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*
Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61802;
Department of Microbiology and Immunology, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Philadelphia, PA 19102;
Departments of Agronomy and Statistics, Purdue University, West Lafayette, IN 47907;
§
Department of Microbiology, Brigham Young University, Provo, UT 84602; and
¶
Neurovirology Research Laboratory, Veterans Affairs Medical Center, and Department of Neurology, University of Utah, Salt Lake City, UT 84148
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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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4%) 3 . Although a
genetic link to susceptibility has been demonstrated, little is known
about the genes that underlie MS. HLA class II genes, including
A3, B7, DR15, and DQ6, have
been implicated in susceptibility, but HLA cannot account for all of
the genetic contribution to disease 4 . Recent genome scans have
verified the importance of HLA in susceptibility to MS, but have been
unable to agree on other contributing loci 4, 5, 6, 7, 8 . The heterogeneity
characteristic of MS contributes to the difficulty in searching for MS
susceptibility genes since the underlying genetic components of the
disease may differ between patients. It has been suggested that the
different clinical subtypes seen in MS are immunogenetically distinct
entities 9, 10 . Consistent with this suggestion is the observation
that the clinical course and prognosis of MS differ by geographic
location 10, 11, 12 . An additional issue complicating the search for
genes affecting MS is the marked difference in susceptibility between
men and women. Women are more susceptible by a 2:1 margin 13 . The
sex-influenced or sex-limited expression of genes complicates the
interpretation of genetic susceptibility. Experimental allergic encephalomyelitis (EAE) is the principal animal model for human MS. EAE can be elicited in genetically susceptible strains of mice by inoculation with either crude CNS tissue homogenate, proteolipid protein (PLP), myelin basic protein, or their encephalitogenic peptides with appropriate adjuvants 14, 15, 16 . Susceptible strains of mice show typical ascending paresis with paralysis of the tail and hindquarters, frequently accompanied by fecal and urinary incontinence. Histologic examination reveals inflammation and mononuclear cell infiltrates in the CNS, particularly in the submeningeal, perivascular, and parenchymal portions of white matter in the spinal cord and brain 16, 17, 18 .
Disease course in murine EAE is dependent on the strain, inducing Ag, and induction protocol 18, 19 . EAE in the SJL mouse is generally a chronic relapsing disease 16 . In contrast to EAE, the spectrum of clinical courses in MS is diverse. A recent report resulted in the definition of several disease classifications, including relapsing/remitting (R/R), primary progressive, secondary progressive, and progressive relapsing MS 20 . Additional MS subtypes classified by severity include benign and malignant MS 20 . While the inflammation and demyelination observed in animals with EAE have made it a useful model for MS, the difference in clinical profiles has led to concern about the suitability of EAE as an experimental counterpart of MS. This concern is addressed in the present study in which we demonstrate that five clinical subtypes are seen in mice when F2 intercross progeny of inbred strains are used.
A promising approach to understanding EAE and MS is to examine the genetic factors involved in both diseases. As with MS, both MHC-linked and non-MHC-linked factors have been associated with susceptibility to EAE 21, 22, 23, 24, 25 . With few exceptions, the genetic dissection of murine EAE has relied on examining susceptibility and resistance among small populations of different highly inbred strains, in which varying disease-modifying genes have been fixed 15, 26 . While this approach controls the genetic heterogeneity inherent in such a complex disease, it fails to provide an adequate model of the complex genetic interactions underlying MS. Failure to identify the complete spectrum of MS disease profiles in murine EAE may be due to lack of variation within inbred lines or to small sample sizes in which differences in disease subtype are not detected.
To better approximate the genetic architecture underlying susceptibility to MS, we created a large F2 population from the EAE-susceptible SJL/J and EAE-resistant B10.S/DvTe inbred lines. We report the identification of five distinct subtypes of murine EAE, namely acute progressive (AP), chronic/nonremitting (CNR), R/R, monophasic remitting/nonrelapsing (M-RNR), and benign EAE. Full genome scanning was used to identify loci important in controlling susceptibility and disease subtype in EAE. We report three novel EAE-modifying loci on chromosomes 16, 7, and 13 (eae11–13, respectively). Unique loci govern susceptibility to R/R (eae12) and M-RNR (eae7 and 13) EAE. Furthermore, we discuss the effect of gender on susceptibility to the particular subtypes of EAE. Our results strengthen the role of murine EAE as a model for human MS, and allow for the dissection of the genetic architecture underlying the different immunopathologic manifestations of disease in the CNS.
