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The Journal of Immunology, 1999, 162: 5106-5111.
Copyright © 1999 by The American Association of Immunologists

A Major Linkage Region on Distal Chromosome 4 Confers Susceptibility to Mouse Autoimmune Gastritis1

Pablo A. Silveira*, Alan G. Baxter2,*, Wendy E. Cain{dagger} and Ian R. van Driel{dagger}

* Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia; and {dagger} Department of Pathology and Immunology, Monash University Medical School, Prahran, Australia


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although much is known about the pathology of human chronic atrophic (type A, autoimmune) gastritis, its cause is poorly understood. Mouse experimental autoimmune gastritis (EAG) is a CD4+ T cell-mediated organ-specific autoimmune disease of the stomach that is induced by neonatal thymectomy of BALB/c mice. It has many features similar to human autoimmune gastritis. To obtain a greater understanding of the genetic components predisposing to autoimmune gastritis, a linkage analysis study was performed on (BALB/cCrSlc x C57BL/6)F2 intercross mice using 126 microsatellite markers covering 95% of the autosomal genome. Two regions with linkage to EAG were identified on distal chromosome 4 and were designated Gasa1 and Gasa2. The Gasa1 gene maps within the same chromosomal segment as the type 1 diabetes and systemic lupus erythematosus susceptibility genes Idd11 and Nba1, respectively. Gasa2 is the more telomeric of the two genes and was mapped within the same chromosomal segment as the type 1 diabetes susceptibility gene Idd9. In addition, there was evidence of quantitative trait locus controlling autoantibody titer within the telomeric segment of chromosome 4. The clustering of genes conferring susceptibility to EAG with those conferring susceptibility to type 1 diabetes is consistent with the coinheritance of gastritis and diabetes within human families. This is the first linkage analysis study of autoimmune gastritis in any organism and as such makes an important and novel contribution to our understanding of the etiology of this disease.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Significant progress has been made in our understanding of the pathogenesis of autoimmunity. Much less is known about its etiology, which appears to depend upon a complex relationship between diverse environmental factors and genetic susceptibility. To shed light on the latter, the genetic control of susceptibility to autoimmune disease induced by neonatal thymectomy in mice was studied. Thymectomy of mice in the first week of life induces a number of autoimmune diseases, including gastritis, thyroiditis, oophoritis, and orchitis (1), that are reminiscent of the thyrogastric cluster of autoimmune diseases in humans. Therefore, thymectomy-induced autoimmune disease serves as a good model for the identification of the ultimate causes of organ-specific autoimmunity. Experimental autoimmune gastritis (EAG)3 is the most thoroughly characterized autoimmune disease induced by neonatal thymectomy (2, 3, 4, 5) and has many features in common with human chronic atrophic (type A; autoimmune) gastritis, namely: chronic inflammatory lesions in the gastric mucosa, depletion of parietal and zymogenic cells, and autoantibodies to the parietal cell H+/K+ ATPase (proton pump) (2, 6). The H+/K+ ATPase is also the primary target Ag of the pathogenic CD4+ T cell response that is responsible for the disease (7, 8, 9). Genetic predisposition is important in gastritis as evidenced by a strong strain dependence in mice (1, 10) and familial clustering of antigastric autoantibodies and gastritis in humans (11). Convincing linkage to any genomic region has not yet been demonstrated, as initial reports of HLA associations were not substantiated in subsequent work (11). The aim of this study was to map the genetic control of autoimmune gastritis in mice with a view to studying syntenic regions in studies of affected human siblings.


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

BALB/cCrSlc and C57BL/6 mouse strains and F1 and F2 progeny were bred and maintained at the Monash Medical School Animal Facility under conventional conditions. Mice were housed at 21°C and were fed Barastock mouse chow (Melbourne, Australia) and water ad libitum. Reciprocal outcrosses were performed to produce F1 and F2 progeny. Mice of both sexes were included in all analyses.

Phenotyping

Mice were thymectomized on day 3, killed at 12 wk of age, and assessed for autoimmune gastritis by histological examination of stomachs and by ELISA for H+/K+ ATPase-specific autoantibodies as described previously (9).

Genotyping

DNA of F2 progeny was extracted from kidneys and subjected to an autosomal genome-wide scan at a 15 cM resolution, using 126 microsatellite markers polymorphic between BALB/c and C57BL/6 strains chosen from the Whitehead Institute simple sequence length polymorphism library (12). An analysis of simple sequence repeat polymorphisms was performed as described previously (13).

