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*
Department of Microbiology and Immunology, MCP Hahnemann University, Philadelphia, PA 19129;
Department of Microbiology and Immunology, School of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802; and
Department of Statistics, Purdue University, West Lafayette, IN 47907
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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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As an initial step in understanding the genetic control of PTX effects in regulating EAE susceptibility, we mapped the locus (Bphs) controlling PTX-induced hypersensitivity to histamine (12). This phenotype has been reported to be associated with susceptibility to EAE (13) and to experimental allergic orchitis (14). Bphs is on chromosome 6 (12) and has been physically located within a yeast artificial chromosome contig encoding Eno2, Tnfrsf7 (Cd27), Ltbr, Tnfrsf1a (Tnfr1), and Vwf (15). However, Bphs does not determine EAE susceptibility in all PTX-dependent strains of mice, and some strains of mice differ in EAE susceptibility but do not differ in histamine sensitivity or Bphs alleles. Therefore, additional loci controlling PTX effects must exist. The purpose of the present study was to examine the genetic control of PTX effects in EAE by using strains of mice that are concordant for both Bphs and H2. Examination of EAE in (B10.S/DvTe x SJL/J) x B10.S/DvTe backcross (BC1) mice conditioned with PTX allows the determination of whether PTX elicits more frequent and/or more severe clinical signs of EAE and the identification of additional loci mediating its effects. We report here that the use of PTX significantly increases the proportion of backcross mice with clinical signs of EAE. One major locus on chromosome 9 controlling PTX effects in EAE susceptibility was found, in contrast to the multiple eae-m loci that are involved in EAE in the absence of PTX. Our results support the hypothesis that PTX is capable of circumventing or overriding many of the genetically determined checkpoints associated with EAE in this strain combination.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(B10.S/DvTe x SJL/J) x B10.S/DvTe backcross mice (BC1) were generated continuously over 12 mo from the same pool of B10.S/DvTe and (B10.S/DvTe x SJL/J) F1 hybrid breeding stock. Inoculation of groups of mice, ranging in age from 6 to 12 wk, was staggered over the same period. Mice were injected s.c. at two sites on the posterior flank (0.15 ml/injection site) with 1.0 mg of SJL/J spinal cord homogenate (SCH), in 0.15 ml PBS, emulsified with an equal volume of CFA (16). A booster injection of SJL/J SCH + CFA, prepared in the same manner as the primary inoculum, was given on day 7. PTX-treated mice received 10 µg of crude PTX (17) i.p. at the time of inoculation and 5 µg 24–48 h later. Ninety-two mice were immunized using SCH, CFA, and PTX (PTX+) and 122 mice were immunized with SCH and CFA alone (PTX-). Mice were monitored daily for symptoms 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. Animals progressing to a score of 4 were euthanized. Animals were observed for 30 or 60 days, at which time they were sacrificed and their brains and spinal cord (SC) were retrieved for histological analysis. 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. Liver tissue was collected for DNA isolation.
Histological evaluation
Brain and SC samples were dissected from calvaria and vertebral columns, respectively, and fixed by immersion in 10% phosphate-buffered Formalin (pH 7.2) at 4°C. Following 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 for routine evaluation and luxol fast blue-periodic acid Schiff reagent for demyelination. Representative areas of the brain and SC, selected for histological evaluation, were chosen based on previous studies (18, 19). These included brain stem, cerebrum, and the cervical, thoracic, and lumbar segments of the SC. Scoring was based on a semiquantitative assessment for the following individual variables: 1) severity of the lesion as represented by each component of the histological assessment; 2) extent and degree of myelin loss and tissue injury (swollen axon sheaths, swollen axons, and reactive gliosis); 3) number of neutrophils/eosinophils comprising the inflammatory exudate; and 4) number of lymphocytes/macrophages comprising the inflammatory exudate. A score was assigned to the entire brain and to the entire SC based on a subjective numerical scale ranging from 0 to 5. A score of zero indicates no lesion, myelin loss, or inflammatory response was present in the tissue evaluated. The remaining scores were as follows: 1, minimal; 2, mild; 3, moderate; 4, marked; and 5, severe lesions, myelin loss, or inflammatory response present in the tissue.
