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The Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892; and
Research Service Veterans Affairs Medical Center and Department of Medicine/Rheumatology, University of Utah, Salt Lake City, UT 84132
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental models of arthritis in rats, such as adjuvant-induced arthritis (AIA) (9, 10, 11, 12, 13, 14, 15, 16, 17) and collagen-induced arthritis (CIA) (18, 19, 20, 21, 22), have been used extensively in studying the roles of autoimmunity and inflammation in the pathogenesis of joint disease. Susceptibility/severity of disease varies significantly among inbred strains. For example, inbred Dark Agouti (DA) rats are markedly susceptible to CIA and AIA, as well as several other autoimmune diseases, whereas inbred Fischer 344 (F344) rats are relatively resistant (23, 24). Most studies indicate that both non-MHC genes and RT1 MHC class II genes are associated with the susceptibility to CIA and AIA in DA rats (25, 26, 27, 28). Recently, our groups, employing a genome-wide scan involving 98 polymorphic markers, localized five QTLs that regulate CIA in (DA x F344)F2 progeny. One QTL (Cia1) is located on chromosome 20 and includes the MHC. The other QTLs (Cia2-5) are located on chromosomes 1, 4, 7, and 10, respectively. In addition, a region on chromosome 8 is suggestive for linkage (29). We, therefore, were interested in determining whether AIA in (DA x F344)F2 progeny is regulated by the same loci.
To determine whether the QTLs previously identified in CIA were also operative in another autoimmune model of arthritis and to identify additional QTLs, we conducted a genome scan to identify QTLs that regulate AIA in (DA x F344)F2 progeny. We have also expanded our previous investigation of CIA (29), and compared the revised CIA analysis with our new AIA analysis. Although CIA and AIA have many clinical similarities, fundamental differences in their pathophysiology are clearly evident and provide an ideal opportunity for defining and comparing the genes that control arthritis susceptibility and severity. This comparison is particularly interesting because AIA predominantly involves T cell-mediated mechanisms, whereas CIA requires both humoral and cellular immunity (11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). Identification of one or more loci common to both models would suggest the existence of genes that regulate the development of autoimmune inflammatory arthritis in response to diverse stimuli. We report the identification of a non-MHC locus on chromosome 4, in addition to the MHC, that regulates both AIA and CIA. We also discuss evidence that these loci may also be involved in multiple additional autoimmune diseases in rats, mice, and humans.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Specific pathogen-free Fischer 344 (F344/NHsd) rats were obtained from Harlan Sprague-Dawley (Indianapolis, IN), and Dark Agouti (DA/Bkl) rats from Bantin & Kingman (Fremont, CA). Using the convention of (female x male) to indicate strain parentage, F1 progeny were generated at the Veterinary Medical Unit, Salt Lake City VAMC from four mating pairs: two (F344 x DA) and two (DA x F344). F2 progeny were subsequently generated using eight mating cages (sib x sib) established with the F1 progeny of one (F344 x DA) mating pair and one (DA x F344) mating pair. The progeny derived from (DA x F344) and (F344 x DA) matings were evaluated for arthritis incidence and severity separately, but no statistically significant differences were detected. Analyses with the combined data are described.
Induction and evaluation of AIA and CIA
For AIA, CFA was prepared by suspending heat-killed Mycobacterium butyricum (Difco, Detroit, MI) in incomplete Freund’s adjuvant (IFA) at 7.5 mg/ml. CFA-induced arthritis was stimulated by injection of 0.1 ml of the CFA emulsion intradermally at the base of the tail, as previously described (16, 17).
For CIA, the rats were injected intradermally on the back with 2 mg/kg bovine type II collagen, prepared as previously described (18, 19, 20, 21, 22). In brief, collagen was suspended in 0.1 M acetic acid at 1 mg/ml and emulsified in an equal volume in IFA (Difco). Seven days after the initial injection, a booster injection of 100 µg bovine type II collagen emulsified in IFA was injected intradermally at the base of the tail.
For clinical evaluation of AIA and CIA, we used a scoring system as follows. The severity of arthritis in the wrist, midforepaw, ankle, and midfoot was scored for each extremity using the following scale: 0, no arthritis; 1, minimal swelling; 2, medium swelling; 3, severe swelling; and 4, severe swelling and non-weight bearing.
The presence of arthritis in the three joints of each of the lateral four digits, counting from lateral to medial (two interphalangeal, and metatarsophalangeal or metacarpophalangeal), was scored as: 0, swelling absent; 1, swelling present.
