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Regular Articles |
From the Department of Veterinary Pathobiology,*
The
University of Illinois at Urbana-Champaign, Urbana, Illinois; the
Department of Microbiology and Immunology,
MCP–Hahnemann University, Philadelphia, Pennsylvania; and the
Department of Statistics,
Purdue University,
West Lafayette, Indiana
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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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Besides the clinical heterogeneity in MS, considerable variation exists in the type and anatomical location of the lesions. Typical MS lesions consist of inflammation and infiltration of T cells and macrophages accompanied by edema, myelin swelling, and endothelial cell activation.11-14 Lucchinetti et al11 described several different patterns of demyelination, including: demyelination with relative preservation of oligodendrocytes; myelin destruction with concomitant, complete destruction of oligodendrocytes; primary destruction or disturbance of myelinating cells with secondary demyelination; demyelination with secondary oligodendrocyte loss; and loss of myelin, oligodendrocytes, axons, and astrocytes. Different immunological pathways including, but not limited to, cytotoxic cytokines, demyelinating antibodies, cell-mediated cytotoxicity, and apoptosis may be responsible for the different patterns of demyelination.11-13 Although the pattern of demyelination is heterogenous between patients, lesions within the same patient tend to be homogenous, suggesting that different mechanisms of demyelination may operate in different patient subgroups, perhaps reflecting an underlying genetic influence.11-13
In addition to the differences in lesion type, variation is seen in the location of MS lesions.14 Patients with primarily progressive MS often exhibit lesions in the spinal cord (SC) without cerebral involvement.15,16 In the classical form of MS, called Charcot’s variant, lesions appear to be randomly distributed, involving the optic nerves, brain stem, cerebellum, and SC.14 Neuromyelitis optica or Devic’s disease is an MS variant characterized by lesions in the optic nerves and SC with significantly less involvement at other sites.14 The fact that Devic’s disease is more prevalent in India and the Far East, particularly Japan, suggests that genetic factors can contribute to the anatomical location of the lesions seen in MS and its variants.10,17
Experimental allergic encephalomyelitis (EAE) is the principal animal model for MS. Inoculation with crude CNS tissue homogenate, purified myelin proteins, or their encephalitogenic peptides with appropriate adjuvants can elicit EAE in genetically susceptible strains of mice.18-20 Autoreactive CD4+ T cells infiltrate the CNS and subsequently recruit additional lymphocytes and mononuclear cells, resulting in inflammation and demyelination.21,22 Clinically, disease is manifest as an ascending paresis followed by paralysis of the tail and hindlimbs, frequently accompanied by fecal and urinary incontinence. Although EAE is typically known as a chronic relapsing disease,20 inducing antigen, induction protocol, and mouse strain can influence the disease course.23-25 Histologically, EAE in SJL/J mice is characterized by white matter lesions primarily in the SC, optic nerve, cerebellum, and the medulla/pons whereas the midbrain, basal gray, and cerebrum are infrequently involved.20,24,25 SC lesions are found in the lumbosacral portion with a more patchy distribution seen rostrally.24
In contrast to the simple relapsing remitting disease pattern of EAE in purebred SJL/J mice, we recently described four distinct clinical subtypes of EAE in our F2 intercross population between the EAE-susceptible SJL/J and EAE-resistant B10.S/DvTe mouse strains, including: relapsing-remitting; monophasic remitting-nonrelapsing; chronic nonremitting; and acute progressive subtypes.26 We identified novel EAE-modifying (eae-m) loci and unique loci with gender-specific effects that govern susceptibility to these distinct subtypes of EAE.26 In this study, we used composite interval mapping (CIM)27-29 to identify quantitative trait loci (QTL) controlling the distribution and severity of CNS lesions in our F2 population. We report the existence of QTL on chromosome 10 that control lesion severity and mononuclear cell infiltration in the brain. Lesions in the SC are controlled by QTL on chromosomes 3, 7, and 12. Furthermore, analysis of the data following stratification by sex revealed significant gender-specific differences in the genetic control of the distribution and severity of lesions. Female-specific QTL were found on chromosomes 2, 9, and 11, whereas male-specific QTL were found on chromosomes 10, 11, 12, 16, and 19.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male and female SJL/J mice were purchased from The Jackson Laboratory (Bar Harbor, ME). B10.S/DvTe mice were generated from breeding stock originally obtained from Dr. Chella David (Mayo Clinic, Rochester, MN). Six hundred and seventy-three F2 animals (322 male and 351 female) were generated continuously throughout the course of 12 months from the same F1 hybrid (B10.S/DvTe x SJL/J) breeding stock in the animal colony at Brigham Young University (Provo, UT). Animals were fed Purina mouse pellets (Ralston-Purina, St. Louis, MO) and acidified water ad libitum.
