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*
Department of Veterinary Pathobiology, University of Illinois, Urbana, IL 61802;
Department of Microbiology, Brigham Young University, Provo, UT 84602;
Department of Microbiology and Immunology, Allegheny University of the Health Sciences, Philadelphia, PA 19102;
§
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107; and
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The Wellcome Trust Center for Human Genetics, Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom OX3 7BN
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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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Analyses of the genetic control of susceptibility and resistance to EAE using inbred strains of mice have implicated both H2 and non-H2 genes (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). The genetic complexity of the disease is further supported by the fact that susceptibility can be inherited as either a dominant or a recessive phenotype depending on the parental strain combination used to generate the F1 hybrid population (10). In the present study, whole genome scanning (17) was used to map the loci governing susceptibility to murine EAE in an F2 population derived from the EAE-susceptible SJL/J and EAE-resistant B10.S/DvTe strains (18, 19). To date, this is the single largest segregating population studied for an experimental model of organ-specific autoimmune disease. The parental strains used to generate this cross are particularly insightful, since SJL/J is the prototypic EAE-susceptible strain, and both SJL/J and B10.S/DvTe have the H2s haplotype (20). Thus, H2-encoded genes should not segregate with disease susceptibility in this cross. However, we report that marker loci linked but distal to H2 on chromosome 17 exhibit significant linkage to EAE susceptibility syntenic with the region identified in human MS genome scans (21). We have designated this locus eae5. Evidence for the existence of this new EAE-modifying locus and QTL controlling the symptoms of EAE is presented.
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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 of the Mayo Clinic (Rochester, MN). (SJL/J x B10.S/DvTe)F1 hybrids and (SJL/J x B10.S/DvTe) x (SJL/J x B10.S/DvTe)F2 progeny were produced in the animal colony at Brigham Young University (Provo, UT). The F2 animals were generated continuously over a 12-mo period using the same pool of F1 hybrid breeding stock. Inoculations of groups of mice ranging in age from 6 to 19 wk were staggered over the same time. 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 conducted as previously described (18). Briefly, 1.0 mg of SJL/J SCH, diluted in 0.15 ml of PBS, was emulsified with an equal volume of CFA and injected s.c. at two sites on the posterior flank (0.15 ml/injection site). A booster inoculation of SJL/J SCH and CFA, prepared in the same manner as the primary inoculum, was given on day 7. Mice were anesthetized with either halothane or ethyl ether before the injections. 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 (22). Animals that progressed to a clinical score of 4 were euthanized. Mice that showed no clinical disease by day 30 were euthanized, and liver tissue was collected for isolation of DNA. Animals exhibiting clinical disease any time between days 10 and 30 were monitored for an additional 30 days and euthanized on day 60. Genomic DNA was isolated from liver tissue as previously described (23).
Mice were included in this study regardless of the type of EAE that
they displayed, and thus, mice with or without relapsing-remitting EAE
are in our study group. No stratification of the animals was performed
for purposes of statistical analysis. The incidence of EAE was recorded
as positive for any mouse with clinical signs of EAE for 1 or more
days. Susceptibility was analyzed as a quantitative trait, using a
disease index generated by averaging the clinical scores for each
animal over the course of the experiment. Severity of disease among
affected animals was analyzed using a severity index generated by
averaging the clinical scores for each animal over the number of days
that it exhibited clinical symptoms. Severity was assessed only in
affected animals. Duration was calculated as the number of days an
animal displayed a clinical score 
1, and onset was the day clinical
signs were first observed.
Genotyping
Microsatellite primers were either purchased from Research Genetics (Huntsville, AL) or synthesized according to sequences obtained through the Whitehead Institute/Massachusetts Institute of Technology mouse genome database (www.genome.wi.mit.edu/cgi-bin/mouse/index). PCR parameters for microsatellite typing were previously described (23, 24, 25, 26). Microsatellite size variants were resolved by electrophoresis on large format denaturing polyacrylamide gels and visualized by autoradiography on Kodak film (Eastman Kodak, Rochester, NY).
