Exogenous soluble tumor necrosis factor receptor type I ameliorates murine experimental autoimmune neuritis

Tumor necrosis factor (TNF) and its receptor (TNFR) have been strongly implicated in the pathogenesis of autoimmune disease. Soluble cytokine receptors may be shed naturally from cell membranes to inhibit cytokine activity. Experimental autoimmune neuritis (EAN) is a CD4 Th1 cell-mediated animal model of Guillain-Barré syndrome (GBS) in humans. In the present study, we investigated the effects of soluble TNFR type I (sTNFR I) in EAN induced in mice by P0 peptide 180-199 and Freund's complete adjuvant. Our data from two different therapeutic regimens indicate that the administration of sTNFR I effectively ameliorated the clinical and pathological signs of EAN, i.e., decreased its severity, shortened its duration, and reduced inflammatory cell infiltration into the peripheral nervous system. The suppression of clinical EAN was accompanied in vitro by a marked reduction in antigen-specific T-cell proliferation and IFN-gamma synthesis by spleen cells from sTNFR I-treated mice, compared to control mice treated with PBS. These data directly demonstrate a pivotal role for TNF in the development of EAN and also suggest that sTNFR I may have therapeutic potential for alleviating GBS in humans.     

CCR5 deficiency does not prevent P0 peptide 180-199 immunized mice from experimental autoimmune neuritis

Experimental autoimmune neuritis (EAN) is an inflammatory autoimmune demyelinating disease of peripheral nervous system (PNS) and represents an animal model of Guillain-Barré syndrome (GBS) in man. The inflammatory cell infiltrating into the PNS is a prerequisite for developing EAN. To explore the role of CC chemokine receptor 5 (CCR5) in the inflammatory process of EAN, we induced EAN in CCR5-deficient (CCR5(-/-)) mice with P0 protein peptide 180-199. We found that CCR5(-/-) mice showed a similar EAN clinical course and severity as well as profile of infiltrating macrophages and T cells in cauda equina (CE) of EAN and the same levels of spleen mononuclear cell (MNC) response to antigen and mitogen when compared with CCR5(+/+) control mice. However, increased IP-10 and MIP-1beta production in sciatic nerves were seen in CCR5(-/-) mice. These results suggest that CCR5 deficiency does not prevent P0 peptide 180-199-immunized mice from EAN. Increased MIP-1beta and IP-10 in sciatic nerves may compensate the CCR5 deficiency and contribute to inflammatory cells infiltrating to the PNS.     

CD4 and CD8 T cells,but not B cells,are critical to the control of murine experimental autoimmune neuritis

Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune disease of the peripheral nervous system that duplicates the clinical, pathological, and electrophysiological features of Guillain-Barré syndrome in humans. However, the molecular pathogenesis of EAN remains controversial. Therefore, for this study, we induced EAN with P0 protein peptide 180-199 in CD4(-/-), CD8(-/-), CD4(-)8(-), and B cell knockout (microMT) mice to further investigate the roles of these cells in EAN. Our results showed that the severity of clinical signs and histopathological manifestations of EAN and the T cell response to P0 peptide 180-199 in CD4(-/-) mice were significantly lower than those in their wild-type counterparts. CD8(-/-) mice also had a milder clinical course, less histopathological change, and a diminished T cell response to P0 peptide 180-199. However, more severe clinical and histopathological manifestations, a stronger T cell response to P0 peptide 180-199, and enhanced IFN-gamma production in the spleen were observed in the EAN of CD4(-)8(-) and microMT mice, but these were not obviously different from those of wild-type mice. Levels of IgG production were similar in sera from CD4(-/-), CD8(-/-), and CD4(-)8(-), and wild-type mice. These findings suggest that the induction and control of murine EAN are dependent on both CD4(+) and CD8(+) T cells and that B cells apparently do not perpetuate the related inflammatory demyelination.     

