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*Lupus
The Journal of Immunology, 2006, 176: 3240-3247.
Copyright © 2006 by The American Association of Immunologists

Contribution of NZB Autoimmunity 2 to Y-Linked Autoimmune Acceleration-Induced Monocytosis in Association with Murine Systemic Lupus1

Shuichi Kikuchi2,*, Marie-Laure Santiago-Raber2,*, Hirofumi Amano*, Eri Amano*, Liliane Fossati-Jimack{dagger}, Thomas Moll*, Brian L. Kotzin{ddagger} and Shozo Izui3,*

* Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; {dagger} Rheumatology Section, Hammersmith Campus, Imperial College School of Medicine, London, United Kingdom; and {ddagger} Division of Clinical Immunology, University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado 80206


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of the Y-linked autoimmune acceleration (Yaa) mutation, which induces an age-dependent monocytosis. Using a cohort of C57BL/6 (B6) x (NZB x B6)F1 backcross male mice bearing the Yaa mutation, we defined the pathogenic role and genetic basis for Yaa-associated monocytosis. We observed a remarkable correlation of monocytosis with autoantibody production and subsequent development of lethal lupus nephritis, indicating that monocytosis is an additional useful indicator for severe SLE. In addition, we identified an NZB-derived locus on chromosome 1 predisposing to the development of monocytosis, which peaked at Fcgr2b encoding Fc{gamma}RIIB and directly overlapped with the previously identified NZB autoimmunity 2 (Nba2) locus. The contribution of Nba2 to monocytosis was confirmed by the analysis of Yaa-bearing B6 mice congenic for the NZB-Nba2 locus. Finally, we observed a very low-level expression of Fc{gamma}RIIB on macrophages bearing the NZB-type Fcgr2b allele, compared with those bearing the B6-type allele, and the development of monocytosis in Fc{gamma}RIIB haploinsufficient B6 mice carrying the Yaa mutation. These data suggest that the Nba2 locus may play a supplementary role in the pathogenesis of SLE by promoting the development of monocytosis and the activation of effector cells bearing stimulatory Fc{gamma}R, in addition to its implication in the dysregulated activation of autoreactive B cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
An as yet unidentified mutation, Y-linked autoimmune acceleration (Yaa)4 (4), present on the Y chromosome of the BXSB strain, is responsible for the accelerated development of lupus-like autoimmune syndrome in BXSB mice and in their F1 hybrids with NZB or NZW mice (1, 2). Yaa by itself is unable to induce significant autoimmune responses in mice without an apparent systemic lupus erythematosus (SLE) background (3, 4), while it can induce and accelerate the development of SLE in combination with autosomal susceptibility alleles present in lupus-prone mice (5). We have shown previously that the Yaa defect is functionally expressed in B cells, but not in T cells (6, 7, 8, 9). Thus, it has been speculated that the Yaa defect may decrease the threshold of BCR-mediated signaling, thereby triggering and excessively stimulating autoreactive B cells (2, 9).

A unique cellular abnormality associated with the Yaa mutation is monocytosis (10). Monocytes reach a frequency of >50% of PBMC in 6- to 8-mo-old BXSB Yaa male mice, but monocytosis was not observed in BXSB.ll (ll for long-lived) and BXSB.H2d mice, both of which fail to develop SLE (11, 12). Our recent analysis of Yaa plus non-Yaa mixed bone marrow chimeras demonstrated no selective production of monocytes of Yaa origin over those of non-Yaa origin, indicating that the development of monocytosis is not due to an intrinsic abnormality in the growth potential of monocyte lineage cells from Yaa-bearing mice (13). This suggests that Yaa-mediated monocytosis may result from an excessive production of monocyte-specific growth factor(s), for example, by macrophages.

It is now well established that SLE is a polygenic disease, in which multiple, unlinked genes are operative in a threshold manner. Among a number of lupus susceptibility loci described in lupus-prone mice (14, 15), the NZB autoimmunity 2 (Nba2) locus, located on the distal portion of NZB chromosome 1, has been shown to be a major genetic contribution from the NZB strain to disease susceptibility in the (NZB x NZW)F1 mouse model of SLE (16, 17). Indeed, C57BL/6 (B6) mice congenic for the NZB-Nba2 locus (B6.Nba2) produce antinuclear Abs, and (B6.Nba2 x NZW)F1 mice develop severe lupus-like kidney disease, similar to (NZB x NZW)F1 mice. Moreover, we have shown recently that the presence of both Yaa and Nba2 is sufficient to induce a lethal form of lupus-like nephritis in B6 mice (17). Notably, analysis of sequence polymorphism has suggested that the Nba2 interval likely contains several lupus susceptibility genes, such as Fcgr2 encoding the inhibitory Fc{gamma}RIIB (18, 19, 20), IFN-inducible p202 (Ifi202) (16), and the signaling lymphocyte activation molecule (SLAM)/CD2 gene family (21).

