Contribution of H-2 and non-H-2 genes in the control of mercury-induced autoimmunity

Manuchehr Abedi-Valugerdi and Göran Möller

Department of Immunology, Wenner-Gren Institute, Arrhenius Laboratories for Natural Sciences, Stockholm University, 10691 Stockholm, Sweden

Correspondence to: M. Abedi-Valugerdi


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Mercury-induced autoimmunity is characterized by a T cell-dependent B cell activation (mainly of IgG1 and IgE isotypes), production of anti-nucleolar autoantibodies (ANolA) and the formation of renal IgG deposits. The autoimmunity is to a large extent controlled by genetic factors. We studied 15 different inbred mouse strains of seven H-2 (mouse MHC) genotypes to determine the importance of H-2 and non-H-2 background genes in mercury-induced autoimmunity. The tested strains exhibited a diverse autoimmune response to mercury. In each H-2 genotype, there was at least one strain which responded to mercury by the production of high levels of IgG1 and IgE Ig as well as by the development of high titers of renal IgG1 deposits. Only mouse strains with H-2s and H-2q genotypes, irrespective of their background genes, produced ANolA after mercury treatment. Only SJL (H-2s) and A.SW (H-2s) mice were highly susceptible to all characteristics of mercury-induced autoimmunity. NZB (H-2d) mice were also highly susceptible, but they did not develop ANolA. Only the DBA/2 (H-2d) strain was found to be resistant to all tested mercury-induced autoimmune manifestations, suggesting that non-responsiveness to mercury in DBA/2 mice was largely influenced by non H-2 genes. These findings imply that H-2 genes mainly determine the susceptibility to mercury-induced ANolA production, whereas non-H-2 genes control the susceptibility to and the severity of the B cell activation and renal IgG deposition.

Keywords: anti-nucleolar autoantibodies, IgE, IgG1, inbred mice, mercuric chloride, renal IgG1 deposits


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Chronic administration of subtoxic doses of the heavy metal ion mercury induce a systemic autoimmune disease in susceptible animals such as mice, rats and rabbits (reviewed in 1–3). In highly susceptible mice, the mercury-induced autoimmunity is characterized by a T cell-dependent polyclonal B cell activation with mainly increased serum levels of IgG1 and IgE antibodies, by the production of autoantibodies, and by the formation of IgG deposits in the kidney (14).

Murine mercury-induced autoimmunity possesses several important and unique features. First, in susceptible mice, mercury (in a T cell-dependent manner) activates the B cells to produce autoantibodies against different intracellular antigens including anti-nuclear and anti-nucleolar (ANolA) autoantibodies (13). Therefore, the murine mercury model can be used to study the role of autoantibodies in the pathogenesis of autoimmune diseases. Secondly, mercury alone is able to activate the immune system in several, but not all mouse strains, to a strong response with autoimmune characteristics. Hence, the murine mercury model provides a unique opportunity to study the importance of genetic and immunological factors in the development of autoimmune disorders.

Several groups have studied the genetics of mercury-induced autoimmunity (511). They have shown that susceptibility to mercury-induced autoimmunity is determined by both H-2 (mouse MHC) and non-H-2 genes (511). However, in each study, the genetic susceptibility was studied with regard to only one or two characteristics of mercury-induced autoimmunity among the inbred mouse strains and/or their F1 and backcross hybrids (511). Therefore, the detailed genetic mechanism controlling responsiveness/resistance to mercury remains obscure.

Our main aim in this study was to investigate the genetics of mercury-induced autoimmunity with regard to main autoimmune parameters in several inbred mouse strains. Our results indicate that H-2 genes determine the production of specific ANolA, while non-H-2 genes mainly influence the expression of other characteristics of mercury-induced autoimmunity.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Mice
Females and/or males A.SW (H-2s), SJL (H-2s), B10.S (H-2s), C57BL/6 (H-2b), 129/SvJ (H-2b), B10ScSn (H-2b), DBA/1 (H-2q), FVB/N (H-2q), CBA (H-2k), CBA/N (H-2k), NZB (H-2d), BALB/c (H-2d), DBA/2 (H-2d), A/J (H-2a) and NZW (H-2z) mice were originally purchased from either Charles River (Charles River Sverige, Uppsala, Sweden) or Harlan (Bicester, UK). Some of these strains, A.SW (H-2s), SJL (H-2s), B10.S (H-2s), NZB (H-2d), B10.ScSn (H-2b), NZW (H-2z) and A/J (H-2a), were further bred and kept in our animal house at the Department of Immunology, Stockholm University. All mice were 6–8 weeks old at the beginning of the experiments.