Linkage analysis

Recombination distances between each marker were determined using the MAPMAKER/EXP program (14). Lengths of chromosomes and order of markers were checked against published maps (15). Genotyping errors were identified manually as double recombinants or by the error checking function of MAPMAKER/EXP and were reamplified. Two approaches to linkage analysis were used. To calculate the linkage of individual markers to autoimmune gastritis, a 3 x 2 contingency table ({chi}2 test of independence) was applied. The significance of linkage achieved by this method was tested by creating an experimentwise threshold using permutation analysis (16). This threshold is simultaneously valid for all markers of the genome and was calculated by permuting the phenotype data for every individual 10,000 times. The highest {chi}2 value for each permutation was collected and subsequently sorted to produce a null distribution of the test statistic within the whole genome. The distribution allowed the calculation of an experimentwise 95% critical threshold (p < 0.05 of type 1 error in entire genome). Markers with an experimental {chi}2 surpassing the experimentwise 95% critical threshold were considered significantly linked to disease.

Interval analysis of linkage to autoimmune gastritis was conducted on two linkage analysis programs. The MapManager/QT program (17) was initially used to perform interval linkage analysis on autoimmune gastritis by entering the trait values as 0 for unaffected mice and 1 for affected mice (Ref. 18; Kenneth Manly, personal communication). The degree of linkage to autoimmune gastritis was reported using a likelihood ratio statistic (LRS) (19). To report the significance of linkage achieved, the program was used to calculate permutation-derived critical threshold values for significant and suggestive linkage, according to Lander and Kruglyak’s specifications (20), for the interval analysis using the methods established by Churchill and Doerge (16, 17, 20). A total of 1000 permutations of phenotypes in the dataset were performed. Disease genes were proposed when the significant linkage thresholds set by this program were surpassed. Qualitative trait analysis was also performed on MAPMAKER/QTL 2.0b using the "penetrance scan" function (Ref. 21; new version supplied by Mark Daly of the Whitehead Institute of Biomedical Research), which optimizes a set of penetrances for each genotypic class. Trait values were entered as 0 or 1 for unaffected and affected mice, respectively. Results of the penetrance scan are given as a logarithm of odds (LOD) score, representing the likelihood that data have arisen due to the effect of a quantitative trait locus with optimized sets of penetrances rather than by the effect of chance (under the null hypothesis that the penetrances for all genotypic classes are equal).

MAPMAKER/QTL and MapManager/QT have individual advantages, and the two programs apply slightly different methods to calculate linkage to binary traits. MAPMAKER/QTL is usually regarded as the tool of choice for the analysis of murine datasets, and its penetrance scan function is ideally suited for performing an interval linkage analysis of binary traits. One disadvantage of the program is its tendency to produce artificially elevated LOD scores in large intervals (>15 cM, 21), which greatly limits its utility for calculating significance thresholds by permutation analysis. MapManager/QT has the advantage of being able to accurately calculate the permutation-derived thresholds specific for individual datasets using methods derived from Churchill and Doerge (16).

Both linkage analysis programs were also used to conduct a quantitative trait linkage analysis of the autoantibody titers in gastritic mice to detect possible disease modifier genes. Autoantibody titers of affected mice were log transformed so as to conform to a normally distributed trait, which is assumed by both programs when scanning for quantitative trait loci (QTL). Chromosomewise and experimentwise permutation thresholds (1000 permutations) were derived for the MapManager/QT analysis and were used to report on the significance of linkage. Chromosomewise thresholds were also determined for the MAPMAKERr/QTL analysis by creating 1000 new traits from the permutation of the original log autoantibody titer. Each trait was then used to scan chromosome 4 for linkage. The highest linkage achieved in each scan was sorted to produce significant (95th percentile, p = 0.05) and suggestive (37th percentile, p = 0.63) thresholds.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Inheritance of autoimmune gastritis in breeding program

