A new animal model of spontaneous autoimmune peripheral polyneuropathy: implications for Guillain-Barré syndrome
© Yang et al.; licensee BioMed Central Ltd. 2014
Received: 23 October 2013
Accepted: 21 December 2013
Published: 8 January 2014
Spontaneous autoimmune peripheral neuropathy including Guillain-Barré Syndrome (GBS) represents as one of the serious emergencies in neurology. Although pathological changes have been well documented, molecular and cellular mechanisms of GBS are still under-explored, partially due to short of appropriate animal models. The field lacks of spontaneous and translatable models for mechanistic investigations. As GBS is preceded often by viral or bacterial infection, a condition can enhance co-stimulatory activity; we sought to investigate the critical role of T cell co-stimulation in this autoimmune disease.
Our previous study reported that transgene-derived constitutive expression of co-stimulator B7.2 on antigen presenting cells of the nervous tissues drove spontaneous neurological disorders. Depletion of CD4+ T cells in L31 mice accelerated the onset and increased the prevalence of the disease. In the current study, we further demonstrated that L31/CD4-/- mice exhibited both motor and sensory deficits, including weakness and paresis of limbs, numbness to mechanical stimuli and hypersensitivity to thermal stimulation. Pathological changes were characterized by massive infiltration of macrophages and CD8+ T cells, demyelination and axonal damage in peripheral nerves, while changes in spinal cords could be secondary to the PNS damage. In symptomatic L31/CD4-/- mice, the disruption of the blood neural barriers was observed mainly in peripheral nerves. Interestingly, the infiltration of immune cells was initiated in pre-symptomatic L31/CD4-/- mice, prior to the disease onset, in the DRG and spinal roots where the blood nerve barrier is virtually absent.
L31/CD4-/- mice mimic most parts of clinical and pathological signatures of GBS in human; thus providing an unconventional opportunity to experimentally explore the critical events that lead to spontaneous, autoimmune demyelinating disease of the peripheral nervous system.
Guillain-Barré Syndrome (GBS) is an acute immune-mediated polyradiculoneuropathy comprising a broad spectrum of clinical variants, including acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN) and the Miller-Fisher Syndrome (MFS). In its typical form, GBS causes rapidly progressive diffuse weakness or paralysis of the four limbs, sensory loss or pain and areflexia . The sudden and unexpected onset of paralysis is devastating for patients and represents one of the serious emergencies in neurology. The pathological substrate for GBS has been well established with immune cell infiltration, demyelination with or without axonal damage in the peripheral nervous system (PNS), nevertheless molecular and cellular mechanisms have not been fully understood. Although experimental allergic neuritis (EAN) induced by immunization with peripheral nerve proteins or adoptive transfer of sensitized T cells [2, 3] has provided valuable information, it has been criticized for its artificial manipulation . Only one animal model with spontaneous autoimmune peripheral polyneuropathy has been reported in non-obese-diabetic (NOD) mice .
T cell costimulation has a central role in autoimmunity . Infection could promote autoimmunity via inducing the co-stimulatory activity in antigen presenting cells(APCs), which are required to induce the expansion of antigen-reactive T cells, migration of T cells to the site of inflammation and the production of inflammatory mediators [7, 8]. Expression of co-stimulatory molecule B7 was enhanced in the CNS of MS patients and in inflamed nerves of GBS patients [9, 10]. Targeting B7.2/CD28 signaling pathway has been fairly common in experimental studies of autoimmune diseases .
We have previously reported that constitutive expression of B7.2 on APCs in the nervous system (L31 mice) led to neurological dysfunction with spontaneous demyelination and immune cell infiltration in the spinal cords and spinal roots . Both T cells and the expression of B7.2 on spinal cord microglia were required for the development of the disease . A dramatic skewing toward CD8+ T cells in the nervous system suggests a critical role of CD8+ T cells in the pathogenesis , which has been further supported by the fact that depletion of CD4+ T cells in L31 mice accelerated the onset and increased the prevalence of the disease .
