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B Cells Are Required for Lupus Nephritis in the Polygenic, Fas-Intact MRL Model of Systemic Autoimmunity¹

Owen T. M. Chan^*, Michael P. Madaio and Mark J. Shlomchik^2,*,

^* Section of Immunobiology and Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510; and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

	Abstract

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B cells are required for both the expression of lupus nephritis and spontaneous T cell activation/memory cell accumulation in MRL-Fas^lpr mice (MRL/lpr). Autoimmunity in the MRL/lpr strain is the result of Fas-deficiency and multiple background genes; however, the precise roles of background genes vs Fas-deficiency have not been fully defined. Fas-deficiency (i.e., the lpr defect) is required in B cells for optimal autoantibody expression, raising the possibility that the central role for B cells in MRL/lpr mice may not extend to MRL/+ mice and, thus, to lupus models that do not depend on Fas-deficiency ("polygenic lupus"). To address this issue, B cell-deficient, Fas-intact MRL/+ mice (J_HD-MRL/+) were created; and disease was evaluated in aged animals (>9 mo). The J_HD-MRL/+ animals did not develop nephritis or vasculitis at a time when the B cell-intact littermates had severe disease. In addition, while activated/memory CD4⁺ and CD8⁺ T cells accumulated in B cell-intact mice, such accumulation was substantially inhibited in the absence of B cells. This effect appeared to be restricted to the MRL strain because it was not seen in B cell-deficient BALB/c mice (J_HD-BALB) of similar ages. The results indicate that B cells are essential in promoting systemic autoimmunity in a Fas-independent model. Therefore, B cells have an important role in pathogenesis, generalizable to lupus models that depend on multiple genes even when Fas expression is intact. The results provide further rationale for B cell suppression as therapy for systemic lupus erythematosus.

	Introduction

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The MRL-Fas^lpr strain (MRL/lpr)³ is a murine model of human systemic lupus erythematosus (SLE), characterized by nephritis, vasculitis, severe splenomegaly and lymphadenopathy, hypergammaglobulinemia and autoantibodies, and lymphocytic infiltrates in the lung and liver (1, 2, 3). These mice have a homozygous fas mutation, lpr, which accelerates autoimmunity (4, 5). In addition, autoimmunity in MRL mice is controlled by multiple unknown background genes (6, 7). The Fas Ag on lymphocytes generally transduces an apoptotic signal (8, 9, 10, 11). This failure of apoptotic cell death contributes to the loss of tolerance which, if unchecked, leads to spontaneous autoimmunity with death from nephritis and vasculitis (50% mortality is 4–5 mo) (2, 3, 12, 13, 14). The congenic, Fas-intact MRL/+ strain also develops a lupus-like syndrome similar to MRL/lpr animals, although disease is delayed and reduced in intensity (2, 15). Arguably, the MRL/+ strain is a better model for SLE since human SLE patients are not generally Fas-deficient and since lymphadenopathy is absent in MRL/+ mice. Both the immunologic disregulation and disease pathogenesis has been much less well-studied in MRL/+ mice than in MRL/lpr mice.

B cells serve as APC for the activation and amplification of autoreactive T cells in the autoimmune MRL/lpr model (16). MRL/lpr mice lacking B cells have markedly reduced numbers of activated and memory T cells (16), and nephritis is attenuated (17). In subsequent studies, it was observed that transgenic MRL/lpr mice (mIgM.MRL-Fas^lpr), only capable of producing the membrane-bound form of Ig, developed interstitial nephritis and vasculitis in the absence of circulating Abs (18). Furthermore, T cell activation and accumulation was intact, indicating that Ag presentation by B cells is important to promote disease. Overall, these studies emphasize the critical role that B cells play in this Fas-deficient MRL/lpr model of lupus.

