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Clin Exp Immunol. Aug 2005; 141(2): 230–237.
PMCID: PMC1809443

Modulation of the immune response in pristane-induced lupus by expression of activation and inhibitory Fc receptors


Altered homeostasis in Fcγ receptor (FcγR) expression has been implicated in the induction of both immune complex-mediated glomerulonephritis and autoantibody production in systemic lupus erythematosus. FcγRI and III are required for immune complexes to activate inflammatory cells, thereby inciting tissue injury. In contrast, FcγRIIB functions as a negative regulator of immune complex-mediated inflammation and autoantibody production. We investigated the role of FcγRI/III versus FcγRIIB on pristane-induced lupus in mice. FcγRI/III and FcγRIIB-deficient (−/−) and control (+/+) BALB/c mice were injected with either pristane or PBS. Proteinuria and glomerular immune deposits were evaluated 9 months after treatment and serial sera were analysed for total IgG levels and lupus-specific autoantibodies. The incidence of nephritis was higher in pristane-treated FcγRIIB−/− mice than pristane-treated FcγRI/III−/− and +/+ mice. Hypergammaglobulinaemia and spontaneous anti-DNA/chromatin autoantibody production were associated with interleukin (IL)-6 over-expression in FcγRIIB−/− mice and were augmented further by pristane treatment when compared to both FcγRI/III−/− and +/+ mice. Lack of either FcγRIIB or FcγRI/III had little effect on both anti-nRNP/Sm and anti-Su production induced by pristane. Our results confirm that spontaneous autoimmunity occurs in the absence of FcγRIIB. Moreover, the lupus-like syndrome induced by pristane in BALB/c mice was regulated by opposing activating and inhibitory FcγRs. Activating FcγRs were required for significant proteinuria and unbridled activation in the absence of FcγRIIB dramatically exacerbated glomerular inflammatory responses. FcγRIIB may be a key modulator that suppresses cell activation in the inflammatory immune response in systemic lupus erythematosus in humans.

Keywords: autoantibodies, Fcγ receptors, neprithis, pristane, SLE


Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production leading to immune complex (IC) formation, resulting in a variety of organ manifestations with a high prevalence of nephritis. The inflammatory process in lupus nephritis (LN) is generally considered to be initiated by interaction between IgG-containing ICs and myeloid-derived effector cells, particularly monocytes/macrophages [1]. This interaction is thought to be mediated by the cellular receptor for the Fc portion of IgG (FcγR) as demonstrated by lack of nephritis in the face of immune complex deposits in NZB/NZW mice lacking FcγRI/III [2]. However, the precise kinetics of events underlying this process remain to be elucidated. Moreover, it is unclear whether the amount and location of IC deposits in the glomerulus is critical or whether an altered balance between activating and inhibitory FcγRs in the context of lesser IC deposits is sufficient.

FcγRs function as a bridge between humoral and cellular immunity. FcγRI and III activate inflammatory cells, such as monocytes/macrophages and neutrophils, through their immunoreceptor tyrosine-based activation motif (ITAM) whereas FcγRIIB, which contain an immunoreceptor tyrosine-based inhibitory motif (ITIM), act as inhibitors [3]. The ligand-binding subunit of both FcγRI and III is a transmembrane molecule with extracellular Ig-like domains, which is associated with an ITAM-containing intracytoplasmic subunit, namely the gamma chain [4]. In contrast, ITIM containing FcγRIIB is not physically associated with nor signal via the gamma chain. ICs co-engage both activation and inhibitory receptors simultaneously, resulting in a cellular response which reflects the expression levels of each pair member. In this manner, FcγRs are capable of setting thresholds for activation and terminating activation signals by ICs. In addition to its inhibitory activity on myeloid cell responses, FcγRIIB is also expressed on B lymphocytes and contributes to maintaining tolerance and limiting IC formation by promoting apoptosis of low-affinity self-reactive B cells in the germinal centre [5]. It also acts as a negative feedback regulator of antibody production and limits the accumulation of autoreactive plasma cells [6,7].

