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*
Centre d’Immunopathologie et de Génétique Humaine, Centre National de la Recherche Scientifique, CHU Purpan,
Ecole Nationale Vétérinaire, and
Institut National de la Santé et de la Recherche Médicale Unit 28, CHU Purpan, Toulouse, France
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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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Given the immunopathological similarities between experimental
autoimmune encephalomyelitis (EAE) and multiple sclerosis 5 , this
animal model provides a useful alternative to identify candidate loci
and better understand the physiologic pathways involved in the disease
process. EAE indeed is an autoimmune disease of the CNS in which the
pathologic changes, i.e., encephalomyelitis and demyelination, are the
consequences of T cell infiltration and recognition of CNS-associated
Ags. The inflammatory CD4+ T cells that mediate EAE secrete
Th1 cytokines, including IL-2, IFN-
, and TNF-ß. By contrast,
CD4+ Th2-type T cells that secrete IL-4, IL-5, IL-6, IL-10,
IL-13, and TGF-ß are important in down-modulating inflammatory
responses 6 and have the ability to suppress both the acute and
relapse phases of EAE 7 .
Genome scans performed on the progeny of experimental crosses between susceptible and resistant strains of rodents help to restrict heterogeneity of complex diseases and thus yield greater statistical power than similar approaches in humans, at the cost of representing only one segment of the genetic spectrum of a disease 8 . The analysis of different strain combinations not only in the mouse 9, 10, 11 but also in other species is therefore essential to elucidate all loci that may contribute to the disease via different pathogenic pathways. Although inbred strains of rats show varying degrees of susceptibility to the induction of EAE 12 , no systematic genetic analysis has been performed in this rodent species to date. Part of the difference between the highly susceptible Lewis (LEW) and resistant Brown Norway (BN) rat strains can be explained by a gene in the MHC or RT1 region 13, 14, 15 . However, this locus is not sufficient to induce EAE, and there is a great deal of additional complexity that appears to be genetically determined 16, 17 . Furthermore, a full-blown inflammatory reaction in the rat is not necessarily sufficient to bring about clinical symptoms, suggesting that these phenotypic traits may be controlled by separate loci 18 .
In this study we investigated factors unlinked to the MHC that control both CNS inflammation and clinical manifestations of EAE by a systematic genome search performed for the first time on the F2 progeny of the LEW and BN rat strains.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Inbred LEW and BN rats were initially obtained from the CSEAL (Centre National de la Recherche Scientifique, Orleans-La Source, France). (LEW x BN)F1 and F2 rats were bred in our facilities and maintained under conventional conditions. Myelin was extracted from guinea pig brain and spinal cord, and purified according to the procedure described by Norton and Poduslo 19 . To induce EAE, rats were immunized at 10–15 wk of age by injecting in each hind footpad 0.1 ml of the antigenic solution (10 mg of purified myelin/ml) emulsified with an equal volume of CFA (Difco, Detroit, MI) supplemented with Mycobacterium tuberculosis (0.5 mg/ml; Difco) and Bordetella pertussis (2 x 109 organisms/ml; Difco). This immunization procedure is known to have no effect on the resistant BN strain, but to induce strong EAE in the F1 hybrids 20 .
Clinical and histological evaluation
Rats were observed daily for clinical signs of neurological dysfunction and were scored on a scale of 0–4. They were sacrificed on day 17 after immunization for histopathological evaluation; brains and spinal cords were removed and fixed in 10% formalin. Specimens were processed through different grades of alcohol and embedded in paraffin. Seven histological sections were cut at 2 µm: two transverse sections of the brain, two longitudinal sections of the cerebellum, and three longitudinal sections of the cervical, thoracic, and lumbosacral cord, respectively. Hematoxylin and eosin staining was used to detect perivascular mononuclear infiltrates. Slides were evaluated blindly by two investigators, and histologic disease was quantitated by counting inflammatory foci with 20 or more aggregated mononuclear cells.