Genetic analysis
Genomic DNA was isolated from liver tissue by standard
techniques and used as template for PCR amplification using
radiolabeled primers as described previously (16). Primers
for microsatellite markers were purchased from Research Genetics
(Huntsville, AL). Alleles at these markers were resolved on denaturing
polyacrylamide gels and read from autoradiographic films directly into
a MapManager QT database (20). Linkage maps were generated
for the PTX+ and PTX-
groups using MapManager QT. Linkage of marker loci to disease
susceptibility was tested by 
2 in 2 x 2
contingency tables. Quantitative trait loci (QTL) were identified by
interval mapping using model 3 of the Zmapqtl program in QTL
Cartographer version 1.13 (21). Traits used for interval
mapping included highest score seen during the course of EAE, severity
index, monocyte/lymphocyte infiltration, suppuration, and demyelination
of brain or SC. Critical values for declaration of significant linkage
were determined by the permutation threshold theory (22).
For this experiment, 1000 permutations of the data were generated to
provide a sampling distribution of the 2 or
the likelihood ratio test (LRT) statistics under the null hypothesis of
no linkage. Each permutation was done by randomly shuffling and
reassigning trait values among the BC1 animals, while holding the
genotypic information fixed. Linkage analysis was then done for each
permuted data set, and the distribution of the maximum test statistic
from each of the 1000 permutations was used to set experimentwise
significance thresholds. Linkages were reported if the test statistic
for a particular marker locus was greater than the experimentwise
critical value calculated for 
= 0.10 (suggestive) or
= 0.05 (significant) for that trait. Significant linkages, or
suggestive linkages that replicate the findings of a previous study,
were given eae locus designations.
Interaction between marker loci
To test the hypothesis that significant QTL interact, we used a regression model containing significant marker loci and two-locus interaction variables between significant marker loci. Regression models with dummy coding for marker loci were analyzed in SAS using PROC REG (23). Significance of the overall model was assessed using an F statistic, and significance of interaction variables was assessed using a T statistic (24).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Signs of EAE were more frequent, and the latency to onset was
significantly shorter, in both males and females in the
PTX+ group (69% affected) compared with the
PTX- group (43% affected) (Table I
). Although the incidence of disease was
higher in PTX+ mice, there was no difference in
susceptibility between males and females within either group. However,
disease as measured by average peak score (or by a severity index, data
not shown) was less severe in the PTX+ group,
especially in females (Table I). A substantial cohort of mice in the
PTX- group developed neuropathology in the
absence of detectable clinical signs. We have recently termed this type
of disease benign EAE (25). Benign EAE was prominent in
PTX- mice: 40% clinically unaffected
PTX- mice showed monocytes and lymphocytes in
their SCs without any outward signs of EAE, whereas only 16% of
unaffected PTX+ mice had this phenotype. This was
not influenced by sex.
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SC and brain samples were obtained from and scored for the occurrence and degree of mononuclear infiltration, suppuration, and demyelination. The character and distribution of CNS histopathological lesions observed in this study were consistent with those reported in previous studies (18, 19, 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. CNS tissue response ranged from mice with no tissue injury to those with loss of myelin, reactive gliosis, swollen axon sheaths, and swollen axons. In all mice with histopathology, 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 reported previously (19).
When mice from the two treatment groups were examined for the presence
of histopathology in the CNS (brain or SC), the
PTX+ group again had a higher incidence of
affected mice than the PTX- group for either CNS
site (data not shown). Differences between males and females were not
observed for histopathological traits in the brain or SC of
PTX+ mice. In contrast, female mice in the
PTX- group had significantly greater brain
involvement than males (Table II).