The study of FcγRI/III and IIB-deficient (−/−) mice has provided evidence of the role of these receptors in mediating the mechanisms involved in the development of several autoimmune, IC-mediated experimental diseases, including myelin oligodendrocyte glycoprotein-induced encephalomyelitis, collagen-induced arthritis and collagen-induced Goodpasture's syndrome [8,9]. Moreover, it has been suggested that a defect in inhibitory FcγRIIB may lead to the spontaneous development of SLE along with IC-mediated glomerulonephritis with the appropriate genetic background [10,11].

To further define the role of FcγR in SLE we studied BALB/c mice lacking the common FcR γ chain (FcγRI/III) or FcγR IIB treated with pristane which induces a lupus-like syndrome in mice [12].

Materials and methods


Female BALB/c FcγRIIB−/−, FcγR common gamma chain−/− (lacking functional FcγRI and III, termed FcγRI/III in this paper), and age/sex-matched control (+/+) mice (Taconic Farms, Germantown, NY, USA), aged 8–12 weeks, were housed under specific pathogen-free conditions and injected once intraperitoneally with either 0·5 ml of pristane (2, 6, 10, 14-tetramethylpentadecane, Sigma Chemical Co., St Louis, MO, USA) or an equal volume of phosphate-buffered saline (PBS). Serum samples were collected from the tail vein before treatment, 2 weeks later and then at 1-month intervals. At 9 months proteinuria was measured by enzyme-linked immunosorbent assay (ELISA) specific for albumin following the manufacturer's instructions (Bio-rad Inc., Hercules, CA, USA). Mice were euthanized, peritoneal lavage performed and kidneys removed.

Renal pathology

All samples were evaluated by a single renal pathologist (BPC) in a blinded manner, as reported previously [12]. For light microscopy (LM), tissue was fixed in 4% paraformaldehyde and 3 µm paraffin sections were stained with periodic acid schiffs (PAS).

For immunofluorescence (IF), tissue was embedded in OCT compound (Sakura, Japan) and 4 µm unfixed frozen sections were stained with 1: 20 fluoroscein isothiocyanate (FITC)-conjugated goat anti-mouse IgG1, 2a, 2b or 3 or IgM (Southern Biotechnology, Birmingham, AL, USA), or with rabbit anti-mouse C3 (Cappel, Durham, NC, USA). Glomerular staining was graded according to intensity on a 0–4+ scale (0 = no staining, 4+ = maximum intensity staining) and the pattern of staining (predominantly mesangial versus capillary) was recorded. Background was defined as the strongest level of staining observed in PBS-treated +/+ mice and only staining above background was considered positive.


Total levels of IgG1 and IgG2a were measured by sandwich ELISA using 1: 200 000 diluted sera, as described previously [12]. Capture antibodies were goat anti-mouse κ/l light chain (Southern Biotechnology) whereas alkaline phosphatase-labelled goat anti-mouse IgG1 and 2a (1: 1000 dilution, Southern Biotechnology) served as secondary antibodies. Isotype standards were used for standard curve-fitting.

Anti-chromatin autoantibody levels were determined using 1: 500 diluted sera, as reported previously [13]. Binding was detected by alkaline phosphatase-conjugated goat anti-mouse IgG (1: 1000, Southern Biotechnology). A high titre positive MRL/lpr serum served as standard.

ELISA for cytokines was performed on culture supernatants of peritoneal cells using rat monoclonal antibody (mAb) pairs for mouse interleukin (IL-6), interferon (IFN)-γ, IL-12 and tumour necrosis factor (TNF)-α (PharMingen, San Diego, CA, USA). Samples were added undiluted and recombinant mouse cytokines served as standards (PharMingen). After incubation with biotinylated rat anti-mouse cytokine-specific antibodies, 100 µl/well of 1: 1000 streptavidin-alkaline phosphatase (Southern Biotechnology) was added, and the reaction was developed.

Indirect IF

The Crithidia luciliae assay (The Binding Site, Birmingham, UK) was used to analyse sera (1 : 20) for anti-dsDNA. FITC-conjugated goat anti-mouse IgG (1: 60, Southern Biotechnology) was used as the second antibody. A high titre positive MRL/lpr serum served as positive control.


Autoantibodies to cellular proteins were analysed by immunoprecipitation of [35S]methionine-labelled cell extract from K562 (human erythroleukaemia) cells, as described [14]. Specificity of autoantibodies was confirmed using murine prototype sera for nRNP/Sm and Su.