However, it is unknown whether B cells play a similar, central role in polygenic lupus where Fas is intact. Fas is expressed on activated B cells (19), and mixed bone marrow chimeras and allophenic mice suggest that Fas-deficiency is required in both B and T cells for optimal autoantibody production (20, 21). Thus, the role of B cells may be substantially different in Fas-intact vs Fas-deficient lupus models. The current study seeks to address the role of B cells in the Fas-intact, multigenic autoimmunity model, the MRL/+ strain. To do so, we created and analyzed B cell-deficient MRL/+ mice (J_HD-MRL/+).

	Materials and Methods

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Mice

The J_HD-MRL/+ strain was created by crossing MRL/+ mice with J_HD-MRL/lpr animals (17). The J_HD-MRL/lpr mice were backcrossed to the MRL/lpr background for seven generations and had >99.6% of MRL background genes. The subsequent J_HD/+/Fas^lpr/Fas^wild-type progeny were intercrossed, and homozygous J_HD/J_HD/Fas^wild-type/Fas^wild-type mice were selected to carry out the future intercrosses. To produce the J_HD-BALB strain, the J_HD mutation was backcrossed onto the BALB/c background for eight generations (resultant mice had 99.8% of BALB/c background genes). Intercrossing yielded homozygous J_HD/J_HD mice, creating the J_HD-BALB animals.

The genotypes of the mice were determined by PCR. The J_HD mutation was detected using the neo PCR, as previously described (16). The Fas^lpr genotypes were determined as previously described (16).

Reagents

The following mAbs were used as FACS reagents: CD19 (1D3-biotin; PharMingen, San Diego, CA), B220 (RA3-6B2-FITC), CD4 (H129.19-CyChrome; PharMingen), CD8 (53-6.7-Quantum Red; Sigma, St. Louis, MO), CD44 (Pgp-1-FITC), CD62L (Mel-14-biotin), anti-mouse F_c receptor (2.4G2). Streptavidin-conjugated PE (Molecular Probes, Eugene, OR) was added as a secondary step for the biotinylated reagents. RA3-6B2, Pgp-1, Mel-14, and 2.4G2 were purified from hybridoma supernatants on protein G columns (Pharmacia, Piscataway, NJ) after ammonium sulfate precipitation and were conjugated as described (22).

Pathologic evaluation of nephritis

Kidneys were bisected, fixed in 10% buffered formalin, and embedded in paraffin. Sections were stained with hematoxylin and eosin. The severity of nephritis and vasculitis was graded based on a semiquantitative scale using the parameters previously described (23). Briefly, a 0–4+ scale was used for each compartment (glomerular, interstitial, and vascular) with pathology graded according to specified criteria as absent, mild, moderate, or severe. For comparative purposes, all of the tissue sections were scored by one observer (M.P.M.), who was blinded to their origin.

FACS

FACS analysis was conducted as previously described (22).

Statistics

All analyses were conducted using StatView 4.5 (Abacus Software, Berkeley, CA) for the Macintosh. Significance was assessed using the nonparametric Mann-Whitney U test. A p value of <0.05 was considered significant.

	Results

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B cell development is arrested in J_HD-MRL/+ mice

Mice homozygous for the J_HD mutation (J_HD-MRL/+) did not produce B cells, as expected (Fig. 1 and Refs. 16, 17, 24). Additionally, serum IgM was not detectable in J_HD-MRL/+, confirming the lack of functional B cells (Fig. 1C).

View larger version (15K): [in this window] [in a new window]   FIGURE 1. The JHD mutation inhibits B cell maturation in MRL/+ mice. FACS analysis of splenocytes from 62-wk-old wild-type MRL/+ (A) and JHD-MRL/+ (B) mice are shown. The upper right quadrant identifies B cells via the CD19 and B220 cell surface markers. B cell intact mice have CD19+/B220+ cells, while these cells are undetectable in JHD-MRL/+ mice. C, The serum IgM levels of a cohort of B cell-intact and B cell-deficient MRL/+ mice (MRL/+, n = 13; JHD-MRL/+, n = 4); the absence of circulating Ab corroborates the failure of JHD-MRL/+ mice to produce B cells. C, The mice were 62–64 wk old. The horizontal black bars indicate the median scores.