To further define the pathogenic role of monocytosis in the development and progression of lupus-like autoimmune syndrome and the possible contribution of Nba2 to Yaa-associated monocytosis, we determined in the present study the correlation of monocytosis with serological parameters and lupus nephritis in B6 x (NZB x B6.Yaa)F1 backcross (BC) male mice bearing the Yaa mutation and mapped the NZB-derived susceptibility locus predisposing to the development of monocytosis. Our results showed a remarkable association of monocytosis with increased production of various autoantibodies and subsequent development of lupus nephritis, indicating that monocytosis is a useful marker for severe disease in this model. In addition, a major NZB locus contributing to monocytosis was mapped to a chromosome 1 interval that overlapped with the Nba2 locus. Finally, we showed the possible role of the NZB-type Fcgr2b allele encoding the inhibitory Fc{gamma}RIIB, one of the candidate lupus susceptibility genes present in the Nba2 interval, in the development of Yaa-induced monocytosis.


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

NZB mice were purchased from The Jackson Laboratory. B6 mice bearing the Yaa mutation (B6.Yaa) were established by repeated backcrossing (n >20), as described previously (4). (NZB x B6.Yaa)F1 and B6 x (NZB x B6.Yaa)F1 BC mice were obtained by local breeding in our animal facility. B6.Nba2 congenic mice bearing the NZB-Nba2 locus were generated as described previously (16). Mice deficient in Fc{gamma}RIIB (Fc{gamma}RIIB–/–) or in Fc{gamma}RIII (Fc{gamma}RIII–/–), provided by Dr. J. Ravetch (Rockefeller University, New York, NY) (22) and by Dr. J. S. Verbeek (Leiden University Medical Center, Leiden, The Netherlands) (23), were backcrossed for eight and five generations with B6 mice, respectively. Fc{gamma}RIIB+/– haploinsufficient B6 mice bearing the Yaa mutation were generated by intercrossing Fc{gamma}RIIB–/– B6 females and B6.Yaa males. Mice double-deficient in both Fc{gamma}RIIB and Fc{gamma}RIII were provided by Dr. Verbeek (24). Mice deficient in FcR {gamma}-chains (FcR{gamma}–/–), which lack functional expression of both Fc{gamma}RI and Fc{gamma}RIII, with a pure B6 background were provided by Dr. T. Saito (RIKEN Research Center for Allergy and Immunology, Yokohama, Japan) (25). The genotype of the NZB- and B6-type Fcgr2b alleles was determined by PCR with 5'-GTTGATCTTCATTTTACAGAC-3' and 5'-TCTGTGCCCTAGTCCTGAATC-3', as described (18). Blood samples were collected by orbital sinus puncture. All experiments described in this study were approved by the Cantonal Veterinary Office of Geneva, Switzerland.

Flow cytometric analysis

Flow cytometry was performed using two- or three-color staining of PBMC and peritoneal cavity cells and analyzed with a FACSCalibur (BD Biosciences). The following mAb were used: anti-CD11b (M1/70), anti-Ly6C/G (Gr-1), anti-CD11c (N418), anti-F4/80, anti-Fc{gamma}RII/III (2.4G2), and anti-B220 (RA3–6B2). Mean percentage of CD11b+ monocytes (±SD) among PBMC in 10-mo-old B6 male mice (n = 15) was 10.3 ± 3.0. Mice displaying percentages of monocytes >3 SD above the mean of B6 males (>19.3%) were considered as positive for monocytosis.

Serological assays

Serum levels of IgG autoantibodies against chromatin and heat-denatured DNA were determined by ELISA as described previously (16, 26). Results are expressed in units per milliliter in reference to a standard curve obtained with a serum pool of MRL-Faslpr mice. Serum levels of gp70-anti-gp70 immune complexes (IC) were quantified by ELISA combined with the treatment of sera with 10% polyethylene glycol (average m.w. 6000), which precipitates only Ab-bound gp70 but not free gp70, as described previously (12). Results are expressed as µg/ml gp70 by referring to a standard curve obtained with a serum pool of NZB mice with known amounts of gp70.

Histopathology

Kidney samples were collected when mice were moribund or at the end of the experiment (18 mo of age). Histological sections were stained with periodic acid-Schiff reagent. The extent of glomerulonephritis was graded on a 0–4 scale based on the intensity and extent of histopathological changes, as described previously (4). Glomerulonephritis with grade 3 or 4 was considered a significant contributor to clinical disease and/or death.

