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The Journal of Neuroscience, July 1, 2001, 21(13):4564-4571
Neuronal Survival after CNS Insult Is Determined by a Genetically
Encoded Autoimmune Response
Jonathan
Kipnis,
Eti
Yoles,
Hadas
Schori,
Ehud
Hauben,
Iftach
Shaked, and
Michal
Schwartz
Department of Neurobiology, The Weizmann Institute of Science,
76100 Rehovot, Israel
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ABSTRACT |
Injury to the CNS is often followed by a spread of damage
(secondary degeneration), resulting in neuronal losses that are substantially greater than might have been predicted from the severity
of the primary insult. Studies in our laboratory have shown that
injured CNS neurons can benefit from active or passive immunization
with CNS myelin-associated antigens. The fact that autoimmune T-cells
can be both beneficial and destructive, taken together with the
established phenomenon of genetic predisposition to autoimmune
diseases, raises the question: will genetic predisposition to
autoimmune diseases affect the outcome of traumatic insult to the CNS?
Here we show that the survival rate of retinal ganglion cells in adult
mice or rats after crush injury of the optic nerve or intravitreal
injection of a toxic dosage of glutamate is up to twofold higher in
strains that are resistant to the CNS autoimmune disease experimental
autoimmune encephalomyelitis (EAE) than in susceptible strains. The
difference was found to be attributed, at least in part, to a
beneficial T-cell response that was spontaneously evoked after CNS
insult in the resistant but not in the susceptible strains. In animals
of EAE-resistant but not of EAE-susceptible strains devoid of
mature T-cells (as a result of having undergone thymectomy at birth),
the numbers of surviving neurons after optic nerve injury were
significantly lower (by 60%) than in the corresponding normal animals.
Moreover, the rate of retinal ganglion cell survival was higher when
the optic nerve injury was preceded by an unrelated CNS (spinal cord)
injury in the resistant strains but not in the susceptible strains. It
thus seems that, in normal animals of EAE-resistant strains (but not of
susceptible strains), the injury evokes an endogenous protective
response that is T-cell dependent. These findings imply that a
protective T-cell-dependent response and resistance to autoimmune
disease are regulated by a common mechanism. The results of this study
compel us to modify our understanding of autoimmunity and autoimmune
diseases, as well as the role of autoimmunity in non-autoimmune CNS
disorders. They also obviously have far-reaching clinical implications
in terms of prognosis and individual therapy.
Key words:
protective autoimmunity; encephalitogenicity; neuroprotection; autoimmune disease; CNS; EAE
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INTRODUCTION |
Any CNS insult (e.g., trauma,
stroke, or ischemia) inevitably results in a loss of neurons that is
substantially greater than might be expected from the severity of the
injury. This is because the insult triggers a cascade of events,
starting with degeneration of the directly injured neurons and leading
to the eventual degeneration (secondary degeneration) of neurons that
escaped the initial injury. This spread of damage involves compounds
that are essential for the survival and function of neurons yet become
toxic when their physiological concentrations are exceeded. Among the
injury-related mechanisms that might underlie the posttraumatic spread
of damage are biochemical and metabolic changes in oxygen and glucose
use, energy state, lipid-dependent enzymes, free radicals, eicosanoids, tissue ions, biogenic amines, endogenous opioids, and excitatory amino
acids (Hovda et al., 1991 ; Yoshino et al., 1991; Yoles et al., 1992;
Faden, 1993; Liu et al., 1994). These changes cause alterations in
cellular homeostasis, excitotoxicity, local production of agents
harmful to nerve cells, and a loss of trophic support from targets, all
of which result in secondary neuronal loss. The presumed mechanisms of
secondary degeneration have served as a basis for the development and
evaluation of various pharmacological interventions for the treatment
of CNS injuries. The therapeutic approach of preventing or decreasing
the secondary degeneration accompanying CNS trauma is termed
neuroprotection (Faden and Salzman, 1992; McIntosh, 1993; Smith et al.,
1995).
T-cells are important players in the adaptive arm of the immune system.
They respond to antigens through interactions of their specific antigen
receptor with the antigen presented by major histocompatibility complex
molecules and a group of costimulatory molecules. When activated, they
can kill their target cells or produce cytokines that activate or
suppress the growth, or differentiation of other cells. Thus, T-cells
play a central role in the protection of tissues against foreign
invaders, as well as in tissue maintenance.
