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Max Planck Institute of Psychiatry, Section of Neuroimmunoendocrinology, D-80804 Munich, Germany; and the Department of Neuroimmunology, Max Planck Institute of Neurobiology (C.L.), D-82152 Martinsried, Germany
Address all correspondence and requests for reprints to: Dr. J. M. H. M. Reul, Max Planck Institute of Psychiatry, Section of Neuroimmunoendocrinology, Kraepelinstrasse 2–10, D-80804 Munich, Germany. E-mail: reul{at}mpipsykl.mpg.de
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Introduction |
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Several observations indicate that HPA axis function may be one factor influencing susceptibility to autoimmune diseases. Originally, this concept was derived from studies on adjuvant-induced arthritis in the Lewis (LEW) and Fischer (F344) rat strains (12, 13, 14). Intriguingly, these animals show reciprocal characteristics in terms of their HPA axis response and susceptibility to arthritis; whereas F344 rats mount a robust HPA axis response and are resistant to arthritis, LEW rats exhibit a blunted response and are highly susceptible. The possible importance of the HPA axis in determining disease susceptibility in this strain combination is underlined by the fact that LEW and F344 rats share a similar MHC locus (RT1l and RT1lv1, respectively) (15), which is crucially involved in the induction of pathogenic autoimmune responses. The concept that low HPA axis responsiveness is a general predictor of an increased susceptibility to autoimmune diseases was further supported by studies on experimental autoimmune encephalomyelitis (EAE). The EAE-resistant rat strains Brown Norway (BN) or PVG are both characterized by a robust HPA axis response (9, 16), whereas LEW rats are highly susceptible (9, 11, 16). In this paradigm, all three strains have different MHC haplotypes (15), indicating that the HPA axis may be the deciding influence determining disease susceptibility. Clearly, if a blunted HPA axis response was a predisposing factor for autoimmune disease, this would have a major clinical impact in terms of both prediction and the development of novel therapeutic strategies. However, a prerequisite for the clinical application of this hypothesis would be its consistence across a spectrum of genotypes that mimics the genetic diversity of man. We therefore investigated the association between HPA axis responsiveness and disease susceptibility using two different EAE paradigms in three MHC-disparate rat strains: LEW (RT1l), BN (RT1n), and Dark Agouti (DA; RT1av1). In the rat, the classical EAE paradigm, immunization with myelin basic protein (MBP), leads to inflammatory disease mediated by invading T cells and macrophages (17). In contrast, the novel EAE paradigm induced by immunization with myelin oligodendrocyte glycoprotein (MOG) is mediated by the synergy of inflammatory cells with demyelinating anti-MOG antibodies (17). MOG-induced EAE closely reproduces the demyelinating pathology of the multiple sclerosis (MS) lesion, and therefore serves as a more adequate animal model of MS (17, 18, 19).
We report that HPA axis responsiveness to a mild psychological stressor, exposure to novelty, does not predict susceptibility to EAE. Moreover, both the HPA axis response to EAE and central nervous system (CNS) GC-binding receptors appear normal in all strains analyzed.
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Materials and Methods |
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56 x 34 x 20 cm
(length x width x h)]. All experimental procedures were
approved by the Bavarian government and performed in compliance with
international animal welfare standards. Complete Freund’s adjuvant
(CFA) and heat-killed Mycobacterium tuberculosis (H37Ra)
were purchased from Life Technologies, Inc. (Rockville,
MD). Purified protein derivative was purchased from the State
Serum Institute (Copenhagen, Denmark). Whole MBP was purified
from guinea pig brain (20). Recombinant protein corresponding to the
N-terminal sequence of rat MOG (amino acids 1–125) was expressed in
Escherichia coli and purified to homogeneity (21). The
purified protein in 6 M urea was then dialyzed against 20
mM sodium acetate buffer (pH 3.0) to obtain a soluble
preparation that was stored frozen at -20 C.
Induction of EAE
Guinea pig MBP (50 µg/rat) or recombinant rat MOG (50
µg/rat) corresponding to the extracellular IgG-like domain (amino
acids 1–125) of the native protein were emulsified in CFA containing
heat-killed Mycobacterium tuberculosum (H 37Ra; 225
µg/rat) and injected sc at the base of the tail in a total volume of
100 µl. Control animals were injected with an emulsion of PBS in CFA.