P0 protein peptide 180-199 together with pertussis toxin induces experimental autoimmune neuritis in resistant C57BL/6 mice

The C57BL/6 mice strain is known to be reputedly resistant to induction of experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome in human by bovine peripheral myelin (BPM), and P2 protein or the P2 protein peptide 57-81. The P0 peptide 180-199 is a stronger neuritogenic antigen than the P2 peptide 57-81. We found that this synthetic peptide induced both clinical and pathological characteristics of an acute monophasic EAN in C57BL/6 mice. Only male mice were more sensitive to EAN induction with the P0 peptide 180-199. Intravenously administrated pertussis toxin (PT) had an adjuvant effect that increased the incidence of P0 peptide 180-199-induced EAN as well as the inflammation and demyelination in the peripheral nerves. Spontaneous and P0 peptide 180-199 stimulated proliferation of peripheral T-cells were enhanced by PT-treatment as well. The enhancing effect was lower before onset of the disease (Day 6 post immunization) (p.i.) as compared to the early phase of the disease (Day 22 p.i.). Thus, P0 peptides together with PT are able to break tolerance to myelin in C57BL/6 mice.     

P0 glycoprotein peptides 56-71 and 180-199 dose-dependently induce acute and chronic experimental autoimmune neuritis in Lewis rats associated with epitope spreading

Two synthetic peripheral nerve myelin P0 protein peptides, an immunodominant (amino acids 180-199) and a cryptic (amino acids 56-71) one, induced an acute or chronic course of experimental autoimmune neuritis (EAN) in Lewis rats, when given at low dose (50-100 microg/rat) or high dose (250 microg/rat), respectively. Corresponding to the different clinical course, pathological changes and immune responses were found: (1) Onset of clinical signs of P0 peptide 56-71 (P0 56-71) induced EAN was 1-3 days later than in P0 peptide 180-199 (P0 180-199) induced EAN at all immunizing doses, whereas the peak of the disease occurred at a similar time point post immunization (p.i.), i.e. at days 14-16 p.i. in P0 56-71 induced EAN and at day 16 p.i. in P0 180-199 induced EAN. (2) Intramolecular epitope spreading as assessed by delayed type hypersensitivity response occurred in P0 56-71 induced EAN at both low and high antigen doses and in P0 180-199 induced EAN at high antigen dose (250 microg/rat) only. (3) P0 180-199 stimulated higher levels of interferon-gamma production in P0 180-199 induced EAN than in P0 56-71 induced EAN and vice versa. (4) Histopathologic evaluation revealed a similar grade of mononuclear cell infiltration in the sciatic nerves of both types of EAN, but more severe demyelination was found in P0 180-199 induced EAN compared to P0 56-71 induced EAN. The results support the hypothesis that high dose autoantigen immunization induces extensive determinant spreading and chronic course of autoimmune diseases.     

Soluble TNFR1 inhibits the development of experimental autoimmune neuritis by modulating blood-nerve-barrier permeability and inflammation

The role of TNFalpha/LTalpha during EAN induced by active immunization with peripheral nerve myelin was examined by administering a recombinant soluble chimeric form of human TNF receptor 1 (TNFR1-IgG). TNFalpha and LTalpha do not directly contribute to neurological deficit during EAN since treatment with TNFR1-IgG after onset failed to alter the course of disease. Prophylaxis with a single dose of TNFR1-IgG delayed the onset of EAN and was accompanied initially by inhibition of blood-nerve-barrier permeability and inflammation. Subsequently, the number of infiltrating macrophages and blood-nerve-barrier permeability increased but the disease symptoms remained mild for five days (on average a limp tail) after which severe EAN developed. The antibody titer to peripheral nerve myelin was unaltered by prophylaxis with TNFR1-IgG. The markedly altered tempo of disease onset after TNFR1-IgG prophylaxis indicates that TNFalpha and/or LTalpha have a key role in the development of blood-nerve-barrier permeability and the coupling of macrophage activation and recruitment to peripheral nerve pathology during EAN.     

