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*
Neuroimmunology Unit and
Rheumatology Unit, Department of Medicine, Karolinska Hospital, Stockholm, Sweden; and
Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in the spinal cord. Eae4 had a larger
influence on disease incidence among rats that were homozygous for the
RT1av1 MHC haplotype (RT1av1 rats) compared
with RT1n/av1 rats, suggesting an interaction between
Eae4 and the MHC. Homozygosity for the DA allele at
markers in Eae4 and in the MHC was sufficient for EAE.
Thus, Eae4 is a major genetic factor determining
susceptibility to EAE in this cross of DA rats. In addition, there was
support for linkage to phenotypes of EAE on chromosomes 1, 2, 5, 7, 8,
12, and 15. The chromosome 12 region has been shown previously to
predispose DA rats to arthritis, and the chromosome 2 region is
syntenic to Eae3 in mice. We conclude that
Eae4 and probably the other identified genome regions
harbor genes regulating susceptibility to neuroinflammatory disease.
The identification and functional characterization of these genes may
disclose critical events in the pathogenesis of multiple sclerosis;
understanding these events could be essential for the development of
new therapies against the disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The first evidence of a genetic influence on susceptibility to MS was
the demonstration of an association between the disease and certain HLA
haplotypes 2, 3 . The familial aggregation of MS has later been shown
to be genetically determined 4, 5 . Furthermore, the inheritance
pattern (e.g., the drop in concordance rate for MS between monozygotic
(
25%) and dizygotic twins (2%) 6, 7) suggests that MS is a
complex disease that is influenced by several genes 8 and probably by
environmental factors. A number of genes with a putative influence on
the inflammatory process in MS have been tested for association with or
linkage to MS. The TCR 
9, 10 and ß chains 11, 12, 13, 14, 15 , myelin
basic protein 16 , and Ig heavy chain loci 17, 18, 19 have shown
association or linkage to MS in some studies, but these results have
not been confirmed in other studies 20, 21, 22, 23, 24, 25, 26 . Furthermore, a number of
chromosome regions that may harbor MS-predisposing genes have been
identified in four genome scans of MS families 27, 28, 29, 30 , but none of
these fulfill the criteria for genome-wide significant linkage 31 .
This may be due to genetic heterogeneity (e.g., different genes
predispose individuals to disease in different families) and/or to a
low impact on disease susceptibility of MS-regulating genes. As a
consequence, very large family materials will be required to detect
linkage 32 , and such materials may be difficult to collect.
An alternative to human genetic studies is to define the quantitative trait loci (QTLs) regulating the proper experimental models of the disease, which may lead either to the identification of genes predisposing to MS or to the definition of disease pathways. Immunizing certain inbred rat and mouse strains with CNS Ags induces experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the CNS resembling MS. A few QTLs influencing EAE susceptibility have been identified in the mouse 33, 34, 35 . The human syntenic chromosome region to one of these QTLs has some impact on MS in a Finnish MS population 36 . However, it is likely that other animal models for MS will reveal additional genes of interest.
Most EAE models are monophasic with sparse or no demyelination 37 . A
more MS-like relapsing/remitting demyelinating disease can be induced
in Dark Agouti (DA) rats by immunization with homogenized whole
spinal cord and adjuvant 38 . In this DA rat model, there is prolonged
inflammatory activity and expression of proinflammatory cytokines such
as IFN- in the CNS 39 . We have demonstrated previously that the
incidence of severe EAE in DA rats is almost 100% after immunization
with spinal cord, whereas Brown Norway (BN) rats are resistant
to EAE induction; this difference is controlled by both MHC and non-MHC
genes 40 .
We report here the first genome-wide search for non-MHC QTLs showing linkage to EAE in the rat. A new MHC-dependent QTL with major influence on EAE was identified in this F2 intercross between DA(RT1av1) and BN(RT1n) rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DA rats were originally obtained from Zentralinstitut für Versuchstierzucht (Hannover, Germany); BN rats were provided by Prof. Hedrich (Medizinische Hochschule, Hannover, Germany). An F2 intercross, originating from DA females and BN males, was bred at the Biomedical Center in Uppsala, Sweden. All rats were bred and kept under specific pathogen-free conditions. They were free from pathogens as determined by a health monitoring program for rats at the National Veterinary Institute in Uppsala.