In the current study, we used L31 mice on a genetic background where CD4+ T cells were depleted (CD4-/-) to investigate whether constitutive expression of B7.2 could also drive spontaneous demyelination in the PNS and to seek insights for GBS in human. We observed that in addition to motor deficits as reported previously, L31/CD4-/- mice also developed sensory disorders, including numbness to mechanical stimuli and hypersensitivity to thermal stimulation. Severe demyelination, massive infiltration of macrophages, CD8+ T cells, and axonal damage were found predominantly in the PNS, while changes in the spinal cords could be secondary to the PNS damage. The data revealed that L31/CD4-/- mice mimic most parts of clinical and pathological aspects of GBS, suggesting constitutive expression of B7.2 in APCs could be a new and useful animal model of GBS for mechanistic studies.
L31 mice with constitutive expression of co-stimulatory B7.2/CD86 were generated with MHC I promoter and Igμ enhancer . L31/CD4-/- mice have been described previously  and were maintained by successive backcross to C57BL/6 mice for more than 7 generations. C57BL/6 mice bred and housed in the same facility were used as controls. All procedures were in accordance with the guidelines of the Canadian Council on Animal Care, and approved by the animal care committee of McGill University. In total, 49 L31/CD4-/- and 18 C57BL/6 mice (controls), aged at 2-6 months, were included in the study. 29 L31/CD4-/- symptomatic mice and 6 C57BL/6 mice were monitored for their clinical scores and behavioral responses. 20 L31/CD4-/- mice were euthanized before disease onset, as pre-symptomatic mice for tissue collection.
Instruments and reagents
All instruments and reagents have been used in the study were listed in Additional file 1: Table S1.
Assessment of neurological disorders
All mice included in the current study had their disease onset between 2-4 months after birth. Animals whose clinical score ≥4 were excluded from sensory tests.
Clinical scores for motor deficits: 0 = normal; 1 = reduced tonus of tail and/or limp tail; 2 = weakness of one hind limb, staying in clasping or outstretching position when lifted by the tail; 3 = weakness of two hind limbs, both staying in clasping or outstretching position when lifted by the tail; 4 = paresis or splaying of one hind limb; 5 = paresis or splaying of two hind limbs; 6 = moribund or death. L31/CD4-/- transgenic mice with clinical score at 0 were defined as pre-symptomatic mice.
Rotarod assay was used to assess mouse motor coordination. The task included a speed ramp from 0 to 30 rpm over 60 s, followed by an additional 240 s at the maximal speed. The time that each animal walked on the rod before falling was recorded. A decrease in walking time is suggestive of motor impairment.
von Frey Test was performed to test paw sensitivity to mechanical stimuli. Calibrated monofilaments were applied to the plantar surface of the hindpaw and the 50% threshold to withdraw was calculated as previously described . A decrease in threshold suggests the development of mechanical allodynia.
Acetone Test was used to evaluate sensitivity to cold stimuli. Total duration of acetone evoked behaviors (flinching, licking or biting) was measured for 1 minute after one drop of acetone (~25 μl) was applied to the plantar surface of the hindpaw. An increase of withdrawal duration indicates the cold allodynia.
Hot plate (55°C) was used as an unpleasant sensory heat stimulus to measure pain response. The latency to paw-licking, squeaking, or distressful behavior was measured. A decrease in latency suggests the development of heat hypersensitivity.
For histological studies Lumbar spinal cords, L4-L6 DRGs, dorsal roots and sciatic nerves were collected with transcardiac perfusion of 4% paraformaldehyde or cold saline. L4-L6 DRG, roots and sciatic nerves were cut either longitudinally into 12 μm sections or at 5 μm cross-sections with a cryostat. Lumbar spinal cords were cut into 25 μm-thick sections using microtome.
For flow cytometric studies Mice were deeply anaesthetized with isoflurane. Approximately 1 cm long of lumbar spinal cord and 2 cm long of sciatic nerves were collected. Samples were diced into very small pieces in RPMI-1640 medium with streptomycine/penicilline and 10% fetal bovine serum.