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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). (SJL/J x B10.S/DvTe)F1 hybrids and (SJL/J x B10.S/DvTe)F2 progeny were generated in the animal colony at Brigham Young University (Provo, UT). F2 animals were generated continuously over the course of 12 mo from the same F1 hybrid breeding stock. Animals were fed Purina mouse pellets (Ralston-Purina, St. Louis, MO) and acidified water ad libitum.
Induction and evaluation of EAE
Induction of EAE using SJL/J spinal cord homogenate emulsified in CFA was conducted as previously described 27 . Starting on day 10, mice were monitored for clinical symptoms and graded from 1–4, 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 floppy tail and urinary or fecal incontinence 28 . Animals that progressed to a clinical score of 4 were euthanized. Mice that showed no clinical disease by day 30 were killed, and tissues were collected. Animals exhibiting clinical disease anytime from day 10 to day 30 were monitored for an additional 30 days for remission and relapse. Information on age, sex, coat color, and day of disease onset was recorded for each animal.
Pathologic evaluation
Animals were killed, and the brain and spinal cord were removed and fixed by immersion in 10% phosphate-buffered formalin. Transverse sections for light-microscopic analysis were cut at 5 µm from paraffin-embedded materials and stained with hematoxylin and eosin or luxol fast blue/periodic acid Schiff stain. Representative areas of the brain and spinal cord were selected for histologic evaluation based on previous reports 16, 17 and included cerebrum, cerebellum-midbrain, and spinal cord at the cervical, thoracic, and lumbar levels.
Genotyping and linkage analysis
Genomic DNA was isolated from liver tissue, and PCR parameters
for microsatellite typing were as previously described 29 .
Microsatellite size variants were resolved by autoradiography
on Kodak film (Eastman Kodak, Rochester, NY). A linkage map was
generated with 172 informative microsatellite markers using
the Kosambi mapping function in the MAPMAKER/EXP computer
package 30, 31 . Linkage of marker loci to disease subtype was
determined using 2 x 3 
2 tests for independence of
marker genotypes between affected and unaffected groups.
Permutation-derived critical values for declaration of significant
linkage 32 were calculated for 
= 0.10 and = 0.05 from the
distribution of the 2 statistic from 1000 permutations
of our data under the null hypothesis of no linkage at each marker.
Significant linkages were reported if the 2 statistic
for a particular marker locus was greater than the critical value at
= 0.05. Suggestive linkages ( = 0.10) were reported where
results replicate significant linkages identified in other studies. For
identification of sex-specific loci, linkage analysis was performed on
the population as a whole, and for males and females separately.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A large cohort of (SJL/J x B10.S/DvTe)F2 mice
(n = 633) was inoculated with SJL/J spinal cord
homogenate and CFA for the induction of EAE. Brain and spinal cord
tissues were examined for histopathology. CNS lesions were found in 454
animals (Table I
), 247 of which also
exhibited clinical signs of EAE. Females were more susceptible to CNS
inflammation than males. While 85% of females had either brain or
spinal cord lesions, only 57% of males had such lesions
(2 = 58.21, p = 2.3 x
10-14). Given the bias in susceptibility between males and
females to histopathologic lesions, it is interesting that similar
numbers of males and females progressed from histologic to clinical
signs of EAE (2 = 2.17, p = 0.14).
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A). Mice with CNR EAE had an
acute initial attack, followed by gradual progression of disease (Fig. 1B). We observed two forms of remitting EAE. R/R EAE was
characterized by cycles of relapses with more or less complete recovery
during remissions (Fig. 1C). M-RNR EAE was defined as having
no subsequent clinical signs of EAE after the initial episode (Fig. 1D). Forty-five mice were classified as AP, 56 as CNR, and
146 as remitting, with 68 R/R and 78 M-RNR (Table II). Significant differences were
observed in the number of males and females for both R/R and M-RNR EAE.
Susceptibility to R/R EAE was biased toward females (2 =
3.99, p = 0.046), and M-RNR EAE was biased toward males
(2 = 6.46, p = 0.011). We also observed
a difference in the number of males and females with CNR EAE, although
this result was not statistically significant (2 = 3.08,
p = 0.08). Neither age at immunization nor caging
effects were significant factors in susceptibility to clinical or
histologic disease within our population as a whole, or among males and
females separately (data not shown).