Induction and Evaluation of EAE
Induction of EAE was carried out as previously described.30 Briefly, 1.0 mg of SJL/J SC homogenate, diluted in 0.15 ml of phosphate-buffered saline, was emulsified with an equal volume of complete Freund’s adjuvant and injected subcutaneously at two sites on the posterior flank (0.15 ml/injection site). A booster injection of SJL/J SC homogenate plus complete Freund’s adjuvant, prepared in the same manner as the primary inoculum, was given 7 days after the primary injection. Starting on day 10, mice were monitored for clinical signs and graded from 0 to 4 as follows: 0, no clinical expression of disease; 1, floppy tail without hind limb weakness; 2, hind limb weakness with or without flaccid tail; 3, hind leg paralysis and floppy tail; and 4, hind leg paralysis accompanied by a floppy tail and urinary or fecal incontinence.31 Animals with a score of 4 were euthanized. Mice that had no symptoms by day 30 were euthanized. Animals exhibiting symptoms any time between days 10 and 30 were monitored for an additional 30 days and euthanized on day 60.
Histopathological Evaluation
Brain and SC were dissected from the calvaria and vertebral columns of all animals and fixed by immersion in 10% phosphate-buffered formalin (pH 7.2) at 4°C. After adequate fixation, brain and SC were trimmed and representative transverse sections embedded in paraffin, sectioned at 5 µm, and mounted on glass slides. Sections were stained with hematoxylin and eosin (H&E) for routine evaluation and luxol fast blue-periodic acid Schiff reagent for evaluation of myelin. Representative areas of the brain and SC, including brain stem, cerebrum, cerebellum, and the cervical, thoracic, and lumbar segments of the SC, were selected for histopathological evaluation based on previous studies.20,24,25 The following components of the lesions were assessed: 1) severity of the lesion as represented by each component of the histopathological assessment; 2) extent and degree of myelin loss and tissue injury (swollen axon sheaths, swollen axons, and reactive gliosis); 3) severity of the acute inflammatory response (predominantly neutrophils); and 4) severity of the chronic inflammatory response (lymphocytes/macrophages). A score was assigned separately to the entire brain and SC for each lesion characteristic based on a subjective scale ranging from 0 to 5. A score of 0 indicates no lesions; 1 indicates minimal; 2, mild; 3, moderate; 4, marked; and 5, severe lesions. Occasional mice had eosinophils admixed with the dominant neutrophilic inflammatory response.
Genotyping and Linkage Analysis
Genomic DNA was isolated from liver, and polymerase chain reaction parameters for microsatellite typing were as previously described.32 Microsatellite size variants were resolved by autoradiography on Kodak film (Eastman Kodak, Rochester, NY). A linkage map was generated with 173 informative markers on the 19 autosomes using the Kosambi mapping function in the MAPMAKER/EXP computer package.33,34 CIM was used for localization of QTL affecting EAE lesions, because this method allows for more precise definition of intervals containing QTL than classical interval mapping.27-29 In addition, CIM avoids the identification of ghost loci.29 CIM combines classical interval mapping with multiple regression. Markers flanking the test interval are added to the regression model to control for the presence of linked QTL. Additional markers, unlinked to the test interval, but with significant effects on the trait are added to the model to control for the genetic background. The most significant markers unlinked to the test interval are chosen using a linear regression model with a forward/backward selection procedure in the SRmapqtl program of QTL Cartographer v1.13 (http://statgen.ncsu.edu/qtlcart/cartographer.html).35 CIM was performed using model 6 of the Zmapqtl program in QTL Cartographer, with a window size of 10 cM and the 20 most significant background markers selected from the output of SRmapqtl. Tests of significant linkage for a QTL are reported in the form of a likelihood ratio test (LRT) statistic. CIM was performed for the combined population (males and females) as well as for males and females separately. Analysis for the combined population was performed with an additional covariate in the regression model to control for differences in lesions between the sexes in our population.