Genotyping and statistical analysis

DNA was extracted from tail samples kept at –70°C before use. Genotypes were determined by PCR using 95 selected microsatellite markers distributed over all 19 autosomes (Table I), purchased from either Research Genetics or Invitrogen Life Technologies. PCR amplification was conducted with RED TaqDNA polymerase (Sigma-Aldrich) using a GeneAmp PCR system 9700 thermal cycler (Applied Biosystems), as described previously (27). The positions of the microsatellite markers with respect to the centromere were obtained from the Mouse Genome Database at <www.informatics.jax.org>. The linkage software program MapMaker/QTL was used to identify quantitative trait locus (28). Percentages of monocytes and autoantibody levels were log10 transformed. A threshold for suggestive linkage was set at log likelihood of the odds (LOD) > 1.9, p < 0.0034, and for significant linkage at LOD >3.3, p < 0.0001, based on the recommendation of Lander and Kruglyak (29). Percentages of monocytes were correlated with serological parameters and histological grades of glomerular lesions by the Spearman rank correlation method, and p values were calculated using StatView 5.0 software (SAS Institute). Comparison of percentages of monocytes and their subsets and of fluorescence intensities with 2.4G2 mAb staining on macrophages and B cells between different groups of mice was performed with the Wilcoxon two-sample test. p values <0.05 were considered significant.


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  		Table I. Polymorphic microsatellite markers used

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
Development of monocytosis in B6 x (NZB x B6.Yaa)F1 BC mice bearing the Yaa mutation

We have shown previously an age-dependent development of monocytosis in (NZB x B6.Yaa)F1 male mice bearing the Yaa mutation that parallels the progression of SLE (13). At 10 mo of age, all (NZB x B6.Yaa)F1 Yaa males (n = 17) displayed strongly increased percentages of CD11b+ monocytes, as determined by flow cytometric analysis (mean ± SD, 37.3 ± 9.7%; Fig. 1). In contrast, the levels in B6.Yaa male mice were markedly lower (13.8 ± 5.3%; p < 0.0001), and only 1 of 12 mice was positive for monocytosis.


Figure 1
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  		FIGURE 1. Levels of circulating monocytes in 10 mo-old male B6. Yaa, (NZB x B6.Yaa)F1 and B6 x (NZB x B6.Yaa)F1 BC mice bearing the Yaa mutation. The percentage of CD11b+ monocytes in PBMC was determined by flow cytometric analysis. Mean values are indicated by horizontal lines. Each symbol represents an individual animal of B6.Yaa (n = 12), F1 (n = 17), and BC Yaa males (n = 110).

 
To determine the NZB genetic contribution to the Yaa-induced monocytosis in (NZB x B6.Yaa)F1 male mice, a total of 110 B6 x (NZB x B6.Yaa)F1 male BC mice bearing the Yaa mutation were produced and studied. At 10 mo of age, 37% (41 of 110) of BC mice displayed monocytosis (Fig. 1).

Association of monocytosis with the development of autoimmune responses and lupus nephritis

The development of monocytosis among BC progeny was assessed in relation to serum levels of nephritogenic antinuclear autoantibodies (anti-DNA and antichromatin) and gp70-anti-gp70 IC at 10 mo of age. Correlation analyses showed a highly significant association between monocytosis and increased titers of these three serological parameters (p < 0.0001; Fig. 2). When histological scores of glomerular lesions (grades 0–4), determined at sacrifice of moribund animals or at 18 mo of age, were plotted against percentages of monocytes at 10 mo of age, we observed a remarkable correlation of the extent of monocytosis with the development of lupus-like glomerulonephritis (p < 0.0001; Fig. 3A). Indeed, BC mice with monocytosis developed more severe glomerulonephritis (grade ≥3) than mice without monocytosis (p < 0.0001; Fig. 3B). 78% (32 of 41) of mice with monocytosis, but only 25% (17 of 69) of mice without monocytosis developed lethal glomerulonephritis by 18 mo of age.


Figure 2
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  		FIGURE 2. Correlation of blood levels of monocytes and serum levels of IgG anti-DNA, antichromatin and gp70 IC in 10-mo-old B6 x (NZB x B6.Yaa)F1 male BC mice bearing the Yaa mutation. The percentage of CD11b+ monocytes in PBMC was determined by flow cytometric analysis. Serum levels of anti-DNA and antichromatin autoantibodies, expressed as U/ml, and gp70 IC, expressed as µg/ml, were determined by ELISA. Each symbol represents an individual animal of BC Yaa males (n = 110).