Immunohistochemistry and image acquisition
List of antibodies used in the study
Primary antibodies for IHC
Rabbit anti ionized calcium-binding adaptor molecula 1 (Iba-1)
17 kDa EF hand protein expressed on macrophages and microglia
Synthetic peptide of C-terminus Iba-1 N’-PTGPPAKKAISELP-C’
Rat anti mouse CD86
LPS-activated CBA/Ca mouse splenic B cells
Rabbit anti protein gene Product 9.5 (PGP9.5)
All mammalian species, PGP9.5 expressed on neuronal cell bodies and axons in central and peripheral neural system
Human PGP 9.5 Protein purified from pathogen-free human brain
Rabbit anti human activating transcription Factor 3 (ATF3)
Mouse, rat and human, ATF3 expressed on damaged neurons
A peptide mapping at the C-terminus of human ATF-3
Rat anti mouse CD8 alpha
Mouse CD8 alpha
Mouse thymus/spleen cells
1:2000 (fresh frozen tissues with short fixation)
Rabbit anti glucose transporters-1 (Glut1)
Mouse, rat and human, Glut1expressed on endothelial cells and perinurium
Synthetic peptide corresponding amino acids with the C-terminus of human GLUT-1 coupled to KLH (C-ELFHPLGADSQV)
Secondary antibodies for IHC
Alexa fluor 594 goat anti-rabbit IgG
IgG heavy chains and all classes of IgG light chains from rabbit
Molecular probes (Invitrogen)
Alexa fluor 488 goat anti-rabbit IgG
IgG heavy chains and all classes of IgG light chains from rabbit
Molecular probes (Invitrogen)
Alexa fluor 594 rabbit anti-rat IgG
IgG heavy chains and all classes of IgG light chains from rat
Molecular probes (Invitrogen)
Alexa fluor 488 rabbit anti-rat IgG
IgG heavy chains and all classes of IgG light chains from rat
Molecular probes (Invitrogen)
4′,6-diamidino-2-phenylindole dihydrochloride (DAPI)
Fluoro myelin red fluorescent myelin stain
Molecular probes (Invitrogen)
Flow cytometric antibodies
FITC rat anti-mouse CD11b
Mouse CD11b+ cells
C57BL/10 splenic T cells and concanavalin A-activated C57BL/10 splenocytes
Rat anti-mouse CD45 APC
Mouse CD45+ cells
Rat anti-mouse CD8 alpha PerCP-Cy5.5
Mouse CD8+ cells
Rat anti-mouse CD86 (B7.2) PE
Mouse B7.2+ cells
Flow cytometric analysis
Single-cell suspensions and blocking were prepared as described previously . Samples were then stained with specific fluorochrome-conjugated antibodies for 25 min at 4°C. Staining specificity was identified by omitting antibodies, and correlation of spectral overlap was done by using negative and positive compensation beads. Cellular events were acquired using a LSR Fortessa flow cytometer and data was analyzed using Flow Jo software. Detail information of antibodies used here was listed in Table 1.
Evaluation of blood-neural barrier permeability
Blood nerve barrier (BNB), blood spinal cord barrier (BSCB) and blood brain barrier (BBB) permeability was assessed using a micromolecular tracer sodium fluorescein (NaFlu). The protocol was adopted and modified from previous studies . Briefly, NaFlu was administrated intravenously (10%; 2 ml/kg) and allowed to circulate for 30 min. Then, mice were transcardially perfused with cold saline for 10 min to remove intravascular NaFlu. The choroid plexuse, meninge and epineurium were removed before nervous tissues were dissected into different regions: brain, cervical and lumbar spinal cords, and sciatic nerves. Following tissue homogenization, the concentration of NaFlu in supernatant was measured with spectrophotofluorometer. NaFlu was expressed as g/g of tissue.
Data is presented as means ± SEM. Unpaired t-test was used to determine significance between groups. A value of P < 0.05 was accepted as statistically significant.
Constitutive expression of B7.2 in APCs primed resident macrophages in sciatic nerves and microglia in spinal cords
L31/CD4-/- mice developed spontaneous motor and sensory neurological disorders
Poor coordination was observed in both pre-symptomatic (clinical score = 0, ≥ 2 months old) and symptomatic L31/CD4-/- mice (clinical score ≥1). The latency of fall in Rotarod test dropped from 98.60 ± 12.01 sec in wild type mice to 45.50 ± 7.27 sec in pre-symptomatic mice. Symptomatic mice could only stand on the running rod for 12.5 ± 2.72 sec (Figure 2B).