The total score for each extremity was calculated by summing the scores of the individual joints of each extremity with arthritis. The maximum score for each extremity was, therefore, 20, and the maximum total joint score was 80.
Scores were obtained two times per week by a single observer unaware of the genetic constitution of the animals. The maximum arthritis score for each animal was determined as the highest score during the 6-wk observation period. These scores are highly correlated with histologic or radiologic evaluations of disease severity. All experimental groups contained control rats of both parental strains. Scores in the text are indicated by mean ± SD in the text.
Genotypic analysis
DNA was prepared by standard procedures (30), and genotypes were
determined by PCR amplification of polymorphic DNA fragments containing
simple sequence repeats. For the genome-wide QTL analysis, 150 markers
were used to genotype animals from the phenotypic extremes (severely
affected versus mildly affected animals) of the F2 progeny
(Table I
). The markers were selected to give a spacing interval of less
than 20 cM. The map of these markers covered 1535 cM, which is
estimated to be more than 95% of the rat genome. The sequences of the
PCR primers and amplification protocols are described at ARB Rat
Genetic Database (31), Wellcome Trust/Oxford University Rat Genetic
Database (32), and Whitehead Institute/MIT Rat Genetic Database (33).
Primers for most of these markers are available from Research Genetics
(Huntsville, AL). Linkage maps were generated using the MAPMAKER/EXP
version 3.0b (34, 35).
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Nonparametric analysis of disease susceptibility and severity
was evaluated with the Mann-Whitney test. Linkage of individual simple
sequence length polymorphism (SSLP) markers to disease
susceptibility/severity was evaluated by a 
2 test of
independence using a 2 x 2 contingency table comparing allele
frequencies in the high and low arthritis score animals (36), i.e.,
homozygous DA progeny contributed two DA alleles to the allele
frequency, homozygous F344 progeny contributed two F344 alleles, and
heterozygous progeny contributed one DA and one F344 allele.
Significant cosegregation of marker alleles with a QTL, which
controlled arthritis severity, and its mode of inheritance were also
evaluated with the MAPMAKER/QTL program, version 1.1b (37). We used the
arcsin square root as a variance stabilizing transformation for
normalizing the phenotypic distribution (38). As recently suggested
(39), the threshold for suggestive linkage is a LOD score of 2
corresponding to a p value of 2.4 x 10-3,
and the threshold for significant linkage is a LOD score of 3.4
corresponding to a p value of 7.2 x 10-4
in dominant inheritance mode. In free inheritance mode, the threshold
for suggestive linkage is a LOD score of 2.8 corresponding to a
p value of 1.6 x 10-3, and the threshold
for significant linkage is a LOD score of 4.3 corresponding to a
p value of 5.2 x 10-5.
Comparative maps of the Aia2 and Aia3/Cia3 homologous regions among rats, mice, and humans
The rat map was constructed from data obtained in this study. Locations of additional genes on this map were estimated from data in ARB Rat Genetic Database (31). The mouse map and the human cytogenetic map were extracted from data in Mouse Genome Database (40) and Genome Database (41), respectively. The most likely positions of various autoimmune disease susceptibility loci were deduced from our new data and review of the literature (42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As shown in Figure 1, we compared
the incidence and severity of CIA (as previously reported, 29) with AIA
in parental DA, parental F344, F1, and F2 rats
during 6 wk following immunization. DA rats were extremely susceptible
to induction of severe CIA and AIA, exhibiting maximum arthritis scores
(see Materials and Methods) of 62 ± 10 (mean ±
SD) for CIA and 60 ± 22 for AIA. However, F344 rats were highly
resistant to CIA and moderately resistant to AIA (mean maximum score:
CIA = 0; AIA = 8 ± 6). The incidence of disease in
F1 progeny in both models was 100%, but the mean severity
was different in the F1 progeny than in the two parental
strains (mean maximum arthritis score of F1 progeny:
CIA = 40 ± 14; AIA = 50 ± 4). The F2
population showed a wide range of maximum arthritis scores: CIA (0–73,
n = 502), AIA (0–78, n = 546). But, 23
and 5% of the F2 population failed to develop CIA and AIA,
respectively.
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We have previously reported highly significant cosegregation of
CIA susceptibility/severity with several MHC markers, including
Tnfa (a marker for TNF: Cia1, LOD score =
78.5), which is located within the class III region of the rat MHC
(29). For our new study of AIA, we genotyped 80 severely (arthritis
index >64) and 80 mildly affected (arthritis index <17) rats from the
(DA x F344)F2 progeny (n = 546, Expt.
1) with SSLP markers spanning rat chromosome 20 (Table I
).