 

Figure 3
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  		FIGURE 3. Association of blood levels of monocytes and subsequent development of glomerulonephritis in B6 x (NZB x B6.Yaa)F1 male BC mice bearing the Yaa mutation. The percentage of CD11b+ monocytes in PBMC was determined by flow cytometric analysis at 10 mo of age. A, The intensity of glomerular lesions was scored on a 0–4 scale. Results from individual mice (n = 110), sacrificed either moribund or at the end of an 18-mo observation period, are shown. B, BC mice were divided into two groups according to the presence or absence of monocytosis. Mice displaying percentages of monocytes >3 SD above the mean of B6 males (>19.3%) were considered as positive for monocytosis: Mono+ (n = 41) and Mono– (n = 69). Mean histological grades of glomerular lesions are indicated by horizontal lines. Incidence of severe glomerulonephritis (grade ≥3) was significantly increased in BC mice having monocytosis, compared with those lacking monocytosis (p < 0.0001). Each symbol represents an individual animal of BC Yaa males.

 
Contribution of Nba2 to Yaa-associated monocytosis

To map the chromosomal loci responsible for the regulation of monocytosis, B6 x (NZB x B6.Yaa)F1 male BC mice were genotyped for microsatellite markers polymorphic between B6 and NZB mice. The analysis of percentages of monocytes at 10 mo of age, using MapMaker/QTL software, revealed significant linkage with a single chromosomal region peaking in the vicinity of Fcgr2b at 92.3 centiMorgans (cM) from the centromere of NZB chromosome 1, with a LOD score of 3.64 (p = 4.22 x 10–5; Fig. 4). This locus directly overlapped with the Nba2 interval (~90–98 cM from the centromere), which is known to control the overall production of lupus autoantibodies (16, 17). In contrast to Nba2, no linkages were apparent with three lupus susceptibility loci, H2 on chromosome 17, Nba5 (NZB autoimmunity 5) on chromosome 7, and Sgp3 (serum gp70 production 3) on chromosome 13, previously identified in the same BC mice (17), although we noted a trend for the linkage of the H2 locus with monocytosis (LOD score of 1.47, p = 0.009, Table II).


Figure 4
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  		FIGURE 4. Linkage of chromosome 1 marker with monocytosis in B6 x (NZB x B6.Yaa)F1 male BC mice bearing the Yaa mutation. The percentage of CD11b+ monocytes in PBMC was determined by flow cytometric analysis at 10 mo of age. LOD scores were generated with MapMaker/QTL software. The horizontal dotted line represents the threshold for suggestive linkage. Two microsatellite markers, D1Mit15 and D1Mit36, are not shown because their positions (87.9 and 92.3 cM from the centromere, respectively) are too close to that of Fcgr2b (92.3 cM).

 

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  		Table II. Loci linked with monocytosis and SLE-related autoimmune traits in B6 x (NZB x B6.Yaa)F1 male BC mice bearing the Yaa mutation

 
To confirm the contribution of Nba2 to the development of monocytosis, we assessed the development of monocytosis in B6 mice bearing an Nba2 interval flanked by markers D1Mit47 and D1Mit461 (~23 cM interval). As expected from the results obtained with BC mice, 67% (10 of 15) of B6.Nba2 male mice bearing the Yaa mutation developed significantly increased percentages of monocytes at 10 mo of age (mean ± SD, 30.3 ± 17.1%; Fig. 5), in parallel to the development of lupus-like autoimmune manifestations (17). In contrast, monocytosis was hardly observed in B6.Nba2 females lacking the Yaa mutation (11.6 ± 3.2%; p < 0.001), which fail to develop severe SLE (16, 17).


Figure 5
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  		FIGURE 5. Levels of circulating monocytes in 10-mo-old B6.Nba2, Fc{gamma}RIIB+/– B6, and WT B6 mice. The percentage of CD11b+ monocytes in PBMC was determined by flow cytometric analysis at 10 mo of age. Mean values are indicated by horizontal lines. Each symbol represents an individual animal (12–15 mice in each group). •, Nba2, Fc{gamma}RIIB+/–, and WT male mice bearing the Yaa mutation; {circ}, Nba2, Fc{gamma}RIIB+/–, and WT female mice lacking the Yaa mutation.