L31/CD4-/- mice also developed sensory disorders. Symptomatic animals exhibited numbness to von Frey hair as paw withdrawal thresholds reached at 3.48 ± 0.15 g, while wild type and pre-symptomatic mice responded at 0.78 ± 0.07 g and 0.83 ± 0.21 g, respectively (Figure 2C). However, they were hypersensitive to cold and heat stimulation. Duration of withdrawal in acetone test was increased (Figure 2D) and the hot plate latency was decreased (Figure 2E) in symptomatic mice. Interestingly, thermal hypersensitivity appeared prior to motor dysfunctions, since alteration in response to cold and heat stimulation was observed in pre-symptomatic mice (Figure 2D-E).
Demyelination and axonal damage in peripheral nerves of symptomatic L31/CD4-/- mice
Massive immune cell infiltration in the sciatic nerves of symptomatic L31/CD4-/- mice
Limited demyelination and immune cell infiltration in the spinal cords of L31/CD4-/- mice
Disruption of blood nerve barrier in the sciatic nerves of diseased L31/CD4-/- mice
Focal inflammatory reaction in the DRG and the roots of pre-symptomatic L31/CD4-/- mice, preceding disease onset
We report here that mice that have been genetically modified to have an increased expression of co-stimulator B7.2 on APCs of the nervous system developed spontaneous autoimmune peripheral polyneuropathy. Pathological changes were characterized by immune cell infiltration, demyelination and axonal damage in peripheral nerves, with restricted damage in spinal cords. The infiltration of immune cells was initiated, prior to the disease onset, in the DRG and the spinal roots where the BNB is physiologically fenestrated.
L31/CD4-/- mice mimic clinical and pathological aspects of GBS in human
The most common initial symptoms of GBS are numbness, paresthesia, weakness and pain in the limbs or some combination of these symptoms. The main feature is progressive bilateral and relatively symmetric weakness of the limbs, and the weakness progresses over a period of 12 hours to 28 days before a plateau is reached . Our results demonstrated that L31/CD4-/- mice replicated many clinical aspects of this complex human autoimmune disease, including both sensory and motor deficits, and a temporal course of an acute onset and a stable progression [21–23]. L31/CD4-/- mice also imitated pathological changes in GBS, with characteristic lymphocytes and macrophages-associated demyelination and axonal damage at the peripheral nerves, suggesting these mice might represent more closely axonal variants of GBS. Although it remains to be determined what are the specific antigens (myelin or axon or both) for autoimmune response, demyelination in peripheral nerves of L31/CD4-/- mice is still distinguishable with myelin loss secondary to Wallerian degeneration by the massive infiltration of T cells which was initiated prior to the damage of the nervous tissues. Comparable to what we observed restricted damage in spinal cords, loss of myelinated fibers in posterior tracts or inflammatory infiltrates/spinal microglia activation in the grey matter have been reported in human GBS [24, 25]. Similar neurological deficits and pathological changes in peripheral nerves were also detected in L31 mice (data not shown). The L31/CD4-/- mouse model had many similarities with the EAN [3, 26], one of the essential tools in the research of autoimmune demyelinating diseases of the PNS. However the use of EAN was restricted due to the administration of powerful immune adjuvants to break-down self-tolerance. The field lacks of spontaneous and translatable models for mechanistic studies. The impressive resemblance between the L31/CD4-/- mouse model and human GBS implies it as an unequivocal experimental setting for spontaneous autoimmune peripheral polyneuropathy, especially as it allows taking advantage of the wealth of genetic resources on the C57BL/6 background.
