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The Journal of Immunology, 2006, 177: 1646-1654.
Copyright © 2006 by The American Association of Immunologists

Genetic Dissection of the Effects of Stimulatory and Inhibitory IgG Fc Receptors on Murine Lupus1

Qingshun Lin*,{dagger}, Yan Xiu*, Yi Jiang§, Hiromichi Tsurui*, Kazuhiro Nakamura*, Sanki Kodera*, Mareki Ohtsuji*, Naomi Ohtsuji*, Wakana Shiroiwa*,{dagger}, Kazuyuki Tsukamoto*, Hirofumi Amano{ddagger}, Eri Amano{ddagger}, Katsuyuki Kinoshita{dagger}, Katsuko Sudo, Hiroyuki Nishimura||, Shozo Izui#, Toshikazu Shirai* and Sachiko Hirose2,*

* Department of Pathology, {dagger} Department of Obstetrics and Gynecology, and {ddagger} Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan; § Central Laboratory of First Clinical College, China Medical University, Shenyang, China; Animal Research Center, Tokyo Medical University, Tokyo, Japan; || Toin Human Science and Technology Center, Department of Biomedical Engineering, Toin University of Yokohama, Yokohama, Japan; and # Department of Pathology and Immunology, Centre Médical Universitaire, Geneva, Switzerland


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Immune complex (IC)-mediated tissue inflammation is controlled by stimulatory and inhibitory IgG Fc receptors (Fc{gamma}Rs). Systemic lupus erythematosus is a prototype of IC-mediated autoimmune disease; thus, imbalance of these two types of Fc{gamma}Rs is probably involved in pathogenesis. However, how and to what extent each Fc{gamma}R contributes to the disease remains unclear. In lupus-prone BXSB mice, while stimulatory Fc{gamma}Rs are intact, inhibitory Fc{gamma}RIIB expression is impaired because of promoter region polymorphism. To dissect roles of stimulatory and inhibitory Fc{gamma}Rs, we established two gene-manipulated BXSB strains: one deficient in stimulatory Fc{gamma}Rs (BXSB.{gamma}–/–) and the other carrying wild-type Fcgr2b (BXSB.IIBB6/B6). The disease features were markedly suppressed in both mutant strains. Despite intact renal function, however, BXSB.{gamma}–/– had IC deposition in glomeruli associated with high-serum IgG anti-DNA Ab levels, in contrast to BXSB.IIBB6/B6, which showed intact renal pathology and anti-DNA levels. Lymphocytes in BXSB.{gamma}–/– were activated, as in wild-type BXSB, but not in BXSB.IIBB6/B6. Our results strongly suggest that both types of Fc{gamma}Rs in BXSB mice are differently involved in the process of disease progression, in which, while stimulatory Fc{gamma}Rs play roles in effecter phase of IC-mediated tissue inflammation, the BXSB-type impaired Fc{gamma}RIIB promotes spontaneous activation of self-reactive lymphocytes and associated production of large amounts of autoantibodies and ICs.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Receptors for the Fc portion of IgG are widely expressed on a variety of immune cells and positively or negatively regulate immune responses and inflammatory cascades (1, 2, 3, 4, 5). Three distinct classes of IgG FcRs, Fc{gamma}RI, Fc{gamma}RII, and Fc{gamma}RIII, have been defined. In humans, there are three genes for Fc{gamma}RI (A, B, and C), three genes for Fc{gamma}RII (A, B, and C), and two genes for Fc{gamma}RIII (A and B), while in mice each class is encoded by a single gene (Fc{gamma}RI, Fc{gamma}RIIB, and Fc{gamma}RIII) (1, 2, 3). Fc{gamma}RI and Fc{gamma}RIII exist as an oligomeric complex together with a common {gamma} chain (FcR{gamma}), and upon cross-linking by IgG immune complexes (ICs),3 they transduce stimulatory signals into cells through FcR{gamma} chain-associated intracellular ITAMs. In contrast, Fc{gamma}RIIB is a monomeric receptor without FcR{gamma} and transduces inhibitory signals via intracellular ITIMs.

Fc{gamma}RI and Fc{gamma}RIII are known to trigger various inflammatory effector functions, such as phagocytosis, Ab-mediated cellular cytotoxicity, and release of inflammatory mediators. Notably, the deficiency of FcR{gamma} chain contributing to stimulatory signals renders mice resistant to the induction of various autoimmune diseases, such as type II collagen-induced arthritis (6), anti-glomerular basement membrane Ab-induced glomerulonephritis (7), and experimental autoimmune hemolytic anemia (8). There is also a report that FcR{gamma} deficiency protects against spontaneously occurring IC-type-glomerulonephritis in a lupus model of (NZB x NZW)F1 mice (9). Fc{gamma}RIIB receptor, in contrast, negatively controls such inflammatory responses by cross-linking with stimulatory receptors via IgG ICs. Fc{gamma}RIIB also negatively regulates BCR-elicited activation of B cells, when cross-linked with BCR via IgG ICs, leading to down-regulation of B cell proliferation and Ab synthesis. In Fc{gamma}RIIB-deficient mice, several kinds of experimentally induced autoimmune diseases, such as type II collagen-induced arthritis (6, 10), type IV collagen-induced Goodpasture’s syndrome (11), myeloid oligodendrocyte glycoprotein-induced encephalomyelitis (12), and anti-glomerular basement membrane Ab-induced glomerulonephtitis (7), are exacerbated. Albeit in a strain-dependent fashion, aged Fc{gamma}RIIB-deficient mice spontaneously develop lupus-like glomerulonephritis in association with autoantibody production (13).