HgCl2 treatment
Mercury treatment was carried out as described before (12). Briefly, groups of different mouse strains (four to 14 mice per group) were injected s.c. with either 0.1 ml of HgCl2 solution (1.6 mg/kg body wt) or 0.1 ml of a sterile 0.9% NaCl solution (control mice) every third day for 4 weeks.

Blood, spleen and kidney collection
At the end of each experiment, mercury- and saline-treated mice were bled by retro-orbital puncture under light ether anaesthesia. Thereafter, the same mice were killed by cervical dislocation, and their spleens and kidneys were removed. The blood of each mouse was allowed to clot at 4°C and serum was separated after centrifugation. The sera and kidneys were stored at –20°C until used.

Protein A plaque assay
Splenic single-cell suspensions were prepared by teasing spleens gently with forceps in BSS. All cell suspensions were washed 3 times and resuspended in BSS. Antibody-secreting cells of different Ig classes and subclasses were enumerated in cell suspensions by using a Protein A plaque assay as described by Gronowicz et al. (13). Rabbit anti-mouse IgM, IgG1, IgG3 (Organon Teknika, Durham, NC) and IgG2b (Nordic Immunological Laboratories, Tilburg, The Netherlands) were used as developing reagents. In this study, the results for IgG1 antibody-secreting cells are shown.

ELISA for mouse IgE antibody
Total mouse serum IgE Ig was determined by a sandwich ELISA assay as described previously (14). We used a rat anti-mouse IgE mAb, R35-72 (PharMingen, San Diego, CA) as the capture antibody and a biotinylated rat anti-mouse IgE mAb, R35-92 (PharMingen), as the detection antibody.

Detection of ANolA
The presence of IgG1 ANolA in the sera was determined by an indirect immunofluorescence method. We used rat liver sections as a substrate and FITC-conjugated goat anti-mouse IgG1 (Southern Biotechnology, Birmingham, AL) as the detecting antibody (14). The initial dilution for the sera was 1:50. The highest serum dilution at which nucleolar fluorescence could be detected was defined as the titer of IgG1 ANolA.

Detection of renal IgG1 deposits
The presence of glomerular deposits of IgG1 Ig was detected by a direct immunofluorescence method, as described previously (14). Briefly, 5 µm thick kidney cryostat sections were fixed in acetone and incubated with serial dilutions of FITC-conjugated goat anti-mouse IgG1 antibody (Southern Biotechnology). The initial dilution for FITC-conjugated antibody was 1:40. When at this dilution no specific green fluorescence was detected, the result was recorded as `0'. The highest dilution of the conjugated antibody at which a specific green fluorescence could be seen was defined as the end-point titer of the glomerular deposits.

Statistical analysis
Numbers of antibody-secreting cells of different isotypes, serum IgE levels, serum titers of IgG1 ANolA and titers of glomerular deposits of IgG1 antibodies were shown as the means + 1 SE. We estimated SE, since it represents the expected SD of the statistic in the case where a large number of samples (here animals) had been used. The differences between these parameters in mercury- and saline-injected mice and in mercury-injected strains carrying a specific H-2 genotype were analyzed with the Wilcoxon–Mann–Whitney (rank sum) test. For the differences between the titers of renal IgG1 deposits and serum IgG1 ANolA, the reciprocal titers were considered for calculation of mean + SE values.