Immune responses in the CNS are relatively restricted, resulting in the
status of the CNS as an immune-privileged site (Streilein, 1995). The
unique nature of the communication between the CNS and the immune
system can be observed, for example, in the dialog between the CNS and
T-cells. In the CNS, under normal conditions, activated T-cells can
cross the blood-brain barrier and enter the CNS parenchyma. However,
only T-cells capable of reacting with a CNS antigens seem to persist
there (Hickey et al., 1991). Comparative studies of the T-cell response
at sites of axotomy in the CNS and the peripheral nervous system (PNS),
using T-cell immunocytochemistry, revealed a significantly greater
accumulation of endogenous T-cells in injured PNS axons than in injured
CNS axons (Moalem et al., 1999a). Moreover, in cases of
inflammation, the CNS showed a high potential for elimination of
T-cells via apoptosis, whereas such elimination was less effective in
the PNS and was almost absent in other tissues, such as muscle and skin
(Gold et al., 1997). These findings, suggesting that the T-cell
response to CNS injury is relatively limited, prompted us to examine
how boosting of the T-cell response at a site of CNS injury affects the
outcome of secondary degeneration.
Recent studies in our laboratory showed that systemic injection of
activated T-cells directed against CNS myelin-associated self-proteins,
or peptides derived from them, reduces the secondary degeneration of
neurons after crush injury of the rat optic nerve (Moalem et al.,
1999b; Kipnis et al., 2000). It was further shown that passive transfer
of T-cells reactive to myelin proteins or active immunization with
myelin-associated antigens promoted recovery from spinal cord contusion
by protection of spared neurons (Hauben et al., 2000a,b). These
findings prompted the suggestion that autoimmunity, usually considered
detrimental, can under certain circumstances be beneficial (Schwartz et
al., 1999a,b; Schwartz and Cohen, 2000). Our additional studies
demonstrated that beneficial autoimmunity is not merely a reflection of
immune manipulation but is a physiological response to trauma (Yoles et
al., 2001).
These findings raised some key questions, which are addressed in the
present study. Can a beneficial autoimmune response be manifested by
all individuals? If not, is the ability to manifest a beneficial
autoimmunity determined by an individual's genetic predisposition to
the development of autoimmune disease? In other words, will the outcome
of identical CNS insults (mechanical or biochemical) differ in
individuals who differ in their susceptibility to autoimmune disease?
Susceptibility to the development of autoimmune diseases is a
complicated phenomenon. Animals of a particular strain are defined as
"resistant" to autoimmune disease development if they do not develop a disease after active immunization with any of the
myelin-associated self-proteins and "susceptible" if they develop
the disease after experimental challenge with one of the several known
myelin-associated proteins that can cause the disease, such as
proteolipid protein (PLP) (Bebo et al., 1998), myelin basic protein
(MBP) (Kerlero de Rosbo et al., 1995), or myelin oligodendrocyte
glycoprotein (MOG) (Mendel et al., 1995). Regulation of the immune
response in general, and of the autoimmune response in particular, may take place on more than one physiological level. Accordingly, malfunction of control mechanisms in susceptible strains or individuals may occur at different levels in the hierarchy of autoimmune
regulation. Mechanisms of control might include (1) appropriate
presentation of the antigen in a complex with major histocompatibility
complex (MHC) molecules, (2) the ability to evoke regulatory
T-cells, and (3) neuroendocrine effects on immune cell regulation and activation.
In the present study, using injured optic nerves of rats and mice as
models, we show that the extent of degeneration that inevitably follows
any CNS insult of given severity is controlled by the immune system and
is manifested by the ability of individuals that are resistant to
autoimmune disease (and the inability of those that are susceptible) to
display a beneficial T-cell-dependent response. We show that the
survival rate of retinal ganglion cells (RGCs) in adult mice or rats,
after crush injury of the optic nerve or intravitreal injection of
glutamate at a toxic dosage, was up to twofold higher in strains that
are resistant to CNS autoimmune diseases than in susceptible strains.
The difference was found to be attributable to a beneficial
T-cell-dependent response, which was spontaneously evoked after CNS
insult in the resistant but not in the susceptible strains. These
results suggest the existence of a close association between resistance
to autoimmune diseases and ability to evoke protective T-cell-dependent immunity.
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MATERIALS AND METHODS |
Animals. Inbred female adult Lewis (Lew), Sprague
Dawley (SPD), and Fisher (F344) rats and adult mice of the BALB/c/OLA,
BALB/c/OLA nu/nu, C57BL/6J, C57BL/6J nu/nu,
SJL/J, B10.PL, F1(SJL/J×BALB/c/OLA), C3H.SW, and C3H/HeJ strains
(8-12 weeks old) were supplied by the Animal Breeding Center of The
Weizmann Institute of Science under germ-free conditions. Note that not
all the resistant strains used in this work have been classified as
absolutely experimental autoimmune encephalomyelitis (EAE)-resistant
but showed varying degree of resistance. The rats and mice were housed
in a light- and temperature-controlled room and matched for age in each
experiment. Animals were handled according to the regulations
formulated by the Institutional Animal Care and Use Committee.