Genetic typing
Spleens were taken from all rats and were frozen at -70°C. DNA was prepared by digesting homogenized tissue with protein K and performing a phenol/chloroform extraction. The RT1 phenotypes of the F2 hybrids were determined by flow cytometry on PBL using two mAbs recognizing the RT1.D molecule of the BN and the RT1.B molecule of the LEW rat, respectively. Microsatellite marker loci were chosen at approximately 20-cM intervals based on the genetic map of the rat 21 . PCR amplifications were performed in a GeneAmp PCR System 9600 (PE Applied Biosystems) in 20-µl volumes using 100 ng of genomic DNA, 0.5 U of Taq DNA polymerase (Promega, Madison, WI), 10 mM Tris-HCl (pH 9), 50 mM KCl, 1.5 mM MgCl2, 0.2 mM of each dNTP, and 0.5 µM of each primer. An oligonucleotide of each pair was labeled with one of the fluorescent dyes, 6-FAM, HEX, or TET (PE Applied Biosystems). Thirty cycles of 94°C for 30 s, 55°C for 30 s, and 72°C for 30 s were generally used, although some primer pairs required a slightly higher or lower annealing temperature for optimum amplification. Multiloading of six to nine amplification products and an internal lane standard labeled with the ROX dye (PE Applied Biosystems) onto 6% denaturing polyacrylamide gels was performed on an ABI 373 DNA Sequencing System.
Data analysis
Construction of a linkage map based on the
F2 progeny was performed using MAPMAKER/EXP 3.0
22 . Positions of anchor loci were obtained from Jacob et al. 21 .
All genotypes with a logarithm of odds (LOD) of error >1.0 were
rescored and retyped if necessary. Association of individual markers
with EAE was assessed by comparing the genotype distributions of
affected and unaffected animals using Pearson’s 
2
statistics. LOD scores were calculated using MAPMAKER/QTL (version
1.9). Since the clinical score does not follow a normal distribution,
mapping of loci influencing EAE was performed using the penetrance scan
function implemented in this version of the software. Briefly, this new
function optimizes a set of penetrances (a probability of affectation,
or trait = 1) for each genotypic class, yielding a LOD score
representing how much more likely the data are to have arisen due to
the effect of a quantitative trait locus (QTL) with the optimized set
of penetrances than to the effect of chance (under the null hypothesis
that the penetrances for each genotypic class are equal and that no
quantitative trait locus is present). x = (2
loge 10) LOD following a -squared distribution with
2 degrees of freedom for the experimental cross used in this study;
pointwise significance levels corresponding to the different LOD scores
were determined from the appropriate 2 table.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 233 rats were immunized with purified myelin and
observed daily for clinical signs of neurological dysfunction. The
incidence of clinical disease according to strain is shown in Table I
. As expected, all the LEW rats
developed severe EAE, whereas none of the BN rats developed the
disease. The incidence of EAE in the F2
generation was 31.1%, a decrease of 63% from that in the
F1 generation, consistent with a polygenic mode
of inheritance. Because previous studies have implicated a MHC-linked
locus in the control of EAE susceptibility, we initially determined the
phenotypes of the entire F2 population for the
RT1 locus. The incidences of clinical disease in rats homozygous for
the LEW haplotype, heterozygous, and homozygous for the BN haplotype
were 53, 34, and 0%, respectively (Table I). This is consistent with
the interpretation that the LEW allele of an MHC-linked gene is
necessary, but not sufficient, to confer EAE susceptibility in the
(LEW x BN)F2 progeny, and that non-MHC loci
also contribute to the control of the disease. As previously reported
23 , the highest clinical scores were not significantly different
among F2 rats homozygous for the EAE-predisposing
MHC haplotype and those heterozygous (by Wilcoxon rank-sum test,
p = 0.13), which is not in favor of a strong dose
effect of Lewis MHC alleles on disease severity in this intercross.
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. None of the
F2 animals homozygous for the MHC BN haplotype
(49 rats) had inflammatory infiltrates. In the subset of the
F2 progeny with at least one LEW haplotype (147
rats), there was no animal with clinical symptoms that did not also
have histological inflammation, although 51 of 112 rats (45.5%) with
an inflammatory reaction had no clinical illness. This is consistent
with the previous observation that a full-blown inflammatory reaction
in the rat is not necessarily sufficient to bring about clinical
symptoms 18 . Of note, similarly to CFA-inoculated mice 24 , the LEW
rats we injected with CFA in saline did not demonstrate clinical
manifestations of EAE or CNS inflammatory cell infiltration. In multiple sclerosis, the extent of abnormality shown by magnetic resonance imaging is not related to the degree of clinical disability 25 . Similarly, we found no correlation between the number of inflammatory foci and the clinical score in the F2 animals with histological lesions examined in this study (by Kruskal-Wallis test on ranks, p = 0.27). The topography of the lesions may in some cases explain the silent nature of the disease. However, differences in mRNA expression of pro- and anti-inflammatory cytokines in the spinal cords of rats of different strains have been shown to correlate with their susceptibility to EAE 17 . It is thus possible that the secretion by the infiltrating cells of cytokines able to down-regulate the inflammatory response may protect some rats against progression to clinical disease.
