotechnology Associates, Birmingham, AL). After another washing, the cells were viewed with an epifluorescence microscope.
Histopathology
Peritoneal tissue sections were removed from pristane-treated BALB/c mice 7 months after treatment. For light microscopy, tissue was fixed in 4% paraformaldehyde and 4-µm paraffin sections were stained with hematoxylin and eosin.
Granuloma Formation
Intraperitoneal injection of pristane is followed by engulfment of the oil by phagocytic cells. The phagocytes become organized into polyplike structures or lipogranulomas (
19,20). A typical lipogranuloma from a pristane-treated BALB/c mouse is illustrated in Figure 1A. Large polypoid masses adherent to the serosal surface of the peritoneal cavity are apparent. Numerous oil droplets are seen within these masses and are shown at higher power in Figure 1B. Although pristane droplets are taken up into macrophages by phagocytosis (
20), many of the droplets illustrated in Figure 1B are considerably larger than a cell. Palisading of cells surrounding these large oil droplets is readily apparent. This pattern is very reminiscent of the organization of epithelioid macrophages around large foreign bodies, including certain biomaterials such as silicone implants (
21).
Figure 1. Pristane granuloma. Hematoxylin-eosin staining of a lipogranuloma attached to the peritoneal mesothelium of a BALB/c mouse injected 6 months earlier with pristane (0.5 mL intraperitoneally). (A) Low-power view showing abdominal skeletal muscle on either side of the centrally located polypoid lipogranuloma. Original magnification 100 . (B) High-power view showing oil droplets of various sizes within the lipogranuloma. Note the flattened, epithelioid cells encapsulating the larger oil droplets. Original magnification 400 . (C) High-power view showing lymphocytic infiltrate in the vicinity of multiple small oil droplets contained within the lipogranuloma. Original magnification 400 .
Like pristane, the tissue reaction to silicone gel is characterized by poorly organized granulomas with cystic spaces, presumably containing the foreign material (22). Silicone granulomas are in many respects typical foreign body-type granulomas, containing aggregates of epithelioid macrophages surrounded by dense infiltrates of lymphocytes and neutrophils. Lymphocytic infiltrates also are apparent in pristane granulomas (Figure 1C). Plasma cells are prominent in these lesions and in BALB/c mice may develop into plasmacytomas (19). Plasma cells also may be prominent in silicone granulomas (23).
The pathogenesis of oil granulomas is incompletely understood. However, in view of the hydrophobicity of pristane, some similarities with the inflammatory response to silicone and other hydrophobic biomaterials may be expected. The initial event is likely to be the interaction of plasma proteins, such as fibrinogen, with the material (24,25). Subsequently, additional host proteins bind to the monolayer of partially denatured proteins coating the material. The adsorbed proteins may play a crucial role in recruiting inflammatory cells. The rapid binding of C3b to a hydrophobic foreign material is followed by conversion to the hemolytically inactive, but still opsonic, iC3b form (26). Phagocytic cells such as monocytes and macrophages can recognize diverse foreign molecules through a variety of pattern receptors, including receptors for complement component C3 and fibrinogen--two of the proteins that bind tightly to the surfaces of biopolymers. Complement receptor 3 (CR3, CD11b/CD18, Mac-1), a receptor for iC3B, appears to play a critical role in the attachment of monocytes or other phagocytic cells to hydrophobic materials (26). Fibrinogen, another serum protein that adsorbs to foreign bodies, also is a ligand for CR3 (27) and may play a role in the recruitment of inflammatory cells (28).
In addition to CR3, macrophage class A scavenger receptors (29) are involved in the adherence of macrophage cell lines to serum-coated polystyrene wells, and therefore also could play a role in the recognition of foreign materials such as pristane (30). Ligation of macrophage Fc receptors, CR3, or scavenger receptors can have important effects on macrophage activation (31,32). In view of the apparent coating of pristane oil droplets by epithelioid cells (Figure 1B), it will be of interest to investigate the role of CR3, scavenger receptors, and other macrophage surface receptors mediating innate immunity in the development of lipogranulomas in pristane-treated mice. Recent studies in our laboratory suggest that macrophages in these lesions are the likely source of several cytokines critical for the development of autoimmunity in pristane-treated mice, notably interleukin (IL)-6 and IL-12 (12,33). Further studies will be necessary, however, to establish the mechanism by which these macrophages recognize pristane and become activated by it.