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Analysis of the F2 progeny revealed multiple loci that
control EAE and its subtypes (Tables III
and IV). Overall disease susceptibility
(Table III) is linked to two major loci seen previously by quantitative
analysis 33 , eae4 on chromosome 7 at 25–51 cM, and
eae5 on chromosome 17 at 22–23 cM. A locus on chromosome 16
with suggestive linkage to susceptibility by quantitative analysis 33
is again suggestive of linkage by this qualitative analysis
(2 = 15.2, 90% experimentwise cutoff = 14.82). We
now give this a provisional designation eae11, based on the
identification of a significant quantitative trait locus for spinal
cord histopathology in this region (Blankenhorn et al., in
preparation). Analysis of the data when stratified by sex shows
evidence of sexually dimorphic effects at eae4 and
eae11 (Table III). As previously described 33 , the allele
from B10.S is associated with susceptibility at eae4, and
the allele from SJL is associated with susceptibility at
eae5 and eae11.
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). AP EAE is
controlled by a locus on chromosome 3 near D3Mit25 at 29 cM
(2 = 15.2, 90% experimentwise cutoff = 14.31). Our
findings replicate the identification of eae3, a locus
influencing overall EAE susceptibility in both F2 34 and
backcross 35 progeny. Consistent with the findings of Encinas et al.
35 , who also used the B10.S/SgMedJ and SJL/J strains, susceptibility
is recessive, and inherited from the SJL parent. R/R EAE is linked to a
newly identified locus on chromosome 7 at 16 cM (eae12).
Maximum linkage was at D7Mit227 (2 = 17.5,
95% experimentwise cutoff = 15.46). Eae12 is proximal
to another EAE susceptibility locus on chromosome 7, eae4
(26–50 cM). Stratification of the data by sex indicated that the
effect of eae12 on susceptibility was greater in females
than in males (2 for females = 16.5, and for
males = 6.16). Susceptibility to M-RNR EAE is linked to chromosome
13 near D13Mit66 at 37 cM (eae13). In contrast to
eae12, the effect of eae13 was greater in males
(2 for males = 20, and for females = 2.02).
Susceptibility is associated with the SJL allele. A locus on chromosome
11 at 47–52 cM (eae7), identified in a previous report
affecting severity and duration of symptoms 33 , is also associated
with M-RNR EAE. Maximal linkage is at D11Mit36
(2 = 20.4, 95% experimentwise cutoff = 15.87).
Susceptibility is associated with the SJL allele at eae7. No
significant loci were detected for susceptibility to the CNR or benign
forms of EAE. Stratification of the data to exclude clinically affected
animals revealed a locus suggestively linked ( = 0.10) to benign EAE
on chromosome 6 at 30 cM (D6Mit17: 2 = 14.15,
90% experimentwise cutoff = 14.02).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MS is characterized by a number of different clinical subtypes 20 that are mirrored in our intercross. Patients with R/R MS have repeated exacerbations or relapses with subsequent clinical recovery and remission of disease activity. In our F2 mouse population, 27% of affected animals had the R/R subtype. R/R EAE is more frequent in females than in males. We observed a monophasic form of EAE (M-RNR) in 32% of affected animals in our population, consisting of an acute attack, followed by complete recovery, without further clinical signs. In contrast to R/R EAE, susceptibility to M-RNR EAE was greater in males than in females.
Several progressive subtypes of MS have been described, including primary progressive, secondary progressive, and progressive relapsing 20 . Each of these subtypes is characterized by a steady accumulation of neurologic deficits over time, with some variation between the subtypes in the amount of recovery between relapses. The CNR EAE subtype in our population is analogous to these progressive forms of MS, accounting for 23% of affected animals. AP EAE, seen in 18% affected mice, resembles the malignant MS subtype. Both are characterized by swift progression of disease resulting in severe disability or death a short time after onset.
Benign MS accounts for up to 20% of MS cases 12 . This mild disease subtype is characterized by a lack of neurologic deficit for 15 yr after onset 20 . The finding of incidental cases of MS in autopsy series unsuspected in life suggests that the disorder can in fact be entirely subclinical 36 . It is known that mice can have histologic signs of EAE, such as lymphocytic and monocytic CNS infiltrates, without exhibiting clinical signs 16, 17 . This benign subtype of EAE was seen in 54% of animals with histologic lesions.