Clinical disease was scored on the following scale: 0.5, partial loss
of tail tone; 1.0, complete tail atony; 2.0, hind limb weakness; 3.0,
hind limb paralysis; and 4, moribund. Experiments were terminated when
more than 30% of animals showed a clinical score greater than 3 for
more than 24 h or when disease progression was very rapid and
severe. The incidence of adjuvant-induced arthritis was low (<10%)
using the base of the tail as an immunization site, but animals
exhibiting signs of arthritis were excluded from further analysis.
Measurement of hormone levels
For determining plasma levels of ACTH and corticosterone (CORT),
great care was taken to keep rats undisturbed the night before the
experiment. The animals were anesthetized in a glass jar containing
saturated halothane (Hoechst, Frankfurt am Main, Germany)
immediately after removal from their home cage between 0700–0800 h;
Trunk blood was collected after decapitation in ice-chilled,
EDTA-coated tubes containing 140 µg aprotinin (Trasylol,
Bayer Corp., Leverkusen, Germany). The whole
procedure was performed in less than 30 sec. To induce novelty stress,
animals were taken from their home cage and placed individually in new
cages for 30 min before collecting trunk blood. This time point
represents peak plasma levels of corticosterone, which for this study
is the most important HPA hormone, and the descending slope of plasma
ACTH levels. It has been shown previously that at 30 min during novelty
stress, corticosterone and ACTH responses show parallel changes (22, 23). Blood samples were centrifuged at 4 C for 10 min, and plasma
aliquots were stored at -80 C for analysis by RIA (ICN Biomedicals, Inc., Costa Mesa, CA). The inter- and intraassay
coefficients of variance for ACTH were 7% and 5%, respectively, with
a detection limit of approximately 2 pg/ml. For CORT, the inter- and
intraassay coefficients of variance were 7% and 4%, respectively,
with a detection limit of 0.15 µg/100 ml.
Surgery and [3H]steroid binding assay
For corticosteroid binding measurement, naive rats were
bilaterally adrenalectomized under halothane anesthesia to deplete
their body of endogenous corticosteroids. After surgery, drinking water
was supplemented with 0.9% NaCl. Twenty-four hours after adrenalectomy
the animals were anesthetized with halothane and decapitated. Trunk
blood was collected, plasma samples were prepared as described above,
and the absence of CORT was verified by RIA. Immediately after
decapitation, the hippocampus, hypothalamus, frontal cortex, amygdala,
and the anterior pituitary were dissected, snap-frozen in liquid
nitrogen, and stored at -80 C. The samples were homogenized (100 mg
wet weight/ml) in 5 mM Tris-HCl (pH 7.4) containing 5%
glycerol, 10 mM sodium molybdate, 1 mM EDTA,
and 2 mM ß-mercaptoethanol using an ice-cooled glass
homogenizer with a Teflon pestle (10 strokes at 900 rpm). The
homogenate was centrifuged at 100,000 x g at 2 C for
60 min, and the supernatant (cytosol) was collected. All of the
following steps were performed at 2–4 C.
Mineralocorticoid receptors (MR) were measured in aliquots of cytosol
incubated in duplicate for 20–24 h with [3H]aldosterone
(84 Ci/mmol; NEN Life Science Products DuPont, Dreiech,
Germany) in a concentration range of 0.1–10 nM in
the presence of a 100-fold excess of the specific glucocorticoid
receptor (GR) ligand RU28362
[11ß,17ß-dihydroxy-6-methyl-17
-(1-propionyl)androsta-1,4,6-triene-3-one]
to prevent [3H]aldosterone from binding to GR.
Nonspecific binding was assessed by incubating cytosol with
[3H]aldosterone in the presence of a 1000-fold excess of
unlabeled CORT.
Binding to the cytosolic GR was determined by incubation in duplicate with [3H]dexamethasone (86 Ci/mmol; Amersham Pharmacia Biotech, Braunschweig, Germany) at concentrations ranging from 0.2–10 nM. The binding of dexamethasone to MR was evaluated by adding a 100-fold excess of RU 28362. Nonspecific binding was assessed by adding a 1000-fold excess of unlabeled dexamethasone.