Nucleic acid sequencing
Total RNA was isolated from adult liver of SJL/J and B10.S/DvTe
mice using TRIzol reagent (Life Technologies, Grand Island, NY) 3 days
after injection with SCH and CFA as detailed above. RT-PCR was
performed to obtain IA
and IAß cDNA. Briefly, the first-strand
cDNA was synthesized by reverse transcription of 1.0 µg of total RNA
primed with poly(dT16) oligonucleotide and Superscript II
reverse transcriptase (Life Technologies). cDNAs for IA and IAß
were PCR amplified using Taq polymerase and specific primer pairs
flanking the mRNA-coding regions of each locus. The amplified fragments
were TA cloned into pCR 2.1-TOPO vector (Invitrogen, San Diego, CA) and
screened by PCR. Insert-positive plasmid DNAs were sequenced using
vector primers and the ABI PRIZM Dye Terminator Reading Reaction Cycle
Sequencing Kit on a model 373A automated DNA sequencer (Perkin-Elmer,
Applied Biosystems Division, Foster City, CA). At least two duplicate
clones for each PCR fragment were sequenced from both insert termini.
Genomic exons were sequenced for both IA and IAß alleles by PCR
amplification of the individual exons of each locus. Specific
oligonucleotide primer pairs flanking each exon were designed, and the
PCR-amplified fragments were cloned and sequenced as described above.
Qualitative and quantitative trait linkage analysis
Qualitative trait linkage analysis was performed using
information derived from a genome scan of 150 polymorphic, autosomal
microsatellite markers on 291 affected and 390 unaffected
F2 mice. A 
2 test statistic for
each marker locus was derived using 2 x 3 contingency tables to
test for linkage to disease susceptibility. Linkage maps were generated
using the Kosambi map function within the MAPMAKER/EXP computer
package (27).
Quantitative trait linkage analysis was conducted by analysis of variance using disease index (susceptibility) and clinical parameters (severity of symptoms, duration of symptoms, and day of onset) as the dependent variables and microsatellite marker genotypes as independent variables as well as interval mapping using MAPMAKER/QTL under the assumptions of a free genetic model. The experimentwise critical value for declaration of significant linkage to QTL identified by interval mapping was p = 0.05 (28). Threshold values were generated using the permutation function of MapManager QT (mcbio.med.buffalo.edu/mapmgr.html) with 1000 permutations of our dataset for each respective phenotype. When significant linkage was observed in our study, a new disease-modifying locus was proposed (e.g., eae5); such designations are also given to loci that are newly confirmed by our results (e.g., eae8; see Discussion).
Interaction between marker loci
For each trait (disease index, severity of symptoms, and duration of symptoms), the score was regressed on the significant loci for the respective parameter. Since it had only one locus reaching significant levels, the day of onset was not included in this analysis. Models were analyzed in SAS using PROC GLM (29, 30). Linear regression was performed with and without two-locus interaction variables for each disease parameter. The significance of the interaction was assessed using an F statistic for the variance of the interaction variables.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B10.S/DvTe, SJL/J, (B10.S/DvTe x SJL/J)F1
hybrid, and F2 intercross mice were studied for
susceptibility to EAE (Table I
).
B10.S/DvTe mice are resistant (0 of 10; 0%), and SJL/J mice are highly
susceptible (25 of 29; 86%) to the induction of EAE. In
(B10.S/DvTe x SJL/J)F1 hybrids, neither
susceptibility nor resistance, as reflected by disease frequency (8 of
15; 53%), was inherited as a fully penetrant dominant phenotype. Of
750 F2 progeny studied, 334 (45%) exhibited
signs of EAE, and 416 (55%) did not. The mean day of onset in the
F2 population (19 days) was significantly delayed
compared with that in the susceptible SJL/J parental strain (15 days;
p < 10-5), suggesting that segregating
alleles affect the timing or progression of disease. The frequencies of
EAE observed in the F2 population significantly
deviated from normal Mendelian ratios for single, fully penetrant gene
models (p < 10-5), a result that
is consistent with previous reports concerning the genetic control of
EAE in mice (31, 32, 33, 34).
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Disease frequency maps to chromosomes 7 and 17
Of the 150 marker loci analyzed, the most significant linkage to
susceptibility/disease index was seen with markers on chromosomes 7 and
17. Linkage on chromosome 7 showed the highest probability in the
interval between markers D7 Mit85 through D7
Mit39 (Table II). This independently
confirms the linkage to this region reported in a prior mapping study
using different inbred mouse strains (31), and the locus in this region
is now designated eae4. The allele of eae4
associated with increased susceptibility and higher index score is
derived from the B10.S parent and is inherited in a recessive fashion.