Grading of susceptibility to mercury-induced immune responses
In the Results and Discussion sections, terms such as minimal or no, low (slight), intermediate and high are used to express the response status to mercury regarding the formation of IgG1 Ig and the development of renal IgG1 deposits. These terms are used based on the above-mentioned statistical tests and on the magnitude of the mercury-induced immune responses. For instance, for induction of IgG1 antibody formation, a minimal or no response (increase) was applied when there was not any significant difference between mercury- and saline-injected mice. Low (slight), intermediate and high response (increase) were used when mercury-injected mice exhibited either a 2- to 3-fold (low) or a 3- to 6-fold (intermediate) and/or a >6-fold (high) significant increase in the splenic IgG1 antibody-secreting cells as compared with those found in saline-treated controls.

For mercury-induced renal IgG1 deposits, minimal or no increase (in the titers or levels) was used when at the dilution of 1:40 (FITC-conjugated anti-mouse IgG1), no specific fluorescence was detected in the kidney sections of mercury-injected mice. Low, intermediate and high titers (levels) of renal IgG1 deposits were used when the mean value for the end-point titers (see the method for detection of IgG1 deposits) of glomerular deposits in mercury-injected mice were either 1:40–1:80 (low) or 1:80–1:160 (intermediate) and/or >1:160 (high) respectively.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Analysis of mercury-induced IgG1 and IgE antibody production in various mouse strains of different H-2 genotypes
In order to carry out a complete study on the genetics of murine mercury-induced autoimmunity, groups of 15 inbred mouse strains of seven different H-2 genotypes, e.g. H-2s(SJL, A.SW, B10.S), H-2q (FVB/N, DBA/1), H-2d (NZB, BALB/c, DBA/2), H-2b (C57BL/6, 129/SvJ, C57BL/10ScSn), H-2k (CBA, CBA/N), H-2a (A/J) and H-2z (NZW), were continuously treated with mercury and/or as controls, with saline for 4 weeks. We chose a 4-week treatment, because, in our hands, most of the mercury-induced autoimmune characteristics have already been established in the responder strains at this time point. At the end of each experiment, spleens were used to enumerate the IgG1 antibody-secreting cells, sera were tested for the presence of IgE and ANolA, and the kidneys were analyzed for the accumulation of IgG1 Ig. We selected these four parameters, because they represented the major characteristics of murine mercury-induced autoimmunity (14).

We first investigated mercury-induced IgG1 and IgE responses as parameters for B cell activation by mercury. All tested mouse strains of H-2s genotype (SJL, A.SW and B10.S) responded to mercury by the production of high numbers of splenic IgG1 antibody-secreting cells as well as high serum levels of IgE Ig (Fig. 1a and bGo). However, the magnitude of IgG1 synthesis in the B10.S strain was lower than that in SJL and A.SW strains (Fig. 1aGo).



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Fig. 1. Groups of different inbred mouse strains of seven H-2 genotypes were repeatedly injected s.c. with either mercuric chloride (solid bars) or physiological saline (open bars) for 4 weeks. At the end of each experiment the mice were bled and killed. The spleens were tested for IgG1 antibody-secreting cells (a) by using a Protein A plaque assay and the sera were tested for IgE antibodies (b) by using an ELISA method. Data are shown as mean + 1 SE. Significant differences between the parameters in mercury- and saline-injected mice (different H-2 genotypes) and in mercury-injected strains (within a particular H-2 genotype) were calculated by the Wilcoxon–Mann–Whitney test. *P < 0.05; **P < 0.01; ***P < 0.001. Only in A.SW and C57BL/6 mice a serum dilution of 1:20 was considered as the basis for absorbance for IgE antibodies. NS, not significant

 
There was a variation in mercury-induced IgG1 response in strains of H-2d genotype (Fig. 1aGo). For instance, only the NZB strain exhibited a high increase in IgG1 antibody-secreting cells, whereas BALB/c and DBA/2 mice showed either a slight or a minimal increase in the number of IgG1 antibody-secreting cells respectively (Fig. 1aGo). NZB and BALB/c, but not DBA/2, mice also developed a significant increase in the serum levels of IgE Ig after mercury treatment (Fig. 1bGo).