Crush injury of the optic nerve in rats and mice. Animals
were deeply anesthetized by intraperitoneal injection of 2% XYL-M (xylazine, 10 mg/kg; VMD, Arendonk, Belgium) and Ketaset (ketamine, 50 mg/kg; Fort Dodge Laboratories, Fort Dodge, IA). The rat optic nerve
was exposed using a binocular operating microscope, and calibrated
cross-action forceps were used to inflict a crush injury on the nerve
1-2 mm from the eye. Mice were subjected to severe crush injury of the
intraorbital portion of the optic nerve. The uninjured contralateral
nerve was left undisturbed.
Intravitreal glutamate injection. The right eye of an
anesthetized animal was punctured with a 27 gauge needle in the upper part of the sclera, and a 10 µl Hamilton syringe with a 30 gauge needle was inserted as far as the vitreal body. A total volume of 1 µl of L-glutamate (200 nmol) dissolved in
saline was injected.
Measurement of secondary degeneration in rats. Secondary
degeneration of optic nerve axons and their attached RGCs was measured by retrograde labeling of RGCs after postinjury application of the
fluorescent lipophilic dye
4-(4-(didecylamino)styryl)-N-methylpyridinium iodide
(4-Di-10-Asp) (Molecular Probes Europe BV, Leiden, The Netherlands),
distal to the lesion site, 2 weeks after crush injury. Because only
axons that are intact can transport the dye back to their cell bodies,
application of the dye distal to the lesion site after 2 weeks ensures
that only axons that survived both the primary damage and the secondary
degeneration will be counted. This approach enabled us to differentiate
between neurons that are still functionally intact and neurons in which
the axons are injured but the cell bodies are still viable, because
only those neurons whose fibers are morphologically intact can take up
dye applied distally to the site of injury and transport it to their cell bodies. Using this method, the number of labeled RGCs reliably reflects the number of still-functioning neurons. Labeling and measurement were performed as follows. The right optic nerve was exposed for the second time, again without damaging the retinal blood
supply. Complete axotomy was performed 1-2 mm from the distal border
of the injury site, and solid crystals (0.2- to 0.4-mm-diameter) of
4-Di-10-Asp were deposited at the site of the newly formed axotomy.
Five days after dye application, the rats were killed. The retina was
detached from the eye, prepared as a flattened whole mount in 4%
paraformaldehyde solution, and examined for labeled RGCs by
fluorescence microscopy.
Retrograde labeling of retinal ganglion cells in mice. Mice
were anesthetized and placed in a stereotactic device. The skull was
exposed and kept dry and clean. The bregma was identified and marked.
The designated point of injection was at a depth of 2 mm from the brain
surface, 2.92 mm behind the bregma in the anteroposterior axis and 0.5 mm lateral to the midline. A window was drilled in the scalp above the
designated coordinates in the right and left hemispheres. The
neurotracer dye FluoroGold (5% solution in saline; Fluorochrome,
Denver, CO) was then applied (1 µl, at a rate of 0.5 µl/min in each
hemisphere) using a Hamilton syringe, and the skin over the wound was sutured.
Assessment of retinal ganglion cell survival in mice. Mice
were given a lethal dose of pentobarbitone (170 mg/kg). Their eyes were
enucleated, and the retinas were detached and prepared as flattened
whole mounts in 4% paraformaldehyde solution. Labeled cells from four
to six selected fields of identical size (0.7 mm2) were counted. The selected fields
were located at approximately the same distance from the optic disk
(0.3 mm) to overcome the variation in RGC density as a function of
distance from the optic disk. Fields were counted under the
fluorescence microscope (magnification of 800×) by observers blinded
to the identity of the retinas. The average number of RGCs per field in
each retina was calculated.
Spinal cord contusion in rats. Rats were anesthetized, and
their spinal cords were exposed by laminectomy at the level of T8. A 10 gm rod was dropped onto the laminectomized cord from a height of 50 mm,
using the NYU impactor (Basso et al., 1996a,b; Hauben et al., 2000a).
Sham-operated rats were laminectomized but not contused.
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RESULTS |
Rate of retinal ganglion cell survival after optic nerve insult in
mice correlates with resistance to autoimmune disease induction
We initially selected strains of rats or mice that differ in their
susceptibility to EAE, a CNS autoimmune disease associated with CNS
myelin proteins. The mice used in the following experiments were
susceptible to the development of EAE after challenge with different
CNS self-proteins emulsified in complete Freund's adjuvant. As
discussed below, the susceptibility of each of the selected strains to
EAE is similar to their susceptibility to other autoimmune diseases. We
selected strains that are susceptible or resistant not only to one
myelin-associated protein but to several. Optic nerves were subjected
to severe crush injury in mice of five strains [B10.PL, C57BL/6J,
SJL/J, BALB/c/OLA, and F1(SJL/J×BALB/c/OLA); n = 6-8
in each strain] known to differ in their resistance to EAE. Three days
before injury, the RGCs of these mice had been stereotactically labeled
with a neurotracer dye injected into the superior colliculus.