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). These markers reside near H2 and could indicate
linkage to eae1, the H2-encoded class II locus
known to influence EAE susceptibility (15). Linkage of an EAE-modifying
gene to H2 was surprising because both parental strains
possess the H2s haplotype (20). The identity of
H2 between SJL/J and B10.S/DvTe mice was verified in two
ways. First, 10 microsatellite markers encoded within H2
(D17 Mit13, D17 Mit21, D17 Mit214,
D17 Mit231, D17 Mit31, D17 Mit32,
D17 Mit33, D17 Mit34, D17Nds2, and
D17Nds3) were tested for polymorphisms. None of these
markers was polymorphic between the two strains. Secondly, IA and
IAß cDNA samples were cloned and sequenced from each parental strain
as were the genomic exons. The IA molecule is the only class II
molecule expressed in mice bearing the H2s
haplotype, and thus any immune response effects due to differences
between B10.S/DvTe and SJL/J H2 regions would be expected to
map to this locus. No differences were found between B10.S/DvTe and
SJL/J sequences for either IA or IAß (826 bp covered for the
-chain cDNA, and 792 bp for the ß-chain cDNA). Similarly, no
differences were found in the H2 exons of the genomic DNA
from each parent. Collectively, our results suggest that the EAE
susceptibility locus mapping in this region is probably not
eae1, but a separate locus distal of H2. We have
designated this locus eae5. The disease-associated allele of
eae5 is derived from the SJL/J parent and the trait is
codominant. Identification of QTL-modifying clinical parameters of disease
QTL controlling the phenotypes of severity, duration, and day of
onset of disease were detected by analysis of variance and interval
mapping. Three severity QTL were revealed: two on chromosome 11
(eae6 and eae7) and one on chromosome 2
(eae8; Table III). Two of the
three QTL, eae6 and eae8, have previously been
associated with susceptibility to EAE (33, 34). In the present study,
both chromosome 11 QTL independently achieved significance for severity
of disease. Eae8 on chromosome 2 achieved only suggestive
significance with this parameter, but it has been given an
EAE-modifying locus designation by virtue of its replication with the
previous study (33).
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). Another QTL (eae9) with
significant linkage to duration is found on chromosome 9, in the
interval between D9 Mit22 and D9 Mit105.
SJL-derived alleles at eae6 and eae7 determine
shorter duration of illness, whereas this phenotype is seen in
heterozygotes for eae9.
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). The interval for eae10 is
25 cM distal to another EAE-modifying locus, eae3,
previously reported by two groups to affect EAE susceptibility (32, 33). Therefore, eae10 and eae3 are probably
distinct modifiers of EAE.
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Multiple linear regression analysis
Multiple linear regression was used to analyze the effects of marker loci on each specific disease phenotype. Significant marker loci for disease index (eae4 and eae5), severity (eae6, eae7, and eae8), and duration (eae6, eae7, and eae9) were analyzed as independent variables in multiple linear regression analyses, with the appropriate disease score as the dependent variable. To investigate possible interactions between significant marker loci for each disease parameter, two-locus interaction terms were added to the multiple linear regression models as independent variables. None of the interaction terms was significant (p > 0.05). Without these interaction variables, statistical significance was achieved for disease index (F = 6.77; p < 0.0001), severity (F = 5.51; p < 0.0001), and duration (F = 10.70; p < 0.0001), confirming the identification of these QTL.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Linkage studies of any genetically complex disease, such as EAE, are subject to a demanding standard for analysis; the criteria set for evidence of significant linkage are stringent (28, 37), and repetition between studies is required for validation of any linkage found (33). Multiple chromosomal regions, including intervals on chromosomes 1 to 5, 7 to 12, 14, 16, and 17 to 19 have been implicated as containing disease-modifying genes. However, only those EAE-modifying loci that independently display statistically significant linkage or confirm a previous association are noted in this report (28). Ten genomic intervals were found that meet one or both criteria. For susceptibility to EAE these include marker loci on chromosomes 7 (eae4) and 17, distal to H2 (eae5). QTL for EAE severity, duration, and onset were identified on chromosomes 11 (eae6, and eae7), 2 (eae8), 9 (eae9), and 3 (eae10).