Statistical analysis

Frequencies of autoantibodies were compared by Fisher's exact test. The Mann–Whitney U-test was used to compare levels of total IgG, anti-chromatin, cytokines and proteinuria. P < 0·05 was considered statistically significant.


Intraperitoneal injection of the hydrocarbon oil pristane causes the development of a lupus-like syndrome in virtually any strain of mouse [15]. This syndrome is characterized by the induction of both high levels of lupus-specific autoantibodies and IC-mediated proliferative glomerulonephritis [12].

Lack of FcγRIIB−/− increases frequency and severity of pristane-induced nephritis

The role of FcγRI/III or FcγRIIB deficiency on pristane-induced nephritis was examined 9 months after treatment. At this time-point there was no statistically significant difference in mortality rates between groups of mice. As shown in Table 1, pristane caused nephritis, as evidenced by proteinuria (mean 60·8 mg/dl) in +/+ mice, whereas severity of proteinuria was significantly increased in FcγRIIB−/− mice (mean 260·1 mg/dl; P < 0·05). Glomerular IgG deposition, typically in a capillary pattern, was increased in pristane-treated FcγRIIB−/− mice compared to +/+ and FcγRI/III−/− mice (Table 1, Fig. 1). Mice that exhibited IgG deposits commonly were positive for all subclasses and had C3 deposits (not shown). However, pristane-treated FcγRIIB−/− mice exhibited more prominent IgG2a staining (Fig. 1). Neither proteinuria nor immune deposits were seen in the control PBS-treated mice with the exception of the FcγRIIB−/− group of mice, where some spontaneous mesangial IgG deposits were seen (Table 1, Fig. 1). There were marked differences in the severity of inflammatory glomerulonephritis in the absence of FcγRII. Glomerular cellularity was normal in pristane-treated WT and FcRI/III−/− mice, indicating a lack of inflammatory/proliferative response. In contrast, in the absence of FcγRII, increased sclerosis and crescent formation was seen, indicative of severe glomerulonephritis. Together these results indicate that: (1) loss of inhibitory FcγR regulation markedly increases susceptibility to pristane-induced nephritis, as shown by the increased disease severity in FcγRIIB−/− animals (Fig. 1). Disease severity in FcγRII−/− was associated with increased glomerular IgG deposition, in particular of the IgG2a isotype and inflammatory glomerular lesions; (2) activating FcγR-mediated mechanisms appear essential for induction of pristane-induced proteinuria because proteinuria was abrogated in FcγRI/III−/− mice despite the persistence of the deposition of glomerular IgG and complement.

Fig. 1
Renal histology and direct immunofluorescence (IF). Renal tissue was obtained from mice 9 months after treatment. Paraffin processed tissue sections were stained with PAS. Unfixed frozen sections (4 µm) were stained by direct IF with fluoroscein ...
Table 1
Renal pathology

Pristane exacerbates spontaneous autoantibody production in FcγRIIB−/− BALB/c mice

PBS-treated FcγRI/III and IIB−/− mice appeared healthy and had life spans similar to PBS-treated+/+ animals. However, PBS-treated FcγRIIB−/− mice displayed polyclonal hypergammaglobulinaemia with total IgG1 and IgG2a levels significantly higher compared to both +/+ mice and FcγRI/III−/− mice (Fig. 2, P < 0·05 by Mann–Whitney U-test). Moreover, some of the PBS-treated FcγRIIB−/− mice spontaneously developed high levels of anti-chromatin autoantibodies with age (Fig. 3a, P < 0·05 versus PBS-treated +/+ and FcγRI/III−/− mice, by Mann–Whitney U-test). Pristane treatment markedly enhanced both total IgG (Fig. 2) and spontaneous anti-chromatin production (Fig. 3b) in FcγRIIB−/− mice with levels significantly higher than +/+ and FcγRI/III−/− mice (P < 0·05 by Mann–Whitney U-test). Notably, 60% of PBS-treated FcγRIIB−/− mice also developed anti-dsDNA autoantibodies spontaneously (Table 2, P < 0·05 by Fisher's exact test). Thus, it might be expected that this spontaneous production of anti-dsDNA would be exacerbated by pristane, as was the case for anti-chromatin. However, the absence of FcγRIIB had little effect on the induction of anti-dsDNA by pristane and the frequency of anti-dsDNA was similar in pristane-treated FcγRIIB−/−, RI/III−/− and +/+ mice (Table 2). Finally, the loss of FcγRI, III or IIB did not influence either spontaneous or pristane-induced anti-nRNP/Sm and anti-Su production (Fig. 4). Indeed, these autoantibodies were not generated in any of the PBS-treated mice and there was no statistically significant difference in anti-nRNP/Sm and anti-Su production between pristane-treated FcγRI/III−/−, IIB−/− and +/+ mice (Table 2). These results imply that the loss of FcγRIIB results in spontaneous production of anti-dsDNA and anti-chromatin in normal BALB/c mice. Pristane acts synergistically in FcγRIIB-deficient mice with respect to hypergammaglobulinaemia and anti-chromatin autoantibody generation. Importantly, in contrast to anti-DNA/chromatin, FcγR regulated pathways do not appear to be involved in the mechanisms that lead to an immune response against nRNP/Sm and Su. Taken together, FcRγIIB deficiency promotes autoimmune nephritis by several mechanisms: (1) removal of a tolerogenic checkpoint in the promotion of spontaneous autoantibody production; (2) amplification of the magnitude of anti-chromatin production; and (3) enhancement of the glomerular inflammatory response to deposited ICs.