Cosegregation of genotype with phenotype was noted over a 30-cM
interval on this chromosome, with the strongest association between
markers D20Arb8 and D20Arb2 (RT1.N1)
(Table I). This interval includes MHC
class I, II, and III genes. Interval analysis using MAPMAKER/QTL
confirmed a strong QTL in this region (LOD score = 17.9 at
Tnfa). Its inheritance was consistent with dominant mode,
i.e., the DA allele acted dominantly to promote disease severity. We
have named this locus Aia1. To facilitate comparison of AIA
with CIA, we extended our previous analysis of CIA (29) by analyzing
the same SSLP markers spanning rat chromosome 20 that we used for
the AIA analysis. We cannot separate Aia1 from
Cia1 (Fig. 2, a and
b).
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genotype closely
reflects the genotype of the entire MHC region. The MHC region
influenced susceptibility differently in these two models. For CIA, in
(DA x F344)F2 progeny, the MHC genotype had a
relatively strong effect on disease susceptibility. For CIA, 43.4,
94.6, and 93.7% of rats with 0, 1, or 2 DA alleles at the
Tnfa locus developed arthritis (Fig. 3a, c, and e). For AIA,
however, the MHC genotype had much weaker effects on disease
susceptibility, i.e., 90.4, 96.2, and 96.8% of rats with 0, 1, or 2 DA
alleles at the Tnfa locus developed arthritis (Fig. 3, b, d, and f). On the other hand, MHC
genotype clearly correlated with disease severity in both models. For
CIA, the mean severity scores of arthritis-affected rats with 0, 1, and
2 DA alleles at the Tnfa locus were 12 ± 15, 35
± 16, and 42 ± 16, respectively. For AIA, the mean severity
scores of arthritis-affected rats with 0, 1, and 2 DA alleles at the
Tnfa locus were 34 ± 20, 48 ± 16, and 50 ±
17, respectively. In F2 rats with 0 DA alleles, the
susceptibility and severity in AIA were significantly greater than
those of CIA (Mann-Whitney test: p < 0.01). In other
words, F2 progeny with 0 DA MHC alleles typically developed
mild disease, but the range of arthritis scores was wide in AIA and was
more restricted in CIA than in AIA. Furthermore, F2 progeny
with 1 or 2 DA MHC alleles developed more severe disease than progeny
that were homozygous for the F344 MHC alleles in both AIA and CIA, but
the range of arthritis scores was wide. In summary, the MHC genotype
clearly influenced disease expression for both AIA and CIA, but this
genotype information alone for any individual F2 rat was an
imprecise prognostic factor for determining disease susceptibility or
severity.
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To complete the genome scan of AIA, we examined 80 severely and 80
mildly affected F2 rats with AIA for chromosomes 1, 4, 7,
8, and 10, which contain Cia2–5, as well as a suggestive
locus on chromosome 8. Maximum arthritis scores were greater than 64 in
80 severely affected rats and were lower than 17 in 80 mildly affected
rats. For the remainder of the genome scan, we evaluated 40 severely
(arthritis index >66) and 40 mildly affected (arthritis index <6)
F2 rats. For markers (e.g., chromosomes 3, 6, 15, and 19)
that showed trends for nonrandom genotype distributions
(p < 0.05) after genotypic analysis of 40
severely and 40 mildly affected F2 rats, additional
genotyping was done to include the 80 severely and 80 mildly affected
F2 rats. We found evidence of genotype-phenotype
cosegregation with multiple chromosome 4 SSLP markers (Table I). The
strongest association was with chromosome 4 markers between
D4Arb26 and D4Arb16 (Ampp) (D4
Mgh15, p = 2.4 x 10-3) (Table I). Since this significance level, by definition (39), is suggestive
for linkage, we conducted a replication experiment with a second group
of (DA x F344)F2 progeny (n = 110,
Expt. 2). In this replication experiment, we genotyped severely
affected (n = 28, arthritis index >64) and mildly
affected (n = 24, arthritis index <17) rats that had
arthritis scores equivalent to those in experiment 1. We again detected
cosegregation with chromosome 4 markers, but the strongest association
was with D4Arb24 (p = 4 x
10-4) (Table II). Because
the chromosomal segment associated with AIA extended over multiple
markers and an interval of approximately 50 cM, we suspected that this
chromosome contained more than 1 QTL. We, thus, further analyzed our
combined data from experiment 1 and 2 (n = 656) for
chromosome 4 using MAPMAKER/QTL (Fig. 2d). An interval
between D4Arb26 and D4Arb30 showed
significant linkage with a LOD score of 5.8 in the dominant inheritance
mode. We have named this locus Aia2. Aia2 is a unique locus
for AIA because additional genotyping with markers spanning the genomic
interval containing Aia2 of the phenotypically highest and
lowest 15% of the CIA F2 population with at least 1 DA MHC
allele did not reveal a corresponding CIA regulatory locus (Fig. 2, c and d). A second interval between
D4Arb30 and D4Arb16 had a maximum LOD score of
3.9 in free inheritance mode. Since this QTL was detected in both
experiments 1 and 2 (Tables I and 2), we have defined this locus as
Aia3. Aia3, like Cia3, was strongly linked to
D4Arb24 (Fig. 2, c and d), suggesting
that this region of chromosome 4 contains a QTL that regulates both AIA
and CIA. Both Aia3 and Cia3 appear to act
additively.