Locus eae4
Locus eae4 maps to a large interval of central chromosome 7 identical with that reported by Baker et al. (31). Replication of linkage in two independent experiments provides additional validation for the identity of a significant QTL in this interval. Susceptibility is associated with a recessive B10.S allele at eae4, since heterozygotes do not show increased incidence of EAE. It is interesting to note that eae4 does not contribute to severity of symptoms once disease is initiated. Characterization of eae4 may therefore help delineate the differences between susceptibility and disease-modifying loci and their respective roles in the pathogenesis of autoimmune disease (38).
Locus eae5
Locus eae5 is strongly linked to susceptibility to EAE
owing to an SJL-derived allele at this locus. Locus eae5 is
linked to H2, but is probably not a classical MHC-linked
immune response gene for several reasons. First, B10.S and SJL/J mice
have the same H2 haplotype (20). Secondly, the best map
location for eae5 is slightly distal of H2.
Nevertheless, it was still possible that SJL/J and B10.S/DvTe might
differ at IA, the MHC class II molecule responsible for
encephalitogenic peptide presentation in these strains. We therefore
conducted a direct test of this possibility by sequencing the
IA and IAß alleles of both parental strains.
Since the cDNA and exonic sequences were identical (data not shown) and
neither parental strain expresses IE, structural differences in class
II loci can be ruled out as being responsible for the phenotype of
eae5. A weak association in this region of chromosome 17 was
noted by Baker et al. (34). Taken together, these results place
eae5 distal to H2, syntenic with the HLA-linked
region (www.ncbi.nlm.nih.gov/) identified in a human MS mapping a
study (21). This supports the existence of a non-HLA-encoded molecule
that may account for some of the linkage of MS to HLA.
Other significant and suggestive linkages to the clinical disease
parameters (severity, duration, and onset) of EAE were found in this
study. QTL linked to severity of disease (eae6,eae7, and eae8) were not important in controlling the
frequency/susceptibility of EAE but, rather, influenced the severity of
the signs among affected animals. The chromosome 11 (eae6
and eae7) linkages reflect new localizations that are
different from previously reported EAE susceptibility loci (31, 32, 33, 34) and
encompass some intriguing candidate genes, including cytokines,
chemokines, and other immunoregulatory loci
(www.informatics.jax.org/mgd.html). In this regard, it is known that in
SJL/J mice, EAE is a Th1-dependent disease, and the resistance of B10.S
mice to the induction of EAE is secondary to an Ag-specific defect in
the generation of Th1 cells that produce IFN-
(39). Exposing myelin
basic protein-reactive T cells from B10.S mice to IL-12 restored both
IFN- production and encephalitogenic activity (39). It is worth
noting that Il12b maps to proximal chromosome 11 (19 cM)
(www.informatics.jax.org/mgd.html) in the region containing
eae6 (1–28 cM from the centromere of chromosome 11).
Interestingly, preliminary results in our F2 and
bidirectional backcrosses (data not shown) suggest the possible
existence of an additional QTL segregating in the central region of
chromosome 11 between eae6 and eae7 (30–50 cM)
near the lymphokine cluster and Tpm1, a locus that may
regulate the development of Th1/Th2-type responses (40).
The region of chromosome 11 containing eae7 (45–60 cM distal to the centromere) also contains two other susceptibility loci involved in organ-specific autoimmune diseases. Idd4 (at 44 cM) is a susceptibility locus for insulin-dependent diabetes mellitus in the NOD mouse (17), and Orch3 (at 44.5 cM) is a susceptibility locus in autoimmune orchitis (25). Candidate genes in this region of chromosome 11 include those encoding the family of small cytokines, nitric oxide synthase-2 (Nos2, at 46 cM), and cyclic nucleotide phosphodiesterase 1 (Cnp1, at 60 cM), a candidate autoantigen in MS (41) (www.informatics.jax.org/mgd.html). Nos2 encodes the inducible nitric oxide synthase enzyme (NOS2), which is considered a good candidate in autoimmune disorders because nitric oxide is known to play a pathogenic role in inflammatory situations (42). Inhibition of the NOS2 enzyme or of nitric oxide and its byproducts, such as peroxynitrite, is successful in blocking or ameliorating disease symptoms in both diabetes and EAE (43).