Fig. 2
Total IgG levels. Total IgG1 and IgG2a levels after 9 months of PBS or pristane treatment were analysed by enzyme-linked immunosorbent assay (ELISA). Mean values are indicated by a line. *P < 0·05; **P < 0·05 versus PBS-treated ...
Fig. 3
IgG Anti-chromatin autoantibodies. Sera from mice obtained before phosphate-buffered saline (PBS) (a) or pristane (b) treatment, at 0·5 months and monthly thereafter, were analysed for anti-chromatin by enzyme-linked immunosorbent assay (ELISA). ...
Fig. 4
IgG anti-nRNP/Sm autoantibodies. Sera from mice obtained 10 months after treatment were analysed by immunoprecipitation. Representative samples are shown. Lane 1 shows a reference serum immunoprecipitating the characteristic bands for anti-nRNP/Sm (A, ...
Table 2
Autoantibody production

Spontaneous B cell hyperresponsiveness is associated with IL-6 overproduction in FcγRIIB−/− mice

Alteration in the cytokine milieu is a common feature both in human and experimental lupus [16], and has been reported in pristane-induced lupus [12]. Thus, it was of interest to examine the influence of dysregulated FcγR balance on the production of key regulatory and proinflammatory cytokines. Levels of cytokines were examined in culture supernatants of peritoneal cells after 48 h of stimulation with anti-CD3, lipopolysaccharide (LPS) or concanavalin A (Con A). IL-6 was over-produced in PBS-treated FcγRIIB−/− mice compared to +/+ animals (Fig. 5, P < 0·05 by Mann–Whitney U-test), whereas no difference in IL-12, IFN-γ or TNF-α secretion was detected between the two groups of mice. In accordance with previous findings [17], pristane treatment markedly enhanced the production of all these cytokines, including IL-6 (data not shown), confirming their potential pathogenic role in pristane-induced lupus. However, this increased expression was independent of FcγR as levels were similar in all groups of pristane-treated mice (data not shown). These findings suggest that spontaneous dysregulation of B cell activity observed in FcγRIIB−/− mice is due, at least in part, to IL-6 overproduction which drives the immune response against DNA/chromatin [13]. However, the altered cytokine milieu typical of pristane-induced lupus appears independent of FcγRs.

Fig. 5
Interleukin (IL)-6 production. Peritoneal cells from mice 10 months after phosphate-buffered saline (PBS) treatment were cultured for 48 h in Dulbecco's modified Eagle's medium in non- stimulated condition (NS) and in the presence of anti-CD3 (2 µg/ml), ...


The activating FcγRs, FcγRI and III, are required for the development of spontaneous lupus nephritis in NZB/NZW mice [2] as well as in induced models of anti-GBM nephritis [18]. However, FcγRI and III are not involved in the development of nephritis in MRL/lpr [19]. Because secreted antibody is not required for MRL disease [20], this suggests that autoreactive T cells rather than ICs are the principal mediators of glomerular MRL injury, while B cells are required as antigen-presenting cells. We report here that pristane-induced nephrits is dependent on activating FcγRs, supportive of a general and primary role for these receptors in linking pathogenic IC formation and glomerular disease.