As with MS 13 , females in our population were more susceptible to EAE
than males. Differences between males and females in susceptibility to
EAE have been known for some time. Recent reports have begun to
characterize and explain these differences 37, 38, 39, 40, 41 . In a model using
myelin basic protein as the inducing Ag, young SJL/J males were
entirely resistant to disease induction, while females were susceptible
37 . Another model using PLP peptide 139–151 as the inducing Ag found
that SJL/J males undergo a monophasic disease, while females exhibit a
chronic relapsing disease 38 . Consistent with these observations,
M-RNR EAE in our population was more frequent in males than in females,
and R/R EAE was more frequent in females than males. Interestingly,
given the extreme gender bias in susceptibility to histopathologic
signs of EAE, males and females progressed in similar proportions to
clinical signs of EAE. This observation suggests that the sexual
dimorphism in susceptibility to EAE may be regulated by genes
controlling the ability of inflammatory mediators to infiltrate the
CNS. In this respect, a recent study has implicated sex hormones in the
homing of mononuclear cells to the CNS and the production of IFN-
in
the induction phase of EAE 41 .
Genetic analysis
Loci controlling susceptibility to EAE were found on chromosomes 7 (eae4), 17 (eae5), and 16 (eae11), and have been identified in a previous report by quantitative analysis 33 . Significance of these loci is confirmed in this report by qualitative methods. Analysis of the data when stratified by sex suggests a sex-specific effect at both eae4 and eae11. In addition to these loci, we have found that loci on chromosomes 3 (eae3), 7 (eae12), 11 (eae7), and 13 (eae13) affect the clinical subtype of EAE.
Two previous reports have identified an EAE susceptibility locus on chromosome 3 (eae3) on an interval between 30 and 53 cM 34, 35 . In our population, eae3 is linked with susceptibility to AP EAE. Susceptibility is associated with the SJL allele. A locus controlling susceptibility to Theiler’s murine encephalomyelitis virus-induced demyelination (Tmevd2) is also found on this region of chromosome 3 42 . Eae3 and Tmevd2 may in fact represent a single gene or gene cluster involved with demyelinating disease or CNS pathology 42 . Susceptibility loci to autoimmune ovarian dysgenesis and insulin-dependent diabetes mellitus (Aod2 and Idd3, respectively) also map to this region of chromosome 3, although proximal of eae3 43, 44 .
A newly identified locus on chromosome 7 (eae12) is linked to R/R EAE. A sex-specific effect at this locus may explain the increased susceptibility of females to this disease subtype. Interesting candidate genes in the region of eae12 include myelin-associated glycoprotein (Mag), an EAE-inducing Ag at 11 cM, and TGF-ß1 at 6.5 cM (www.informatics.jax.org). Two groups have linked susceptibility to systemic lupus erythematosus to this region of chromosome 7 45, 46 . This colocalization may represent a single gene important for autoimmunity in general. A recent study has implicated a region on chromosome 19q syntenic with eae12 in susceptibility to MS in North American/Northern European Caucasian and Chinese populations 47 .
In contrast to eae12, a locus on chromosome 13
(eae13) is linked to susceptibility to M-RNR EAE in males,
but not females. The SJL allele at this locus is responsible for
increased susceptibility to the M-RNR disease subtype. A sex-specific
effect at eae13 may give males a greater ability to control
disease once it is initiated. It is tempting to speculate that
eae13 might be directly responsive to testosterone levels.
In this regard, it has been reported that castrated males immunized
with PLP peptide 139–151 display a relapsing form of EAE in contrast
to intact males that display a monophasic disease 41 . In light of the
sex-specific effect at eae13, it is interesting to note the
presence of rsl, a locus controlling the regulation of
sex-limited protein in this region of chromosome 13 48 . Steroid 5
-reductase 1 (Srd5a1) at 39 cM, which is involved in the
synthesis of dihydrotestosterone, is an interesting candidate gene for
both rsl and eae13. Other candidate genes in this
region include Il9 at 35 cM, Ctla2a at 36 cM, and
Ctla2 at 38 cM (www.informatics.jax.org/).