Similar to H-2d mice, mouse strains of H-2b genotype also exhibited a varied B cell activation in response to mercury (Fig. 1a and bGo). For example, C57BL/6 and 129/SvJ mice produced high numbers of IgG1 antibody-secreting cells and exhibited a significant increase in the serum levels of IgE Ig, whereas C57BL/10ScSn showed only an intermediate increase in the splenic IgG1 antibody-secreting cells (Fig. 1aGo) and no change in the serum IgE levels (Fig. 1bGo).

In mouse strains of H-2q genotype (FVB/N and DBA/1), chronic injection with mercury also induced an intermediate IgG1 antibody response (Fig. 1aGo). In addition, in response to mercury, both strains showed a significant increase in the serum IgE levels (Fig. 1bGo).

Mercury induced a weak B cell activation in mice carrying H-2k (CBA and CBA/N) genotype (Fig. 1a and bGo). Mercury was able to induce a low increase in IgG1 antibody-secreting cell only in CBA/N but not in CBA mice (Fig. 1aGo). However, in a kinetic study performed in CBA mice, we observed that these mice when treated with mercury for 3 weeks were able to exhibit a statistically significant, but low increase in the splenic IgG1 antibody-secreting cells (not shown). As shown in Fig. 1Go(b), neither CBA nor CBA/N showed a significant increase in the serum IgE levels.

Mercury-treated A/J (H-2a) mice developed an intermediate increase in the splenic IgG1 antibody-secreting cells and in serum levels of IgE (Fig. 1a and bGo)

Finally, NZW (H-2z) mice reacted strongly to mercury treatment by formation of large number of splenic IgG1 antibody-secreting cells (Fig. 1aGo). A non-significant increase in the serum levels of IgE Ig was also observed in the mercury-treated NZW mice (Fig. 1bGo). Taken together, these findings indicate that mercury is able to induce B cell activation in various mouse strains of different genotypes.

Mercury induces ANolA production only in mouse strains of H-2s and H-2q genotypes.
Production of ANolA is possibly the most interesting characteristic of mercury-induced autoimmunity. ANolA react with fibrillarin, a 34 kDa protein, which is associated with the U3, U8, U13, U14, X and Y small nucleolar RNAs in vertebrates (15). Interestingly, ANolA autoantibodies with anti-fibrillarin specificity have also been detected in a subset of patients with systemic scleroderma (16). Several studies have demonstrated that only mouse strains with certain H-2 genotypes produced ANolA after treatment with mercury (57). We also found that only mouse strains of H-2s (SJL, A.SW and B10.S) and H-2q (FVB/N and DBA/1) genotypes, irrespective of their non-H-2 background genes, produced high levels of IgG1 ANolA after treatment with mercury (Fig. 2Go). In strains such as NZB (H-2d), C57BL/6 (H-2b) and NZW (H-2z), mercury induced an intense B cell activation mainly of IgG1 isotype (Fig. 1aGo), but the produced antibodies were not directed against nucleolar antigens (Fig. 2Go).



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Fig. 2. Groups of different inbred mouse strains of seven H-2 genotypes were repeatedly treated s.c. with either mercuric chloride (solid bars) or physiological saline (open bars) for 4 weeks. At the end of each experiment the mice were bled and killed. The sera were tested for the presence of ANolA by using an indirect immunofluorescence method. Data are shown as mean + 1 SE. Significant differences between the parameters in mercury- and saline-injected mice were calculated by the Wilcoxon–Mann–Whitney test. *P < 0.05; **P < 0.01; ***P < 0.001.