Induction and clinical assessment of EAE
Groups of 50 F2 rats at a time were immunized and
clinically evaluated in Uppsala or at the Karolinska Institute in
Stockholm. Rats were between 11 and 17 wk old at the start of the
experiment.
The rats were anesthetized with ether and injected s.c. at the dorsal base of the tail with 200 µl of emulsion containing homogenized DA rat spinal cord mixed 1/1 (w/v) with IFA (Difco, Detroit, MI) complemented with 20 mg/ml of Mycobacterium tuberculosis, strain 37 RA (Difco) (CFA) 38 . Rats were examined daily for signs of EAE and weighed every fourth day from day 7 postimmunization until sacrifice at day 30 postimmunization. Clinical scoring was as follows: 0 = no illness, 1 = flaccid tail, 2 = moderate paraparesis (i.e., unsteady walk), 3 = severe paraparesis (i.e., lying down), and 4 = tetraparesis or moribund. An index of maximum weight loss was calculated as follows: (weight at immunization - lowest weight after immunization)/weight at immunization.
Immunohistochemistry
To obtain a phenotype measuring the degree of inflammation in
the spinal cord, infiltrating cells were analyzed as described
previously 38 . Briefly, 15 mm of the lumbar spinal cord was
snap-frozen in liquid nitrogen. Cryostat sections were melted onto
microscopic slides and exposed to appropriate dilutions of the
following mAbs to rat cell surface Ags: OX39 = anti-IL-2R 41
(Seralab, Cramley-Down, U.K.); OX6 = anti-MHC class II 42 .
OX6 was purified from the culture supernatants of hybridomas 43 .
The avidin-biotin peroxidase method was used for staining (ABC
Vectastain Elite kit, Vector Laboratories, Burlingame, CA). Omission of
the primary Ab served as a negative control. Sections of peripheral
lymphoid tissue served as positive controls. The spinal cord sections
from different rats were assessed without access to other phenotype or
genotype data for individual rats. The number of OX39-stained cells on
whole sections was counted using x20 magnification. The areas of the
sections were measured by image analysis, and the number of stained
cells/100 mm2 was calculated 44 . OX6-stained infiltrates
were semiquantitatively scored as follows: 0 = no cellular
infiltrates (i.e., no staining), 1 = a few perivascular
infiltrates, 2 = perivascular infiltrates and moderate staining of
the parenchyma, and 3 = perivascular infiltrates and massive
staining of the parenchyma.
In situ hybridization for detection of IFN- mRNA
IFN- mRNA expression in the spinal cord was assessed with in
situ hybridization in spinal cord sections from the first 174 immunized
rats of the total 352 rats. In situ hybridization was performed
essentially as described previously 45 . Briefly, cryostat sections of
lumbar spinal cords were thaw-mounted onto ProbeOn slides (Fisher,
Pittsburgh, PA). A mixture of four different labeled synthetic
oligonucleotide probes was used to detect IFN- mRNA. A sense probe
with a nucleotide sequence for exon 4 of IFN- was used as a control.
[-35S]Deoxyadenosine 5'--thiotriphosphate
(New England Nuclear, Boston, MA) and terminal deoxynucleotidyl
transferase (Amersham, Little Chalfont, U.K.) were used for the
labeling of oligonucleotides. After emulsion autoradiography, cells
expressing numerous grains over their cytoplasm were counted as
reported previously 45 , and numbers of positive cells/100
mm2 were calculated 44 .