Significance of the QTL identified by CIM was evaluated by
permutation theory.36
Critical values for the declaration
of significance were determined by the distribution of the maximum LRT
statistic from 1,000 permutations of our data under the null hypothesis
of no linkage. Each permutation was done by randomly shuffling the
trait values while maintaining genotype data, and re-analyzing the
data. Significant linkage was declared when the observed LRT statistic
equaled or exceeded 95% of the permuted values generated under random
conditions (
= 0.05).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Representative areas of the CNS including brain stem, cerebrum, cerebellum, and the cervical, thoracic, and lumbar segments of the SC were evaluated for lesion severity, and the degree of mononuclear cell infiltration, acute inflammation, and demyelination. The character and distribution of CNS lesions observed in this study were consistent with those reported in previous studies.20,24,25 Inflammatory responses in susceptible animals ranged from those with a predominantly neutrophilic response admixed with a smaller monocytic/lymphocytic component, to those with a predominantly monocytic/lymphocytic response. In a few animals, occasional eosinophils were admixed with the neurophilic exudate. CNS tissue responses ranged from mice with no lesions to those with loss of myelin, reactive gliosis, swollen axon sheaths, and swollen axons. In all mice with lesions, the inflammatory response had a perivascular distribution that was predominantly observed in the meninges and in the white matter. In the SC, predilection for the nerve root entry zone was observed, as previously reported.25
CNS lesions were found in 488 of the 673 (B10.S/DvTe x SJL/J) F2
mice (Table 1)
. Of the histologically
affected animals, 282 also exhibited clinical signs of EAE. Whereas
85% of females had CNS lesions, only 58% of males had CNS lesions
(chi-square = 61.8, P = 3.8 x
10-15). Additionally, lesions in the brain and
SC were more severe in females than males (P <
0.0001 for each variable: lesion severity, mononuclear cell
infiltration, acute inflammation, and demyelination, determined by a
Mann-Whitney signed rank test). Within the group of mice with CNS
lesions (188 males and 300 females), similar numbers of males and
females had clinical signs of EAE (102 males and 180 females,
chi-square = 1.56, P = 0.21).
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A CIM approach was used to identify QTL for each lesion
characteristic (severity, mononuclear cell infiltration, demyelination,
and acute inflammation) in the brain and SC. Analyses were carried out
for the complete F2 population and on males and females separately. In
the combined population, a single QTL affecting lesion severity and
mononuclear infiltration in the brain was found on chromosome 10 in an
interval from 4 to 19 cM (Table 2
, Figure 1A
). We designate this newly found QTL:
eae15. Two QTL affected lesion severity and mononuclear cell
infiltration in the SC, one on chromosome 7 from 37 to 52 cM, and
another on chromosome 12 from 3 to 29 cM (Table 2
; Figure 1, B and C
).
Whereas the QTL on chromosome 7 has been previously identified as an
eae-m locus, eae4,26,37
the QTL on
chromosome 12 designated eae16 represents a newly identified
interval. The SJL/J allele at eae15 and eae16
confers a more severe phenotype and the B10.S/DvTe allele at
eae4 confers a more severe phenotype (Table 2)
. QTL on
chromosomes 3, 7, and 12 were significantly linked to demyelination in
the SC (Table 2
; Figure 1, D and E
). The interval from 4 to 23 cM on
chromosome 3 represents a newly identified QTL designated:
eae20. The QTL on chromosome 7 resides on an interval from
18 to 50 cM, and overlaps with a previously identified QTL on
chromosome 7: eae4.26,37
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Stratification of our population by sex allowed us to identify QTL
with sex-dependent effects. In females, we identified a single QTL on
chromosome 9 between 25 and 35 cM affecting acute inflammation in the
SC (Table 3
, Figure 2A
). This QTL resides in the interval
containing eae9, a QTL identified previously controlling
duration of disease among affected animals.37
A B10.S/DvTe
allele at this locus increases neutrophilic infiltrates (Table 3)
.
Lesion severity and mononuclear infiltration in females were linked to
QTL on chromosomes 2 and 11 (Table 3
; Figure 2, B and C
). The QTL on
chromosome 2 resides in an interval from 30 to 69 cM, a locus we
designate: eae21. Linkage to chromosome 11 is to an interval
between 49 and 71 cM, telomeric of eae7, a locus associated
with severity of clinical signs.38
We designate this newly
identified QTL: eae22. At both eae21 and
eae22, the SJL/J allele increases the severity of the
lesions and mononuclear cell infiltration (Table 3)
.
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, Figure 3A
). Significant linkage to mononuclear
infiltration, lesion severity, and acute inflammation was found on
chromosome 16 in an interval between D16Mit168 and
D16Mit140 containing eae11, a previously
identified eae-m locus26
(Table 4
, Figure 3B
).
A single locus on chromosome 11 had significant effects on lesion
severity and mononuclear infiltration in the SC (Table 4
, Figure 3C
).
This QTL is linked to an interval between markers D11Mit155
and D11Mit194, just centromeric of eae7 and
telomeric of eae6b, previously identified QTL controlling
severity and duration of disease.38
The SJL/J allele at
this locus, designated eae23, increases lesion severity
(Table 4)
. Two QTL were identified affecting demyelination in the brain
(Table 4
; Figure 3, D and E
). One, designated eae16, is
located on chromosome 12 between 3 and 29 cM, and another on chromosome
19 designated eae19 is located from 26 to 50 cM. At
eae16 and eae19, an SJL/J allele increases
demyelination (Table 4)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our findings indicate that lesion characteristics in EAE are under complex genetic control, influencing both the location and severity of lesions. We identified a QTL on chromosome 10 that controlled the severity of lesions and extent of mononuclear/lymphocyte infiltration in the brain. In the SC, lesions were controlled by QTL on chromosomes 3, 7, and 12. Peak linkage for demyelination on chromosome 7 was nearest the marker D7Mit233 at 40 cM, and peak linkage for lesion severity and mononuclear infiltration was nearest the marker D7Mit39 at 50.3 cM. Whereas both QTL reside on an interval contiguous with eae4, these linkages may reflect separate QTL controlling lesion severity/mononuclear infiltration and demyelination in the SC.