After the incubation period, bound and free [3H]steroid were separated by gel filtration on Sephadex LH-20 (Pharmacia Biotech, Uppsala, Sweden), and bound radioactivity was measured by liquid scintillation counting. The protein content of the aliquots was determined by the method of Lowry, using BSA as a standard.
The binding data were expressed as femtomoles per mg protein, and nonspecific binding was subtracted from total binding to yield specific binding. GR levels were calculated by subtraction of nonspecific binding as well as binding of [3H]dexamethasone to MR. Total binding (Bmax) and binding affinity (Kd) were derived from Scatchard analysis.
Data presentation and statistical analysis
Data are presented as the group mean ± SEM;
group sizes are 8–10 in all experiments. Means were compared by one-
or two-way ANOVA and Duncan’s post-hoc test as
indicated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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)
were similar in BN and DA rats (60.8 ± 12.2 and 50 ± 8
pg/ml, respectively), whereas the LEW rat produced lower baseline
levels of ACTH [27.3 ± 7.1 pg/ml; by one-way ANOVA: F(1, 14)
= 3.32, P = 0.055, by Duncan’s post-hoc
test: P < 0.05]. Thirty minutes of novelty stress
induced a pronounced increase in plasma levels of ACTH in all three rat
strains [by two-way ANOVA: effect of strain: F(2, 40) = 6.75,
P = 0.003; effect of stress: F(1, 40) = 38.01,
P 
0.0005; two-way interaction: F(2, 40) = 3.99,
P = 0.026; Fig. 1a]. In BN and DA rats plasma ACTH
reached comparable levels (346 ± 63.3 and 306.5 ± 86.2
pg/ml, respectively), whereas the rise of ACTH in LEW rats was
significantly less [103.4 ± 28.7 pg/ml; by one-way ANOVA:
F(2, 42) = 8.67, P = 0.001] than that in DA and BN
rats (P < 0.05, by Duncan’s post-hoc
test).
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), but strain differences were more pronounced. In undisturbed
animals, plasma CORT levels were low, ranging from 0.09 ± 0.08 to
0.3 ± 0.16 µg/dl in DA and BN rats, whereas the levels in LEW
rats were significantly higher at 1.7 ± 0.7 µg/dl [by one-way
ANOVA: F(2, 21) = 5.18, P = 0.015; by Duncan’s
post-hoc test, P < 0.05]. Again, stress
induced significant elevations of CORT in all strains [by two-way
ANOVA: effect of strain: F (2, 42) = 8.67, P =
0.001; effect of stress: F(1, 42) = 82.68, P
0.0005; two-way interaction: F(2, 42) = 11.98, P
0.0005]. DA and BN rats responded with a similar elevation of
circulating hormone levels in response to novelty stress (28.1 ±
4.8 and 21.0 ± 2.7 µg/dl, respectively). In contrast, plasma
CORT concentrations in LEW rats reached less than half the levels of
the other rat strains [6.7 ± 2 µg/dl; by one-way ANOVA:
F(2, 21) = 10.39, P = 0.0007; by Duncan’s
post-hoc test, P < 0.05]. These data
reproduce earlier work on the depressed function of the HPA axis in the
LEW rat (12, 14), and demonstrate that the DA rat, like the BN rat (16, 24), is a high responder strain.
Brain GC receptor levels in DA, LEW, and BN rats are
similar
The hippocampus contains high amounts of glucocorticoid-binding
receptors and is thought to play an important role in the regulation of
the HPA axis by providing tonic inhibitory input to the hypothalamus
(25). All three strains revealed comparable levels of hippocampal GR at
120–130 fmol/mg (Table 1) with similar
affinities of approximately 1 nM (Kd derived
from Scatchard analysis). Hippocampal MR densities were also similar
(62–72 fmol/mg; Table 1) in the three rat strains, and receptor
affinity derived from Scatchard analysis was within the expected range
of 0.2–0.4 nM.
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) confirmed the finding that receptor levels are
similar in BN, DA, and LEW rats, with interstrain variations not
exceeding 15%. Levels of GR were similar to those in the hippocampus,
ranging from 104–136 fmol/mg, whereas MR levels were lower than those
in the hippocampus, ranging from 10–20 fmol/mg in these brain
regions.