Suppression of autoimmune neuritis in IFN-gamma receptor-deficient mice

Experimental autoimmune neuritis (EAN) is an animal model of the human disease Guillain-Barré syndrome. In this autoimmune inflammatory disease, CD4(+) T cells mediate demyelination in the peripheral nervous system (PNS). Infiltrating macrophages and T cells as well as cytokines like interferon (IFN)-gamma are intimately involved in causing pathogenic effects. To investigate the role of IFN-gamma in cell-mediated EAN, IFN-gamma receptor-deficient mutant (IFN-gammaR(-/-)) C57BL/6 mice and corresponding wild-type mice were immunized with P0 peptide 180-199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant. IFN-gammaR(-/-) mice exhibited later onset of clinical disease. The disease was also less severe than in wild-type mice. Fewer IL-12-producing but more IL-4-producing cells were found in sciatic nerve sections from IFN-gammaR(-/-) mice than from wild-type mice on day 24 postimmunization, i.e., at the peak of clinical EAN. At the same time, IFN-gammaR(-/-) mice had less infiltration of inflammatory cells, including macrophages, CD4(+) T cells, and monocytes, into sciatic nerve tissue and less demyelination. However, numbers of IFN-gamma-secreting cells from the spleen were significantly augmented in the IFN-gammaR(-/-) mice, reflecting a failure of negative feedback circuits. The IFN-gammaR deficiency did not affect the production of anti-P0 peptide 180-199-specific antibodies. These results indicate that IFN-gamma contributes to a susceptibility for EAN in C57BL/6 mice by promoting a Th1 cell-mediated immune response and suppressing a Th2 response.     

IL-18 deficiency inhibits both Th1 and Th2 cytokine production but not the clinical symptoms in experimental autoimmune neuritis

IL-18 deficient (IL-18-/-) mice were used to investigate the role of IL-18 in the pathogenesis of experimental autoimmune neuritis (EAN) which was induced by immunization of the mice with P0 protein peptide 180-199. The clinical course was not different between IL-18-/- and wild-type mice. The splenic mononuclear cell (MNC) proliferation was also similar in both animal groups. However, the percentages of IFN-gamma, IL-10 and IL-12 positive cells were decreased among infiltrating MNC of cauda equine in IL-18-/- mice. This indicates that IL-18 deficiency inhibits the production of both Th1 and Th2 cytokines in the target organ of mice with EAN.     

Increased susceptibility to experimental autoimmune neuritis after upregulation of the autoreactive T cell response to peripheral myelin antigen in apolipoprotein E-deficient mice

Experimental autoimmune neuritis (EAN), an acute demyelinating inflammatory disease of the peripheral nervous system (PNS), is a good model for the human counterpart, Guillain-Barré syndrome. Apolipoprotein E (ApoE), a 34 kDa glycosylated protein with multiple biological properties, has been linked both with the innate immune response of mice and with neurological disease. The present study investigated the previously unexplored role of ApoE in autoimmune-mediated demyelination. ApoE-deficient (apoE -/-) mice exhibited a greater susceptibility to EAN induced by the PNS myelin P0 protein peptide 180-199, as compared to wild type (apoE +/+) mice. The augmented susceptibility seen in apoE -/- mice was associated with increased inflammatory cell infiltrates in the PNS during the effector phase. Although the 2 groups of mice exhibited no quantitative or proportional differences in splenic lymphocyte populations, the apoE -/- mice showed enhanced antigen-specific proliferation of T cells of spleen, which is related to modified macrophage function, upregulation of Th1 and downregulation of Th2-autoreactive responses to P0 peptide. These effects were shown as increased numbers of IFN-gamma expressing cells in the spleen and of IFN-gamma, IL-12 and TNF-alpha expressing cells in the PNS, as well as a decreased IL-10 production by splenic cells in apoE -/- mice. In addition, apoE -/- mice had enhanced antigen-specific antibody responses, which might have contributed to their aggravated EAN. These data provide strong evidence that apoE acts as an inhibitor of this inflammatory and demyelinating disease by upregulating IL-10, as well as by inhibiting Th1 responses and antigen-specific antibody formation. These data may aid the development of new and more effective therapeutic strategies for inflammatory and demyelinating diseases such as Guillain-Barré syndrome.     

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade enhances incidence and severity of experimental autoimmune neuritis in resistant mice

Experimental autoimmune neuritis (EAN), an autoimmune inflammatory demyelinating disease of the peripheral nervous system, represents an animal model of the human Guillain-Barré syndrome. EAN can be induced by active immunization in several animals, including Lewis rats. In contrast, most strains of mice including the widely used C57BL/6 (B6) strain are reputedly resistant to the induction of EAN. In the present study, we demonstrate that in B6 mice, anti-CTLA-4 monoclonal antibody administration in conjunction with immunization with the P0 protein derived peptide 180-199 can induce clinical and pathological definite EAN. Upregulating effects of CTLA-4 blockade on initial and ongoing EAN are demonstrated. CTLA-4 blockade augmented cellular infiltration and enhanced demyelination in the target organ sciatic nerves as well as increased T cell proliferation in lymph node cells. Moreover, serum levels of IFN-gamma and IL-4 were increased. Thus, manipulation of CTLA-4/B7 costimulatory pathway by CTLA-4 blockade can promote autoreactivity and break the relative tolerance to peripheral autoantigen P0 in resistant B6 mice.     