At 7 mo of age, the MRL/+ control mice developed glomerulonephritis (GN), vasculitis, and interstitial nephritis, consistent with prior reports (15, 25, 26). However, in the absence of B cells, renal disease was abrogated. As illustrated in Fig. 2, GN, interstitial nephritis, and vasculitis did not develop in the J_HD-MRL/+ strain. By semiquantitative analysis, the median renal disease scores of a cohort of B cell-deficient mice were 0.5 (glomeruli, 0.5; tubules, 0; vessels, 0) (Fig. 3). At comparable ages, the wild-type MRL/+ mice had significantly more disease than the J_HD-MRL/+ strain [glomeruli, 1.5 (p < 0.003); tubules, 1.5 (p < 0.002); vessels, 1.5 (p < 0.0003)].

View larger version (193K): [in this window] [in a new window]   FIGURE 2. Lack of nephritis in the absence of B cells. Representative kidney sections (hematoxylin and eosin) from MRL/+ mice are shown on the left side: 26 (A), 39 (C), and 26 wk (E). Sections from JHD-MRL/+ mice are shown on the right side: 39 (B), 38 (D), and 39 wk (F). Vasculitis (A), interstitial nephritis (C), and glomerulonephritis (E) develop in MRL/+ mice but not in JHD-MRL/+ mice (B, D, and F). Original magnification x100 (A–D) or x400 (E, F).

View larger version (13K): [in this window] [in a new window]   FIGURE 3. Renal disease scores show lack of nephritis in the absence of B cells. Kidneys from MRL/+ (n = 19) and JHD-MRL/+ (n = 6) mice were assessed for lesions and graded on a 0 (normal) to 4 (maximum disease) scale in a blinded fashion (see Materials and Methods). Ages ranged from 57 to 70 wk for both cohorts. Shown are the scores for the glomeruli (A), tubules (B), and vessels (C). Each dot represents an individual mouse, and the horizontal black bars indicate the median scores. Significance was determined by the Mann-Whitney U test, and p values are indicated in the graphs.

We and others have found that MRL/lpr mice accumulate memory and activated CD4⁺ and CD8⁺ T cells (16, 27); however, this has not been investigated in MRL/+ mice. Analysis of T cells from the splenocytes of aged MRL/+ mice revealed that a majority of CD4⁺ and CD8⁺ cells bore the memory phenotype (CD44^high, CD62L^low), while naive cells (CD44^low, CD62L^high) comprised the minority (Figs. 4 and 5). Thus, the T cell activation and memory cell formation pattern in MRL/+ mice is similar to MRL/lpr mice, although it is not as extreme. On the other hand, the percentage of naive T cells is increased and the percentage of memory T cells is decreased in J_HD-MRL/+ mice, compared with B cell-intact MRL/+ mice (Fig. 5). B cell-intact mice also had significantly greater numbers of activated (CD44^high, CD62L^high) and memory CD4⁺ and CD8⁺ cells than B cell-deficient animals (Figs. 5, B and D). Wild-type MRL/+ mice had 5.2-fold more activated CD4⁺ cells (p < 0.0006), 7.8-fold more memory CD4⁺ cells (p < 0.0001), 4.8-fold more activated CD8⁺ cells (p < 0.0003), and 5.1-fold more memory CD8⁺ cells (p < 0.0001) than J_HD-MRL/+ mice. However, there was no difference in naive cell numbers between the B cell-intact and B cell-deficient cohorts.

View larger version (58K): [in this window] [in a new window]   FIGURE 4. Spontaneous T cell activation is inhibited in the absence of B cells. Representative three-color FACS contour plots of splenocytes are shown from MRL/+ (A and C) and JHD-MRL/+ (B and D) mice. CD4high and CD8high-gated cells were analyzed for CD44 (FITC) and CD62L (PE) expression, and the percentages for each activation subset are shown. The ages of the animals depicted were 38–40 wk.