Genome scan and statistical analysis
Genomic DNA from the F2 animals were prepared from
tail tips according to a standard protocol 46 . Genotypes were
determined by amplification of polymorphic DNA fragments containing
simple sequence length polymorphisms (SSLPs) by PCR essentially as
described previously 47 , except that the primers were end-labeled
with [-33P]ATP. Primers were obtained from
Research Genetics (Huntsville, AL) or from Genset (Paris, France). Some
primers were a kind gift of Dr. Howard J. Jacobs (Whitehead Institute
for Biomedical Research, Cambridge, MA). The PCR
products were size-fractionated on 6% polyacrylamide gels
and visualized by autoradiography. All genotypes were scored
manually and double-checked.
The MHC haplotypes of individual rats were determined with an SSLP in
the TNF- gene 48 .
RT1n/av1 (n = 180) and RT1av1 (n = 91) rats were analyzed as separate groups to eliminate any MHC influence on EAE susceptibility. The RT1n rats (n = 81) were not analyzed further, because only five of these rats developed EAE. A genome-wide scan was performed on 45 RT1n/av1 rats that were selected to include the 23 rats with the highest cumulative score and 22 rats with no clinical signs of EAE. Both groups had a similar distribution with regard to sex and age at immunization. They were also distributed equally between different immunization sessions. These rats were genotyped with 228 SSLPs (Map Version 2.0 MGH/MIT/March 1997, http://www.genome.wi.mit.edu/rat/public/mar97/index.html). The genotype at each marker was determined as DA homozygous (D/D), heterozygous (D/B), or BN homozygous (B/B). A few genotypes were excluded because the genotype was difficult to determine or no band had been amplified. However, the median number of genotypes determined for each marker was 45.
Marker mapping was performed with the MAPMAKER computer package 49 .
Approximately 77% of the genome laid within a distance of 10 cM from
an SSLP (Table I
).
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2 test statistic with 2 degrees of freedom
(df) was used to determine whether there was a significant
difference (p 
0.05) in genotype distribution
at individual markers among the 45 rats between rats with a positive
clinical score and rats with no clinical signs of EAE. For such
markers, the genotypes at nearby markers were also determined. The
remaining 135 RT1n/av1 rats were also genotyped in these
genome regions. The median number of genotypes determined for each
marker was 178. Next, all 180 RT1n/av1 rats were analyzed
using the Kruskal-Wallis test to determine whether the different
genotypes at individual markers differed with regard to 1) clinical
phenotypes: (a) maximum score and (b) score at different days; and 2)
histopathological phenotypes in the CNS: (a) degree of MHC class
II-positive infiltrates, (b) number of IL-2R-expressing cells, and (c)
number of IFN- mRNA-expressing cells. Finally, in those
regions in which there was support for an influence on any of the
studied phenotypes (p 0.01) when analyzing
all RT1n/av1 rats, the 91 RT1av1 rats were
genotyped. In this group, the median number of genotypes determined for
each marker was 90. To estimate the relative influence on the risk of developing the disease associated with an allele at a QTL, an odds ratio was calculated as follows: (affected with the allele x unaffected without the allele)/(affected without the allele x unaffected with the allele) 50 .
Kendall’s coefficient, 
, was applied for a nonparametric analysis
of correlation.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As reported previously, DA rats are highly susceptible to
protracted/relapsing EAE, whereas BN rats are resistant 40 .
In the F2 intercross reported here, 136 of the 352 rats
(39%) showed some degree of clinical signs of EAE (Fig. 1A). A total of 81 rats (23%)
displayed severe disease with paraparesis. The onset of disease was
from day 10 postimmunization. Most rats had recovered completely by day
20, and only 25 rats showed signs of neurological defects for >7 days
in total (Fig. 1B), some of which developed a relapsing
disease course. Six rats died or were sacrificed because of severe
tetraparesis during the experiment. Maximum disease score was
positively correlated with weight loss ( = 0.5835). Sex, body
weight, or age at immunization did not have a significant influence on
the incidence of EAE (data not shown).