Significantly more surviving RGCs (mean ± SE per square
millimeter for all values recorded here) were found 1 week after
axonal injury in BALB/c/OLA mice (a strain resistant to EAE; 1645 ± 26) than in mice of two EAE-susceptible strains: B10.PL mice
(1239 ± 51) and C57BL/6J mice (1251 ± 117) (susceptible
strains that develop EAE when challenged with MBP and MOG,
respectively) (Fig. 1a).
Similarly, the number of surviving RGCs measured 2 weeks after optic
nerve injury in the mouse strains SJL/J and F1(SJL/J×BALB/c/OLA)
(susceptible strains that develop EAE when challenged with PLP and MBP,
respectively) were 439 ± 46 and 447 ± 25 and were
significantly lower than those obtained in EAE-resistant BALB/c/OLA
mice (638 ± 31) (Fig. 1b). There were no differences
in the total numbers of RGCs in the retinas of undamaged nerves of any
of the tested strains (3500 ± 100). The above results suggested
that a genetic predisposition to autoimmune disease, regardless of the
identity of the myelin-associated antigen that triggers it, is
correlated with a relatively more severe outcome of CNS injury. To
verify this tentative conclusion, we used congenic mice (C3H.SW and
C3H/HeJ) that differ only in their H-2 haplotype and are known to
respond differently to challenge by MOG peptides (only the C3H.SW mice
develop EAE) (Duong et al., 1994; Mendel et al., 1995). Two weeks after
optic nerve injury, significantly more surviving RGCs were found in the
C3H/HeJ mice (738 ± 48) than in the C3H.SW mice (545 ± 23)
(Fig. 1c).
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Figure 1.
Survival rate of retinal ganglion cells after
optic nerve injury is associated with resistance to the autoimmune
disease EAE. The RGCs of adult C57BL/6J, B10.PL, BALB/c/OLA
(a), BALB/c/OLA, SJL/J, F1(SJL/J×BALB/c/OLA)
(b), and C3H.SW and C3H/HeJ
(c) mice were retrogradely labeled with the
neurotracer dye FluoroGold injected stereotactically into the superior
colliculus. Three days later, the mice were subjected to severe crush
injury of the intraorbital portion of the optic nerve. One
(a) or 2 (b, c)
weeks after optic nerve crush injury, the retina was detached from the
eye, prepared as a flattened whole mount, and examined for labeled RGCs
by fluorescence microscopy. One week after the injury, survival rates
were significantly lower in B10.PL and C57BL/6J mice than in resistant
BALB/c/OLA mice (p < 0.01)
(a). Similar results were obtained in SJL/J
(p < 0.01) and F1(SJL/J×BALB/c/OLA) mice
(p < 0.001), in which RGC survival rates
were significantly lower than in the resistant BALB/c/OLA mice
(b). RGC survival rates were significantly higher
in C3H/HeJ mice (EAE-resistant) than in congenic (EAE-susceptible)
C3H.SW mice (p < 0.001)
(c). The average numbers of RGCs on the uninjured
side were similar (~3500 RGCs per square millimeter) in all mouse
strains. **p < 0.01; ***p < 0.001; Student's
t test.)
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Secondary degeneration in injured rat optic nerve correlates with
susceptibility to experimental autoimmune encephalomyelitis
In the mouse model used for the above experiments, the severe
crush injury damages all of the axons at the same time. Cell body death
is then inevitable, and differences in the physiological response to
trauma in this model are therefore assessed in terms of the rate of
cell body death. This explains why the differences among the groups,
although significant, were small. To examine the link between secondary
degeneration (degeneration of initially spared neurons because of the
hostility of their extracellular environment) and susceptibility to
autoimmune diseases, we used the model of partial crush injury of the
rat optic nerve, in which some of the neurons are intentionally left
undamaged and, in the absence of any intervention, will undergo
secondary degeneration (Yoles and Schwartz, 1998). The injury was
inflicted in rats of three strains: F344, SPD (both resistant to EAE),
and Lew (susceptible to EAE after MBP challenge). Lew and F344 rats
possess the same alleles of the rat MHC RT1.B locus, except
for a single allele in the nonclassical region corresponding to the
mouse Qa-Tla (Kunz et al., 1989). These two strains differ in their
neuroendocrine balance. However, it was shown recently that their
differences with respect to susceptibility to autoimmune disease
development, after active immunization with CNS self-proteins, can be
attributed to differences in the immune regulatory network that is
upregulated to a much greater extent in F344 rats than in Lew rats (Sun
et al., 1999). Interstrain differences in hypothalamus pituitary axis,
which might also contribute to the differences in the outcome of CNS
injury, have not yet been investigated in these two strains. The
outcome of the injury, in terms of the survival of neurons that had
escaped the primary injury, was significantly better in the two
EAE-resistant strains (F344, 43 ± 3; SPD, 60 ± 4) than in
the susceptible strain (Lew, 28 ± 2 or 32 ± 3; tested in
two different experiments; n = 6 in each) (Fig.