A QTL controlling the severity of symptoms achieves suggestive linkage on the distal end of chromosome 2. Given the previous report that susceptibility maps to this region (33) using the same markers in the same strain combination, this QTL is now a confirmed EAE-modifying locus. A notable candidate gene in this region is CD40 (www.informatics.jax.org/mgd.html).
Marker loci on chromosome 9 were significantly linked to duration of
symptoms (eae9, 28–34 cM). The general trend of shorter
duration is due to a heterozygous effect of alleles at this QTL. This
genomic interval contains CD3, Thy-1, and
Igif (IFN--inducing factor), all located at 26 to 28 cM
(www.informatics.jax.org/mgd.html). In addition, Idd2, a
diabetes susceptibility locus, has been mapped to this region (44).
Loci eae6 and eae7 also exert an effect on
duration of EAE, with shorter duration contributed in a dominant
fashion by the SJL/J allele at both QTL. Thus, the SJL/J-derived
alleles at eae6 and eae7 are associated with
shorter duration but lesser severity of clinical signs.
The earlier onset of disease seen in SJL/J mice compared with
F1 hybrids (Table I) is linked to a locus on
chromosome 3 (eae10). According to our model, this QTL
should act only in a recessive manner, because F1
mice take longer to get sick, and in fact, in the
F2, eae10 is recessive. The interval
containing eae10, from 64 to 79 cM on chromosome 3, has few
attractive candidate genes: egf (epidermal growth factor),
Cfi (complement component factor i), nfkb1
(NF-
light chain gene enhancer), and Ptgfr (PGF receptor)
located at 66 to 76 cM (www.informatics.jax.org/mgd.html).
Suggestive linkage to the various phenotypes of EAE was observed with marker loci on chromosomes 1, 4, 5, 8, 9, 10, 12, 16, 18, and 19. A notable QTL, exhibiting suggestive linkage with disease index (LOD = 3.17; significance cutoff = 3.26) resides in the interval between D16 Mit110 and D16 Mit50 (21–34 cM). F2 mice with an SJL-derived allele at this locus are much more likely to develop EAE. This QTL colocalizes with Aod1 (24 cM), the locus controlling susceptibility to day 3 thymectomy-induced autoimmune ovarian dysgenesis (24). Although our study is the only one that shows an effect from a QTL on chromosome 16 in EAE, our results, nevertheless, replicate linkage of susceptibility to organ-specific autoimmune disease in general to this region of chromosome 16 (35). These results suggest that Aod1 and the EAE susceptibility locus in this region may be the same gene. Two candidate genes mapping within the interval that could readily be involved in susceptibility to both autoimmune diseases are the costimulatory molecules CD80 (28 cM) and CD86 (26.9 cM) (www.informatics.jax.org/mgd.html). As the first step in testing this hypothesis directly, we are currently sequencing both alleles from the two parental strains used to map Aod1 (C57BL/6J and A/J) and SJL/J and B10.S/DvTe.
Similarities and differences exist between our results and those of
Encinas et al., who conducted a linkage analysis of EAE susceptibility
using a (B10.S x SJL/J) x B10.S backcross population and a
markedly different induction protocol (33). In our study, whole SCH and
CFA were used for inoculation, whereas in the Encinas study, an
encephalitogenic peptide of proteolipid protein (amino acids 139–151)
was used to induce EAE in conjunction with CFA and pertussis toxin. The
use of SCH as immunogen has advantages over defined peptides because it
does not require the use of pertussis toxin for disease induction (18),
and it contains all the primary encephalitogens of the CNS. Other
differences between the two studies are that with a BC1 population, the
loci identified primarily govern dominant traits, whereas in our
F2 cross we can, in theory, more easily detect
recessive and interacting loci. Additionally, we found independently
significant linkages for EAE that are unique to our
F2 cross on chromosomes 9 and 11. A summary of
all EAE-modifying loci that have either achieved significance or been
confirmed by additional experiments to date is given in Table VI.
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Several groups have exploited homology mapping to investigate the
genetics of MS susceptibility (46, 47, 48). For example, Kuokkanen et al.
reported the mapping of a MS locus in the region of 5p14–5p12 (36).