View larger version (41K): [in this window] [in a new window]   FIGURE 5. B cells are necessary for the accumulation of activated and memory CD4+ and CD8+ T cells in MRL/+ mice. Percentages of total spleen CD4+ (A) and CD8+ (C) T cells were obtained for the naive (CD44low, CD62Lhigh), activated (CD44high, CD62Lhigh), and memory (CD44high, CD62Llow) subsets as shown in Fig. 4. Cell numbers for CD4+ (B) and CD8+ (D) T cells were calculated by multiplying total cell percentages of each activation subset by the total spleen cell number for each mouse. Columns show the averages of percentages (A and C) or cell numbers (B and D) of a cohort of mice. Error bars represent one SD. For the cell number graphs, the ratio of T cells from B cell-intact mice to T cells from B cell-deficient cells is shown for each activation subset. Sample sizes for cell percentages and numbers are: MRL/+ (n = 22) and JHD-MRL/+ (n = 9). All mice were 38–70 wk of age. p values are indicated above the columns in each graph, as determined by the Mann-Whitney U test.

B cells in normal mice do not promote accumulation of activated and memory T cells

The previous results indicate that B cells promote the accumulation of activated and memory-phenotype T cells in MRL/+ mice. To determine whether this effect was specific to an autoimmune strain, we conducted similar analysis on age-matched B cell-intact or B cell-deficient BALB/c mice (J_HD-BALB). In contrast to MRL/+ mice, there was no difference in the naive, activated, or memory CD4⁺ T cell percentages between B cell-intact and B cell-deficient BALB/c animals (Fig. 6A). As shown earlier, B cell-intact MRL/+ mice had considerably greater numbers of memory CD4⁺ T cells than naive cells (5.4-fold greater) (Fig. 5). By contrast, in B cell-intact BALB/c mice, there were equal numbers of naive and memory CD4⁺ T cells (p = 0.6) (Fig. 6). This shows, that although BALB/c mice do accumulate some memory T cells with age as expected (28), this is not nearly as extensive as in MRL/+ mice. The numbers of CD4⁺ T cells for all activation subsets were proportionally lower in J_HD-BALB mice than in B cell-intact BALB/c mice due to smaller spleen sizes. However, there was no relative change in the proportion of either activated or memory cells in B cell-intact or B cell-deficient mice (Fig. 6B). Taken together, the results indicated that B cells from nonautoimmune mice do not promote the accumulation of memory and activated-phenotype CD4⁺ T cells as observed in the autoimmune MRL/+ strain.

View larger version (25K): [in this window] [in a new window]   FIGURE 6. B cells do not promote the accumulation of activated and memory CD4+ T cells in normal mice. This figure is organized as Fig. 5. A, p values are indicated above the columns in each graph, as determined by the Mann-Whitney U test. B, The ratio of T cells from B cell-intact mice to T cells from B cell-deficient cells is shown for each activation subset. Sample sizes for cell percentages and numbers were: B cell-intact BALB/c (n = 10) and B cell-deficient BALB/c (n = 7). Mice were 22–65 wk of age.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

The traditional role of B cells in lupus pathogenesis is as the source of pathogenic autoantibodies. However, emerging data suggest that B cells are also likely to function as APC to Ag-specific T cells. Supporting this concept is the mIgM.MRL-Fas^lpr strain, which produces B cells with only membrane-bound Ig and no secreted Ig. This strain still developed interstitial nephritis, vasculitis, and activated and memory T cell accumulation, even in the absence of circulating Ab (18). These results demonstrate an Ab-independent role of B cells, most likely Ag presentation, as an important mechanism in lupus-like autoimmunity. By analogy to the mIgM.MRL-Fas^lpr model, the significant reduction of CD4⁺ and CD8⁺ activated/memory T cells in J_HD-MRL/+ mice suggests that B cells play a role as APCs for T cells in the MRL/+ strain, as well.