Finally, levels of GR and MR were determined in the anterior pituitary
(Table 1), one of the main components of the HPA axis. MR levels were
intermediate compared with those in the other brain regions, reaching
an average of 26 fmol/mg in BN and DA rats. GR levels in the anterior
pituitary were lower compared with those in the CNS regions, reaching
approximately 85 fmol/mg in BN and DA rats. In LEW rats, both MR and GR
were approximately 30% lower than in the other strains.
HPA axis responsiveness is not a predictor of susceptibility to
EAE
Using the classical MBP-induced paradigm of EAE, we confirmed
previous studies (11, 26, 27, 28) that reported LEW and DA rats as
susceptible and BN rats as highly resistant (Fig. 2a). LEW rats developed clinical signs of
disease as early as 9 days postimmunization [pi; mean clinical score
(mcs), 0.8 ± 0.3], which reached a severity of mcs =
3.4 ± 0.1 on day 13 pi. Disease in DA rats was slightly delayed,
with the first signs of paralysis on days 11–12 pi and a mean clinical
score of 0.8 ± 0.4 reached on day 13 pi In contrast, none of the
BN rats developed any signs of clinical disease. Interestingly, this
pattern of resistance/susceptibility does not correlate with the HPA
axis characteristics of these strains, as the HPA axis responses to
novelty stress in the susceptible DA rat were indistinguishable from
those in the resistant BN strain.
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). LEW rats suffering from MBP-induced
EAE showed a significant elevation of plasma CORT [9.4 ± 2.4
µg/dl; compared with CFA controls, 3.4 ± 0.8 µg/dl; by
one-way ANOVA: F(1, 17) = 5.22, P = 0.036]. This
was also the case in DA rats suffering from MBP-induced EAE levels
[11.1 ± 2.6 µg/dl; compared with CFA controls, 1.5 ± 0.4
µg/dl; by one-way ANOVA: F(1, 29) = 15.87, P =
0.0004]. In contrast, BN rats failed to exhibit elevated plasma levels
of CORT (0.3 ± 0.2 µg/dl vs. 1.8 ± 0.6 µg/dl
in controls). Plasma CORT levels in control animals immunized with CFA
did not show any strain differences [by one-way ANOVA: F(2, 31) =
1.41, P = 0.26], whereas strain differences existed
after immunization with MBP [by one-way ANOVA: F(2, 33) = 7.48,
P = 0.0021]. These data indicate that clinical disease
in MBP-induced EAE is associated with HPA axis activation in
susceptible strains. As no disease activity is induced by immunization
with MBP in the BN rat, no conclusion regarding HPA axis activation can
be drawn in this strain.
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, a and b).
After immunization with MOG (n = 8–10 for all strains), the
alleged standard high susceptibility LEW strain did not develop any
clinical disease until day 17 pi after immunization with 50 µg
MOG/CFA. After immunization with 100 µg MOG/CFA, LEW rats developed a
late onset, milder, and less rapidly progressive disease than DA and BN
rats, with the onset of clinical symptoms from day 14 pi (Fig. 2b).
Animals were killed for hormone measurement on day 17 pi (mcs, 2.6
± 0.2). In contrast, the DA rat developed a highly aggressive disease
that progressed rapidly, such that all animals had to be killed on day
11 pi (mcs, 3.4 ± 0.6). Also, BN rats developed severe clinical
disease as early as day 9 pi, and on day 13 pi had a mcs of 3.7 ±
0.2 (Fig. 2b), which is in striking contrast to their complete
resistance to MBP-induced EAE. This enabled us to look for any
correlation between HPA axis activity and disease in all three strains
in a single disease paradigm.
As with MBP-induced disease, clinical disease was associated with HPA
axis activation (Fig. 3b). In LEW rats CORT levels remained unchanged
until clinical disease developed [1.6 ± 0.6 vs.