Because animals were not all euthanized at the same time points
subsequent to the manifestation of their disease, overall between-group
comparisons could not be made for histological traits. However, we
could analyze a subset of EAE-susceptible mice from each treatment
group (51 PTX+ and 37
PTX-) that were sacrificed within 1 wk of their
last clinical sign, because the lesions in these mice would be expected
to be comparable. Surprisingly, the extent of demyelination at either
CNS site was substantially less severe in the
PTX+ than in the PTX-
subset (the mean value for SC demyelination in these
PTX+ mice was 1.39 ± 0.7 and for the
PTX- mice was 2.32 ± 0.63,
p < 1 x 10-8; the mean
value for brain demyelination in PTX+ mice was
0.25 ± 0.44 and for the PTX- subset was
0.89 ± 0.88, p = 0.0002).
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Genome scanning was performed on both the
PTX+ and PTX- cohorts. We
analyzed both the binary trait of EAE incidence (or susceptibility) and
the quantitative traits of severity and histopathology. For
PTX+ mice, linkage to the binary trait of
susceptibility was found in an interval that is marked by D9
Mit105 (2 values were 11.7 and 9.3,
indicating probability of linkage at = 0.05 and =
0.1, respectively). This effect came largely from male mice
(2 = 17.0). A QTL designated eae9
has previously been identified in the same interval in an
F2 intercross with the same parental strains
(16). In the PTX- cohort, linkage
to susceptibility was found to markers on chromosome 8, peaking at
D8 Mit190 (2 = 18.6,
= 0.1).
Loci that showed evidence of linkage to severity or histopathological
signs of EAE are given in Table III. In
the PTX+ cohort, we again found linkage to a
single major QTL (eae9) between D9 Mit22 and
D9 Mit24. The SJL-derived allele at eae9 is
associated with increased severity. Stratification by sex revealed that
one phenotype of eae9 is to increase monocyte/lymphocyte
infiltration in the SC in males. No linkage to any other locus,
including previously identified eae-m loci, was seen in
PTX+ mice. In contrast, five linkages were seen
in the PTX- cohort, including two QTL previously
shown to play a role in this strain combination (16, 25).
The most significant QTL in the PTX- cohort is
on chromosome 8 between D8 Mit3 and D8 Mit31.
Susceptibility, severity, and SC demyelination are associated with the
B10.S-derived allele at this locus, which we have designated
eae14. In addition to eae14, a locus on
chromosome 11 that colocalizes with eae7 (16)
contributed to severity in this cohort. As in the
F2 intercross between these same strains,
sex-specific linkages were seen in the PTX-
mice. Females from the PTX- group showed linkage
to chromosome 10 for severity of clinical signs in an interval between
D10 Mit126 and D10 Mit10. We have designated this
locus as eae17. A QTL controlling severity of mononuclear
infiltrates in the SC was mapped to a broad region of chromosome 16.
Increased severity of inflammation was associated with inheritance of
the SJL allele at this locus, which was previously designated as
eae11 (25). In PTX-
males, a strong QTL was mapped to chromosome 18. The SJL-derived allele
at this locus (eae18) resulted in greater infiltration and
demyelination in the SC. No QTL for brain histopathology met
experimentwise cutoffs for suggestive ( = 0.10) or significant
( = 0.05) linkage in either cohort.