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=
0.3583) as well as with the number of IL-2R-expressing cells ( =
0.2165) and IFN- mRNA-expressing cells ( = 0.1568) in the spinal
cord. IFN- mRNA expression showed a stronger correlation with EAE
score late after immunization (e.g., = 0.2872 with score on day 24
postimmunization). Fig. 1
, C–E shows the distribution of
the histopathological phenotypes in the F2 generation. Genetic regulation of EAE phenotypes
MHC had a significant influence on maximum score, due to an
influence on the incidence of EAE but not on disease severity (i.e.,
maximum score among affected rats) (Table II). The RT1av1 MHC haplotype
was EAE-predisposing (Table III). Genes
within the MHC also controlled the degree of MHC class II-positive
infiltration and the number of IL-2R- and IFN- mRNA-expressing cells
in the spinal cord (Table II).
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). Although
there was support for an influence on all measured phenotypes for some
genome regions, others seemed to influence only one
phenotype.
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).
This QTL was designated Eae4. Eae4 had a larger
influence on EAE susceptibility among the RT1av1 rats than
among the RT1n/av1 rats. The odds ratio for Eae4
was 15.4 in the former group compared with 1.8 in the latter, assuming
a recessive DA predisposing influence on EAE (Table V). The observed frequency of EAE
affected rats among RT1av1 rats homozygous for DA alleles
at the marker D9Mgh5 was slightly higher than expected if
Eae4 and the MHC had an additive effect on EAE
susceptibility (calculation not shown).
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).
Eae4 also influenced the incidence of EAE late after
immunization. This influence was compatible with a recessively acting
EAE-permissive DA allele. Finally, Eae4 showed linkage to
the number of IFN- mRNA-expressing cells in the spinal cord (Fig. 2).
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). On
chromosome 2, at the marker D2Mgh11, the BN allele was EAE
predisposing. On chromosome 7, at the marker D7Mgh9, there was support
for linkage to maximum score and degree of inflammation in the spinal
cord. The regions on chromosomes 2 and 7 only showed evidence of
linkage to EAE phenotypes among the RT1n/av1
rats. In addition, in a region on chromosome 8, there was support for
linkage to maximum score among both the RT1av1 and
RT1n/av1 rats (p = 5.8 x
10-3). At the marker D8Mit7, heterozygosity predisposed to
EAE. In other chromosomal regions, there was support for linkage to the degree of inflammation in the spinal cord. Notably, on chromosome 12, the marker MDH2 was linked to number of IL-2R-expressing cells among both the RT1av1 and RT1n/av1 rats (p = 3.0 x 10-4). Rats with DA alleles at this marker had a higher number of IL-2R-expressing cells in the spinal cord. Furthermore, on chromosomes 8 and 15, there was support for linkage to the number of IL-2R-expressing cells. Finally, regions on chromosomes 1, 5, and 12 showed suggestive linkage to the degree of MHC class II expression in the spinal cord.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eae4 on chromosome 9 had a major influence on the incidence
of EAE among the RT1av1 rats. This QTL also showed support
for linkage to the incidence of EAE late after immunization, which
suggests that Eae4 promotes the chronic disease course of
EAE in DA rats. This possibility is supported by two additional
observations. First, the influence of Eae4 on the incidence
of EAE late after immunization was compatible with recessively acting
genes, and the inheritance pattern of the protracted relapsing disease
course of EAE in the DA rat has been shown in a previous study to be
compatible with recessively acting DA alleles 40 . Second, rats
homozygous for the DA allele at markers in this region had a higher
number of IFN- mRNA-expressing cells in the spinal cord late after
immunization; IFN- expression has been shown previously to correlate
with clinical signs of EAE 39, 45, 51 .
In view of the strong impact of Eae4 on disease, it is
important to identify the disease susceptibility gene or genes within
this QTL and to define the pathogenic mechanisms. The demonstrated
influence of Eae4 on IFN- mRNA expression may be
pathogenic in EAE. The most direct evidence of IFN--mediated
pathogenic mechanisms in neuroinflammation is the observation that
transgenic IFN- expression in the CNS causes MS-like inflammatory
lesions 52, 53 . Although IFN- has a potential pathogenic influence
in EAE, other studies suggest that IFN- may just be a disease marker
54 . We are now breeding Eae4 congenic strains that will
enable detailed studies of the pathogenic mechanisms regulated by this
QTL. Possible candidate genes located in the region of Eae4
on chromosome 9 are also analyzed for influence on EAE.