3.4 ± 0.8 µg/dl on day 13 pi; by one-way ANOVA: F(1, 17) =
2.6, P = 0.12; 15.9 ± 2.1 vs. 7.4
± 1.1 µg/dl 17 days pi; by one-way ANOVA: F (1, 15) = 9.7,
P = 0.007; Fig. 3b]. Both DA [30.4 ± 8
vs. 1.5 ± 0.4 µg/dl on day 11 pi; by one-way ANOVA:
F(1, 25) = 28.17, P 0.0005] and BN [11.1
± 1.9 vs. 3.4 ± 0.8 µg/dl on day 13 pi; by one-way
ANOVA: F(1, 18) = 23.2, P = 0.0001] rats exhibited
marked elevations of plasma CORT on days 11 and 13 pi. Basal levels of
CORT were not significantly different between CFA-immunized animals of
all strains at the early time points (compare Fig. 3a). However, basal
CORT was elevated in LEW rats on day 17 pi (3.4 ± 0.8 µg/dl on
day 13 pi vs. 7.4 ± 1.1 µg/dl on day 17 pi; by
one-way ANOVA: F(3, 37) = 8.027, P = 0.0003],
possibly indicating a nonspecific CFA effect at this late time point.
EAE-induced CORT levels were different between strains [by one-way
ANOVA: F(2, 29) = 5.94, P = 0.0069].
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Discussion |
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GCs interact with the immune system at multiple levels and are known to exert both immune suppressive and immune stimulatory effects (30). They influence T cell survival and proliferation, suppress inflammatory cytokines, and have many systemic effects that influence the homeostasis of an organism and hence the environment in which immune responses take place (10, 31). Conversely, immune responses and in particular inflammation stimulate GC production by the HPA axis (32, 33), providing a regulatory feedback loop. This feedback regulation is of vital importance, as abrogation of the endogenous GC response renders animals vulnerable to overshooting inflammatory and immune responses (32). In EAE, CNS inflammation strongly activates the HPA axis, and the resulting elevation of GC levels is necessary for recovery from disease (11). Surgical or pharmacological interruption of this response results in lethal EAE in susceptible strains (11) and can render some resistant strains susceptible to disease induction (9). Conversely, treatment with exogenous GCs can block disease in a dose-dependent fashion (9, 27). In contrast, disruption of endogenous GC homeostasis by GC treatment followed by untapered withdrawal can lead to relapse-induction (27). Clearly, endogenous GCs are of central importance in controlling disease processes in EAE, but it was uncertain whether genetic variations in HPA axis function at the level of either hormone production or the expression of central GC receptors provides a major susceptibility factor for EAE.
In response to the mild psychological stressor novel environment, two different HPA axis response patterns could be discerned in the three strains studied. BN and DA rats mounted a robust HPA axis response as indicated by high circulating levels of ACTH and CORT, whereas the response in LEW rats was blunted. These data confirm published reports on the HPA axis characteristics in LEW and BN rats (9, 12, 14, 16, 24), whereas the HPA axis response of the DA rat had not been investigated previously.
CNS glucocorticoid-binding receptors are of foremost importance in the regulation of the HPA axis (34, 35). Hence, dysregulation/dysfunction in central receptor expression may have far-reaching consequences with respect to immune regulation (10). However, measurement of MR and GR in the hippocampus, hypothalamus, frontal cortex, and amygdala revealed no major differences in receptor densities among LEW, BN, and DA rats, with strain differences not exceeding 15% in any region. Only in the anterior pituitary were marked differences in receptor densities observed among strains, as in the LEW rat levels of both MR and GR were 30% lower than those in the DA or BN rat. The functional significance of this finding with respect to HPA axis function remains to be investigated. Unfortunately, our receptor measurements in female rats cannot be compared directly to the results of previous studies that were generally performed in male rats of other strains. It is well known that both strain and gender can have an influence on brain GC receptor expression (36, 37, 38). Furthermore, major differences in the experimental protocol regarding both the animals (e.g. adrenalectomy 15 days before receptor measurement) (39) and the binding assay itself (e.g. method of separation of bound and unbound steroid) (39) prohibit direct comparison. Nevertheless, previous work using a similar experimental protocol also failed to reveal differences in brain GR and MR binding between male animals of high (F344) and low (LEW) HPA axis responder strains (40). The same researchers report reduced stress-induced nuclear trans-location of GR in LEW compared with F344 rats (37); however, this does not seem to indicate impaired receptor regulation, as it corresponds with significantly lower stress-induced CORT levels in the LEW rat. In summary, there seems to be no indication for a profound genetic effect on the expression of central glucocorticoid receptors in the three rat strains investigated in this study.