2a,b).
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Figure 2.
Survival of neurons after partial crush injury of
the optic nerve in Lew, SPD, and F344 rats. The optic nerves of
adult Lew, SPD, and F344 rats were subjected to a partial crush injury
1-2 mm from the eye, using calibrated cross-action forceps. Two weeks
later, the optic nerves were exposed for the second time, and the
fluorescent dye 4-Di-10-Asp was applied distally to the injury site.
Five days after dye application, the retinas were detached from the
eyes and prepared for fluorescence microscopy as described in Figure 1.
The amount of endogenous neuroprotection was significantly greater in
F344 and SPD rats (p < 0.01 and
p < 0.001, respectively), known to be resistant to
EAE induction. **p < 0.01; ***p < 0.001;
Student's t test.
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Our recent studies in Lew and SPD male rats after contusive injury of
the spinal cord, a model that allows repeated noninvasive assessment of
recovery by examination of functional activity, showed that the
response to trauma is profoundly affected by strain differences. A 3 month follow-up of the spontaneous recovery from identical contusions
at the level of T7 revealed that, in the Lew rats, known to be
susceptible to autoimmune disease development, there was almost
complete paralysis of the hind limbs (measured by mobility in an open
field) (Hauben et al., 2000), whereas significant walking ability was
observed in the EAE-resistant SPD rats (U. Hauben, E. Agranov, and M. Schwartz, unpublished observations).
EAE-resistant rats show better postinjury neuronal survival than
susceptible rats because of their beneficial T-cell-dependent
response
The better postinjury neuronal survival in the resistant animals,
if it indeed reflects a T-cell-dependent response, could be the result
of either an injury-evoked beneficial T-cell-dependent response that
occurs in the resistant but not in the susceptible strains or an
injury-evoked destructive immunity that occurs in the susceptible but
not in the resistant strains. To examine these possibilities, we
measured secondary degeneration after optic nerve injury in adult
EAE-susceptible and EAE-resistant rats that were devoid of mature
T-cells as a result of having undergone thymectomy at birth. When
compared with their respective nonthymectomized controls, the number of
surviving neurons in the resistant (SPD) rats was significantly lower
(by 60 ± 7%), whereas in the susceptible (Lew) rats it was not
significantly affected (Fig.
3a). These findings imply
that, in normal SPD rats, the spontaneous T-cell-dependent response to
injury is beneficial for CNS recovery and thus, in the absence of such
a response, i.e., after thymectomy, recovery is worse. In contrast, in
the susceptible Lew rats, this beneficial T-cell-mediated response is
apparently missing and might even be replaced by a response that is
deleterious to nerve survival; thus, in the absence of T-cells, i.e.,
after thymectomy, recovery is either unaffected or slightly improved
(Fig. 3a). This interpretation was further substantiated by
comparing the survival rate of RGCs in Lew rats with that in SPD rats
in response to optic nerve crush sustained 2 weeks after contusive
injury to the spinal cord. This experiment was designed on the basis of
a previous study in our laboratory showing that, in SPD (resistant)
rats, the number of surviving RGCs after optic nerve injury inflicted
7-17 d after spinal cord contusion is significantly higher than after
optic nerve injury in sham-operated rats (Yoles et al., 2001). It was further shown that this conditioning effect is mediated by T-cells. The
ratios (expressed as a percentage) of the RGC survival rate in spinally
contused rats to that in rats without previous spinal cord injury were
compared between the two strains. The comparison showed that, in
contrast to the finding in the resistant SPD rats in which the number
of surviving RGCs after optic nerve injury in the preconditioned group
was significantly better (by 80 ± 15%) than in controls, in the
susceptible Lew rats the effect of previous injury of the spinal cord
on recovery from optic nerve injury was slightly worse, but the
difference was not significant (Fig. 3b).
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Figure 3.
T-cell dependence of physiological differences in
the response to optic nerve crush injury in EAE-resistant and
EAE-susceptible rats. a, Adult Lew and SPD rats, which
had undergone thymectomy 1 d after birth, and normal adult control
rats were subjected to optic nerve crush, and their RGCs were counted 2 weeks later, as described in Figure 2. Significantly fewer labeled RGCs
were seen in the thymectomized SPD rats than in the normal SPD rats
(p < 0.01). In Lew rats, the opposite was
seen, but the effect was not significant (p > 0.1). b, Lew and SPD rats, thymectomized 1 d
after birth, were subjected to contusive injury of the spinal cord at
the level of T7 or T9 using the NYU impactor. Sham-operated rats were
laminectomized but not contused. After 2 weeks, both sham-operated and
contused rats were subjected to optic nerve crush and counting of
surviving RGCs, as described in Figure 2. Significantly more labeled
RGCs were seen in the preinjured SPD rats than in the sham-operated SPD
controls (p < 0.05). In Lew rats,
differences in the number of labeled RGCs between the preinjured and
the sham-operated rats after optic nerve injury were not significant
(p > 0.1). *p < 0.05;