This locus was identified by scanning the human genome in regions
syntenic to eae2, the EAE susceptibility gene previously
mapped to murine chromosome 15 (Table VI) (32). Such observations
support the use of genetic analysis of murine EAE in the identification
of loci involved in MS. Several groups confirmed linkage at or near
HLA located on chromosome 6p21 (21). Notably, Ebers et al.
found linkage to D6S461, which lies just outside
HLA in the region syntenic to mouse chromosome 17 encoding
eae5 (48). We also note that eae7 is syntenic
with human chromosome 17, which includes an MS susceptibility locus at
17q22 (46, 49). It is clear that a further dissection of mouse
EAE-modifying loci will shed light on these syntenic relationships and
on the issue of susceptibility loci for demyelinating disease in
general.
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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, 2001 South Lincoln Ave., University of Illinois, Urbana, IL 61802. E-mail address:
3 Abbreviations used in this paper: MS, multiple sclerosis; CNS, central nervous system; EAE, experimental allergic encephalomyelitis; SCH, spinal cord homogenate; QTL, quantitative trait loci; LOD, logarithmic odds.
Received for publication January 13, 1997. Accepted for publication April 13, 1998.
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C. Teuscher, J. Y. Bunn, P. D. Fillmore, R. J. Butterfield, J. F. Zachary, and E. P. Blankenhorn Gender, Age, and Season at Immunization Uniquely Influence the Genetic Control of Susceptibility to Histopathological Lesions and Clinical Signs of Experimental Allergic Encephalomyelitis: Implications for the Genetics of Multiple Sclerosis Am. J. Pathol., November 1, 2004; 165(5): 1593 - 1602. [Abstract] [Full Text] [PDF]
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J. Reddy, Z. Illes, X. Zhang, J. Encinas, J. Pyrdol, L. Nicholson, R. A. Sobel, K. W. Wucherpfennig, and V. K. Kuchroo Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis PNAS, October 26, 2004; 101(43): 15434 - 15439. [Abstract] [Full Text] [PDF]
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 D. C. Chen, J. Saarela, R. A. Clark, T. Miettinen, A. Chi, E. E. Eichler, L. Peltonen, and A. Palotie Segmental Duplications Flank the Multiple Sclerosis Locus on Chromosome 17q Genome Res., August 1, 2004; 14(8): 1483 - 1492. [Abstract] [Full Text] [PDF]
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M. Jagodic, K. Becanovic, J. R. Sheng, X. Wu, L. Backdahl, J. C. Lorentzen, E. Wallstrom, and T. Olsson An Advanced Intercross Line Resolves Eae18 into Two Narrow Quantitative Trait Loci Syntenic to Multiple Sclerosis Candidate Loci J. Immunol., July 15, 2004; 173(2): 1366 - 1373. [Abstract] [Full Text] [PDF]
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B. Greve, L. Vijayakrishnan, A. Kubal, R. A. Sobel, L. B. Peterson, L. S. Wicker, and V. K. Kuchroo The Diabetes Susceptibility Locus Idd5.1 on Mouse Chromosome 1 Regulates ICOS Expression and Modulates Murine Experimental Autoimmune Encephalomyelitis J. Immunol., July 1, 2004; 173(1): 157 - 163. [Abstract] [Full Text] [PDF]
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M. Polanczyk, S. Yellayi, A. Zamora, S. Subramanian, M. Tovey, A. A. Vandenbark, H. Offner, J. F. Zachary, P. D. Fillmore, E. P. Blankenhorn, et al. Estrogen Receptor-1 (Esr1) and -2 (Esr2) Regulate the Severity of Clinical Experimental Allergic Encephalomyelitis in Male Mice Am. J. Pathol., June 1, 2004; 164(6): 1915 - 1924. [Abstract] [Full Text] [PDF]
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P. D. Fillmore, E. P. Blankenhorn, J. F. Zachary, and C. Teuscher Adult Gonadal Hormones Selectively Regulate Sexually Dimorphic Quantitative Traits Observed in Experimental Allergic Encephalomyelitis Am. J. Pathol., January 1, 2004; 164(1): 167 - 175. [Abstract] [Full Text] [PDF]