Mechanistically, both eae12 and eae13 may be involved in epitope spreading, a phenomenon associated in some reports with relapses 49 . Eae12 may be involved with presentation of secondary CNS Ags, or access to the CNS of T cells reactive to secondary Ags. Conversely, eae13 could inhibit epitope spreading associated with relapses by causing a shift in the response to secondary CNS Ags from a pathogenic Th1 response to a protective Th2 response.
An additional locus significant in M-RNR EAE is eae7 on chromosome 11. Eae7 was identified in a previous report for its effect on severity and duration of symptoms 33 . Shorter duration of symptoms and decreased severity of disease were associated with the SJL allele at this locus. Consistent with these observations, in the present study, the SJL allele predisposes for a shorter, less severe (M-RNR) disease subtype. An interesting candidate gene in this region is the inducible nitric oxide synthase gene (Nos2) at 46 cM. Nitric oxide and other intermediates in the nitric oxide synthesis pathway have been implicated in the CNS pathology in EAE 50 . Consistent with the effect of eae7 in M-RNR EAE, increasing evidence suggests that the Nos2 gene can have a protective role in EAE 51, 52 . Other candidate genes in the region include the family of small cytokines (Scya1–12) at 46–48 cM (www.informatics.jax.org/). Susceptibility loci for two other autoimmune disorders colocalize to this region of chromosome 11, Orch3 in autoimmune orchitis at 44.5 cM, and Idd4 in insulin-dependent diabetes mellitus at 44 cM 53, 54 .
The appearance of different EAE subtypes in our population and the unique genetic components underlying disease subtype emphasize the usefulness of large F2 populations in the genetic dissection of complex traits. F2 populations allow for more complex genetic interaction between loci, resulting in increased variation in phenotypes and emergence of new phenotypes unobserved in less complex models. A large population allows for the observation and genetic analysis of subtle differences in phenotype that may be attributed to random variation in smaller populations. Of particular interest in our population are the genetic differences governing the susceptibility to particular disease subtypes and the influence of sex on these genetic differences. It is worth noting that appropriate genetic modeling using other EAE-S strains such as PL/J, B10.PL/SnJ, and BALB/cByJ may reveal additional clinical, histopathologic, and sex-specific effects not observed in our population. Investigation of the genetics underlying different disease subtypes in EAE may lead to a greater understanding of the genetic control of immune system regulation in general, e.g., underlying control of tolerance, Th1/Th2 dichotomy, tissue-specific homing of lymphocytes, and mechanisms of suppression of ongoing immune responses. Further analysis of loci with sex-specific effects may explain the general immunologic differences between males and females, and lead to a better understanding of the interplay between the endocrine and immune systems.
Recent genome scans have not resulted in the expected identification of MS susceptibility loci in the human genome 4, 5, 6, 7, 8 . Difficulty in controlling for gene interaction (epistasis) in an outbred population, and the strong sexual dimorphism in the expression of disease may explain these disappointing results. Our observations suggest that different disease subtypes have different underlying genetic control, and that this control may differ between the sexes. Thus, underlying genetic differences may explain the heterogeneity in disease course and prognosis characteristic of MS. Differences in disease between the sexes, and between patients with different disease courses may be responsible for confounding the interpretation of human MS genetic data or masking the presence of susceptibility loci. In light of our findings, MS genetic studies should be stratified more stringently with respect to sex and disease type.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Cory Teuscher, Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL 61802. E-mail address:
3 Abbreviations used in this paper: MS, multiple sclerosis; AP, acute progressive; CNR, chronic/nonremitting; CNS, central nervous system; EAE, experimental allergic encephalomyelitis; M-RNR, monophasic remitting/nonrelapsing; PLP, proteolipid protein; R/R, relapsing/remitting.
Received for publication September 24, 1998. Accepted for publication December 2, 1998.
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E. P. Blankenhorn, R. J. Butterfield, R. Rigby, L. Cort, D. Giambrone, P. McDermott, K. McEntee, N. Solowski, N. D. Meeker, J. F. Zachary, et al. Genetic Analysis of the Influence of Pertussis Toxin on Experimental Allergic Encephalomyelitis Susceptibility: An Environmental Agent Can Override Genetic Checkpoints J. Immunol., March 15, 2000; 164(6): 3420 - 3425. [Abstract] [Full Text] [PDF]
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