In this context, we previously found that autoimmune disease-prone mouse strains, such as NZB, BXSB, MRL, and NOD, share deletion polymorphism in the AP-4 binding site of the Fcgr2b promoter region (14) and that this polymorphism is functionally linked to down-regulation of Fc{gamma}RIIB expression levels on activated B cells, leading to up-regulation of IgG autoantibodies and autoimmune disease (15). Evidence from genetic studies on human systemic lupus erythematosus (SLE) also revealed a significant association between SLE and the promoter region polymorphisms in inhibitory FCGR2B gene (16, 17). However, other groups also reported an association with stimulatory Fc{gamma}R genes (18). As stimulatory and inhibitory Fc{gamma}R genes are tightly linked on chromosome 1 in both humans and mice, genetic dissection of the contributing genes has been difficult. Thus, how and to what extent each Fc{gamma}R is involved in the pathogenesis in an individual with SLE remains unclear. In the present study, we examined this issue using SLE-prone BXSB mice.

The BXSB strain of mice, a recombinant inbred strain obtained from the crosses of C57BL/6 (B6) and SB/Le strains, spontaneously develops SLE characterized by IC-type glomerulonephritis in association with the production of various autoantibodies, including those to nuclear components (19). Spontaneous development of thrombocytopenia associated with anti-platelet autoantibodies and splenomegaly is also a characteristic feature (20, 21, 22). Peripheral expansion of monocytes is unique in these mice and is closely associated with the disease severity (23, 24). The disease occurs much earlier and is more severe in males due to the involvement of a mutant Y chromosome-linked autoimmune acceleration gene (Yaa) (25). The Yaa gene introduced into nonautoimmune-prone strains of mice, such as B6, fails to elicit autoimmune disease (26), indicating the critical involvement of BXSB genetic background for the Yaa-mediated disease. To dissect the roles of stimulatory and inhibitory Fc{gamma}Rs in the pathogenesis of SLE, we generated a mutant BXSB strain expressing normal levels of inhibitory Fc{gamma}RIIB and compared its autoimmune disease features with those of another newly generated mutant BXSB strain deficient in stimulatory Fc{gamma}RI/III expression, with reference to the findings in wild-type BXSB mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Mice

BXSB and B6 mice consomic for BXSB Y chromosome (B6.Yaa) were purchased from the Shizuoka Laboratory Animal Center and The Jackson Laboratory, respectively. The FcR{gamma} chain-deficient B6 strain was a gift from Dr. C. Ra (Nihon University School of Medicine, Tokyo, Japan) (27). FcR{gamma}-deficient BXSB (BXSB.{gamma}–/–) and B6-type Fcgr2b promoter region-bearing BXSB (BXSB.IIbB6/B6) were established by selective backcrossing of (BXSB x FcR{gamma}-deficient B6)F1 to BXSB over 30 generations, followed by brother-sister mating, and the chromosomal segment of FcR{gamma}-deficient B6 introduced into the BXSB genetic background was identified using microsatellite marker polymorphisms and genotyping of the Fc{gamma}RIIB promoter region and knockout FcR{gamma} chain gene (Fcer1g). All mice used were housed under identical conditions, and all experiments were performed in accordance with our institutional guidelines. Only male mice were analyzed in the present studies.

Genotyping

DNA was extracted from mouse tail tissue. Genotyping of the Fcgr2b promoter region was done by PCR using 5' and 3' primers: 5'-GTAAGTGGTTGTGGGTACCTTTATT-3' and 5'-CGCAGCTCAGAAGTCATTTGCCTCA-3'. PCR products were electrophoresed on 18% polyacrylamide gels. Genotyping of the knockout FcR{gamma} chain gene was done using 5' (neo-specific) and 3' primers: 5'-GCCAACGCTATGTCCTGATAG-3' and 5'-GGAATTCGATGCTGTCCTGTTTTTGTA-3'. PCR products were electrophoresed on 2% agarose gels. After electrophoresis, PCR products were visualized with ethidium bromide staining. Genotyping of microsatellite markers was done as described elsewhere (15).

Renal function

Renal function was evaluated by the measurement of blood urea nitrogen (BUN) using a Urea Nitrogen B test kit (E 279-36201; Wako), according to the manufacturer’s instructions.

Serum levels of IgG and IgG anti-DNA Abs

Measurements of total IgG and IgG Abs to denatured DNA were conducted by ELISA as described elsewhere (15). DNA-binding activities were expressed in units, referring to a standard curve obtained by serial dilution of a standard serum pool from (NZB x NZW)F1 over 8 mo old, containing 1000 unit activities/ml.