In this study we show that FcγRIIB acts as an inhibitor of immune complex mediated tissue damage in pristane-induced lupus. Pristane-treated mice lacking this receptor have an increased frequency of anti-DNA/chromatin antibodies, increased glomerular IgG deposition and more severe nephritis compared to +/+ mice. Despite extensive IC-deposition in WT mice and the presence of proteinuria, glomerular inflammatory lesions were mild while severe glomerulonephritis was present in FcγRIIB−/− mice. This suggests that the consequences of loss/dysregulation of FcγRIIB could contribute to the pathogenesis of LN by enhancing monocyte/macrophage activation through lowering of the threshold for activating FcγRs [21] and by promoting B cell autoreactivity [10].

In the absence of the chronic inflammatory hydrocarbon compound pristane, PBS-treated FcγRIIB−/− mice had some spontaneous IgG glomerular immune deposits but no proteinuria, suggesting that an altered balance between activating and inhibitory FcγRs in the context of only limited amounts of IC deposits is not sufficient for the onset of overt renal disease. Thus, it is likely that the innate inflammatory response to pristane may contribute to disease pathogenesis beyond the induction of autoantibodies. Other pathogenic factors, such as Th1 cytokines, which are known as classic activators of monocytes/macrophages, may be prominent in this experimental model of LN. In this context, we recently reported that IFN-γ and IL-12−/− mice are entirely protected from nephritis after pristane treatment, whereas the absence of IL-4 has no influence on the development of renal disease [12,14].

We found that in pristane-treated FcγRIIB−/− mice compared to +/+ mice both IgG and complement deposits were predominantly in a capillary pattern, indicating the presence of subepithelial and/or subendothelial deposits [22]. This suggests that the location of ICs may also be of some importance. In particular, subendothelial immune deposits may be a prerequisite for the development of more severe proliferative glomerular pathology [23]. Further, alteration in glomerular IgG subclass distribution may conceivably influence the disease severity and course. We observed the prevalence of IgG2a deposits in pristane-treated FcγRIIB−/− mice compared to IgG1 in pristane-treated +/+ mice. However, few studies have addressed the role of glomerular IgG-subclass distribution in the pathogenesis of LN, despite evidence that different subclasses have different biological properties [24].

FcγRIIB acts to maintain tolerance by limiting B cell antigen receptor activation and deleting autoreactive lymphocytes that might arise during somatic hypermutation. Moreover, FcγRIIB−/− C57BL/6 mice have been reported to develop spontaneously a syndrome resembling lupus with autoantibodies to nuclear antigens and IC glomerulonephritis in a strain-dependent manner [10]. We provide evidence here that spontaneous production of lupus-specific autoantibodies, such as IgG anti-dsDNA and IgG anti-chromatin, also occurs in BALB/c mice, suggesting that the absence of FcγRIIB promotes autoimmunity in a fashion not dependent on specific genetic backgrounds. However, these mice had normal viability and evidence of nephritis was not seen in any of them. Thus, emergence of autoimmune end-organ damage, rather than disease susceptibility itself, may be under the control of epistatic or environmental modifiers. SLE gene modifiers, such as yaa and lpr, have been found to influence the onset of overt renal disease in the FcγRIIB−/− C57BL/6 model [11], whereas the administration of pristane exacerbates autoantibody production and IC-mediated nephritis in FcγRIIB−/− BALB/c mice. In particular, the higher levels of anti-chromatin detected in pristane-treated FcγRIIB−/− mice may account for the higher incidence of nephritis observed in these animals compared to pristane-treated +/+ mice.