A requisite role of B cells has also been demonstrated for autoimmune diabetes in nonobese diabetic (NOD) mice. B cell-deficient NOD.Igµ^null and B cell-depleted NOD mice did not develop insulitis or insulin-dependent diabetes mellitus, supporting the idea that B cells are critical for the initiation and/or activation of autoreactive T cells (29, 30). In related work, Falcone et al. (31) showed that B cell-deficient NOD mice did not spontaneously respond to 65-kDa glutamate decarboxylase, while B cell-intact mice did, concluding that B cells were required as APCs for the generation of autoimmune T cell responses. In these studies, it was concluded that APC function was important since autoantibodies, though present, are not typically found within lesions. Further studies, for example, using the mIgM transgene, would be required to establish this point.

Whether the role of B cells in MRL mice is due to intrinsic B cell abnormalities is not clear from our data. It is also possible that B cells, while required, are functionally normal and only serve to bring out intrinsic T cell abnormalities. However, Kakkanaiah et al. (32) have recently shown that MRL genes confer intrinsic properties to B cells, such as the propensity to make anti-Sm Abs, thus raising the possibility that abnormal B cells per se are required for activation of T cells. This issue clearly requires more work and may eventually be approachable by adoptive transfer or genetic methods. In this regard, it is interesting that the NZM2410 model of SLE provides genetic evidence of intrinsic abnormalities of B cells in disease (33, 34). SLE susceptibility loci (Sle1, Sle2, Sle3) were identified, and congenic strains containing these individual genomic intervals were created. Sle2 induced B cell hyperactivity in the B6.NZMc4 congenic (35). Also, mixed bone marrow (BM) chimeras of B6.NZMc1 and nonautoimmune congenic C57BL/6 (B6) strains indicated that anti-chromatin autoantibodies were produced only by B cells derived from B6.NZMc1, suggesting that Sle1 in B cells is essential for the development of autoimmunity (36). Furthermore, CD69 expression on CD4⁺ T cells was increased in B6.NZMc1 BM recipients compared with B6 BM recipients, suggesting that T cell activation was derived from a loss of tolerance in the B cell compartment. Although a direct role for B cells demonstrated by genetic deletion has not yet been shown for NZM2410-related strains, it seems likely and would be consistent with the accumulated data.

Our results are the first to show via gene-targeting a critical role of B cells in a model of systemic autoimmunity that does not largely depend on a single gene inactivation, such as Fas-deficiency. Indeed, among the many autoimmunity-prone strains bearing knockout alleles of genes important to the immune system, the B cell-deficient knockouts demonstrate the most complete inhibition of disease (Refs. 16, 17 , and the current study). The influence of B cells as both autoantibody secretors and as APC for T cells highlighted here is also consistent with the work of Wakeland and colleagues (33, 34, 35, 36) on the NZM2410 polygenic lupus model and even with that of several groups studying polygenic diabetes. Our work showing that B cells are critical in a Fas-independent setting, taken together with these other studies, suggest that B cells would play a similar, critical role in human lupus and possibly other autoimmune diseases. By extending the evidence that B cells are essential for multiple aspects of immune disregulation and pathogenesis to a polygenic lupus model, the present work provides further rationale for B cell suppression as a novel therapy for lupus (16).

	Acknowledgments

 
We thank Drs. Joseph Craft and Mark Mamula for critically reading this manuscript.

	Footnotes

 
¹ This work was supported by National Institutes of Health Grant R01-AR44077. O.T.M.C. was supported by National Institutes of Health Training Grant AI07019.

² Address correspondence and reprint requests to Dr. Mark Shlomchik, Laboratory Medicine, Yale University School of Medicine, 333 Cedar Street, Box 208035, New Haven, CT 06520-8035. E-mail address:

³ Abbreviations used in this paper: MRL/lpr, MRL-Fas^lpr; B6, C57BL/6; BM, bone marrow; SLE, systemic lupus erythematosus.

Received for publication May 4, 1999. Accepted for publication July 1, 1999.

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