**p < 0.01; Student's t test.
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Survival of neurons after injection of a toxic dose of glutamate
correlates with resistance to autoimmune disease induction
The finding that the neuronal survival rate in EAE-resistant mice
was higher than in EAE-susceptible mice after mechanical injury
prompted us to examine whether the same applies after biochemical insult produced by direct exposure of the neuronal cell bodies to
glutamate, the main mediator of neurotoxicity in CNS trauma or stroke
(Juurlink et al., 1998). We found that RGC survival, measured by
retrogradely labeling the RGCs and then counting the labeled cells 1 week after intraocular glutamate injection, was significantly higher in
the resistant BALB/c/OLA mice (2170 ± 48) than in susceptible
C57BL/6J mice (1408 ± 129; n = 12 in each group)
(Fig. 4a). The association
between neuronal survival after glutamate toxicity and susceptibility
to autoimmune disease was further strengthened by our findings in the
congenic mice C3H/HeJ and C3H.SW, which differ only in their H-2
haplotype. The number of RGCs that survived an intravitreal injection
of a toxic dose of glutamate was higher in the resistant C3H/HeJ mice
(1090 ± 74) than in the susceptible C3H.SW mice (807 ± 65;
n = 6 in each group) (Fig. 4b).
Interestingly, intraocular injection of glutamate into rats yielded a
similar correlation between RGC loss and EAE susceptibility (F344 rats,
1627 ± 40; Lew rats, 1220 ± 70) (Fig. 4c) to
that seen in the mice (Fig. 4a,b).
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Figure 4.
Glutamate toxicity is correlated with
susceptibility to autoimmune disease. Glutamate (200 nmol) was injected
intravitreally into EAE-susceptible and EAE-resistant strains of mice
(C57BL/6J and BALB/c/OLA, respectively), the congenic mice C3H.SW and
C3H/HeJ (differing in H-2 haplotype), and rats (Lew and F344). One week
after glutamate injection, more surviving RGCs were found in mice of
EAE-resistant strains (C3H/HeJ and BALB/c/OLA) than in susceptible
strains (C3H.SW and C57BL/6J) (p < 0.001 in
both a and b). As with the mice,
significantly more RGCs were seen in the retinas of EAE-resistant rats
(F344) than in the retinas of EAE-susceptible rats (Lew)
(c, p < 0.001). No differences in
the numbers of RGCs between susceptible and resistant strains were
observed on the uninjured side in either rats or mice. ***p < 0.001; Student's t test.
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These results demonstrated that recovery from CNS trauma, regardless of
the nature of the insult, is better in rats and mice that are endowed
with a higher resistance to induction of CNS-associated autoimmune
disease. The higher rate of RGC survival observed in EAE-resistant rats
than in EAE-susceptible rats after glutamate insult may result, as
shown in the case of axonal injury (Fig. 3), from an insult-induced
T-cell-dependent beneficial response that is present in the former and
absent in the latter. To verify this possibility, we compared the
effect of glutamate injection in normal adult SPD rats with that in
adult SPD rats lacking mature T-cells as a result of having undergone
thymectomy at birth. The number of surviving RGCs was significantly
lower in the rats devoid of T-cells (1221 ± 66) than in the
normal rats (1627 ± 39) (Fig. 5a). Additional confirmation
came from experiments using transgenic mice with defective development
of the cortical epithelium of the thymus (nude mice), leading to a
deficiency of mature T-cells. We compared the effects of toxic
concentrations of glutamate in the nude mice and their matched
wild-type controls from two strains (Fig. 5b). In the
genetically resistant BALB/c/OLA strain, the number of surviving RGCs
after exposure to glutamate toxicity was significantly lower in the
nude mice than in the normal mice [1188 ± 51 (n = 6) compared with 2170 ± 48 (n = 13)]. In
contrast, there were no significant differences in RGC survival between nude and normal mice of the EAE-susceptible C57BL/6J strain [1408 ± 129 (n = 17) compared with 1259 ± 45 (n = 12)].
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Figure 5.
Glutamate evokes a self-protective autoimmune
response in mice and rats genetically resistant to EAE induction.
Normal adult SPD rats and adult SPD rats that had undergone thymectomy
at birth were injected intravitreally with glutamate (200 nmol). One
week later, the numbers of surviving RGCs were determined by retrograde
labeling with 4-Di-10-Asp. Significantly fewer surviving RGCs were seen
in the thymectomized rats than in the normal controls
(a, p < 0.01). After glutamate
toxicity, nude mice of a genetically susceptible strain (C57BL/6J)
showed no differences in RGC survival rates compared with their
wild-type counterparts, whereas RGC survival rates in nude mice of a
genetically resistant strain were significantly decreased
(p < 0.001) (b).
*p < 0.05; ***p < 0.001; Student's
t test.