While B cell intrinsic phenomena have been implicated in the development of spontaneous autoimmunity in FcγRII−/− C57BL/6 [11], other FcγRII-bearing cell types may contribute. Absence of IL-6 abrogates anti-DNA/chromatin production in pristane-induced lupus [13]. IL-6 production is regulated by FcγRs and stimulation of monocytes through cross-linking of activating FcγRs induces and augments IL-6 secretion [25]. We show here that IL-6 production is enhanced in peritoneal cells from FcγRIIB−/− mice after LPS stimulation, suggesting that loss of FcγRIIB may impact the function of its downstream phosphatases, SHIP and SHP-1 in other cell surface receptor signalling pathways, resulting in more global regulatory consequences in response to ligands other than Fc regions of antibodies. Our findings raise the possibility that IL-6 overproduction may contribute to the polyclonal B cell activation and spontaneous generation of anti-DNA/chromatin antibodies in FcγRIIB−/− mice [26]. Failure of negative feedback inhibition of this phenomenon, brought about by FcγRIIB deficiency, may thus result in IL-6 overproduction. Given the fundamental importance of IL-6 production on B cell development, activation and terminal differentiation [27], its overexpression may sustain hyperresponsiveness of B lymphocytes in FcγRIIB−/− mice. In this respect constitutive expression of IL-6 receptor on B cells in conjunction with spontaneous IL-6 production has been reported to maintain B cell activation and autoantibody secretion in SLE patients [28].

In conclusion, dysregulation of FcγR expression in BALB/c mice lacking FcγRIIB increases their susceptibility to systemic autoimmunity resulting in increased disease severity. The inhibitory signalling cascade via FcγRIIB appears to be critical for limiting the development of pristane-induced IC nephritis. Future studies are needed to determine the relevance of these observations to human LN. However, there is mounting evidence for an important role for FcγRs in human SLE, as polymorphisms in the genes of these receptors has been found to influence the risk for disease development and the clinical manifestations of the disease [2932]. Future therapeutic strategies aimed at alteration of the immune response through manipulation of IgG–FcγR interactions by the use of antibodies capable of ligating and stimulating inhibitory FcγRIIB [33] could be explored.


This study was supported by the National Institutes of Health NIDDK K08 DK02890-02 (HR) and the National Arthritis Foundation (RC). The authors would like to thank Dr Franco Silvestris and Dr Franco Dammacco (University of Bari, Italy) for facilitating Dr Calvani's research efforts at the University of Florida.