Induction of Autoantibodies by Pristane and Mercuric Chloride
Intraperitoneal injection of pristane is associated with two phases of autoantibody production (8). IgM anti-ssDNA and antihistone autoantibodies predominate during the early phase, occurring approximately 2 weeks after treatment. These autoantibodies are not lupus specific. In contrast, lupus-specific autoantibodies such as anti-dsDNA, anti-Sm, and antiribosomal P are generated during the late phase, 2-6 months after treatment. Interestingly, the autoantibody specificities vary between strains. For example, sera from pristane-treated BALB/c and SJL mice exhibit distinct patterns of staining in immunofluorescence assays (11) (Figure 2). Sera from BALB/c mice treated 6 months earlier with pristane displayed predominantly speckled nuclear staining, sparing the nucleoli (Figure 2A). In contrast, sera from pristane-treated SJL mice stained the cytoplasm intensely, with only weak nuclear staining (Figure 2B), whereas sera from PBS-treated SJL mice of the same age did not stain (Figure 2D). The SJL strain is of particular interest due to its predilection to produce antifibrillarin autoantibodies in response to mercuric chloride treatment (34,35). Antifibrillarin autoantibodies were associated with nucleolar immunofluorescence, as illustrated in Figure 2C. Thus, two chemicals, mercuric chloride and pristane, induced very different types of autoantibodies in SJL mice, as indicated by immunofluorescence assays. Pristane-treated animals developed autoantibodies primarily directed at one or more cytoplasmic antigens (Figure 2B), whereas mercuric chloride-treated mice developed autoantibodies specific for the nucleolar autoantigen fibrillarin (Figure 2C).
Figure 2. Indirect immunofluorescence. Indirect immunofluorescence of autoantibodies to nuclear and cytoplasmic antigens was performed using methanol-fixed HeLa cells as substrate (11). Mouse sera were tested at a 1:40 dilution and binding of autoantibodies was detected using fluorescein isothiocyanate-conjugated goat antimouse IgG (-chain-specific, 1:40 dilution). (A) Serum from a pristane-treated BALB/c mouse. (B) Serum from a pristane-treated SJL mouse. (C) Serum from a mercuric chloride-treated SJL mouse. (D) Serum from a saline-treated SJL mouse. Sera were obtained 6 months after treatment.
The different patterns of autoantibody production in BALB/c versus those in SJL mice suggested by immunofluorescence studies were confirmed by immunoprecipitation assays (Figure 3). Sera from BALB/c mice immunoprecipitated a group of proteins comigrating with proteins immunoprecipitated by a human anti-nRNP reference serum and designated A, B´/B, C, D, E/F, and G. They are components of the U1 small nuclear ribonucleoprotein (snRNP) particle, a complex of all of these proteins with a single molecule of U1 small nuclear RNA (36,37). The U1 snRNP can be immunoprecipitated as a particle both by anti-nRNP and by anti-Sm autoantibodies. Pristane-treated BALB/c mice produce both anti-nRNP and anti-Sm autoantibodies (38), and their sera immunoprecipitate the U1 snRNP particle specifically (Figure 3). Pristane-treated BALB/c mice produce additional lupus-associated autoantibodies, including anti-Su (100/102-kDa doublet) (Figure 3) as well as anti-dsDNA, anti-ssDNA, and antichromatin (12). Titers of these autoantibodies can be as high as in human lupus (39). In striking contrast, sera from pristane-treated SJL mice immunoprecipitated a group of three polypeptides that comigrate with the ribosomal P0, P1, and P2 proteins recognized by human reference serum with antiribosomal P autoantibodies (Figure 3, right panel, lanes 1-5). SJL sera did not immunoprecipitate components of the U1 snRNP, whereas BALB/c sera did not immunoprecipitate P0, P1, or P2. Serum from a saline-treated control SJL mouse failed to immunoprecipitate any of the proteins (Figure 3, right panel, lane 6).