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| |
DISCUSSION |
The results of this study demonstrate a link between the rate of
neuronal survival after CNS insult and the resistance to autoimmune
disease development. This link was found to be mediated by an
injury-induced beneficial T-cell response that was present in the
genetically resistant animals but not in the susceptible ones (defined
in terms of the development of EAE after challenge with any
myelin-associated antigen). The beneficial T-cell-dependent response
evoked by the insult was found to be independent of the type of the
insult (mechanical or biochemical) or the location (axon or cell body)
of the primary insult.
Different strains are known to respond differently to myelin-associated
antigens and to show different susceptibilities to EAE (Arnon, 1981).
The source of the differences has been located in both the MHC class II
antigens and elsewhere. Congenic mice (C3H.SW,
H-2b, and C3H/HeJ,
H-2k), differing only in their H-2
haplotype, were found to differ in their susceptibility to EAE (Duong
et al., 1994). Mice that share the same H-2 haplotype (SJL/J and B10.S)
were also found to have different susceptibilities to EAE, and the
source of this difference is located outside of the MHC class II
antigens (Livingstone et al., 1995; Kuchroo and Weiner, 1998).
Similarly, Lew and F344 rats were found to differ in their
susceptibilities to autoimmune diseases not associated with H-2.
Although these two strains differ in their neuroendocrine interactions,
difference in regulatory T-cells could explain the difference in
susceptibility (Sun et al., 1999).
All strains examined in this study exhibited the same relationship
between outcome of injury and resistance to autoimmune disease,
regardless of whether the insult was mechanical (primarily affecting
the axons and involving myelin-associated antigens) or biochemical
(directly affecting the cell bodies and presumably involving antigens
other than those associated with myelin). Moreover, the outcome of both
mechanical and biochemical CNS injury was worse in transgenic nude mice
or animals devoid of T-cells because of neonatal thymectomy than
in the corresponding wild type. In contrast, among susceptible strains,
the outcome of the injury in animals without T-cells did not differ
from that in their wild-type counterparts. Because T-cell-mediated
mechanisms disappeared in thymectomized and nude animals, it is
suggestive that the differences in the outcome of CNS injury in strains
of different susceptibilities are T-cell dependent. It further suggests
that a beneficial T-cell-dependent response is present in resistant but
not in susceptible strains.
In animal studies of traumatic CNS injury worldwide, no effort was made
to find a link between neuronal recovery and the resistance or
susceptibility of a particular strain to autoimmune disease. Studies
have attempted to link the outcome of neuronal trauma to genetic
(Friedman et al., 1999; Mattson et al., 2000) or anatomic (Yang et al.,
1997) differences between strains, but no attention was directed to the
possibility that the response to trauma is controlled by the immune
system. Indeed, the traditional view was that if CNS insult evokes any
immune response at all, it could only be detrimental for neuronal
survival. Our results strongly suggest that animals of different
strains differ in the amount of beneficial (neuroprotective)
T-cell-dependent autoimmunity that they develop in response to CNS
insult. Thus, a genetic background determining susceptibility to
autoimmune CNS diseases will predispose the individual to a severe
outcome from CNS insult.
One of the major factors determining whether or not an autoimmune
disease will develop in a particular individual appears to be the
presence or absence, not of autoreactive T-cells (which are found in
patients with the autoimmune disease multiple sclerosis, as well as in
healthy individuals), but of mechanisms that regulate the proper
functioning of the autoreactive T-cells (for review, see Shevach,
2000). It is not clear, however, from the present study whether the
same T-cells, depending on the regulatory conditions and the tissue
context, can either beneficially affect the neurons or cause myelin
damage. It is possible that the autoimmune T-cell response evoked by a
traumatic insult is common to all individuals, and the nature of the
subsequent T-cell regulatory response, determining whether the effect
is beneficial or harmful, differs in resistant and susceptible
individuals. Preliminary data from our laboratory (J. Kipnis, I. Shaked, T. Mizrachi, and M. Schwartz, unpublished observations)
(Schwartz and Kipnis, 2001) show that protective autoimmunity is a
multicellular response exhibited by a network of autoimmune T-cells,
including the classical CD4+ cells
(considered to be the T-cells that mediate autoimmune disease development) and regulatory T-cells (evoked in response to the CD4+ cells). The presence of the
CD4+ T-cells without the regulatory
T-cells is not neuroprotective and may even be destructive to myelin.