Genetic mapping
To map the non-MHC loci that control EAE in the rat, the subset of the F2 progeny with EAE-predisposing MHC genotypes (146 DNAs available) was typed for 103 informative markers distributed on all autosomes and the X chromosome and covering 84.4% of the genome with a spacing of 20 cM or less. As previously shown, the F2 rats require at least one MHC haplotype of the susceptible LEW strain to develop a disease phenotype. The 49 rats homozygous for the MHC BN haplotype indeed were asymptomatic and were thus excluded from the investigation to increase the power of the tests.
No locus segregating with incidence or severity of histological disease was detected in addition to the MHC by MAPMAKER/QTL 26 . This may be due to the nonhomogeneous nature of the CNS-infiltrating cells in the F2 progeny. It is indeed likely that infiltration by cells secreting pro- and anti-inflammatory cytokines is independently controlled by several loci. A precise functional analysis of the inflammatory foci may thus be necessary before such genes can be identified.
To map the loci that control clinical manifestations of EAE, the
genotype distribution of rats with clinical disease (n
= 60) was first compared with that of rats of the resistant phenotype
(no clinical or histologic lesions; n = 35). When a
criterion of p < 0.05 was used for the purpose of
completeness, a difference in these distributions was detected for
markers on chromosomes 9, 10, 13, and 17 (Table II). These chromosomes were subjected to
a QTL scan 26 , using the penetrance scan function implemented in
MAPMAKER/QTL 1.9. As shown in Fig. 1, a
region on chromosome 10 fell short of significant linkage, with a LOD
score peak of 4.10 (p = 8 x
10-5) at D10 Mgh10, close to the generally accepted 4.3
(p = 5.2 x 10-5) threshold
corresponding to a genome-wide significance level of 0.05 27 . A LOD
score of 3.45 (p = 3.6 x
10-4) above the 2.8 (p = 1.6
x 10-3) threshold for suggestive linkage 27 was
obtained with marker D13 Mgh1 on chromosome 13. However, none of the
markers tested within 30 cM from D13 Mgh1 (D13 Mit1, D13 Mgh3, and
D13Uwm1) was informative in the present cross, and although genotyping
for marker D13 Mgh1 was repeated twice to exclude typing errors, this
result should be considered provisional. Of note, EAE incidence was
lower in LEW/LEW homozygotes at locus D13 Mgh1 than in LEW/BN
heterozygotes or BN/BN homozygotes, providing another example of an
allele from a control strain contributing to increased susceptibility
11, 28, 29 . Two additional regions on chromosomes 9 (peak LOD score
of 2.69 at D9 Mgh4; p = 2 x 10-3)
and 17 (peak LOD score of 2.87 between markers D17 Mit4 and D17 Mit5;
p = 1.3 x 10-3) fell short of
suggestive linkage. As shown in Table II, the genotype distribution for
these markers in rats with inflammatory foci but no clinical expression
was not significantly different from the expected 1:2:1 ratio. As a
consequence, comparison of rats with clinical EAE (n =
60) with those showing no clinical expression of the disease
(n = 86) leads to a lower significance than comparison
of rats with the most extreme phenotypes. This suggests that the group
of rats with inflammatory foci but no clinical expression may be
heterogeneous or lack genes that control progression to clinical
disease.
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, we observed significant linkage of a
trait controlling resistance to clinical symptoms in rats presenting
with histological disease with markers located near the centromere of
chromosome 4. The QTL scan of chromosome 4 detected a peak LOD score of
4.33 (p = 4.7 x 10-5) at
locus D4 Mgh1 (Fig. 1). Since no marker centromeric to D4 Mgh1 and
informative in this cross was available for typing, it cannot be
excluded that the locus controlling EAE in this region lies within the
5.8-cM region that separates this marker from the centromere 30 .