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P. D. Fillmore, M. Brace, S. A. Troutman, E. P. Blankenhorn, S. Diehl, M. Rincon, and C. Teuscher Genetic Analysis of the Influence of Neuroantigen-Complete Freund's Adjuvant Emulsion Structures on the Sexual Dimorphism and Susceptibility to Experimental Allergic Encephalomyelitis Am. J. Pathol., October 1, 2003; 163(4): 1623 - 1632. [Abstract] [Full Text] [PDF]
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 G Ramsaransing, A Teelken, V M Prokopenko, A. Arutjunyan, and J De Keyser Low leucocyte myeloperoxidase activity in patients with multiple sclerosis J. Neurol. Neurosurg. Psychiatry, July 1, 2003; 74(7): 953 - 955. [Abstract] [Full Text] [PDF]
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R. J. Butterfield, R. J. Roper, D. M. Rhein, R. W. Melvold, L. Haynes, R. Z. Ma, R. W. Doerge, and C. Teuscher Sex-Specific Quantitative Trait Loci Govern Susceptibility to Theiler's Murine Encephalomyelitis Virus-Induced Demyelination Genetics, March 1, 2003; 163(3): 1041 - 1046. [Abstract] [Full Text] [PDF]
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J. Karlsson, X. Zhao, I. Lonskaya, M. Neptin, R. Holmdahl, and A. Andersson Novel Quantitative Trait Loci Controlling Development of Experimental Autoimmune Encephalomyelitis and Proportion of Lymphocyte Subpopulations J. Immunol., January 15, 2003; 170(2): 1019 - 1026. [Abstract] [Full Text] [PDF]
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J. Saarela, M. Schoenberg Fejzo, D. Chen, S. Finnila, M. Parkkonen, S. Kuokkanen, E. Sobel, P. J. Tienari, M.-L. Sumelahti, J. Wikstrom, et al. Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22-q24 Hum. Mol. Genet., September 15, 2002; 11(19): 2257 - 2267. [Abstract] [Full Text] [PDF]
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 K. Norose, A. Yano, X.-M. Zhang, E. Blankenhorn, and E. Heber-Katz Mapping of Genes Involved in Murine Herpes Simplex Virus Keratitis: Identification of Genes and Their Modifiers J. Virol., March 7, 2002; 76(7): 3502 - 3510. [Abstract] [Full Text] [PDF]
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 J. Jirholt, A.-K. Lindqvist, J. Karlsson, A. Andersson, and R. Holmdahl Identification of susceptibility genes for experimental autoimmune encephalomyelitis that overcome the effect of protective alleles at the eae2 locus Int. Immunol., January 1, 2002; 14(1): 79 - 85. [Abstract] [Full Text] [PDF]
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 M. Grattan, Q.-S. Mi, C. Meagher, and T. L. Delovitch Congenic Mapping of the Diabetogenic Locus Idd4 to a 5.2-cM Region of Chromosome 11 in NOD Mice: Identification of Two Potential Candidate Subloci Diabetes, January 1, 2002; 51(1): 215 - 223. [Abstract] [Full Text] [PDF]
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 S. M. Ibrahim, E. Mix, T. Bottcher, D. Koczan, R. Gold, A. Rolfs, and H.-J. Thiesen Gene expression profiling of the nervous system in murine experimental autoimmune encephalomyelitis Brain, October 1, 2001; 124(10): 1927 - 1938. [Abstract] [Full Text] [PDF]
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S. Aubagnac, M. Brahic, and J.-F. Bureau Viral Load Increases in SJL/J Mice Persistently Infected by Theiler's Virus after Inactivation of the {beta}2m Gene J. Virol., August 15, 2001; 75(16): 7723 - 7726. [Abstract] [Full Text] [PDF]
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 D. G. Alleva, E. B. Johnson, J. Wilson, D. I. Beller, and P. J. Conlon SJL and NOD macrophages are uniquely characterized by genetically programmed, elevated expression of the IL-12(p40) gene, suggesting a conserved pathway for the induction of organ-specific autoimmunity J. Leukoc. Biol., March 1, 2001; 69(3): 440 - 448. [Abstract] [Full Text]
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J. A. Encinas, M. B. Lees, R. A. Sobel, C. Symonowicz, H. L. Weiner, C. E. Seidman, J. G. Seidman, and V. K. Kuchroo Identification of genetic loci associated with paralysis, inflammation and weight loss in mouse experimental autoimmune encephalomyelitis Int. Immunol., March 1, 2001; 13(3): 257 - 264. [Abstract] [Full Text] [PDF]