Figure 3. Determination of autoantibody specificities by immunoprecipitation. Sera from pristane-treated BALB/c and SJL mice were tested for immunoprecipitation of radiolabeled proteins from K562 cells (7). BALB/c sera (n = 5) immunoprecipitated protein components of U1 small nuclear ribonucleoproteins (snRNPs) (A, B´/B, C, D, E/F, G) as well as the 100/102-kDa Su antigens. In contrast, SJL sera (n = 5) immunoprecipitated the ribosomal P antigens P0, P1, and P2. Lane 6 shows immunoprecipitation using serum from a phosphate-buffered saline-treated SJL mouse (negative control). Immunoprecipitates using human reference sera containing anti-Su, nuclear ribonucleoprotein antigen (anti-nRNP) (specific for components of the U1 snRNP), or antiribosomal P (r-P) are shown on the left for comparison. Positions of molecular weight markers are indicated on the right.
Autoantibody production by pristane-treated mice is highly cytokine dependent (12). IL-6 plays a critical role in the production of anti-dsDNA and antichromatin autoantibodies but has less effect on anti-nRNP/Sm and anti-Su autoantibody production in this model. IL-6 is a pleiotropic cytokine thought to be of pivotal importance to immune regulation through its action on B and T cells (40). It is produced in large quantities by macrophages that have engulfed pristane and serves as a key plasmacytoma growth factor (41,42). As in pristane-induced lupus, IL-6 also has been implicated in the pathogenesis of anti-DNA antibodies and nephritis in (NZB NZW)F1 mice (43). Interestingly, patients with IL-6-secreting tumors such as atrial myxomas produce autoantibodies (44).
In addition, microbial stimulation appears to be an important cofactor in the induction of autoantibodies by pristane, as the disease is milder in specific pathogen-free mice (housed in barrier cages with autoclaved food, water, and bedding) than in conventionally housed animals (45). Not only are pathogen-free BALB/c mice less susceptible to the development of lupuslike disease, they also are refractory to plasmacytoma induction by pristane (46). The mechanism of this effect remains unclear but could reflect stimulation of cytokine production by microbial products such as lipopolysaccharide, a powerful inducer of IL-6 production.
Immune Complex-Mediated Glomerulonephritis in Pristane-Treated Mice
In addition to autoantibodies characteristic of SLE, BALB/c and SJL mice treated with pristane develop renal lesions strongly resembling lupus nephritis (8,11). These are characterized by glomerular deposition of IgG, IgM, and complement, and marked mesangial hypercellularity progressing to severe mesangiocapillary lesions. Significant proteinuria develops in association with the evolution of mesangiocapillary lesions. Although anti-dsDNA autoantibodies are implicated in the pathogenesis of lupus nephritis, the renal lesions in pristane-treated mice develop well before the onset of anti-dsDNA autoantibody production. Their pathogenesis currently is being investigated. The induction of severe nephritis sets pristane-induced lupus apart from other forms of chemically induced lupuslike disease such as procainamide-induced lupus in which nephritis is extremely unusual (Table 1).
Implications for the Pathogenesis of Autoimmune Disease
SLE has long been considered primarily a genetic disease (47). Clearly, hereditary factors are of primary importance in many cases of the disease and in spontaneous mouse models of lupus, where multiple disease susceptibility loci have been mapped (47,48). However, the induction by pristane of a disease closely resembling SLE in a variety of mouse strains raises the possibility that environmental agents could be important triggers of sporadic lupus. In addition to the BALB/c and SJL strains presented here, C57BL/6, DBA/1, DBA/2, A.SW, and other strains develop lupus-specific autoantibodies and/or nephritis after pristane treatment (49).