Such a regulatory T-cell response may be related to the T-cell response
described recently as "the third function of the thymus" (Seddon
and Mason, 2000). In addition, it may be affected by neuroendocrine
balance, as appeared to be the case in F344 rats. Indeed, it was shown
recently that the resistance of F344 rats to autoimmune disease
development, after active immunization with CNS self-proteins, can be
attributed to the presence of an immune regulatory network (Sun et al.,
1999). It seems that such T-cell-dependent regulatory mechanisms exist in resistant individuals or strains but are lacking or malfunctioning in susceptible ones. This further supports our early proposal that the
spontaneous autoimmune response is beneficial and becomes destructive
(causing an autoimmune disease) only when the regulatory mechanism
breaks down (Cohen and Schwartz, 1999; Schwartz et al., 1999a; Schwartz
and Cohen, 2000). The existence of a regulatory mechanism that inhibits
the development of an autoimmune disease, although not of an autoimmune
response, may explain the high incidence of autoimmune T-cells often
found in healthy individuals. It may also explain the observed
occurrence of multiple autoimmune diseases in a single, probably
susceptible, individual when the resistance breaks down (Bellone et
al., 1991; Oshima et al., 1998; Zhu et al., 1998; Ligier and Sternberg,
1999; Yocum, 1999; Goebels et al., 2000). Such a mechanism can also
explain why non-autoimmune CNS degenerative diseases progress
differently in different individuals.
Our studies may suggest that an upstream mechanism(s) regulates the
response to stress signals associated with pathogen-free tissue damage
(i.e., to self-antigens) in such a way as to derive the beneficial
T-cell-dependent response and not an autoimmune disease. Several
hypotheses have been proposed for controlling the response to self
(Burnet, 1959; Jerne, 1974; Cohen, 1992; Matzinger, 1994). Our results
point to an immune response to trauma that operates not by
distinguishing between self and non-self antigens but rather according
to how the response to self is regulated and what characterizes the
phenotype of the beneficial anti-self response.
The results of this study strongly suggest that an individual's
genetically determined predisposition to autoimmune diseases seems to
be crucial not only for prognosis of damage after CNS injury but also
for planning therapy, because what is applicable to resistant
individuals or strains might not be helpful in those that are
susceptible. An understanding of the genetic basis of the mechanisms
that control the beneficial T-cell-dependent response evoked by CNS
trauma may lead to the discovery of ways to boost the immunological
conditions needed for recovery from CNS acute insults, for arresting
the progression of chronic degenerative CNS disorders, and for
avoidance of autoimmune disease.
| |
FOOTNOTES |
Received Nov. 9, 2000; revised April 4, 2001; accepted April 13, 2001.
This work was supported by Proneuron Ltd. (Ness-Ziona, Israel) and in
part by grants from the Glaucoma Research Foundation and the Alan Brown
Foundation for Spinal Cord Injury awarded to M.S. We thank S. Smith for
editing this manuscript and A. Shapira for animal maintenance. M.S.
holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology.
J.K. and E.Y. contributed equally to this work.
Correspondence should be addressed to Dr. Michal Schwartz, Department
of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot,
Israel. E-mail: michal.schwartz{at}weizmann.ac.il.
| |
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The Tissue-Specific Self-Pathogen Is the Protective Self-Antigen: The Case of Uveitis
J. Immunol.,
November 15, 2002;
169(10):
5971 - 5977.
[Abstract]
[Full Text]
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M. Schwartz and J. Kipnis
Multiple Sclerosis as a By-Product of the Failure to Sustain Protective Autoimmunity: A Paradigm Shift
Neuroscientist,
October 1, 2002;
8(5):
405 - 413.
[Abstract]
[PDF]
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H. Schori, F. Lantner, I. Shachar, and M. Schwartz
Severe Immunodeficiency Has Opposite Effects on Neuronal Survival in Glutamate-Susceptible and -Resistant Mice: Adverse Effect of B Cells
J. Immunol.,
September 15, 2002;
169(6):
2861 - 2865.
[Abstract]
[Full Text]
[PDF]
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S. Bakalash, J. Kipnis, E. Yoles, and M. Schwartz
Resistance of Retinal Ganglion Cells to an Increase in Intraocular Pressure Is Immune-Dependent
Invest. Ophthalmol. Vis. Sci.,
August 1, 2002;
43(8):
2648 - 2653.
[Abstract]
[Full Text]
[PDF]
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T. B. Jones, D. M. Basso, A. Sodhi, J. Z. Pan, R. P. Hart, R. C. MacCallum, S. Lee, C. C. Whitacre, and P. G. Popovich
Pathological CNS Autoimmune Disease Triggered by Traumatic Spinal Cord Injury: Implications for Autoimmune Vaccine Therapy
J. Neurosci.,
April 1, 2002;
22(7):
2690 - 2700.
[Abstract]
[Full Text]
[PDF]
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E. Hauben, A. Ibarra, T. Mizrahi, R. Barouch, E. Agranov, and M. Schwartz
Vaccination with a Nogo-A-derived peptide after incomplete spinal-cord injury promotes recovery via a T-cell-mediated neuroprotective response: Comparison with other myelin antigens
PNAS,
December 18, 2001;
98(26):
15173 - 15178.
[Abstract]
[Full Text]
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TOP
ABSTRACT
INTRODUCTION