After characterization of the HPA axis in the three rat strains, we compared different EAE paradigms, immunization with MBP vs. immunization with MOG, to mimic some of the heterogeneity in immune effector mechanisms involved in MS. In the rat, MBP-induced EAE is a purely inflammatory disease initiated by T cells that mediate a local inflammatory response within the CNS. The neurological deficit is then mediated by products of activated macrophages recruited into the lesion (17). T cells and macrophages are both known to be sensitive to glucocorticoid suppression (10, 41), and pharmacological doses of glucocorticoids can abrogate EAE after immunization with MBP (27). The clinical profiles obtained after immunization with MBP reproduced earlier studies in all three strains (11, 26, 27, 28). However, we did not find a consistent association of high HPA axis responses with resistance to disease, in that BN rats were resistant and DA rats were susceptible to MBP-induced disease despite both having a robust HPA axis response. In contrast, in LEW rats, high disease susceptibility is associated with depressed HPA axis function (42).
Strikingly, this pattern of disease susceptibility (LEW>DA>BN) was completely reversed in MOG-induced EAE. In particular, BN rats are resistant to MBP-induced EAE, but they developed a fulminate, lethal form of EAE after immunization with MOG despite their robust HPA response. In contrast, the LEW rat proved to be much less susceptible to MOG-induced EAE than the other strains and developed a late-onset, milder form of disease. Only the DA rat was susceptible to EAE induced with either MOG or MBP; however, again in this rat strain the general susceptibility to EAE is in stark contrast to its robust HPA axis response. There is, therefore, no clear-cut association of HPA axis characteristics as determined by a psychological stressor and susceptibility to EAE in either of the paradigms investigated in this study. However, it is conceivable that there exist major differences in HPA axis activation by novelty stress and CNS inflammation during EAE. To exclude the possibility that any of the strains fails to respond to the inflammatory stimulus, we measured plasma CORT after induction of EAE. All animals exhibited HPA axis activation coinciding with clinical symptoms of EAE in both MOG- and MBP-induced EAE, indicating that all three strains can respond to CNS inflammation.
The original observation regarding the association of a robust HPA axis response with resistance to autoimmune disease was made in streptococcal cell wall-induced arthritis. These studies compared juvenile LEW and F344 rats (13, 14), which are histocompatible and share very similar MHC haplotypes (15). This led to the assumption that immune reactions in these strains should be similar, and that differences in the HPA axis could account for the differences in susceptibility, a concept that was rapidly extended to EAE (9, 16). However, it is known that MHC-unrelated background genes also have a major influence on disease susceptibility (4, 9, 43), but it is unclear whether they are related to HPA axis function or modulate other disease-related processes. Interestingly, at least in some strains (PVG.RT1u, AO, and BN), the function of the HPA axis is actually irrelevant for disease resistance, as even its complete ablation by adrenalectomy fails to render these strains susceptible to EAE (9, 42). Furthermore, in both the present and earlier studies (16) resistant animals failed to show any signs of HPA axis activation. This indicates that disease resistance may not be directly influenced by differences in HPA axis responsiveness to stress or by differences in basal early morning levels of CORT that were highest in the susceptible LEW rat. However, indirect influences on the general reactivity of the immune system or the development of the immune response after active immunization cannot be excluded. These findings question the general applicability of data derived from stress experiments to disease models characterized by completely different modes of HPA axis activation.
In summary, our data indicate that although a functional HPA axis is crucial to control the disease process in susceptible strains of rats (9, 11), there exists no general association of HPA axis responsiveness with disease susceptibility. This is true both for different disease paradigms in a single inbred rat strain as well as for a single disease paradigm in different strains. Susceptibility to EAE is a strain-specific trait determined by both the genotype and the identity of the target autoantigen. This is of particular importance as it is becoming increasingly clear that in many human autoimmune diseases including MS, no single target autoantigen may exist. Rather, the pathogenic process may involve a mixture of responses to various endogenous antigens (18). Hence, HPA axis characteristics cannot serve a predictive function regarding disease susceptibility in either the experimental or the clinical context.
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Acknowledgments |
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Footnotes |
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2 This work was supported by the Volkswagen Foundation (Grant I/70
543).
Received March 30, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,
P < 0.05, effect of EAE within one strain
comparing CFA vs. EAE (by one-way ANOVA).