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) with one SSLP marker on
chromosome 3, and two markers on chromsome 15. The genomic interval on
chromosome 15 containing these markers had a maximum LOD score of 3 in
the free inheritance mode, while the chromosome 3 interval had a LOD
score of 2.7. Thus, the genomic interval on chromosome 15, but not the
Chr3 interval, meets criteria for suggestive linkage (39).
Interestingly, the putative disease-enhancing allele on chromosome 15
is derived from the F344 strain. Since our previously reported genomic scan analysis of CIA involved only 98 SSLP markers and incompletely spanned the rat genome (29), all markers not previously evaluated in CIA, which were evaluated in the study of AIA, were also analyzed in CIA F2 progeny to insure that the genomic scans of AIA and CIA were comparable. In other words, 150 markers, which we estimate cover more than 95% of the rat genome, were analyzed for both CIA and AIA. No additional CIA QTLs, however, were identified with this additional analysis. In particular, markers on chromosomes 3 and 15 showed no evidence for linkage in CIA (data not shown).
Comparative maps of Aia2 and Aia3/Cia3 among rats, mice, and humans
To examine homologies between mouse and human chromosomal regions
and the chromosomal regions associated with Aia2 and
Aia3/Cia3 on rat chromosome 4, we constructed comparative
maps of these three species. The region including Aia2 and
Aia3/Cia3 on rat chromosome 4 was homologous to mouse
chromosome 6 and human chromosomes 7p, 7q, 2p, 3p, 3q, 10q, and 12p
(Fig. 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although the Ags that initiate RA remain elusive, several subtypes of HLA DR4, including the shared epitope in many ethnic groups, are associated with RA (55, 56). The effect of HLA class II genes on the expression of RA is controversial. Some studies support an association with susceptibility and others with severity (55, 56, 57, 58, 59). We examined the effects of the MHC on susceptibility and severity in both AIA and CIA. Our study shows that the MHC region influences susceptibility and severity differently in these two models. For CIA, in (DA x F344)F2 progeny, MHC genotype had a relatively strong effect on disease susceptibility. For AIA, however, MHC genotype had a much weaker effect on disease susceptibility. Moreover, MHC genotype clearly exerted strong regulatory effects on disease severity in both models. But, in F2 rats with 0 DA alleles, CIA severity was milder than that of AIA. In both models, we noted many rats that were F344 homozygous at the MHC locus developed arthritis, and, conversely, many rats that were DA homozygous at the MHC locus failed to develop arthritis. In other words, our data demonstrate that non-MHC genotypes also contributed significantly to determining susceptibility and severity. Other studies have also indicated that DA non-MHC genes enhance arthritis susceptibility (25, 26, 27, 28, 29).
Among the non-MHC QTLs, Aia3 and Cia3 are especially interesting because they map to overlapping genomic regions and may be the same locus. Moreover, these loci are potentially of more general interest. Iddm1 and Lyp (lymphopenia), in the progeny of diabetic BB rats, cosegregate with this genomic region (47). The Lyp/Iddm1 locus is also associated with the risk of development of autoimmune thyroiditis, independent of diabetes (60). It is also interesting that RA, diabetes, and thyroid disease cluster in families of some RA patients (61, 62). Aia3/Cia3 also appear to have a homologue in experimental autoimmune uveitis in the rat. In (F344 x LEW)F2 rats, a locus very close to Aia3/Cia3 on chromosome 4 has been identified (45). It remains to be definitively demonstrated whether or not Aia3, Cia3, Iddm1, Lyp, and the chromosome 4 QTL in experimental autoimmune uveitis are allelic, but in any event, rat chromosome 4, in addition to the MHC, appears to contain important genes that regulate several forms of autoimmune disease.