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Multiple linear regression was used to test the hypothesis that significant QTL interact. Significant marker loci for disease severity (D8 Mit190, D11 Mit98, and D10 Mit42), SC demyelination (D8 Mit190 and D18 Mit3), and SC monocytic/lymphocytic infiltration (D8 Mit190, D16 Mit50, and D18 Mit3) were analyzed as independent variables in multiple linear regression analyses with the appropriate phenotype as the dependent variable. To investigate possible interactions between significant marker loci, two-locus interaction terms were added to the regression models as independent variables. None of the interaction terms was significant (p > 0.05). Without interaction variables, statistical significance was achieved for disease severity (F = 13.59, p < 0.0001), SC demyelination (F = 10.54, p < 0.0001), and SC monocytic/lymphocytic infiltration (F = 6.31, p = 0.0005).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PTX has many effects on the immune system, aside from its vasoactive
amine-sensitizing activity (6, 7). Because our animals
were not segregating for the Bphs phenotype, which is
believed to be associated with BBB permeability changes, we expect that
other genetically regulated PTX-mediated phenotypes will be present in
our cross. The mechanism by which PTX affects EAE in this backcross
could therefore be related to one of its other known activities
(5). For example, PTX causes a generalized lymphocytosis
that is accompanied by a depletion of lymphocytes in the spleen, lymph
node, and thymus due to the failure of cells to migrate back to the
peripheral lymphoid tissue (28, 29). PTX is also reported
to be preferentially mitogenic for T cells (30), and it
has been reported to enhance delayed-type hypersensitivity responses in
an Ag-specific manner (31, 32). The enhanced delayed-type
hypersensitivity due to PTX correlates with elevated Ag-specific
production of IFN-
by these cells (33). Additionally,
PTX can induce both Th1 and Th2 immune responses (34, 35)
and can increase expression of the costimulatory molecules B7-1 and
B7-2 on macrophages and B cells, and CD28 on T cells (35).
In this regard, PTX is capable of preventing the induction of
peripheral T cell anergy to murine encephalitogenic peptides, again in
an Ag-specific manner (36); central mechanisms of
tolerance may also be affected by PTX (37). Any of these
or other known roles of PTX might be critical to the development of
clinical signs or neuropathology.
In the genetic analysis of the PTX+ group, only
one locus (eae9) shows evidence of linkage to disease
susceptibility in comparison to five loci in the
PTX- group. Our results therefore suggest that
PTX overcomes these critical genetic checkpoints in the etiology of
autoimmune disease. Eae9 was associated with the extent of
mononuclear infiltration in the SC and severity of EAE clinical signs.
This QTL is located in an interval encoding Blr1/CXCR5,
Il10ra -chain, and Il18 (IFN--inducing factor).
Any of these candidate genes could be responsible for the
eae9-mediated phenotypes mentioned above. Given that PTX can
induce increased IFN- production by T cells, it is interesting to
consider the possibility that eae9 is Il18.
Another possibility is that lymphocytosis could be affected by the
differential action of the chemokine receptor Blr1/CXCR5
alleles. This is particularly intriguing given that the chemokines
Scya1 (T cell activation 3), Scya2 (monocyte
chemoattractant protein (MCP)-1), and Scya12 (MCP-5) are
candidates for eae7 on chromosome 11 (38),
which was also identified in the PTX- backcross
(Table III
). In three separate crosses, therefore, we observed linkage
to either chemokines or their receptors (eae9 and
eae7 in the BC PTX+ and
PTX-, and eae7 in the
F2 in Ref. 38), and thus allelic
differences in the chemokine-signaling pathways may control
susceptibility to EAE by regulating the migration of inflammatory cells
and their access into the CNS.
The five QTL in the PTX- cohort include a novel eae-m locus we have named eae14. eae14 demonstrates significant linkage to disease incidence and severity and to the extent of SC demyelination. This QTL maps to an interval containing several genes of possible relevance to EAE, two of which are glutathione reductase (Gr1) and caspase-3 (Casp3). Glutathione reductase (EC 1.6.4.2) is an enzyme in the cytosol that maintains high levels of reduced glutathione in the cell, which provides significant antioxidant activity. It is expressed in macrophages and in brain. A deficiency in glutathione reductase in either of these tissues could render them susceptible to the toxic effects of free oxygen radicals in the inflammatory site (39). C57BL strains have the GR1a allele and are known to have lower enzyme activity, whereas SJL/J mice have the Gr1b allele and higher enzymatic activity (40). This difference in enzyme activity could explain why B/B homozygotes for eae14 develop more severe disease in the PTX- group. The second candidate gene in this interval is caspase-3, a downstream effector molecule of cellular apoptosis. The active form of caspase-3 is highly expressed in the spleen and less so in the brain (41). It has been hypothesized that apoptosis of T cells might play a role in the resolution of EAE (42, 43, 44).