To determine the mode of inheritance and to map the genes causing susceptibility to autoimmune gastritis in mice, F1 and F2 populations were produced using the BALB/cCrSlc (susceptible) and C57BL/6 (resistant) strains. Progeny were thymectomized on day 3 of life and; at 12 wk, mice were bled for an assessment of anti-H+/K+ATPase autoantibodies by ELISA and killed for histological examination of the stomach. The high incidence of disease, as defined by the coexistence of infiltrates and autoantibodies, within the F1 progeny (30/85, 35%; Table IGo) demonstrated that autoimmune gastritis was inherited as a dominant trait. There was a high concordance in F1 mice between autoantibody production and mucosal lymphocytic infiltration, with 30 of 39 (77%) F1 mice with infiltrates also having autoantibodies. All mice with autoantibodies had infiltrates. The results of the phenotypic analyses of 165 F2 progeny are illustrated in Fig. 1Go, which exhibits the discontinuous distribution of disease among progeny as the titers of autoantibodies in the sera formed a bimodal distribution. Titers of >1:50 were present in 40 of 165 (24%) mice, whereas the remainder had no Ab detectable at this titration. All of the mice with titers of autoantibody of >1:50 also had lymphocytic infiltrate of the gastric submucosa upon histological examination and thus were considered gastritic (Table IGo). Only 9 of 125 (7%) mice with no evidence of autoantibodies at a dilution of 1:50 had evidence of gastric infiltration. These mice were initially excluded from the genetic analysis (Fig. 1Go) because the presence of autoimmunity could not be confirmed. In previous analyses employing in situ DNA nicked-end and 5-bromodeoxyuridine labeling of gastric mucosa in BALB/c strains, there was no correlation between the titers of autoantibody and the severity of gastric pathology,4 supporting the evidence presented here that gastritis in this model is a discontinuous phenotype.


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  		Table I. Incidence of autoimmune gastritis in mice produced in parental strains and F1 and F2 generations1

 


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  		FIGURE 1. Distribution of titers for autoantibodies specific for the H+/K+ ATPase and the presence of lymphocytic infiltrates in the stomachs of F2 progeny. Autoantibody titers were determined by ELISA as described in Materials and Methods. A total of 165 F2 mice were measured, and mice with titers of <1:50 were considered not to have detectable autoantibodies in the sera. The percentage of mice with leukocytic infiltrates in each titer group is displayed.

 
The reciprocal F1 and F2 crosses performed revealed that the sex of the progeny and the direction of the cross did not influence disease incidence (NS; 2 x 2 contingency table, {chi}2 test of independence). This determination allowed us to eliminate the effects of the sex chromosomes and maternal factors on EAG. The total disease incidence of 24% in the F2 progeny was indicative of relatively few disease genes segregating in the cross (approximately one to two assuming dominant inheritance with no epistasis).

Genetic mapping and marker linkage analysis

An autosomal genome scan of 40 gastritic and 41 nongastritic F2 progeny was conducted using 126 polymorphic microsatellite markers with an average marker separation of 15 cM. Extra unaffected mice (116 in total) and an increased density of markers were used in areas showing evidence of linkage to disease. When linkage analysis was performed at each marker using a 3 x 2 contingency table, 11 markers on the distal region of chromosome 4 displayed linkage to EAG that was greater than the 95% experimentwise threshold derived from the permutation analysis ({chi}2 of >=14.84; Table IIGo). This result provided strong evidence for the presence of an EAG susceptibility gene in this region.


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  		Table II. Linkage maps of chromosomes with evidence of linkage of marker loci to EAG by comparing the genotypes of the F2 mice in the gastritic and nongastritic group

 
No other markers surpassed the 95% experimentwise thresholds, although markers on proximal chromosome 6 (D6mit178, D6mit149, D6mit287,and D6mit338), distal chromosome 9 (D9mit8and D9mit24), proximal chromosome 15 (D15mit226and D15mit17), and proximal chromosome 17 (D17mit16 and D17mit24) exhibited a trend toward linkage (p < 0.05; Table IIGo).

Interval analysis using MapManager/QT and MAPMAKER/QTL

The permutation thresholds for reporting the significant and suggestive linkage derived by MapManager/QT in this dataset were LRS >= 15.9 and 9.0, respectively. Applying these thresholds, only two peaks on distal chromosome 4 surpassed the significant linkage threshold (Fig. 2Go). The highest linkage to disease occurred at D4mit148 (LRS = 18.9). The second linkage peak occurred further distal on chromosome 4, at D4mit127 (LRS = 18.8). Suggestive linkage to autoimmune gastritis was found to occur on chromosomes 6 (D6mit149; LRS = 14.5), 9 (between D9mit24 and D9mit18; LRS = 10.6), and 15 (D15mit17; LRS = 9.8) in decreasing order of linkage (data not shown).