L31/CD4-/- model provides genetic background for deciphering molecular and cellular mechanisms in GBS
Co-stimulatory signals play a key role in regulating T cell activation and are believed to have a decisive influence in the induction and penetration of cellular effecter mechanisms in spontaneous autoimmune peripheral polyneuropathy. Sensitization of APCs by increasing the expression of B7.2 through genetic approaches simulates certain common pre-dispositive conditions in GBS, e.g., infection, which is usually the most potent stimulus for B7 expression [27, 28]. T cells are required in the pathogenic sequence of immune-mediated nerve damage , but the relative contributions of CD4+ and CD8+ T cells are controversial. Although most inflammatory infiltrates in the PNS of rats with EAN are CD4+ cells , further studies indicated that CD8+ cells may also be involved in the pathogenesis . The necessity of both CD4+ and CD8+ cells in the genesis of EAN was confirmed by using CD4 and CD8 knock-out mice, where the severity of clinical scores and histopathological manisfestations of P0 peptide induced EAN was significantly lower than those in their wild type counterparts . In human GBS, very limited post mortem and biopsy data is available. However, one autopsy study provided clear evidence for a potential involvement of cytotoxic T cells in demyelination. Wanschitz et al  reported that in all 11 examined subjects, among infiltrated endoneurial T cells, the ratio of CD8+ to CD3+ was around 0.7 to 1.4. The density of CD8/CD3 double positive T cells increased significantly in cases with more than 4 weeks duration of illness. Many of these CD8+ cells were found granzyme B positive; Schwann cells and myelin sheaths were detected with upregulation of MHC class I molecules . In coincidence with the observation in GBS patients, our previous and current studies with L31 and L31/CD4-/- mice demonstrated that 1) altering co-stimulation signals primed APCs in the nervous tissue mice and drove a predominately CD8+ T cell mediated autoimmune reaction , 2) CD8+ cells are able to lead to demyelination in the peripheral nerves if they can find co-stimulation in the PNS; 3) The demyelinating disease can be initiated in the absence of CD4+ T cells, even displaying accelerated disease development and increased expressivity , which indicates an immunoregulatory role for CD4+ T cells in disease pathogenesis. Hence, L31 and L31/CD4-/- mice are unique to understand molecular pathways by which CD8+ T cells are involved in demyelination and axonal damage. Albeit, a characterization of functional phenotypes of CD8+ cells in the demyelinating nerves at different stages of the disease is essential, which will provide insights to understand the roles of CD8+ cells in the pathogenesis. Furthermore, crucial questions with regard to the decisive contribution of macrophages, as well as interaction between macrophages and lymphocytes in the context of demyelination and axonal loss could be explored in L31 and L31/CD4-/- mice. However, whether and to what extent antibody mediated humoral immunity is involved in the disease genesis of L31 and L31/CD4-/- mice need to be determined in future experiments.
Limitation of L31 and L31/CD4-/- mice as a model for human GBS
Most patients with GBS recover spontaneously, 62% had made a complete or almost complete recovery at one year . However, neurological disorders in either L31  or L31/CD4-/- mice, with a sudden onset, seem to persist and remain stable. Whether severe myelin/axonal damage and absence of overt recovery in L31/CD4-/- and L31 mice could be attributed to the lack of CD4+ T cell population in the symptomatic nerves is an intriguing topic for further investigation. Or it might be due to the fact that this model reflects more closely to axonal variants of GBS, since most AMAN patients have more delayed recovery than AIDP  and ASMAN has been associated with a more severe course and poorer prognosis .
Proposed cascade of autoimmune demyelination in L31/CD4-/- (and L31) model: implication for GBS
It remains presently elusive how the cascade of autoimmune responses targeting PNS structures is ignited. The fact that infiltration of immune cells was initiated before disease onset, in the roots and the DRG where the BNB is virtually absent  led us to propose the following cascade: 1) Transgene or infection derived- over-expression of co-stimulator B7.2 sensitizes APCs in the nervous tissue; 2) T cells first access the nervous tissue during immune surveillance through the DRGs and the roots where the endoneurial vasculature is basically permeable to various components in the blood stream; 3) T cells, especially CD8+ T cells that have specificities for PNS self-antigens presented by primed macrophages are engaged in productive antigen recognition and are reactivated due to the high levels of B7.2; 4) In aid with massive infiltration of macrophages, CD8+ T cells exert their cytotoxic effector functions, leading to destructive autoimmunity; 5) CD4+ T cells, could in fact, exert immunoregulatory functions during the disease course.
In conclusion, with constitutive expression of B7.2 in APCs of the nervous tissues, L31/CD4-/- (and L31) mice mimic many clinical and pathological signatures of GBS in human and provides an unconventional opportunity to experimentally explore the critical events that lead to spontaneous, autoimmune demyelinating disease of the PNS.
M.Y. and A.R. are supported by the CIHR Neuroinflammation Training Program. J. Z is a FRSQ research scholar. This work was supported by funding from the Canadian Institutes for Health Research (CIHR) MOP-111129 to J.Z. and from Multiple Sclerosis Society of Canada to S.F. We are grateful to Dr. Jack Antel, Dr. Samuel Ludwin, Dr. Gary Bennett and Dr. Samuel David for their critical review and discussion on the manuscript.
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