Platelet counts and platelet-binding autoantibodies

To measure the platelet count, 100 µl of blood was obtained from the retro-orbital sinus, using heparinized microhematocrit tubes, and was diluted with 400 µl of 1 mg/ml EDTA in PBS supplemented with 0.2% BSA. Then, the platelet number was counted using Cellac {alpha} (MEK-6158; Nihon Kohden). For measurement of platelet-binding autoantibodies, 20 µl of the blood diluted as described above was mixed with 400 µl of Cell Kit CD solution (CK-35; Toa Medical Electronics) and was centrifuged to obtain platelet-rich suspension. The platelet-rich suspension was recentrifuged, and the platelet pellet was incubated with PE-conjugated goat anti-mouse {gamma} chain Abs for 30 min at 4°C. After washing, platelets were suspended in 1% paraformaldehyde in PBS, and platelet-binding Abs were analyzed using a FACSAria (BD Biosciences). The platelet population was gated by forward vs side scatter.

In vitro assay of platelet phagocytosis by macrophages

Mice were i.p. injected with 2 ml of thioglycolate broth, and peritoneal exudate cells were harvested 3 days later. For the platelet phagocytosis assay, platelets obtained from 2-mo-old BXSB mice were prelabeled with FITC-conjugated rabbit anti-mouse thrombocytes (INTER-CELL Technologies) and with Alexa 488-conjugated rabbit anti-FITC (Molecular Probes) Abs and were incubated in vitro with peritoneal exudate cells at 37°C for 3 h. After incubation, ice-cold PBS containing 0.02% BSA and 0.01% sodium azide was added to the cultures to stop the phagocytic reaction. After washing, cells were stained with PE-labeled anti-Mac-1 (CD11b) mAb, and fluorescence intensity was measured using a FACSAria.

Flow cytometric analysis

For analysis of the activation state of lymphocytes, aliquots of 1 x 106 spleen cells were triple stained with PE-labeled anti-CD3, FITC-labeled anti-B220(6B2), and biotin-labeled anti-CD69 mAbs, followed by streptavidin-allophycocyanin. For monocyte analysis, spleen cells were stained with FITC-labeled anti-B220 and PE-labeled anti-CD11b mAbs. For analysis of Fc{gamma}RIIB1 expression levels on PNA+ germinal center (GC) B cells and PNA– non-GC B cells, spleen cells were first stained with PE-conjugated mAb 2.4G2, followed by staining with FITC-labeled anti-B220 mAb and biotinylated peanut lectin (agglutinin) (PNA). After washing, the cells were further stained with streptavidin-conjugated allophycocyanin. Data were analyzed using a FACSAria and FlowJo software (Tree Star).

For Fc{gamma}RIIB and Fc{gamma}RIII expression levels on peritoneal CD11b+ macrophages, peritoneal exudate cells were double stained with conjugated anti-CD11b and PE-conjugated 2.4G2 mAbs. Fluorescence intensity was measured using a FACStar flow cytometer and CellQuest software (BD Biosciences). Reagents for flow cytometric analysis were all purchased from BD Pharmingen.

Histopathology and tissue immunofluorescence

For histopathological examination, tissues were fixed in 4% paraformaldehyde, embedded in paraffin, sectioned 4-µm thick, and stained with H&E or periodic acid-Schiff and hematoxylin (PASH). For immunofluorescence, tissues were embedded in Tissue-Tek OCT compound and frozen in liquid nitrogen. Frozen kidney sections were stained with FITC-labeled goat Abs to IgG or to C3 (ICN Pharmaceuticals) for 60 min at room temperature. For analysis of splenic tissues, frozen sections were stained for 30 min at room temperature with Alexa 488-labeled anti-CD4 and anti-CD8 mAbs, Alexa 647-labeled anti-B220 mAb, and Alexa 546-labeled PNA. Abs and PNA were purchased from BD Pharmingen and Vector Laboratories, respectively, and the labeling of these reagents was done in our laboratory. Color images were obtained using laser scanning microscopy (LSM510META version 3.2; Carl Zeiss).

Statistical analysis

Statistical analysis was done using Mann-Whitney U test for disease phenotypes and Student’s t test for flow cytometric analysis. A value of p < 0.05 was considered to have a statistical significance.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
Establishment of mutant BXSB.IIBB6/B6 and BXSB.{gamma}–/– strains

To evaluate the role of stimulatory Fc{gamma}Rs in BXSB disease, we first generated a congenic BXSB strain that lacked the common FcR{gamma} chain gene (Fcer1g) and was thus deficient in expressing stimulatory Fc{gamma}RI/III Fc{gamma}Rs by introducing a segment of chromosome 1 from FcR{gamma}-knockout B6 mice. This congenic strain did not develop any disease features such as autoantibodies to DNA and platelets, IC-type glomerulonephritis, or splenomegaly (data not shown). However, because the introduced chromosomal segment contained the interval ~18 cM, which includes the B6-type (wild-type) Fcgr2b promoter region (Fig. 1), it remained unknown whether the observed protective effect against the autoimmune disease is due to the deficiency of stimulatory Fc{gamma}Rs or the intact inhibitory Fc{gamma}RIIB of B6 origin. To dissect the roles of these two types of Fc{gamma}Rs, we then established congenic BXSB strains with genetic recombination between the FcR{gamma} chain gene (Fcer1g) and Fcgr2b through additional backcrossing of the ~18-cM congenic BXSB strain to BXSB mice. Among ~2000 meioses in backcrosses, we obtained two congenic lines (Fig. 1)—one provisionally designated BXSB.IIBB6/B6, having intact FcR{gamma} chain and intact (B6-type) inhibitory Fc{gamma}RIIB, and the other BXSB{gamma}–/–, having deficient FcR{gamma} chain and impaired (BXSB-type) inhibitory Fc{gamma}RIIB expression.