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  		FIGURE 2. Linkage to autoimmune gastritis and gastric autoantibodies (calculated in LOD) in F2 mice plotted against genetic distance on chromosome 4. The solid curve represents the interval linkage analysis for autoimmune gastritis performed by MapManager/QT; the experimentwise significance threshold attained by permutation analysis (LRS = 15.9) in the same program is shown as the straight solid line. Linkage in this program was calculated using an LRS score. The dashed curve represents the interval linkage analysis performed using the penetrance scan function on MAPMAKER/QTL. Linkage in this program was calculated in a LOD score. Lander and Kruglyak’s threshold (20) for reporting significant (LOD = 4.3) linkage is displayed as the dashed straight line.

 
The penetrance scan function of the MAPMAKER/QTL program also identified distal chromosome 4 as having linkage to disease. Tightest linkage was observed 0.3 cM proximal of D4Mit148 (LOD = 4.3, Fig. 2Go), which corresponded well with the MapManager/QT analysis. However, the linkage score for this region was higher than that calculated by MapManager/QT (LRS = 2(ln10)LOD = 19.8) (19). As it is likely that the permutation thresholds derived by MapManager/QT were inappropriate for the penetrance scan produced by MAPMAKER/QTL, and because the permutation thresholds for the MAPMAKER/QTL analysis could not be calculated due to the program being prone to producing aberrantly high LOD scores between widely spaced markers (21), the stringent linkage threshold set by Lander and Kruglyak for significant linkage (LOD >= 4.3) was applied (20). The more proximal linkage region of the two on chromosome 4 equaled this threshold. In contrast to the MapManager/QT linkage report, MAPMAKER/QTL linkage values for the more telomeric peak on chromosome 4 indicated a relatively modest contribution to autoimmune gastritis (LOD = 3.9).

All three analyses (marker and interval) consistently demonstrated that the region conferring most susceptibility to autoimmune gastritis lies on distal chromosome 4, with tightest linkage to D4mit148 (Fig. 2Go). Similar results were also obtained when the nine progeny, which did not have autoantibodies but did have mucosal lymphocytic infiltration, were included in the group of affected mice and the analyses were repeated. We have designated this susceptibility gene Gasa1 (Gastritis Type A susceptibility locus 1). The mapping data place the disease gene in a 10:1 confidence interval from D4mit308 through to D4mit343 (~17 cM). Examination of the genotype frequencies of markers within the Gasa1 interval (Table IIGo) indicate that the Gasa1s (c; BALB/cCrSlc) allele affects the disease in an additive or dominant fashion, with homozygosity conferring maximum susceptibility to autoimmune gastritis.

The more telomeric linkage region is centered on D4mit127 (Fig. 2Go) and may represent the presence of another disease gene. The BALB/c homozygous genotype at this locus also confers greatest susceptibility to disease and has a slightly higher penetrance than Gasa1, although penetrance of the heterozygous genotype at this locus is considerably reduced. This region has been tentatively designated Gasa2.

Finally, evidence of suggestive linkage to autoimmune gastritis has been shown on chromosome 6. According to the genotype ratios at the marker of highest linkage (Table IIGo), heterozygosity confers most susceptibility to disease in F2 progeny. Confirmation of this gene will require reproduction of linkage at this locus in an independent mapping study (20).

QTL analysis of autoantibody titers

Autoantibodies to the gastric H+/K+ ATPase pump are not involved in the pathogenesis of autoimmune gastritis (2), and the degree of gastric pathology in neonatally thymectomized BALB/c mice has not been shown to correlate with antiparietal autoantibody titers.4 To determine whether autoantibody titers were affected by distinct modifier genes, a genome scan for QTLs was performed using MAPMAKER/QTL and MapManager/QT analysis of the log autoantibody titers of affected mice (titer of >1:50).

Experimentwise permutation thresholds for significant and suggestive linkage were determined to be LRS >= 16.6 and 9.6, respectively. Using these criteria, only one locus on distal chromosome 4 exhibited suggestive evidence of linkage (LRS = 10.4). Although the linkage region mapped to the same chromosomal segment as Gasa2, inheritance of the C57BL/6 gene predisposed F2 mice to higher autoantibody titers. Examination of the raw data indicated that the significance levels were greatly affected by very high titers in two of only three individual affected mice homozygous for C57BL/6 alleles on distal chromosome 4.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Most studies in murine models of spontaneous autoimmune diseases have characteristically revealed the existence of multiple susceptibility regions (22, 23). According to our data, the major susceptibility gene(s) conferring susceptibility to autoimmune gastritis in the BALB/cCrSlc strain are located on the distal portion of chromosome 4, suggesting that neonatal thymectomy may circumvent the requirement for large numbers of susceptibility genes in spontaneous models of autoimmune disease.