Females with MS outnumber males by approximately 2:1.41 In our mouse population, females were more likely than males to develop the clinical signs and histological lesions of EAE. Among mice with lesions however, males and females progressed in similar proportions to clinical disease. We hypothesize that the differences in EAE between males and females are determined in the early stages of disease, and govern the migration and infiltration of inflammatory cells into the CNS. In this respect, castrated male SJL mice immunized with proteolipid protein residues139 to 151 to induce EAE have widespread perivascular inflammation in the SC at clinical relapse.42 Intact males fail to relapse, and have no indication of inflammation in the SC, suggesting that susceptibility to CNS lesions in male SJL mice is in part controlled by testosterone.42,43 Hormone-sensitive genes controlling the ability of inflammatory cells to infiltrate the CNS may therefore regulate the sexual dimorphism in EAE. In this respect, we have identified QTL unique to males and females controlling the expression of EAE lesions in our F2 population. The effect of castration on the individual expression of these QTL is currently being studied in our laboratories.
Overall, the genetic component controlling the lesions in males was
stronger (significant QTL on chromosomes 10, 11, 12, 16, and 19) than
in females (significant QTL on chromosomes 2, 9, and 11). The presence
of unique QTL in males and females regulating the severity and
characteristics of lesions in EAE suggests that these QTL are
responsive to sex hormones. In this respect, it is known that females
have a more robust immune response.44,45
Androgen
treatment has been shown to induce a shift in cytokine production,
particularly interleukin-10 toward protective Th2 type
cytokines.46
In an adoptive transfer model using myelin
basic protein, draining lymph node cells (LNC) from male SJL mice
induced less severe EAE, and produced less interleukin-12 and
interferon-
than LNC from female mice.47
In a similar
experiment, LNC from male SJL mice stimulated with proteolipid protein
139 to 151 were less encephalitogenic than LNC from female
mice.48
Androgen treatment of LNC from SJL females
resulted in a decrease in interferon- and an increase in
interleukin-10 production.48
Given the protective effect
of androgens, susceptibility to EAE in males may require a greater
genetic contribution than in females, perhaps explaining the decreased
prevalence of MS in males. A similar situation was observed in a
backcross using the same strains of mice, where EAE was induced with
and without pertussis toxin.49
In this case, mice induced
without pertussis toxin were less susceptible to EAE and had more loci
controlling susceptibility than mice induced with PTX.
We have identified 10 QTL, including seven newly identified loci
governing different aspects of the severity and characteristics of the
lesions in EAE. Different QTL control EAE lesions depending on location
(brain or SC) and sex. Our results reflect the complex nature of
genetic control of EAE. EAE is characterized by multiple disease
subtypes, sexual dimorphism, and susceptibility that is dependent on
multiple minor genes with small individual effects, rather than a few
genes of major biological importance.26,37,38
A summary of
EAE modifying loci identified to date is included in Table 5
. Genetic differences may account for
the remarkable heterogeneity observed between MS patients, and may
therefore be responsible for confounding the interpretation of human MS
linkage data. A mouse-human synteny mapping approach may allow the
identification of candidate loci for MS based on the locations of
murine eae-m loci. In this regard, Kuokkanen et
al50
identified a MS susceptibility locus on chromosome
5p14-p12 based on the existence of an eae-m locus on mouse
chromosome 15 (eae2). Three eae-m loci
identified in our population are syntenic with putative MS
susceptibility loci. Eae5 on mouse chromosome 17 is syntenic
with human 6p21, eae7 on mouse chromosome 11 is syntenic to
human 17q22, and eae12 on mouse chromosome 7 is syntenic to
human 19q.3,51,52
Identification of the genes underlying
these eae-m QTL will be invaluable in characterizing the
molecular basis of the different clinical and pathological subtypes
seen in MS. Further genetic studies should account for the possibility
that differences between MS patients may represent immunogenetically
distinct pathological mechanisms.
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Footnotes |
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Supported by National Institutes of Health grants NS36526 (to C. T. and E. P. B) and AI41747 (to C. T.) and National Multiple Sclerosis Society grants RG2650 and RG3129 (to C. T.).
Accepted for publication May 9, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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