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The fractions of F2 rats homozygous for the
LEW allele, heterozygous, and homozygous for the BN allele at locus D10
Mgh10 that presented with clinical EAE were 61.3, 42.2, and 19.3%,
respectively. The clinical scores were significantly different among
the three groups (by Kruskal-Wallis test on ranks, p =
0.003). This suggests that the LEW allele at this locus acts in an
additive fashion not only to confer EAE susceptibility, but also to
determine disease severity. In contrast, two LEW alleles at locus D4
Mgh1 are necessary to significantly increase disease penetrance over
that observed in rats homozygous for the BN allele. Rats with two LEW
alleles at this latter locus have higher clinical scores than rats with
other genotypes (by Wilcoxon rank-sum test, p =
0.0007), indicating that this predisposing genotype also influences
disease severity. EAE penetrance in animals carrying different genotype
combinations is shown in Table IV. The
frequency of EAE in rats that do not carry a EAE-predisposing genotype
at either locus is 17%, indicating that neither is absolutely required
to confer EAE susceptibility. The EAE-predisposing genotype at locus D4
Mgh1 significantly increases disease penetrance associated with every
D10 Mgh10 genotype, which suggests an additive effect of the gene
products in the development of the disease and is consistent with the
polygenic mode of inheritance of EAE susceptibility.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The strongest linkage was observed for a gene controlling clinical EAE in the rats presenting with histological disease with markers localized on chromosome 4, close to the IL-6 gene 31 . This latter gene is an obvious candidate locus. Indeed, it encodes a cytokine that appears to be required for the establishment of the Th2 cytokine profile and to down-regulate Th1 cytokine production 32 . Since Th2-type cells have been shown to suppress the acute and relapse phases of EAE without significantly reducing mononuclear cell infiltrations within the CNS 7 , this cytokine might well interfere with the initiation of a Th2 response in the F2 rats with CNS infiltration but resistant to clinical EAE. The human region of conserved synteny is on chromosome 7p11.2-p21, and it is interesting to note that evidence for linkage of multiple sclerosis to microsatellite markers localized in this homologous region has been reported by the authors of two of the three genome scans recently performed in humans 33 . Further investigation is now needed to determine whether IL-6 or any other gene contained in the region of interest confers susceptibility to EAE and possibly also to multiple sclerosis.
The other region significantly linked to EAE is located around D10 Mgh10 on rat chromosome 10. It is noticeable that it is homologous to a locus controlling in vitro Th1/Th2 differentiation of CD4+ T cells 34 and EAE severity 10 on mouse chromosome 11. The same region also appears to coincide with ATPS-2, a QTL controlling elevated serum IgE production induced by gold salts in the BN rat strain 35 . This IgE production is mediated by Th2 effector cells 36 . It is thus possible that in the context of distinct genetic and environmental settings, allelic variants of a gene contained in this region contribute to several immunologically mediated pathological states, for instance by regulating the polarization of T cells to either a Th1 or a Th2 immune response. However, whether the locus controlling EAE on rat chromosome 10 and ATPS-2 are allelic or different remains to be determined. Comparison between the rat and mouse genetic maps 31, 37 reveals that this region of interest contains a large number of potentially candidate genes for which allelic variants could generate intrinsic differences between BN and LEW T cells. Such candidates include the IL-4 gene whose product directly promotes Th2 development from naive T cells; other cytokine genes, such as IL-3, IL-5, IL-9, IL-12 p40, and IL-13; and genes encoding transcription factors or signaling molecules expressed in T cells (IFN regulatory factor-1, T cell-specific transcription factor-7, and IL-2-inducible T cell kinase). The production of appropriate congenic strains will allow, through the analysis of recombination events within the region of interest, exclusion of certain candidate genes listed above and reduction of the support interval encompassing the EAE susceptibility locus on rat chromosome 10 to one that is amenable to physical mapping. Such an approach was indeed shown to allow placement of genes involved in polygenic diseases, even if they have incomplete penetrance and subtle effects, to a resolution greater than 1 cM 38 .
The congenic lines produced will also serve to test the hypothesis that the locus controlling EAE on rat chromosome 10 and ATPS-2 may be the same gene. This is of particular interest because the prevalence of IgE-mediated allergic diseases is significantly decreased in patients with multiple sclerosis 39 . This latter observation suggests that the genetic factors that promote susceptibility to Th1-mediated inflammatory diseases in humans may protect against the development of Th2-mediated diseases 39 . In that respect, it is noteworthy that susceptibility to high IgE levels and asthma in humans is linked to the chromosomal region 5q31.1 that contains the IL-4/IL-5 gene cluster 40 and is syntenic to the region of rat chromosome 10 that contains both ATPS-2 and the locus shown in this study to confer susceptibility to EAE.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marie-Paule Roth, CIGH, Centre National de la Recherche Scientifique, Unité Propre de Recherche 8291, Centre Hospitalo-Universitaire Purpan, F-31300 Toulouse, France. E-mail address:
3 Abbreviations used in the paper: CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; BN, Brown Norway; LEW, Lewis; QTL, quantitative trait locus.
Received for publication March 11, 1998. Accepted for publication October 29, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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