 
Analysis of mercury-induced renal IgG1 deposits in various mouse strains of different H-2 genotypes
In susceptible mice, the formation of granular IgG deposits in the kidney glomeruli is one of the major characteristics of mercury-induced autoimmunity (14). In this study, we also examined the development of renal IgG1 deposits in mouse strains of different H-2 genotypes after treatment with mercury. We found that mercury-treated strains, which exhibited high numbers of IgG1 antibody-secreting cells [SJL (H-2s), A.SW (H-2s), NZB (H-2d), 129/SvJ (H-2b) and NZW (H-2z)], also developed high levels of granular deposits of IgG1 isotype in the kidney (Fig. 3Go). BALB/c (H-2d) and FVB/N (H-2q) strains were exceptions to this general finding. Mercury treatment of BALB/c (H-2d) mice resulted in a slight increase in the splenic IgG1 antibody-secreting cells (Fig. 1aGo), but a large increase in the levels of renal IgG1 deposits (Fig. 3Go). In contrast, in response to mercury, FVB/N (H-2q) mice showed an intermediate increase in the number of splenic IgG1 antibody-secreting cells (Fig. 1aGo) and high serum levels of IgG1 ANolA (Fig. 2Go), but developed a minimal or no increase in the levels of renal IgG1 deposits (Fig. 3Go). Our findings suggest that although, in most instances, the development of renal IgG1 deposits correlates with the formation of IgG1 Ig, it cannot be generalized to all strains.



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Fig. 3. Groups of different inbred mouse strains of seven H-2 genotypes were repeatedly treated s.c. with either mercuric chloride (solid bars) or physiological saline (open bars) for 4 weeks. At the end of each experiment the mice were bled and killed. The kidneys were analyzed for the presence of renal deposits of IgG1 antibodies by using a direct immunofluorescence method. Data are shown as mean + 1 SE. Significant differences between parameters in mercury- and saline-injected mice (different H-2 genotypes) and in mercury-injected strains (within a particular H-2 genotype) were calculated by the Wilcoxon–Mann–Whitney test. *P < 0.05; **P < 0.01; ***P < 0.001. NS, Not significant

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In the present study, we investigated the genetic susceptibility/resistance to mercury-induced autoimmunity regarding its three major characteristics, formation of IgG1 and IgE Ig, synthesis of ANolA, and development of renal IgG1 deposits. Considering the mercury-induced IgG1 and IgE production as B cell activation parameters, several conclusions can be drawn from our findings. First, the non-H-2 background genes largely influenced both the susceptibility to and the magnitude of mercury-induced B cell activation. This was supported by the observation that within each tested H-2 genotype, there was at least one mouse strain which could respond to mercury by a high increase in the number of splenic IgG1 antibody-secreting cells as well as in serum IgE levels. Among non-H-2 genes, Th2 cell cytokine genes are of interest, because up-regulation of IL-4, a key Th2 cell cytokine, which plays a major role in Ig isotype switching towards IgG1 and IgE antibodies (17,18), has been shown in response to mercury in susceptible mice and rats (reviewed in 19). In addition, we have also found a close association between IL-4 gene and mercury-induced autoimmunity by using IL-4 knockout mice, in which the mercury-induced IgG1 and IgE antibody production were extensively impaired (12). How mercury activates mainly Th2 cells in the susceptible mice remains to be elucidated.

Second, mercury was able to induce a high increase in the numbers of splenic IgG1 antibody-secreting cells in all tested strains (SJL, A.SW and B10.S) of the H-2s genotype, irrespective of their non-H-2 background genes. Therefore, it is likely that the H-2s genotype could positively affect the magnitude of mercury-induced B cell responses. To further test this likelihood, we are presently introducing the H-2s genotype in those strains which carry non-H-2-resistant genes.

Third, mouse strains that are genetically prone to develop autoimmune diseases are more susceptible to mercury-induced B cell activation. This is supported by three findings. (i) Young (NZBxNZW)F1 hybrids (H-2d/z), which are well known to develop a systemic autoimmune disease similar to human SLE at old age (20), developed an intense antibody formation of different classes and subclasses, including IgM, IgG1, IgG3 and IgE, after mercury stimulation (14). (ii) Young NZB (H-2d) mice (a parental strain of (NZBxNZW)F1 hybrids), which are known to develop autoimmune hemolytic anemia at old age (20), also produced high numbers of IgG1 antibody-secreting cells as well as high serum levels of IgE Ig after treatment with mercury (this study). (iii) Likewise, a strong IgG1 response was also found in mercury-treated NZW (H-2z) mice (this study). In fact, these mice are phenotypically normal, but carry the genes that contribute to the development of autoimmune disease in the (NZBxNZW)F1 hybrids (20). To further advocate this conclusion, we are currently analyzing the effect of mercury in other mouse strains genetically predisposed to develop different autoimmune diseases.