 
We have demonstrated recently that Yaa-induced monocytosis resulted in a selective expansion of only one of the two major monocyte subsets, called "resident" (Gr-1– CD11b+) monocytes (13), which are considered to give rise to tissue-resident macrophages and dendritic cells (DC) (30, 31). In contrast, Gr-1+ CD11b+ monocytes are classified as the "inflammatory" subset that is preferentially recruited to inflamed tissue (30, 31). In 2-mo-old B6.Nba2 male mice bearing the Yaa mutation, the percentage of Gr-1+ CD11b+ inflammatory monocytes was almost comparable to that of the Gr-1– CD11b+ resident monocyte subset (Fig. 6), as was the case in B6 mice (13). However, in 10-mo-old B6.Nba2 Yaa males developing monocytosis, the Gr-1– monocyte subset became dominant over the Gr-1+ subset (p < 0.005), as observed in BXSB and (NZB x B6.Yaa)F1 male mice bearing the Yaa mutation (13). In contrast, the balance of these two subsets changed neither in aged B6.Nba2 female littermates lacking the Yaa mutation nor in B6.Yaa male mice. As observed previously (13), Gr-1+ monocytes were negative for CD11c, while the Gr-1– subset of monocytes from 10-mo-old B6.Nba2 Yaa males displayed significant surface expression of CD11c (data not shown).


Figure 6
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  		FIGURE 6. Selective expansion of the Gr-1– monocyte subset in 10-mo-old B6.Nba2 and B6 Fc{gamma}RIIB+/– Yaa male mice developing monocytosis. PBMC from 2- or 10-mo-old different substrains of B6 mice were stained with a combination of anti-CD11b and anti-Gr-1 mAb. Representative staining profiles for Gr-1 in relation to the staining with anti-CD11b mAb are shown. Percentages of Gr-1+ and Gr-1– CD11b+ monocytes (mean of five mice ± SD) are indicated.

 
Low-level expression of Fc{gamma}RIIB on macrophages bearing the NZB-type Fcgr2b allele

The Fcgr2b allele of the NZB strain has been proposed as a possible lupus susceptibility gene present in the Nba2 interval, because the expression of Fc{gamma}RIIB, a negative regulator of BCR signaling, is defective in germinal center B cells of NZB mice (18, 19). Because Fc{gamma}RIIB also negatively regulates the IC-mediated activation of Fc{gamma}R (22, 32), defective expression of Fc{gamma}RIIB in macrophages of NZB mice could promote their activation via stimulatory Fc{gamma}R in response to autoimmune IC, thereby contributing to the development of monocytosis. Because of the lack of mAb able to specifically recognize Fc{gamma}RIIB of both NZB- and B6-type alleles, it has not yet been determined whether Fc{gamma}RIIB expression is defective in macrophages of NZB mice. To address this question, we compared the expression levels of Fc{gamma}RIIB on two different types of Fc{gamma}RIII-deficient macrophages either from Fc{gamma}RIII–/– B6 mice lacking the ligand-binding Fc{gamma}RIII-specific {alpha}-chains or from FcR{gamma}–/– B6 mice lacking the common FcR {gamma}-chains, the coexpression of which is required for cell surface expression of Fc{gamma}RIII (33). FcR{gamma}–/– B6 mice with a pure B6 background express the B6-type Fc{gamma}RIIB (25), while Fc{gamma}RIII–/– B6 mice generated by backcrossing the mutated 129 interval to B6 mice express the NZB-type Fc{gamma}RIIB, because the Fcgr2b gene cotransferred with the Fcgr3 mutant gene is derived from the 129 strain bearing the NZB-type Fcgr2b allele (20). The respective Fcgr2b genotypes of FcR{gamma}–/– and Fc{gamma}RIII–/– B6 mice were confirmed by PCR (Fig. 7A). Thus, the staining of Fc{gamma}RIII–/– and FcR{gamma}–/– macrophages with 2.4G2 mAb, which recognizes both Fc{gamma}RIIB and Fc{gamma}RIII of any strain of mice, permits to specifically define the expression levels of NZB- and B6-type Fc{gamma}RIIB on these macrophages. When peritoneal resident macrophages from 2-mo-old FcR{gamma}–/– and Fc{gamma}RIII–/– B6 mice were analyzed by flow cytometry, the expression levels of Fc{gamma}RIIB were approximately four times less in peritoneal macrophages bearing the NZB-type Fcgr2b allele (mean fluorescence intensities of three mice ± SD, 54.0 ± 2.8) than in those bearing the B6-type allele (205.7 ± 24.0; p < 0.05; Fig. 7B). In contrast, the 2.4G2 mAb stained equally well B cells bearing either Fcgr2b allele (NZB-type, 189.7 ± 29.5; B6-type, 202.0 ± 11.3), consistent with the finding that the expression levels of Fc{gamma}RIIB on resting B cells were comparable between B6 and NZB mice (18).