Although the precise mechanism of the induction of autoimmune disease by pristane remains unclear, we speculate that the injection of pristane and other oils may stimulate immunologic pathways mimicking those involved in the idiopathic form of the disease. Identifying these pathways may shed light on the pathogenesis of spontaneous lupus. The rapid uptake and/or encapsulation (Figure 1B) of pristane by phagocytic cells argues that the initial defect may lie in the response of these cells to the oil. That possibility also is supported by the importance of macrophage-derived cytokines, including IL-6 (12) and IL-12 (33), in the development of lupus in pristane-treated mice. The influx of CD4+ T cells and B cells into the lipogranulomas suggests that upon contact with the oil, phagocytes may elaborate factors (chemokine possibly) that recruit additional cell populations. How the formation of aggregates of lymphoid tissue in the vicinity of the oil droplets creates a milieu favoring the abrogation of immune tolerance remains a central but unanswered question. Addressing this question will undoubtedly require a better understanding of the immunotoxicologic properties of pristane.
Immunotoxicology of Pristane
Pristane is a medium-chain-length isoprenoid alkane with potent adjuvant activity found in certain mineral oils (50) and derived from the phytyl moiety of chlorophyll (51). Pristane is found ubiquitously throughout the environment, occurring in zooplankton, various geologic sediments, and crude as well as marine and freshwater fish oils. There has been considerable interest in this substance ever since the demonstration by Potter (52) and Anderson (53) that injection of mineral oil or pristane causes plasmacytomas in certain strains of mice such as BALB/cPtAn. We recently found that some, but not all, mineral oils can induce lupus-specific autoantibodies in BALB/c mice similar to those seen with pristane (54). The ability of mineral oil to promote autoantibody formation may have public health implications due to the significant human exposure to this material in the environment.
The use of mineral oil and other paraffinoids is widespread in medications (e.g., laxatives, nose drops, petroleum jelly, baby oils), as a protective coating for foods (e.g., apples, cucumbers, cheese), for food packaging (e.g., milk, baked goods), and as a lubricant in baking (13,17,55,56). The average diet in the United States contains 47.5 g of mineral oil annually (57,58). Human ingestion of mineral oil leads to partial absorption through the intestine and transport to the portal lymph nodes where oil granulomas similar to those in pristane-treated mice form (13,14,16,58). Inhalation of mineral oil or other hydrocarbons causes lipoid pneumonia and the development of pulmonary lipogranulomas (59). This disorder was common among children until the Council on Pharmacy and Chemistry removed nasal inhalant preparations containing petrolatum from the medications included in its list of "New and Nonofficial Remedies." Mineral oil was replaced by other vehicles such as saline (59).
The ability of mineral oil to induce autoimmunity in humans has not been studied extensively. However, there are controversial reports of adjuvant arthritis in humans injected with hydrocarbons or silicone (60). Hydrocarbon exposure also has been linked to the development of Goodpasture syndrome with autoantibodies against components of the glomerular basement membrane (61). Silicone is similar in some respects to pristane: both are inert, hydrophobic substances taken up by phagocytic cells, both have been linked to plasmacytoma induction in mice (62), and both have been associated with autoimmunity. Thus, there could be human analogs of pristane-induced lupus.
Although a variety of chemicals and drugs have been associated with the induction of a lupuslike syndrome, pristane is the only chemical that appears to cause a lupus syndrome with the typical clinical manifestations (nephritis, serositis, arthritis) as well as characteristic autoantibodies (anti-dsDNA, anti-Sm, antiribosomal P). Thus, pristane induces a more prototypical form of the disease than procainamide, quinidine, hydralazine, methyldopa, isoniazid, or minocycline. Lupuslike disease appears to be induced largely independent of genetic background, although there are significant interstrain differences in disease expression.