The PTX- cohort displayed sexual dimorphism. One
linkage to EAE severity was found on chromosome 10 only in
PTX- females. This interval contains several
interesting candidate genes, including matrix metalloproteinase 11
(Mmp11 at 41 cM), tissue inhibitor of metalloproteinase 3
(Timp3 at 49 cM), insulin-like growth factor 1,
(Igf1 at 48 cM), migration inhibitory factor (Mif
at 41 cM), and the aire locus (Ref. 4 and R.
Roper et al., manuscript in preparation). AIRE is a known
autoimmune susceptibility gene in the human autoimmune
polyendocrinopathy candidiasis ectodermal dystrophy (45).
In addition, PTX- females showed linkage to a
QTL on chromosome 16, which colocalizes with eae11 seen in
an F2 cross between these same parental strains
(25). The apparent female specificity of eae11
in the backcross for one of the SC traits is not the same as in the
F2 cross, where only males displayed linkage to
markers in the eae11-defining region (D16 Mit110-D16
Mit140 at 
20–40 cM). This could be due to one of several
reasons: the genetic environment for the F2 and
backcross are different, and we would not expect all of the genetic
effects to be replicated between the experiments. If so, a significant
interaction in the F2 between eae11
and some other locus/loci (a combination not present in the BC1) could
account for the difference. Alternatively, the larger population
studied for the F2 provides more statistical power to detect any QTL,
particularly one with small effects, and perhaps the effects of
eae11 in the backcross males are not observed due to less
power. These are not necessarily the same QTL, because the
eae11 interval is quite broad.
In males from the PTX- cross, the strongest QTL, located on distal chromosome 18, is associated with significant inflammation and demyelination in the SC. This QTL, eae18, resides in an interval that contains the melanocortin receptor (Mc2r at 37 cM) and the myelin basic protein gene (Mbp, at 55 cM). In an earlier report, Baker et al. (46) found an eae-m locus in this region in an (ABH x NOD)F1 x NOD backcross. It is noteworthy that B10.S and SJL/J are also the type strains for Theiler’s murine encephalomyelitis virus-mediated demyelination and loci that control viral persistence have been mapped on both chromosomes 10 and 18 in similar intervals to eae17 and eae18, respectively (47). The chromosome 18 QTL did not predict viral persistence in subsequent testing of congenic lines (48), although the myelin basic protein gene itself contributes to viral persistence in mice segregating for the shiverer mutation (49).
In summary, we have identified two new EAE-modifying loci, one of which is a new locus controlling the effects of PTX in EAE pathogenesis. The precise mechanism of action of this gene remains unknown, but presumably reflects an intermediate phenotype other than PTX-induced vascular permeability changes. The molecular characterization of this QTL will potentially aid in the understanding of environment-gene interactions in autoimmune disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Elizabeth P. Blankenhorn, Department of Microbiology and Immunology, MCP Hahnemann University, 2900 Queen Lane, Philadelphia, PA 19129. E-mail address:
3 Abbreviations used in this paper: PTX, pertussis toxin; EAE, experimental allergic encephalomyelitis; BBB, blood-brain barrier; SC, spinal cord; SCH, SC homogenate; QTL, quantitative trait locus; LRT, likelihood ratio test.
Received for publication October 28, 1999. Accepted for publication January 5, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by sensitized lymphoid cells. Cell. Immunol. 97:238.[Medline]
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