Figure 7
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  		FIGURE 7. A, Fcgr2b allele-specific PCR analysis in different strains of mice. Tail DNA was used as a template for PCR, and the amplified fragments were visualized after electrophoresis on 5% acrylamide gels by staining with ethidium bromide. Lane 1, FcR{gamma}–/– B6; lane 2, Fc{gamma}RIII–/– B6; lane 3, 129; lane 4, B6.Nba2; lane 5, NZB; lane 6, B6. Size difference in PCR products (NZB-type Fcgr2b, 149 bp vs B6-type Fcgr2b, 165 bp) is due to a deletion in the promoter region of the NZB-type Fcgr2b gene (18 ). B, Low-level expression of Fc{gamma}RIIB on peritoneal resident macrophages bearing the NZB-type Fcgr2b allele. Peritoneal cavity cells from 2-mo-old FcR{gamma}–/– or Fc{gamma}RIII–/– B6 mice were stained with a combination of 2.4G2 (anti-Fc{gamma}RII/III), anti-F4/80, or anti-B220 mAb, and gated for F4/80+ macrophages and B220+ B cells. Representative results of 2.4G2 staining for Fc{gamma}RIIB on macrophages and B cells from FcR{gamma}–/– B6 mice expressing the B6-type Fc{gamma}RIIB and Fc{gamma}RIII–/– B6 mice expressing the NZB-type Fc{gamma}RIIB are shown. Shaded histograms indicate the staining of macrophages and B cells from mice deficient in both Fc{gamma}RIIB and Fc{gamma}RIII.

 
Development of monocytosis in Fc{gamma}RIIB haploinsufficient B6 mice bearing the Yaa mutation

We have observed recently that partial Fc{gamma}RIIB deficiency, i.e., heterozygous level of Fc{gamma}RIIB expression, is sufficient to induce the production of anti-DNA autoantibodies in B6 mice in the presence of the Yaa mutation (34). In addition, these mice developed lethal glomerulonephritis with a 50% mortality rate at 16 mo. In view of the possible role of Fc{gamma}RIIB deficiency in the development of Yaa-mediated monocytosis, we determined monocytosis in Fc{gamma}RIIB+/– haploinsufficient B6 males bearing the Yaa mutation. At 10 mo of age, 58% (7 of 12) of Fc{gamma}RIIB+/– B6 Yaa males displayed monocytosis (mean ± SD, 23.1 ± 11.3%; Fig. 5). In contrast, Fc{gamma}RIIB+/– male mice without the Yaa mutation had normal levels of monocytes (9.0 ± 1.6%; p < 0.005). Again, the Gr-1– resident subset became the major population among blood monocytes of Fc{gamma}RIIB+/– Yaa males (Fig. 6).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
A unique cellular abnormality associated with Yaa-mediated lupus-like autoimmune disease is monocytosis (10). The present study was designed to define the pathogenic role and genetic basis for monocytosis by using a cohort of B6 x (NZB x B6.Yaa)F1 male BC mice bearing the Yaa mutation. The results demonstrate that monocytosis is strongly associated with autoantibody production and subsequent development of lupus nephritis, and that an NZB-derived susceptibility locus overlapping with Nba2 on chromosome 1 promotes monocytosis. The contribution of Nba2 to the development of monocytosis was further confirmed by the analysis of B6.Nba2 congenic mice. In addition, we observed much lower levels of Fc{gamma}RIIB expression on macrophages bearing the NZB-type Fcgr2b allele than on those bearing the B6-type allele, and the development of monocytosis in Fc{gamma}RIIB haploinsufficient B6.Yaa male mice. These results suggest that, in addition to its contribution to the dysregulated activation of autoreactive B cells, Nba2 may play a supplementary role in the pathogenesis of SLE by promoting the development of monocytosis.

Analysis of B6 x (NZB x B6.Yaa)F1 mice bearing the Yaa mutation demonstrated a clear association between percentages of monocytes and serum levels of antinuclear autoantibodies and gp70-anti-gp70 IC, both contributing to the development of lupus nephritis. Additionally, the remarkable association between monocyte levels at 10 mo of age and later development (until 18 mo of age) of a lethal form of lupus nephritis indicates that the enumeration of blood monocytes could be an important indicator of ongoing active SLE. The association of monocytosis with the development of severe SLE was further confirmed in Yaa-bearing B6.Nba2 and B6 Fc{gamma}RIIB +/– mice and was consistent with the absence of monocytosis in B6.Yaa mice and BXSB substrains that fail to develop SLE (11, 12). Previous reports have shown a considerable role of infiltrating macrophages in the progression of glomerular lesions (35) and of the implication of Fc{gamma}R in glomerulonephritis, including murine lupus nephritis (25, 36). Thus, monocytosis could promote glomerular inflammation and injury through increased secretion of proinflammatory cytokines, reactive oxygen species, and matrix-specific proteases, possibly as a result of IC-mediated, Fc{gamma}R-dependent activation of infiltrating macrophages. In this regard, it would be of interest to determine the extent of macrophage infiltrates in diseased glomeruli from Yaa-bearing lupus-prone mice, compared with non-Yaa counterparts.