This study did not find significant or suggestive evidence of linkage to loci on chromosomes 3 and 16, for which linkage to neonatal thymectomy-induced autoimmune oophoritis has been reported previously (24, 25). However, Gasa1 maps within the same chromosomal segment as the susceptibility loci of other murine autoimmune diseases, including Nba1 (systemic lupus erythematosus (SLE)) and Idd11 (type 1 diabetes) (13, 26). In addition, the distal linkage peak on chromosome 4 (Gasa2) also maps within the same chromosomal segment as another type 1 diabetes susceptibility locus, Idd9 (27). These results suggest that these loci may represent common susceptibility genes shared by SLE, type 1 diabetes, and EAG (28, 29).

The Gasa1 genetic interval contains several genes that are attractive candidates, including the lymphocyte protein tyrosine kinase (p56lck) Lck (30, 31) and a number of subcomponents of the complement C1q component (including C1qa, C1qb, and C1qc) (32). The p56lck protein is considered a good candidate for autoimmune disorders because of its role in regulating T cell activation and thymocyte development through its delivery of signals via the mature {alpha}ßTCR as well as the pre-TCR (33, 34). Inherited deficiencies in a number of proteins of the classical complement pathway have been associated with various autoimmune diseases (35). In particular, C1q deficiencies have been strongly implicated in both rheumatoid arthritis and SLE (36, 37). It is hypothesized that C1q plays a role in the clearance of apoptotic cells, which might otherwise provide a source of previously unencountered self Ags causing the activation of autoreactive lymphocytes (38). It is unlikely that any role for C1qa, C1qb, and C1qc would involve targeting by autoantibodies, because there is no correlation between the titers of autoantibody and the severity of gastric pathology in this model.4

The Gasa2 region, which is distal to Gasa1 on chromosome 4, contains a number of promising candidate genes that encode for members of the TNF receptor (TNFR) superfamily, including Tnfr2, Cd30, 4-1BB, and Ox-40 (39, 40, 41, 42). These receptors and their ligands are involved in several aspects of immune regulation, including: enhancement of proliferation, induction of apoptosis, cytokine production, activation, differentiation of T cells, and mediation of T-B cell and T monocyte interactions (43). Of these candidates, Tnfr2 and Cd30 are of particular interest. CD30 appears to play a key role in the negative selection of T cells, as CD30 deficient mice show defects in this process (44). Signaling of cells via the type 2 receptor of TNF promotes the release of proinflammatory cytokines (43), and the dysregulation of TNF and its receptors (TNFR 1 and 2) has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis, type 1 diabetes, and SLE (43, 45).

The genetic and experimental simplicity of the system described here holds great promise in testing these candidates or isolating as yet unidentified genes predisposing to autoimmune gastritis. Unraveling the genetics of this disease will provide us with a greater understanding of the mechanisms responsible for causing autoimmune disorders.


   Acknowledgments
 
We thank Drs. Gary Churchill, Ward Wakeland, Kenneth Manly, and Mark Daly for their advice on the statistical analysis of this dataset and Dan Lucas for his help.


   Footnotes
 
1 This work was funded by the National Health and Medical Research Council of Australia. A.G.B. is the recipient of an R. Douglas Wright Fellowship from the National Health and Medical Research Council of Australia. P.A.S. is the recipient of an Australian Postgraduate Research Award. Back

2 Address correspondence and reprint requests to Dr. Alan G. Baxter, Centenary Institute of Cancer Medicine and Cell Biology, Locked bag #6, Newtown NSW 2042, Australia. E-mail address: Back

3 Abbreviations used in this paper: EAG, experimental autoimmune gastritis; LOD, logarithm of odds; LRS, likelihood ratio statistic; QTL, quantitative trait loci; SLE, systemic lupus erythematosus. Back

4 L. M. Judd, P. A. Gleeson, B. H. Toh, and I. R. van Driel. Chronic inflammation in autoimmune gastritis results in disruption of epithelial cell development. Submitted for publication. Back

Received for publication December 4, 1998. Accepted for publication February 5, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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