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J.-F. Subra, B. Cautain, E. Xystrakis, M. Mas, D. Lagrange, H. van der Heijden, M.-J. van de Gaar, P. Druet, G. J. Fournie, A. Saoudi, et al. The Balance Between CD45RChigh and CD45RClow CD4 T Cells in Rats Is Intrinsic to Bone Marrow-Derived Cells and Is Genetically Controlled J. Immunol., March 1, 2001; 166(5): 2944 - 2952. [Abstract] [Full Text] [PDF]
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T. R. Merriman, H. J. Cordell, I. A. Eaves, P. A. Danoy, F. Coraddu, R. Barber, F. Cucca, S. Broadley, S. Sawcer, A. Compston, et al. Suggestive Evidence for Association of Human Chromosome 18q12-q21 and Its Orthologue on Rat and Mouse Chromosome 18 With Several Autoimmune Diseases Diabetes, January 1, 2001; 50(1): 184 - 194. [Abstract] [Full Text]
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R. J. Butterfield, E. P. Blankenhorn, R. J. Roper, J. F. Zachary, R. W. Doerge, and C. Teuscher Identification of Genetic Loci Controlling the Characteristics and Severity of Brain and Spinal Cord Lesions in Experimental Allergic Encephalomyelitis Am. J. Pathol., August 1, 2000; 157(2): 637 - 645. [Abstract] [Full Text] [PDF]
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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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K. Bergsteinsdottir, H.-T. Yang, U. Pettersson, and R. Holmdahl Evidence for Common Autoimmune Disease Genes Controlling Onset, Severity, and Chronicity Based on Experimental Models for Multiple Sclerosis and Rheumatoid Arthritis J. Immunol., February 1, 2000; 164(3): 1564 - 1568. [Abstract] [Full Text] [PDF]
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C. Teuscher, R. J. Butterfield, R. Z. Ma, J. F. Zachary, R. W. Doerge, and E. P. Blankenhorn Sequence Polymorphisms in the Chemokines Scya1 (TCA-3), Scya2 (Monocyte Chemoattractant Protein (MCP)-1), and Scya12 (MCP-5) Are Candidates for eae7, a Locus Controlling Susceptibility to Monophasic Remitting/Nonrelapsing Experimental Allergic Encephalomyelitis J. Immunol., August 15, 1999; 163(4): 2262 - 2266. [Abstract] [Full Text] [PDF]
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 J. T. Chang, E. M. Shevach, and B. M. Segal Regulation of Interleukin (IL)-12 Receptor {beta}2 Subunit Expression by Endogenous IL-12: A Critical Step in the Differentiation of Pathogenic Autoreactive T Cells J. Exp. Med., March 15, 1999; 189(6): 969 - 978. [Abstract] [Full Text] [PDF]
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R. J. Butterfield, E. P. Blankenhorn, R. J. Roper, J. F. Zachary, R. W. Doerge, J. Sudweeks, J. Rose, and C. Teuscher Genetic Analysis of Disease Subtypes and Sexual Dimorphisms in Mouse Experimental Allergic Encephalomyelitis (EAE): Relapsing/Remitting and Monophasic Remitting/Nonrelapsing EAE Are Immunogenetically Distinct J. Immunol., March 1, 1999; 162(5): 3096 - 3102. [Abstract] [Full Text] [PDF]
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J. J. Weis, B. A. McCracken, Y. Ma, D. Fairbairn, R. J. Roper, T. B. Morrison, J. H. Weis, J. F. Zachary, R. W. Doerge, and C. Teuscher Identification of Quantitative Trait Loci Governing Arthritis Severity and Humoral Responses in the Murine Model of Lyme Disease J. Immunol., January 15, 1999; 162(2): 948 - 956. [Abstract] [Full Text] [PDF]
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A. A. Hurwitz, T. J. Sullivan, R. A. Sobel, and J. P. Allison Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits the expansion of encephalitogenic T cells in experimental autoimmune encephalomyelitis (EAE)-resistant BALB/c mice PNAS, March 5, 2002; 99(5): 3013 - 3017. [Abstract] [Full Text] [PDF]
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I. A. Eaves, L. S. Wicker, G. Ghandour, P. A. Lyons, L. B. Peterson, J. A. Todd, and R. J. Glynne Combining Mouse Congenic Strains and Microarray Gene Expression Analyses to Study a Complex Trait: The NOD Model of Type 1 Diabetes Genome Res., February 1, 2002; 12(2): 232 - 243. [Abstract] [Full Text] [PDF]
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