Figure 1
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  		FIGURE 1. Genetic map of the telomeric region on chromosome 1 in interval congenic BXSB strains. The gene segment of the ~18-cM interval on chromosome 1 derived from the FcR{gamma}-deficient B6 strain ({blacksquare}) was introduced into the BXSB strain ({square}) to establish the ~18-cM interval congenic BXSB strain. This strain was further backcrossed to BXSB to obtain BXSB.IIBB6/B6 and BXSB.{gamma}–/– interval congenic strains with the recombination between Fcgr2b and Fcer1g genes. Genotypes were determined by analysis of microsatellite marker polymorphisms, Fcgr2b allele polymorphism, and defective FcR{gamma} chain gene (Fcer1g).

 
Survival and renal disease

BXSB mice began to die at 4 mo of age and 50% mortality rate was observed at 7 mo of age. In contrast, 96 and 71% of BXSB.IIBB6/B6 and BXSB.{gamma}–/– mice, respectively, were still alive at 10 mo of age (Fig. 2A). A significant proportion of 7-mo-old BXSB mice showed a marked increase in serum BUN levels, indicating an age-associated progression of renal failure. In contrast, mean BUN levels in BXSB.IIBB6/B6 were significantly lower than those found in age-matched BXSB mice. BXSB.{gamma}–/– mice also did not develop renal failure even at 7 mo of age (Fig. 2B). Fig. 2C shows representative histopathological and immunofluorescent findings of renal glomeruli. In aged BXSB mice, glomeruli are enlarged, and mesangial cell proliferation and thickening of glomerular capillary walls along with deposition of PAS-positive materials, including IgG and complement component C3, are prominent. In contrast, both BXSB.IIBB6/B6 and BXSB.{gamma}–/– mice show histologically minimal glomerular changes. Intriguingly, however, there was a difference in the immunofluorescence findings between BXSB.IIBB6/B6 and BXSB.{gamma}–/– mice, which showed that while there was a significant amount of IgG and C3 deposited in the mesangial area in the latter, there was minimal deposition in the former.


Figure 2
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  		FIGURE 2. Comparisons of survival rate, renal function, and renal pathology among BXSB, BXSB.IIBB6/B6, and BXSB.{gamma}–/– mice. A, Survival rate estimated by following 9–21 mice in each strain up to 10 mo of age. B, BUN levels measured in 9–39 mice in each strain at 5 and 7 mo of age. Horizontal bar represents mean level. Statistical significance is shown. C, Histological (PASH staining) and immunohistochemical findings (deposition of IgG and C3) of renal glomeruli from 7-mo-old mice. All figures are at the same magnification. The bar in the PASH staining represents 50 µm. Representative results obtained from three mice in each strain.

 
Serum IgG and IgG anti-DNA Ab levels

As shown in Fig. 3, A and B, BXSB mice showed an age-associated increase in serum levels of total IgG and IgG anti-DNA Abs. In BXSB.{gamma}–/– mice, mean serum levels of IgG and IgG anti-DNA Abs were increased with aging in parallel with the deposition of IgG ICs in glomeruli (Fig. 2C) and were comparable to those found in BXSB mice at any given time point. In contrast, serum levels of both IgG and IgG anti-DNA Abs in BXSB.IIBB6/B6 mice were markedly suppressed compared with the levels in BXSB and BXSB.{gamma}–/– mice. The levels in BXSB.IIBB6/B6 mice were as low as those in a control SLE-negative B6.Yaa strain, a B6 strain bearing the BXSB-derived Y chromosome, including the Yaa gene (26).


Figure 3
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  		FIGURE 3. Comparisons of serum levels of total IgG and IgG anti-DNA Abs among BXSB, BXSB.IIBB6/B6, BXSB.{gamma}–/–, and B6.Yaa mice. Total IgG (A) and IgG anti-DNA Ab (B) levels in sera examined in 9–26 mice in each strain at 5 and 7 mo of age. Horizontal bar represents mean level. Statistical significance is shown.

 
Thrombocytopenia and platelet phagocytotic activity of macrophages

Platelet-binding IgG autoantibodies were examined using flow cytometry analysis. As shown in Fig. 4A, large amounts of platelet-binding autoantibodies were detected in BXSB mice; however, no Abs were observed on platelets of derived from BXSB.IIBB6/B6 mice. In BXSB.{gamma}–/– mice, small amounts of platelet-binding autoantibodies were detected (Fig. 4A); however, the mean fluorescence intensity (MFI) was significantly lower than that seen in BXSB mice (Fig. 4B). When platelet counts were examined, BXSB mice developed age-associated thrombocytopenia, whereas this did not develop in both BXSB.IIBB6/B6 and BXSB. {gamma}–/– mice (Fig. 4C).