Assessment of BC mice and B6.Nba2 congenic mice clearly showed a major contribution of the Nba2 locus, located on the distal portion of NZB chromosome 1, to the development of monocytosis. In contrast, we observed a trend only for the linkage of the H2b locus derived from the B6 strain to monocytosis in our BC mice, despite the fact that H2b displayed a linkage with the production of antinuclear and anti-gp70 autoantibodies as strong as Nba2 in our previous study (17). Furthermore, no linkage was observed with the two previously identified loci, Nba5 on chromosome 7 and Sgp3 on chromosome 13, both of which control the production of gp70-anti-gp70 IC and the development of glomerulonephritis. Notably, BXSB mice bearing the H2d haplotype were protected from SLE and monocytosis, compared with wild-type (WT) BXSB mice (H2b) (12). However, this can be interpreted as an indirect effect of H2b, which likely promotes overall production of lupus autoantibodies, thus leading to the presence of autoimmune IC and increased engagement of Fc{gamma}R, which could, in turn, result in an excessive activation of macrophages (13). This hypothesis is in agreement with the lack of monocytosis in B6.Yaa mice bearing the H2b haplotype, which produce only limited levels of autoantibodies. These results indicate that the development of monocytosis may be somehow more specifically linked to the action of candidate genes present in the Nba2 interval.

Among several candidate lupus susceptibility genes present in the Nba2 interval, we paid particular attention to the Fcgr2b gene encoding Fc{gamma}RIIB, a negative regulator of the BCR. It has been shown that the expression of Fc{gamma}RIIB is defective in activated germinal center B cells of NZB mice because of a polymorphism in the promoter region of the Fcgr2b gene (18, 20, 37). Notably, Fc{gamma}RIIB also negatively regulates the IC-mediated activation of stimulatory Fc{gamma}R (Fc{gamma}RI and Fc{gamma}RIII) expressed on macrophages and mast cells (22, 32, 38). In the present study, we demonstrated that peritoneal resident macrophages bearing the NZB-type Fcgr2b allele express far lower levels of Fc{gamma}RIIB than those bearing the B6-type Fcgr2b allele. Given that the development of Yaa-mediated monocytosis is not due to an intrinsic abnormality in the growth potential of monocyte lineage cells (13), we hypothesize that this monocytosis could be related to dysregulated activation of macrophages via Fc{gamma}R engagement by IC, which could result in an overproduction of monocyte-specific growth factor(s) by these macrophages. If this is correct, the defective expression of inhibitory Fc{gamma}RIIB on macrophages of NZB mice might promote activation via stimulatory Fc{gamma}R by autoimmune IC during the course of the disease, and contribute to the development of monocytosis. This concept is further corroborated by the finding that partial Fc{gamma}RIIB deficiency, i.e., heterozygous level of Fc{gamma}RIIB expression, is sufficient to promote the development of monocytosis and lupus-like autoimmune syndrome in B6 mice bearing the Yaa mutation (34). However, because B6 mice carrying 129 chromosome 1 interval corresponding to the Nba2 locus spontaneously develop antinuclear autoantibodies (39), we cannot exclude the contribution of the 129-derived interval cotransferred with the Fcgr2b mutant gene to the development of monocytosis in Fc{gamma}RIIB+/– B6.Yaa mice.

In addition to its possible contribution to monocytosis, the NZB-type Fcgr2b allele is implicated in the development of lupus nephritis. It has been established that activating Fc{gamma}R plays a critical role in the development of IC-mediated tissue lesions, including lupus nephritis, nephrotoxic glomerulonephritis, and autoimmune vasculitis (25, 36, 40, 41). Our preliminary studies have shown enhanced phagocytosis of IgG-opsonized platelets through activating Fc{gamma}R by macrophages bearing the NZB-type Fc{gamma}r2b allele, compared with those bearing the B6-type Fcgr2b allele. Thus, the defective Fc{gamma}RIIB expression in lupus-prone NZB, BXSB, and MRL mice bearing the NZB-type Fcgr2b allele (18, 19, 20) could contribute to the effector phase of IC-mediated lupus nephritis and vascular lesions as a result of excessive Fc{gamma}R-mediated activation of immune effector cells. In addition, monocytosis in Yaa-bearing lupus-prone mice could promote inflammatory processes through increased secretion of proinflammatory cytokines and mediators, thereby accelerating the progression of autoimmune tissue injury.