The onset of lupuslike disease in many cases of human SLE and in the spontaneous murine models [(NZB/W)F1, MRL/lpr, BXSB] appears to be determined primarily by heredity, with environmental factors playing a secondary role. In contrast, the onset of pristane-induced lupus is triggered primarily by exposure to a chemical, whereas genetic factors modulate disease expression. The chemical induction of a full-blown lupus syndrome in mice that are not considered autoimmune prone raises the possibility that chemical exposure to pristane or pristanelike substances could account for certain sporadic cases of lupus developing in patients without a family history of the disease. Environmental exposure to alkanes, paraffins, and other hydrocarbons is common and could be an important trigger of autoimmunity in a subset of patients.
REFERENCES AND NOTES
1. Tan EM. Autoantibodies to nuclear antigens (ANA): their biology and medicine. Adv Immunol 33:167-240 (1982).
2. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271-1277 (1982).
3. Theofilopoulos AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol 37:269-390 (1985).
4. Hess E. Drug-related lupus. N Engl J Med 318:1460-1462 (1988).
5. Mongey AB, Hess EV. The potential role of environmental agents in systemic lupus erythematosus and associated disorders, In: Dubois' Lupus Erythematosus (Wallace DJ, Hahn BH, eds). Philadelphia:Lea and Febiger, 1993;37-48.
6. Rubin RL, Bell SA, Burlingame RW. Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex. J Clin Invest 90:165-173 (1992).
7. Satoh M, Reeves WH. Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J Exp Med 180:2341-2346 (1994).
8. Satoh M, Kumar A, Kanwar YS, Reeves WH. Antinuclear antibody production and immune complex glomerulonephritis in BALB/c mice treated with pristane. Proc Natl Acad Sci USA 92:10934-10938 (1995).
9. Potter M, Wax JS. Genetics of susceptibility to pristane-induced plasmacytomas in BALB/cAn: reduced susceptibility in BALB/cJ with a brief description of pristane-induced arthritis. J Immunol 127:1591-1595 (1981).
10. Wooley PH, Seibold JR, Whalen JD, Chapdelaine JM. Pristane-induced arthritis. The immunologic and genetic features of an experimental murine model of autoimmune disease. Arthritis Rheum 32:1022-1030 (1989).
11. Satoh M, Hamilton KJ, Ajmani AK, Dong X, Wang J, Kanwar YS, Reeves WH. Autoantibodies to ribosomal P antigens with immune complex glomerulonephritis in SJL mice treated with pristane. J Immunol 157:3200-3206 (1996).
12. Richards HB, Satoh M, Shaw M, Libert C, Poli V, Reeves WH. IL-6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. J Exp Med 188:985-990 (1998).
13. Dincsoy HP, Weesner RE, MacGee J. Lipogranulomas in non-fatty human livers: a mineral oil induced environmental disease. Am J Clin Pathol 78:35-41 (1982).
14. Cruickshank B. Follicular (mineral oil) lipidosis. I: Epidemiologic studies of involvement of the spleen. Hum Pathol 15:724-730 (1984).
15. Boitnott JK, Margolis S. Mineral oil in human tissues. II: Oil droplets in lymph nodes of the porta hepatis. Bull Johns Hopkins Hosp 118:414-422 (1966).
16.Stryker WA. Absorption of liquid petrolatum ("mineral oil") from the intestine. Arch Pathol 31:670-692 (1941).
17. Grob K, Huber M, Boderius U, Bronz M. Mineral oil material in canned foods. Food Add Contam 14:83-88 (1997).
18. Ochel M, Vohr HW, Pfeiffer C, Gleichmann E. IL-4 is required for the IgE and IgG1 increase and IgG1 autoantibody formation in mice treated with mercuric chloride. J Immunol 146:3006-3011 (1991).
19. Potter M, MacCardle RC. Histology of developing plasma cell neoplasia induced by mineral oil in BALB/c mice. J Natl Cancer Inst 33:497-515 (1964).
20. Leak LV, Potter M, Mayfield WJ. Response of the peritoneal mesothelium to the mineral oil, pristane. Curr Top Microbiol Immunol 122:221-233 (1985).