Figure 4
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  		FIGURE 4. Comparisons of platelet-binding IgG autoantibodies, platelet counts, platelet phagocytotic potential of macrophages, and Fc{gamma}R expression levels among BXSB, BXSB.IIBB6/B6, and BXSB.{gamma}–/– mice. A, Platelet-binding IgG autoantibodies examined by staining platelets derived from 7-mo-old mice with FITC-labeled anti-mouse IgG. Immunofluorescence intensity was examined using flow cytometry and shown in histogram. Shaded areas indicate the background autofluorescence of platelets. B, Comparison of MFI for platelet-binding IgG in 7–19 mice in each strain at 7 mo of age. Horizontal bar represents mean MFI. Statistical significance is shown. C, Peripheral platelet counts measured using 19–29 mice in each strain at 5 and 7 mo of age. Horizontal bar represents mean count. Statistical significance is shown. D, Platelet phagocytotic activity of macrophages examined by incubating peritoneal exudate cells from 7-mo-old mice with Alexa 488-labeled IgG-coated platelets, followed by staining with PE-labeled CD11b mAb. Flow cytometric profiles of CD11b+ macrophages with phagocytosis of FITC-labeled platelets are shown with percentages of positive cells. Representative results from three mice in each strain. E, The left panel shows flow cytometric profiles of 2.4G2 expression levels (Fc{gamma}RIIB plus Fc{gamma}RIII) on macrophages in histogram, and the right panel shows estimated proportions of Fc{gamma}RIIB (RIIB) and Fc{gamma}RIII (RIII) molecules expressed on macrophages in each strain. For details, see text. Peritoneal exudate cells from 7-mo-old mice were double stained with anti-CD11b and 2.4G2 mAbs, and 2.4G2 levels on CD11b+ macrophages were compared. Closed areas indicate the background staining. Representative results obtained from three to four mice in each strain. Horizontal bar shows SE.

 
Fig. 4D compares the platelet phagocytotic activity of macrophages among BXSB, BXSB.IIBB6/B6, and BXSB.{gamma}–/– mice. Peritoneal exudate cells were incubated with Alexa 488-labeled IgG-coated platelets, followed by staining with PE-labeled anti-CD11b mAb. Flow cytometry analysis revealed that >20% of CD11b+ macrophages showed platelet-engulfing activity in BXSB mice; however, this activity was significantly reduced in both BXSB.IIBB6/B6 and BXSB.{gamma}–/– mice.

We then examined expression levels of stimulatory Fc{gamma}RIII and inhibitory Fc{gamma}RIIB on CD11b-positive peritoneal macrophages by staining cells with 2.4G2 mAb that reacts with both Fc{gamma}RIIB and Fc{gamma}RIII molecules. As shown in Fig. 4E, the highest MFI was observed on BXSB.IIBB6/B6 cells and the lowest on BXSB.{gamma}–/– cells. The level of BXSB cells was in between. Because BXSB.{gamma}–/– and BXSB strains share the same Fcgr2b gene (Fig. 1), the observed difference in 2.4G2 expression on CD11b+ macrophages between these two strains is thought to be due to the defect of Fc{gamma}RIII expression in BXSB.{gamma}–/– mice. Similarly, because there is no sequence polymorphism in Fcgr3 gene between BXSB and BXSB.IIBB6/B6 strains (data not shown), the observed difference in 2.4G2 expression between these two strains is thought to be due to up-regulated Fc{gamma}RIIB expression in BXSB.IIBB6/B6 mice, mediated by the promoter region polymorphism of Fcgr2b gene (14, 15). All these findings strongly suggest that the expression of stimulatory Fc{gamma}Rs on macrophages is crucial for their phagocytosis of opsonized platelets and that this potential is inhibited by up-regulated expression of Fc{gamma}RIIB.

Splenomegaly and subpopulation of spleen cells

Splenomegaly, a characteristic disease feature in aged BXSB mice, did not develop in age-matched BXSB.IIBB6/B6 and BXSB.{gamma}–/– mice (Fig. 5A), and the spleen weight of BXSB.IIBB6/B6 and BXSB.{gamma}–/– mice was comparable to that of B6.Yaa mice (Fig. 5B). Absolute numbers ((mean ± SE) x 106) of spleen cells were 340 ± 50, 96 ± 5, and 131 ± 15 in BXSB, BXSB.IIBB6/B6, and BXSB.{gamma}–/– mice, respectively. Flow cytometric analysis revealed that while the frequencies of CD11b+B220– monocytes/macrophages were markedly increased in the enlarged BXSB spleen, they were significantly reduced in both BXSB.IIBB6/B6 and BXSB.{gamma}–/– mice (Fig. 6A and Table I). This is in contrast to the findings for B220+ B cells and CD3+ T cells per total splenic lymphocytes, and the frequencies were almost identical in BXSB, BXSB.IIBB6/B6, and BXSB.{gamma}–/– mice (Table I). It was noteworthy, however, that when the frequencies of CD69+ activated B cells and T cells were examined, while the frequencies in BXSB. {gamma}–/– were as high as those in BXSB mice, the frequencies in BXSB.IIBB6/B6 were markedly reduced (Fig. 6B and Table I).