Since the gene map of rat chromosome 4 is still relatively
sparse, we generated comparative maps among rats, mice, and
humans, to examine the possibility of identifying overlaps with
autoimmune diseases in other species and to identify candidate genes
(Fig. 4). Rat chromosome 4 and mouse chromosome 6 show strong linkage
conservation. Interestingly, the region homologous to Aia3
in the rat includes loci on mouse chromosome 6 controlling Ab
production (63) and Bordetella pertussis histamine
sensitization (43), which cosegregates with susceptibility to
experimental autoimmune orchitis (64). In addition, 2 loci regulating
diabetes in nonobese diabetic mice (D6Nds1/Idd
and D6Mit52/Idd), and a locus regulating systemic
lupus in mice (D6Mit25/Lbw4) have been mapped to this region
(48, 49, 53). The human homologues of the rat Aia2 and
Aia3 regions are located on chromosomes 2, 3, 7, 10, and 12
(Fig. 4). Of significant interest, these homologous regions contain
candidate genes for many other autoimmune/inflammatory diseases in
humans, such as multiple sclerosis (50, 51, 52), inflammatory bowel disease
(44), and atopy/bronchial asthma (42). Moreover, the Aia3
homologous region is also linked to recently described candidate loci
on human chromosome 3q for rheumatoid arthritis (RA2) and
insulin-dependent diabetes mellitis (IDDM9) (46). Human chromosome 12
may also have a RA candidate locus (46). Numerous candidate genes are
predicted to map in this region of rat chromosome 4 and include
neuropeptide Y, TCR Vß loci, the 
-light chain of Ig, CD8, max
dimerization protein, TGF-, IL-5R -chain, histamine receptor H1,
TNF receptor 1, CD27, CD4, CD9, and the CD69 Ag (Fig. 4).
Thus, our data raise the possibility that like Aia1/Cia1, both Aia2 and Aia3/Cia3 and their homologues in other species will be important in many forms of autoimmune disease. In humans, autoimmune disease frequency is increased significantly in first degree relatives of patients with idiopathic inflammatory myopathies (65). A recent review of published mapping studies also suggested that autoimmune disease regulatory loci tend to cluster within and among species (66). In other words, it appears increasingly likely that many autoimmune disorders share genes that together act as polygenic risk factors.
In summary, our data indicate that at least three genetic loci contribute to disease development in AIA. Their homologues may also be involved in multiple autoimmune diseases in humans, including RA. Aia1 and Aia3 are likely to be identical to Cia1 and Cia3, respectively, and probably influence multiple additional autoimmune diseases. The development of QTL congenic strains involving these loci will provide a powerful approach to identify and characterize the biologic function of the underlying genes. Moreover, our data suggest the possibility of ultimately developing therapies directed at biochemical pathways common to multiple related autoimmune diseases.
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Acknowledgments |
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Footnotes |
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2 Current address: First Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji Kamigyo-ku, Kyoto 602, Japan.
3 Address correspondence and reprint requests to Dr. Ronald L. Wilder, National Institutes of Health, Building 10 Room 9N240 10 Center Drive MSC 1820, Bethesda, MD 20892-1820. E-mail address:
4 Abbreviations used in this paper: RA, rheumatoid arthritis; AIA, adjuvant-induced arthritis; CIA; collagen-induced arthritis; DA, Dark Agouti rat; F344, Fischer 344 rat; LOD, logarithm of the likelihood ratios; QTLs, quantitative trait loci; SSLP, simple sequence length polymorphism.
Received for publication March 10, 1998. Accepted for publication June 9, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 B. C. Carlson, A. M. Jansson, A. Larsson, A. Bucht, and J. C. Lorentzen The Endogenous Adjuvant Squalene Can Induce a Chronic T-Cell-Mediated Arthritis in Rats Am. J. Pathol., June 1, 2000; 156(6): 2057 - 2065. [Abstract] [Full Text] [PDF]
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H.-T. Yang, J. Jirholt, L. Svensson, M. Sundvall, L. Jansson, U. Pettersson, and R. Holmdahl Identification of Genes Controlling Collagen-Induced Arthritis in Mice: Striking Homology with Susceptibility Loci Previously Identified in the Rat J. Immunol., September 1, 1999; 163(5): 2916 - 2921. [Abstract] [Full Text] [PDF]
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 S.-H. Sun, P. B. Silver, R. R. Caspi, Y. Du, C.-C. Chan, R. L. Wilder, and E. F. Remmers Identification of genomic regions controlling experimental autoimmune uveoretinitis in rats Int. Immunol., April 1, 1999; 11(4): 529 - 534. [Abstract] [Full Text] [PDF]
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