Analysis of B6 Nba2 congenic and Fc{gamma}RIIB haploinsufficient mice confirmed that Yaa induces a selective expansion of the Gr-1– monocyte subset (13), which is considered to be a source of resident macrophages and DC (30). Significantly, this subset expressed substantial levels of CD11c, a marker of DC, in parallel to the development of monocytosis. Thus, the possible expansion of DC, as a result of monocytosis, in Yaa-bearing lupus-prone mice might potentiate autoimmune responses, thereby accelerating the progression of the disease. Indeed, our preliminary studies revealed marked increases of the number of mature DC in spleen from aged BXSB Yaa male mice developing monocytosis, compared with BXSB female counterparts without monocytosis. At present, we cannot offer an explanation for the selective expansion of Gr-1– monocytes in Yaa-bearing lupus-prone mice. In this regard, it is worth noting that the expression of one of the IFN-inducible genes, Ifi202, present in the Nba2 interval is markedly increased in NZB mice, compared with B6 mice, because of the promoter region polymorphism (16). Because it has been shown that type I IFN in sera from patients with SLE triggers monocytes to differentiate into DC (42), enhanced expression of the Ifi202 gene could be implicated in the accelerated differentiation of Gr-1+ monocytes to Gr-1– monocytes in Yaa-bearing lupus-prone mice. More recently, lupus susceptibility has been shown to be associated with extensive polymorphisms of the SLAM/CD2 gene family (Cd244, Cd229, Cs1, Cd48, Cd150, Ly108, and Cd84), which is also present in the Nba2 interval (21). Because these genes encode cell surface molecules that play a role in the modulation of cellular activation and signaling in the immune system, they also are good candidates for promoting monocytosis as well as lupus-like autoimmune responses. Analysis of Nba2 subinterval congenic mice will help define the respective contributions of the Fcgr2, Ifi202, and SLAM/CD2 genes to different Nba2-linked autoimmune traits.

Our data indicate that, in addition to its potentiating effect on overall autoimmune responses, Nba2 promotes the development of monocytosis, thereby additionally contributing to the progression of a lupus-like autoimmune syndrome. However, the molecular mechanism responsible for the development of monocytosis and its significance in the pathogenesis of SLE in Yaa-bearing lupus-prone mice still remain to be determined. As we proposed, hyperactivation of macrophages through Fc{gamma}R and excessive production of monocyte-specific growth factors might be mechanisms for the Yaa-associated monocytosis. FcR{gamma}-deficient lupus-prone (NZB x NZW)F1 and MRL-Faslpr mice lacking functional expression of activating Fc{gamma}RI and Fc{gamma}RIII produced autoantibodies and IC as much as WT mice did (36, 43). Therefore, the generation and the analysis of FcR{gamma}-deficient BXSB Yaa mice, which carry the NZB-type allele of the Fcgr2b gene, should provide a more definitive answer on whether the development of Yaa-induced monocytosis is indeed dependent on the activation of Fc{gamma}R, and on whether monocytosis is involved in the accelerated development of autoimmune responses and of autoimmune pathology. Furthermore, we proposed previously that the Yaa defect might decrease the threshold of BCR-mediated signaling, thereby triggering and excessively stimulating autoreactive B cells (2, 9). Thus, it is of interest to define how the Yaa defect could differentially affect both BCR- and Fc{gamma}R-dependent activation pathways. Clearly, the elucidation of the molecular defect of the Yaa mutation is of paramount importance for our understanding of the development of these autoimmune responses and should help identify target molecules central to the development of SLE, thereby facilitating the design of future therapeutic strategies in human SLE.


   Acknowledgments
 
We thank Drs. S. Hirose and T. Winkler for providing us with information on microsatellite markers polymorphic between NZB and B6 mice, and G. Brighouse, S. Jacquier, and G. Celetta for their excellent 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 by a grant from the Swiss National Foundation for Scientific Research and National Institutes of Health Grant AR 37070. L.F.-J. is a recipient of a fellowship from the Arthritis Research Campaign, UK. Back

2 S.K. and M.-L.S.-R. contributed equally to this study. Back

3 Address correspondence and reprint requests to Dr. Shozo Izui, Department of Pathology and Immunology, Centre Médicale Universitaire, 1211 Geneva 4, Switzerland. E-mail address: shozo.izui{at}medecine.unige.ch Back

4 Abbreviations used in this paper: Yaa, Y-linked autoimmune acceleration; SLE, systemic lupus erythematosus; Nba2, NZB autoimmunity 2; Ifi202, interferon-inducible p202; BC, backcross; IC, immune complex; LOD, log likelihood of the odds; DC, dendritic cell; cM, centiMorgan; WT, wild type. Back

Received for publication September 1, 2005. Accepted for publication December 14, 2005.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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