Figure 5
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  		FIGURE 5. A, Representative macroscopic findings of the spleen in BXSB, BXSB.IIBB6/B6, and BXSB.{gamma}–/– mice at 7 mo of age. Splenomegaly is not observed in both BXSB.IIBB6/B6 and BXSB.{gamma}–/– mice. B, Comparisons of spleen weights among BXSB, BXSB.IIBB6/B6, BXSB.{gamma}–/–, and B6.Yaa strains in seven to nine mice at 6~7 mo of age in each strain. Horizontal bar represents mean splenic weight. Statistical significance is shown.

 

Figure 6
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  		FIGURE 6. Comparisons of flow cytometric profiles of spleen cells among aged BXSB, BXSB.IIBB6/B6, and BXSB.{gamma}–/– mice. A, Frequencies of monocytes/macrophages in the spleen. Spleen cells from 6- to 8-mo-old mice were double stained with anti-B220 and anti-CD11b mAbs. The percentage of the CD11b+B220– monocye/macrophage population per total spleen cells is shown. Representative flow cytometry profile obtained from three to five mice in each strain. B, Frequencies of CD69+ activated B and T cells examined using flow cytometry. Spleen cells were stained with a combination of anti-B220, anti-CD3, and anti-CD69 mAbs, and lymphocyte gates were examined. Percentages of CD69+B220+ activated B cells per total B220+ B cells and CD69+CD3+ activated T cells per total CD3+ T cells are shown. Representative flow cytometry profiles obtained from three to five mice in each strain.

 

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  		Table I. Flow cytometric analysis of spleen cellsa

 
Fig. 7A shows representative three-color immunofluorescent staining patterns of spleen sections for T cells (CD4+ T plus CD8+ T cells), B220+ B cells, and PNA+ GC B cells. In wild-type BXSB mice, the white pulp composed of T cells located in the periarteriolar lymphoid sheath and B cells forming lymph follicles outside the periarteriolar lymphoid sheath is expanded in the enlarged spleen, and large GCs are prominent in lymph follicles. In contrast, the white pulp of BXSB.IIBB6/B6 and BXSB.{gamma}–/– mice is intact with normal size and architecture. Of note was the finding, however, that while numerous GCs are formed in BXSB.{gamma}–/–, they are rare in BXSB.IIBB6/B6 mice. It was also to be noted that many T cells are intermingled with B cells in GCs in BXSB and BXSB.{gamma}–/– mice, a finding corresponding to the increased frequency of CD69+ activated T cells in the spleen of these mice (Fig. 6B and Table I).


Figure 7
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  		FIGURE 7. A, Immunofluorescent findings of Fc{gamma}RIIB1 expression levels on GC and non-GC B cells in the splenic white pulps in 7-mo-old BXSB, BXSB.IIBB6/B6, and BXSB.{gamma}–/– mice. Frozen sections were stained with a combination of Alexa 647-labeled anti-B220, Alexa 488-labeled anti-CD4 and anti-CD8 mAbs, and Alexa 546-labeled PNA, and images are obtained using laser scanning microscopy. Representative results obtained from three mice in each strain. B, Flow cytometric profiles of Fc{gamma}RIIB1 expression levels on PNA+ GC B cells and PNA– non-GC B cells shown in the histogram. Spleen cells from 7-mo-old mice were stained with a combination of 2.4G2, anti-B220 mAbs, and PNA, and 2.4G2 expression levels between PNA+ GC B cells and PNA– non-GC B cells are compared. Because B cells mainly express Fc{gamma}RIIB1, 2.4G2 expression on B cells reflects the level of Fc{gamma}RIIB1. Closed areas indicate the background staining. Representative results obtained from three mice in each strain.

 
Fig. 7B shows 2.4G2 expression levels on PNA+ GC B cells and PNA– non-GC B cells examined by flow cytometry analysis using three-color staining with anti-B220 mAb, PNA, and 2.4G2 mAb. Because B cells mainly express Fc{gamma}RIIB1, 2.4G2 expression on B cells reflects the Fc{gamma}RIIB1 expression level. As compared with BXSB.IIBB6/B6 mice, BXSB and BXSB.{gamma}–/– mice showed a marked decrease (approximately one-tenth) in Fc{gamma}RIIB1 expression levels on PNA+ GC B cells, whereas there was no such difference in PNA– non-GC B cells among these three strains examined, in keeping with our previous findings (14, 15).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
Our findings suggest that both stimulatory Fc{gamma}Rs and the impaired inhibitory Fc{gamma}RIIB are critical factors in the pathogenesis of systemic autoimmune disease in BXSB mice. To dissect the roles of the {gamma} chain-associated stimulatory Fc{gamma}RI/III and the impaired inhibitory Fc{gamma}RIIB encoded by the BXSB-type polymorphic Fcgr2b gene, we generated two congenic BXSB strains: one was the BXSB.{gamma}–/– strain, which lacks expression of stimulatory Fc{gamma}RI/III and has BXSB-type impaired inhibitory Fc{gamma}RIIB, and the other was the BXSB.IIBB6/B6 strain, which has intact stimulatory and inhibitory Fc{gamma}Rs. Because the genes encoding the FcR{gamma} chain and Fc{gamma}RIIB are closely linked on chromosome 1, we needed to select interval congenic mice with recombination between the FcR{gamma} chain gene and Fcgr2b gene among a huge number of meioses in the backcross procedure over 30 generations. Two newly established strains both showed markedly prolonged longevity and did not develop any clinical autoimmune disease features, such as renal failure, thrombocytopenia, and splenomegaly; however, mechanisms underlying the observed disease protection differed between the two mutant strains.