21. Kao WJ, Zhao QH, Hiltner A, Anderson JM. Theoretical analysis of in vivo macrophage adhesion and foreign body giant cell formation on polydimethylsiloxane, low density polyethylene, and polyetherurethanes. J Biomed Mat Res 28:73-79 (1994).
22. Travis WD, Balogh K, Abraham JJ. Silicone granulomas: report of three cases and review of the literature. Hum Pathol 16:19-27 (1985).
23. Hill SL, Landavere MG, Rose NR. The adjuvant effect of silicone gel and silicone elastomer particles in rats. Curr Top Microbiol Immunol 210:123-137 (1996).
24. Tang L, Eaton JW. Inflammatory responses to biomaterials. Am J Clin Pathol 103:466-471 (1995).
25. Butler JE, Lu EP, Navarro P, Christiansen B. Comparative studies on the interaction of proteins with a polydimethylsiloxane elastomer. I: Monolayer protein capture capacity (PCC) as a function of protein pI, buffer pH and buffer ionic strength. J Molec Recog 10:36-51 (1997).
26. McNally AK, Anderson JM. Complement C3 participation in monocyte adhesion to different surfaces. Proc Natl Acad Sci USA 91:10119-10123 (1994).
27. Altieri DC, Agbanyo FR, Plescia J, Ginsberg MH, Edgington TS, Plow EF. A unique recognition site mediates the interaction of fibrinogen with leukocyte integrin Mac-1 (CD11b/CD18). J Biol Chem 265:12119-12122 (1990).
28. Tang L, Eaton JW. Fibrin(ogen) mediates acute inflammatory responses to biomaterials. J Exp Med 178:2147-2156 (1993).
29. McKnight AJ, Gordon S. Membrane molecules as differentiation antigens of murine macrophages. Adv Immunol 68:271-314 (1998).
30. Fraser I, Hughes D, Gordon S. Divalent cation-independent macrophage adhesion inhibited by monoclonal antibody to murine scavenger receptor. Nature 364:343-346 (1993).
31. Sutterwala FS, Noel GJ, Clynes R, Mosser DM. Selective suppression of interleukin-12 induction after macrophage receptor ligation. J Exp Med 185:1977-1985 (1997).
32. Marth T, Kelsall BL. Regulation of interleukin-12 by complement receptor 3 signaling. J Exp Med 185:1987-1995 (1997).
33. Shaheen VM, Satoh M, Reeves WH. Unpublished data.
34. Hultman P, Enestrom S, Pollard KM, Tan EM. Antifibrillarin autoantibodies in mercury-treated mice. Clin Exp Immunol 78:470-477 (1989).
35. Reuter R, Tessars G, Vohr HW, Gleichmann E, Luhrmann R. Mercuric chloride induces autoantibodies agains U3 small nuclear ribonucleoprotein in susceptible mice. Proc Natl Acad Sci USA 86:237-241 (1989).
36. Craft J. Antibodies to snRNPs in systemic lupus erythematosus. Rheum Dis Clin North Am 18:311-335 (1992).
37. Reeves WH, Satoh M, Richards HB. Origins of antinuclear antibodies, In: Systemic Lupus Erythematosus (Lahita RG, ed). San Diego:Academic Press, 1999;293-317.
38. Satoh M, Langdon JJ, Hamilton KJ, Richards HB, Panka D, Eisenberg RA, Reeves WH. Distinctive immune response patterns of human and murine autoimmune sera to U1 small nuclear ribonucleoprotein C protein. J Clin Invest 97:2619-2626 (1996).
39. Satoh M, Treadwell EL, Reeves WH. Pristane induces high titers of anti-Su and anti-nRNP/Sm autoantibodies in BALB/c mice. Quantitation by antigen capture ELISAs based on monospecific human autoimmune sera. J Immunol Methods 182:51-62 (1995).
40. Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol 54:1-78 (1993).
41. Nordan RP, Potter M. A macrophage-derived factor required by plasmacytomas for survival and proliferation in vitro. Science 233:566-569 (1986).