Eae4 had a larger influence on EAE among the RT1av1 rats than among the RT1n/av1 rats. A similar difference between individuals homozygous vs heterozygous for an MHC haplotype has been shown in insulin-dependent diabetes 55 . At present, we do not know the cause of this dose-dependent influence of EAE, but it will be analyzed further by studying the influence on EAE of Eae4 congenic rats that carry different MHC haplotypes.
The region on chromosome 2 with support for an influence on the clinical signs of EAE in the present study is located in a region syntenic with Eae3, a QTL in the mouse controlling susceptibility to EAE 33, 56 . This influence on EAE in two species is a strong argument in favor of the importance of the chromosome 2 region in EAE. In this case, the BN allele was EAE-permissive, which shows that relatively disease-resistant strains also carry disease-predisposing genes. This finding may not be surprising with regard to BN rats, considering the strong protective effect of the RT1n MHC haplotype expressed by this strain.
In addition, a region on chromosome 12 showed suggestive linkage to IL-2R expression in the spinal cord. This region colocalizes with a QTL controlling arthritis in DA rats 57 , which suggests that this region harbors one or more genes regulating different organ-specific inflammatory diseases.
It is notable that no region showed genome-wide significant linkage to EAE phenotypes among the RT1n/av1 rats. This could be due to the fact that the genome scan covered <100% of the genome or, more likely, to the fact that the genetic regulation of EAE is complex and involves MHC/non-MHC interactions.
We conclude that the complex genetic regulation of EAE seen in this study may mimic the situation in MS and illustrates the difficulties in human studies to find genes regulating disease. Despite this complexity, our results show that animal studies provide a practical method to dissect the genetic control of neuroinflammatory disease. For this purpose, it will be important to identify and functionally characterize the genes within Eae4 and in the regions on chromosomes 2, 7, 8, and 12 showing linkage to EAE phenotypes, because this may unravel disease pathways of importance in MS.
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Footnotes |
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rs
krings Aktiebolag Foundation, and the following foundations: Novo Nordisk, Petrus och Augusta Hedlund, Ulf Widengrens Minne, and Tore Nilsson. 
2 Address correspondence and reprint requests to Dr. Ingrid Dahlman, Unit of Neuroimmunology, CMM L8:04, Karolinska Hospital, 171 76 Stockholm, Sweden. E-mail:
3 Abbreviations used in this paper: MS, multiple sclerosis; CNS, central nervous system; QTL, quantitative trait locus; DA, Dark Agouti; BN, Brown Norway; EAE, experimental autoimmune encephalomyelitis; SSLP, simple sequence length polymorphism; df, degree(s) of freedom.
Received for publication May 21, 1998. Accepted for publication November 16, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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genes of the T cell receptor: a possible implication in genetic susceptibility to multiple sclerosis. C. R. Acad. Sci. III 304:105.[Medline]
and C alleles associated with multiple and myasthenia gravis. Proc. Natl. Acad. Sci. USA 86:988.3 restriction fragment length polymorphism. J. Clin. Invest. 79:309.
chain polymorphisms in multiple sclerosis. J. Neuroimmunol. 40:41.[Medline]
chain germline gene polymorphisms in multiple sclerosis. Neurology 42:80., interleukin 4, and transforming growth factor ß in experimental autoimmune encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells. J. Neurosci. Res. 40:579.[Medline]
secretion during experimental allergic encephalomyelitis in Lewis rats. J. Neuroimmunol. 31:165.[Medline]
in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development. Mol. Cell. Neurosci. 7:354.[Medline]
. Nat. Med. 3:1037.[Medline]
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