Present findings strongly suggested that lack of stimulatory Fc{gamma}Rs in BXSB.{gamma}–/– mice prevented the disease because of failure to trigger the effecter phase of IC-mediated tissue inflammation. Two notable findings supported this view. First, BXSB.{gamma}–/– mice produced significant amounts of anti-DNA Abs and showed IgG IC deposits in renal glomeruli; nevertheless, they did not develop histopathologically evident glomerulonephritis. Thus, it appears that the glomerular IC deposition itself is {gamma} chain independent, whereas the subsequent development of glomerular damage is {gamma} chain dependent. It is highly possible that some cells in glomeruli positive for stimulatory Fc{gamma}Rs may mediate inflammatory glomerular damages, probably through the production of certain inflammatory mediators. Indeed, earlier studies showed that stimulatory Fc{gamma}RIII expressed on glomerular mesangial cells is essential for progression of glomerulonephritis (28, 29).

Second, although BXSB.{gamma}–/– mice had high frequencies of activated T and B cells in the spleen, comparable to those found in wild-type BXSB mice, they did not develop splenomegaly and the associated thrombocytopenia. One unique feature of immune cells in BXSB mice is an age-associated increase in monocyte/macrophage population (23, 24). Wofsy et al. (23) reported that monocytosis in these mice begins as early as 2 mo of age and is accelerated with aging. As the frequencies of these cells were markedly increased in the spleen of aged BXSB mice in the present studies, this abnormality of monocytes/macrophages appears to be a major cause of splenomegaly in BXSB mice. In this context, Hora et al. (30) reported that via IC stimulation, cells bearing stimulatory Fc{gamma}Rs produce a large amount of M-CSF. Thus, the monocytosis and the associated splenomegaly in BXSB mice is likely to be dependent on the amounts of circulating IgG ICs and the number of cells bearing stimulatory Fc{gamma}Rs. Although BXSB.{gamma}–/– mice bearing activated T and B cells in the spleen may produce IgG ICs, the lack of Fc{gamma}R-mediated stimulatory signals for M-CSF production results in failure to propagate monocytes/macrophages. This assumption is in accord with the finding by Lenda et al. (31) that splenomegaly is dramatically suppressed in MRL/lpr mice, another murine lupus model, if these mice are deficient in M-CSF.

Like BXSB.{gamma}–/– mice, BXSB.IIBB6/B6 mice bearing intact stimulatory and inhibitory Fc{gamma}Rs did not develop autoimmune disease. However, several immunological findings differed between BXSB.{gamma}–/– and BXSB.IIBB6/B6 mice. In contrast to the former, the latter did not show any evidence of glomerular deposits of IgG ICs and the production of anti-DNA and anti-platelet Abs. In these BXSB.IIBB6/B6 mice, as compared with BXSB and BXSB.{gamma}–/– mice, the frequency of activated lymphocytes in the spleen was markedly reduced, and the formation of GC in the spleen was rare. Thus, the mechanism of disease prevention in these mice seems to be more central, leading to the suppression of spontaneous activation of self-reactive lymphocytes and the associated production of IgG autoantibodies and IC formation. Indeed, such suppression was maintained and by follow-up to 16 mo of age, the majorities of BXSB.IIBB6/B6 mice survived in the absence of disease features (data not shown). In this connection, we found earlier that BXSB-type deletion polymorphism in the Fcgr2b promoter region directly affects transcriptional regulation and down-modulates Fc{gamma}RIIB1 expression levels on activated B cells, thereby reducing the potential of inhibitory receptor Fc{gamma}RIIB for IgG Ab synthesis (15). The inhibition of BXSB-unique B cell activation in BXSB.IIBB6/B6 mice is thus thought to be due to the impact of the B6-derived wild-type Fcgr2b promoter region. Fc{gamma}RIIB is not usually expressed on T cells, and hence, the inhibition of T cell activation in BXSB.IIBB6/B6 mice is not simply explained by the direct effect of B6-type Fc{gamma}RIIB. Although the exact mechanism remains unclear, there is a report indicating that both activated B and T cells increase in aged Fcgr2b-deficient B6 mice (13).

The serum level of IgG anti-DNA Abs produced in BXSB.{gamma}–/– mice was as high as that seen in wild-type BXSB, whereas the level in BXSB.IIBB6/B6 was markedly reduced. In contrast to this finding, the production of platelet-binding autoantibodies was relatively suppressed in BXSB.{gamma}–/– mice. In our earlier genetic studies using crosses between NZW and BXSB, while one susceptibility allele for production of anti-DNA and anti-platelet Abs was both tightly linked to the MHC (H-2 complex) on chromosome 17 (21, 22), another allele unique for platelet-binding autoantibodies was linked to the gene Plat for tissue plasminogen activator (tPA) on chromosome 8 (22). Sequence analysis of Plat revealed a single nucleotide polymorphism in the region encoding the catalytic domain of tPA between the NZW and BXSB strains, and BXSB-type polymorphism was significantly associated with high serum levels of platelet-binding Abs and thrombocytopenia (32). tPA converts plasminogen to the active protease plasmin for fibrinolytic activity. Thus, the BXSB-type Plat polymorphism may cause an abnormality in blood coagulation, resulting in aggregation and destruction of platelets, and providing Ags effectively for induction of anti-platelet autoantibodies. It appears that, in BXSB.{gamma}–/– mice, lack of Fc{gamma}RIII molecules prevents the potential of macrophages to phagocytose IgG-opsonized platelets, which down-regulates the production of anti-platelet autoantibodies.