The observation that mercury induced ANolA production only in mouse strains of H-2s and H-2q irrespective of their non-H-2 background genes confirms and supports the results of other studies that mercury-induced ANolA synthesis was under strict control of H-2 genes (57). In fact, it was shown by the use of intra-H-2 recombinant mouse strains that susceptibility could be mapped to the I-A locus of H-2 class II genes (7) and that other H-2 class II loci (I-E) either suppressed (6) or did not influence the mercury-induced ANolA response (7,10). The mechanism by which the I-As and I-Aq gene products can confer the susceptibility to mercury-induced ANolA production remains to be elucidated. However, it is possible that in the mouse, mercury interacts with fibrillarin and alters its chemical structure in such a way that after processing, cryptic antigenic peptides are generated. These cryptic peptides can thereby bind to only certain (here I-As and I-Aq), but not all H-2 molecules and activate non-tolerant T cells (2). This possibility is supported by the finding that mercury was capable of interacting with fibrillarin, and modifying its molecular and antigenic properties (21). It is also possible that in mice of H-2s and H-2q, high-affinity fibrillarin-reactive T cells escape the negative selection in thymus due to the poor self (fibrillarin) binding properties of H-2s and H-2q molecules. In this case, interaction of mercury with either H-2 molecule (s, q) or self (fibrillarin)-peptides bound to H-2 (s, q) might lead to activation of fibrillarin-reactive T cells, which results in the production of ANolA.

Mercury-induced renal IgG1 deposition is another important characteristic of mercury-induced autoimmunity (14). We found that in all tested strains (except for BALB/c and FVB/N) the formation of renal IgG1 deposits correlated with the degree of B cell activation. Since mercury-induced B cell activation was largely controlled by non-H-2 genes, it is likely that non-H-2 genes also regulate the renal IgG1 deposits. It remains to be elucidated why BALB/c mice developed high levels of renal IgG1 deposits, but exhibited a low increase in IgG1 antibody-secreting cells. However, it is possible that mercury treatment damages the kidney glomeruli in such a way that circulating normal IgG1 antibodies can accumulate in this organ. Another possibility is that the formation of IgG1 antibodies is not restricted to only the spleen and that other secondary lymphoid organs such as lymph nodes also produce IgG1 antibodies, which might participate in the formation of renal IgG1 deposits.

The finding that induction of ANolA synthesis did not lead to formation of renal IgG1 deposits in mercury-treated FVB/N (H-2q) mice is reminiscent of the result obtained by Hultman and co-workers in mercury-treated B10.HTT (H-2t3) mice (7). Our results from the FVB/N (H-2q) strain support the suggestion that the mere presence of specific ANolA is not a sufficient condition for development of renal IgG deposits (7).

By considering most of the mercury-induced autoimmune characteristics, our results indicate that only SJL (H-2s) and A.SW (H-2s) mice are highly susceptible to mercury-induced autoimmunity. These strains developed all of the tested autoimmune parameters at maximal levels. NZB (H-2d) mice were also highly susceptible, but they did not develop ANolA. Only the DBA/2 (H-2d) strain was found to be resistant to mercury with regard to tested autoimmune parameters. Resistance to mercury in this strain seems to be largely influenced by non-H-2 genes. CBA and CBA/N were considered as low responders, since the development of mercury-induced immune responses in these strains was at either low or minimal levels. We classified all other strains as either low or intermediate responders, because each of them was able to develop at least one characteristic of mercury-induced autoimmunity. Characterization of mercury highly susceptible and resistant mouse strains enables us to further study the inheritance of susceptibility to mercury-induced autoimmunity.


    Acknowledgments
 
The excellent technical assistance of Mrs Lena Israelsson is gratefully acknowledged. This study was supported by a grant from the Swedish Medical Research Council.


    Abbreviations
 
ANolA anti-nucleolar antibody

    Notes
 
Transmitting editor: H. Bazin

Received 17 January 2000, accepted 22 June 2000.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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