1. Koffler D, Agnello V, Thoburn R, Kunkel HG. Systemic lupus erythematosus: prototype of immune complex nephritis in man. J Exp Med. 1971;134(Suppl.):169s. [PubMed]
2. Clynes R, Dumitru C, Ravetch JV. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science. 1998;279:1052–4. [PubMed]
3. Ravetch JV, Bolland S. IgG Fc receptors. Annu Rev Immunol. 2001;19:275–90. [PubMed]
4. Daeron M. Fc receptor biology. Annu Rev Immunol. 1997;15:203–34. [PubMed]
5. Pearse RN, Kawabe T, Bolland S, Guinamard R, Kurosaki T, Ravetch JV. SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis. Immunity. 1999;10:753–60. [PubMed]
6. Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV. Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice. Nature. 1996;379:346–9. [PubMed]
7. Fukuyama H, Nimmerjahn F, Ravetch JV. The inhibitory Fcgamma receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G(+) anti-DNA plasma cells. Nat Immunol. 2005;6:99–106. [PubMed]
8. Yuasa T, Kubo S, Yoshino T, et al. Deletion of fcgamma receptor IIB renders H-2(b) mice susceptible to collagen-induced arthritis. J Exp Med. 1999;189:187–94. [PMC free article] [PubMed]
9. Nakamura A, Yuasa T, Ujike A, et al. Fcgamma receptor IIB-deficient mice develop Goodpasture's syndrome upon immunization with type IV collagen: a novel murine model for autoimmune glomerular basement membrane disease. J Exp Med. 2000;191:899–906. [PMC free article] [PubMed]
10. Bolland S, Ravetch JV. Spontaneous autoimmune disease in Fc(gamma) RIIB-deficient mice results from strain-specific epistasis. Immunity. 2000;13:277–85. [PubMed]
11. Bolland S, Yim YS, Tus K, Wakeland EK, Ravetch JV. Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(−/−) mice. J Exp Med. 2002;195:1167–74. [PMC free article] [PubMed]
12. Calvani N, Satoh M, Croker BP, Reeves WH, Richards HB. Nephritogenic autoantibodies but absence of nephritis in Il-12p35-deficient mice with pristane-induced lupus. Kidney Int. 2003;64:897–905. [PubMed]
13. Richards HB, Satoh M, Shaw M, Libert C, Poli V, Reeves WH. Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. J Exp Med. 1998;188:985–90. [PMC free article] [PubMed]
14. Richards HB, Satoh M, Jennette JC, Croker BP, Yoshida H, Reeves WH. Interferon-gamma is required for lupus nephritis in mice treated with the hydrocarbon oil pristane. Kidney Int. 2001;60:2173–80. [PubMed]
15. Satoh M, Richards HB, Shaheen VM, et al. Widespread susceptibility among inbred mouse strains to the induction of lupus autoantibodies by pristane. Clin Exp Immunol. 2000;121:399–405. [PMC free article] [PubMed]
16. Kelley VR, Wuthrich RP. Cytokines in the pathogenesis of systemic lupus erythematosus. Semin Nephrol. 1999;19:57–66. [PubMed]
17. Satoh M, Weintraub JP, Yoshida H, et al. Fas and Fas ligand mutations inhibit autoantibody production in pristane-induced lupus. J Immunol. 2000;165:1036–43. [PubMed]
18. Wakayama H, Hasegawa Y, Kawabe T, et al. Abolition of anti-glomerular basement membrane antibody-mediated glomerulonephritis in FcRgamma-deficient mice. Eur J Immunol. 2000;30:1182–90. [PubMed]
19. Matsumoto K, Watanabe N, Akikusa B, et al. Fc receptor-independent development of autoimmune glomerulonephritis in lupus-prone MRL/lpr mice. Arthritis Rheum. 2003;48:486–94. [PubMed]
20. Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med. 1999;189:1639–48. [PMC free article] [PubMed]
21. Clynes R, Maizes JS, Guinamard R, Ono M, Takai T, Ravetch JV. Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors. J Exp Med. 1999;189:179–85. [PMC free article] [PubMed]
22. Satoh M, Kumar A, Kanwar YS, Reeves WH. Anti-nuclear antibody production and immune-complex glomerulonephritis in BALB/c mice treated with pristane. Proc Natl Acad Sci USA. 1995;92:10934–8. [PMC free article] [PubMed]
23. D'Andrea DM, Coupaye-Gerard B, Kleyman TR, Foster MH, Madaio MP. Lupus autoantibodies interact directly with distinct glomerular and vascular cell surface antigens. Kidney Int. 1996;49:1214–21. [PubMed]
24. Imai H, Hamai K, Komatsuda A, Ohtani H, Miura AB. IgG subclasses in patients with membranoproliferative glomerulonephritis, membranous nephropathy, and lupus nephritis. Kidney Int. 1997;51:270–6. [PubMed]
25. Corvaia N, Reischl IG, Kroemer E, Mudde GC. Modulation of Fc gamma receptor-mediated early events by the tyrosine phosphatase CD45 in primary human monocytes. Consequences for interleukin-6 production. Eur J Immunol. 1995;25:738–44. [PubMed]
26. Finck BK, Chan B, Wofsy D. Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. J Clin Invest. 1994;94:585–91. [PMC free article] [PubMed]
27. Muraguchi A, Hirano T, Tang B, et al. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med. 1988;167:332–44. [PMC free article] [PubMed]
28. Nagafuchi H, Suzuki N, Mizushima Y, Sakane T. Constitutive expression of IL-6 receptors and their role in the excessive B cell function in patients with systemic lupus erythematosus. J Immunol. 1993;151:6525–34. [PubMed]
29. van der Pol W, van de Winkel JG. IgG receptor polymorphisms: risk factors for disease. Immunogenetics. 1998;48:222–32. [PubMed]
30. Li X, Wu J, Carter RH, Edberg JC, Su K, Cooper GS, Kimberly RP. A novel polymorphism in the Fcgamma receptor IIB(CD32B) transmembrane region alters receptor signaling. Arthritis Rheum. 2003;48:3242–52. [PubMed]
31. Su K, Wu J, Edberg JC, et al. A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. J Immunol. 2004;172:7186–91. [PubMed]
32. Su K, Li X, Edberg JC, Wu J, Ferguson P, Kimberly RP. A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. II. Differential binding of GATA4 and Yin-Yang1 transcription factors and correlated receptor expression and function. J Immunol. 2004;172:7192–9. [PubMed]
33. Shields RL, Namenuk AK, Hong K, et al. High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem. 2001;276:6591–604. [PubMed]

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