Accumulating evidence supports the importance of murine telomeric chromosome 1 for susceptibility to SLE. The support interval of Lbw7 (33), Nba2 (34), Hig-1 (35), Bxs3 (36), and Sle1 (37) contains several interesting candidate genes, and thus, one can speculate that multiple susceptibility loci for SLE are clustered in this interval. Analysis of sequence polymorphism of candidate genes suggested the possible involvement of Fcgr2b (14, 15, 35, 38), Ifi202 (39), Cr2 (40), and a gene cluster of the SLAM/CD2 family (41) in SLE susceptibility. Because Ifi202, SLAM/CD2 family genes, and Cr2 are not substituted for B6 type in our BXSB.IIBB6/B6 mice (Fig. 1), the observed disease protection in these mice is more likely due to the impact of B6-type polymorphic Fcgr2b. However, our BXSB.{gamma}–/– mice carry B6-derived interval, including Ifi202 and SLAM/CD2 family genes; thus, one may not exclude the possible involvement of these alleles in the disease protection in BXSB.{gamma}–/– mice. Rozzo et al. (39) reported that there are Ifi202 promoter region polymorphisms between NZB and B6 and that the NZB-type polymorphism is possibly involved in lupus autoimmunity. Recently, however, we examined nucleotide sequence of the Ifi202 promoter region and found that BXSB sequence is identical to the reported B6 sequence (39). Thus, the Ifi202 promoter region polymorphism may not be involved in lupus susceptibility in BXSB mice and in disease protection in our BXSB.{gamma}–/– mice as well.

On the other hand, it is known that there are two SLAM/CD2 haplotypes (haplotypes 1 and 2) and that BXSB mice carry the parental SB/Le strain-derived haplotype 2 distinct from that of B6-derived haplotype 1 (41, 45). These SLAM/CD2 family genes were reported to play a role in the modulation of cellular activation and signaling in the immune system (42, 43, 44), and B6 mice congenic for haplotype 2 show increased serum levels of IgG anti-chromatin Abs, suggesting that polymorphic SLAM/CD2 molecules are ideal candidates for autoimmune phenotype (41). However, if the suppression of autoimmune disease in BXSB.{gamma}–/– mice is caused by B6-derived SLAM/CD2 haplotype 1, the activation of T and B cells and the associated autoantibody production are assumed to be suppressed in BXSB.{gamma}–/– mice, as Wandstrat et al. (41) suggested. Because this was not the case in BXSB.{gamma}–/– mice in the present studies, it appears to be more likely that the suppression of disease in these mice may be due to the lack of stimulatory Fc{gamma}Rs, although the B6-derived SLAM/CD2 haplotype 1 may also be involved in part. To clarify this issue, we are now establishing BXSB interval congenic lines carrying an intact FcR{gamma} chain gene and B6-type SLAM/CD2 haplotype.

Abundant evidence has shown that multiple genes or alleles at multiple loci are involved in the pathogenesis of murine and human SLE (46, 47, 48, 49, 50). Clinical manifestations of SLE are extremely diverse and variable, probably because each specific aspect of SLE features is controlled separately by a different combination of susceptibility genes at multiple loci (48, 49, 50). Our present findings, however, stressed the importance of major genes as targets of prophylactic and therapeutic approaches. As in human SLE, the BXSB strain develops a variety of SLE features. Nonetheless, the absence of stimulatory or presence of intact inhibitory Fc{gamma}Rs each can lead to almost complete suppression of the disease phenotypes. More thorough understanding of the mechanisms of disease suppression and the related molecular events mediated by Fc{gamma}Rs may provide new preventive and therapeutic approaches for not only SLE but also other systemic autoimmune diseases. In this respect, a recent report by McGaha et al. (51), demonstrating the successful treatment of SLE in NZM2410, BXSB, and Fcgr2b-deficient B6 mice by reconstitution of irradiated recipients with Fc{gamma}RIIB-expressing retrovirus-transduced bone marrow cells, is encouraging.


   Acknowledgment
 
We thank M. Tanaka for skillful technical assistance.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by a Grants-in-Aid for Scientific Research (B), for Scientific Research on Priority Areas and for Center of Excellence Research from the Ministry of Education, Science, Technology, Sports and Culture, Japan, and a grant from the Organization for Pharmaceutical Safety and Research, Japan. Back

2 Address correspondence and reprint requests to Dr. Sachiko Hirose, Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail address: sacchi{at}med.juntendo.ac.jp Back

3 Abbreviations used in this paper: IC, immune complex; SLE, systemic lupus erythematosus; BUN, blood urea nitrogen; GC, germinal center; PNA, peanut lectin (agglutinin); PASH, periodic acid-Schiff and hematoxylin; MFI, mean fluorescence intensity; tPA, tissue plasminogen activator. Back

Received for publication January 18, 2006. Accepted for publication May 11, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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