42. Lattanzio G, Libert C, Aquilina M, Cappelletti M, Ciliberto G, Musiani P, Poli V. Defective development of pristane-oil-induced plasmacytomas in interleukin-6-deficient BALB/c mice. Am J Pathol 151:689-696 (1997).
43. Finck BK, Chan B, Wofsy D. Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. J Clin Invest 94:585-591 (1994).
44. Jourdan M, Bataille R, Seguin J, Zhang XG, Chaptal PA, Klein B. Constitutive production of interleukin-6 and immunologic features in cardiac myxomas. Arthritis Rheum 33:398-402 (1990).
45. Hamilton KJ, Satoh M, Swartz J, Richards HB, Reeves WH. Influence of microbial stimulation on hypergammaglobulinemia and autoantibody production in pristane-induced lupus. Clin Immunol Immunopathol 86:271-279 (1998).
46. Byrd LG, McDonald AH, Gold LG, Potter M. Specific pathogen-free BALB/cAn mice are refractory to plasmacytoma induction by pristane. J Immunol 147:3632-3637 (1991).
47. Theofilopoulos AN. The basis of autoimmunity. Part II: Genetic predisposition. Immunol Today 16:150-159 (1995).
48. Vyse TJ, Kotzin BL. Genetic susceptibility to systemic lupus erythematosus. Annu Rev Immunol 16:261-292 (1998).
49. Satoh M, Shaheen VM, Reeves WH. Unpublished data.
50. Bendoraitis JG, Brown BL, Hepner LS. Isoprenoid hydrocarbons in petroleum. Isolation of 2,6,10,14-tetramethylpentadecane by high temperature gas-liquid chromatography. Anal Chem 34:49-53 (1962).
51. Avigan J, Blumer M. On the origin of pristane in marine organisms. J Lipid Res 9:350-352 (1968).
52. Potter M, Boyce CR. Induction of plasma-cell neoplasms in strain BALB/c mice with mineral oil and mineral oil adjuvants. Nature 193:1086-1087 (1962).
53. Anderson PN, Potter M. Induction of plasma cell tumours in BALB/c mice with 2,6,10,14-tetramethylpentadecane (pristane). Nature 222:994-995 (1969).
54. Satoh M, Shaheen VM, Richards HB, Yoshida H, Shaw M, Lorenson TD, Rosenbauer RJ, Jennette JC, Reeves WH. Unpublished data.
55. Chung JG, Garrett LR, Byers PE, Cuchens MA. A survey of the amount of pristane in common fruits and vegetables. J Food Comp Anal 2:22-27 (1989).
56. Castle L, Kelly M, Gilbert J. Migration of mineral hydrocarbons into foods. 2: Polystyrene, ABS, and waxed paperboard containers for dairy products. Food Add Contam 10:167-174 (1993).
57. Boitnott JK, Margolis S. Mineral oil in human tissues. I: Detection of saturated hydrocarbons using thin-layer chromatography. Bull Johns Hopkins Hosp 118:402-413 (1966).
58. Wanless IR, Geddie WR. Mineral oil lipogranulomata in liver and spleen: a study of 465 autopsies. Arch Pathol Lab Med 109:283-286 (1985).
59. Spickard A. Exogenous lipoid pneumonia. Arch Intern Med 154:686-692 (1994).
60. Kumagai Y, Shiokawa Y, Medsger TAJ, Rodnan GP. Clinical spectrum of connective tissue disease after cosmetic surgery. Observations on eighteen patients and a review of the Japanese literature. Arthritis Rheum 27:1-12 (1984).
61. Beirne GJ, Brennan JT. Glomerulonephritis associated with hydrocarbon solvents: mediated by antiglomerular basement membrane antibody. Arch Environ Health 25:365-369 (1972).
62. Potter M, Morrison S, Wiener F, Zhang XK, Miller FW. Induction of plasmacytomas with silicone gel in genetically susceptible strains of mice. J Natl Cancer Inst 86:1058-1065 (1994).
Last Updated: September 21, 1999