CD28-B7 costimulation: a critical role for initiation and development of experimental autoimmune neuritis in C57BL/6 mice

CD28 provides a critical costimulatory signal for antigen-specific T cell activation. Because CD28 is an important factor in the development of autoimmune diseases, we investigated its role in T cell-mediated experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome in humans. CD28-deficient mutant (CD28-/-) C57BL/6 mice and corresponding wild-type mice were immunized with P0 peptide 180-199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant. As a result, all wild-type mice developed severe EAN, in contrast, none of the CD28-/- mice manifested clinical signs of disease. Additionally, CD28-/- mice had fewer IL-12 producing cells in sciatic nerve sections and fewer IFN-gamma secreting splenic cells than wild-type mice on day 24 post immunization, i.e., at the peak of clinical EAN. At that time point, CD28-/- mice had milder infiltration of such inflammatory cells as macrophages, CD4+ T cells and monocytes into sciatic nerve tissues and less demyelination than wild-type mice. Moreover, the CD28-deficiency led to reduced production of specific anti-P0 peptide 180-199 antibodies compared with wild-type mice. Evidently, CD28 is required for interaction with B7 to regulate the activation of T and B cells that initiates development of EAN.     

The therapeutic effects of ginkgolides in Guillain-Barré syndrome and experimental autoimmune neuritis

BackgroundGuillain-Barré syndrome (GBS) is an acquired immune-mediated inflammatory peripheral neuropathy. The immune regulation of ginkgolides have been revealed in recent years. We herein investigate the potential therapeutic effects of ginkgolides both on GBS and its animal model, experimental autoimmune neuritis (EAN).MethodsEAN in C57BL/6 mice induced by subcutaneous injection with peripheral nerve myelin P0 protein peptide 180–199 (P0 peptide) were treated with ginkgolides at three different doses. GBS patients were randomly divided into two groups, the experimental group and the control group. The experimental group were treated with ginkgolides as soon as diagnosed.ResultsOur data indicated that ginkgolides administration daily ameliorated the score of EAN and delayed the peak of disease in EAN mice. Ginkgolides also down-regulated the proportions of T helper (Th) 17 cells in EAN spleens. Furthermore, we also found that administration of ginkgolides significantly decreased the levels of interferon (IFN)-γ and interleukin-12 (IL)-12 in GBS patients.ConclusionsOur results suggested that ginkgolides ameliorated the clinical score of EAN through down-regulating the proportions of Th 17 cells. Ginkgolides also suppressed inflammation response by decreasing pro-inflammatory cytokines IFN-γ and IL-12, suggesting ginkgolides had potential therapeutic effects on GBS patients and EAN in the future.     

Hyperpolarisation-activated cyclic nucleotide channel 4 (HCN4) involvement in Tourette's syndrome autoimmunity

Previous studies have shown that interferon-gamma (IFN-γ) is a proinflammatory cytokine that contributes to the pathogenesis of Guillain-Barré syndrome and its animal model, experimental autoimmune neuritis (EAN). Treatments with anti-IFN-γ antibodies improve clinical outcome in GBS patients and EAN animals and administration of IFN-γ markedly worsens EAN. Paradoxically, the mice deficient in IFN-γ remain susceptible to experimental autoimmune encephalomyelitis, an analogous disease in the central nervous system. These observations raise a question whether IFN-γ might be protective in autoimmune demyelinating diseases. To clarify the role of IFN-γ in the pathogenesis of autoimmune demyelinating diseases, we used P0 protein peptide 180-199 to induce EAN in IFN-γ knockout (KO) mice. After the acute phase of EAN, the clinical signs of IFN-γ KO mice were significantly more severe than those of wild type (WT) controls. After antigenic stimulation, the proliferation of splenic mononuclear cells was significantly higher in IFN-γ KO than in WT mice with EAN. At the peak of EAN, the proportion of interleukin (IL)-17A expressing cells in cauda equina (CE) infiltrating cells, and the levels of IL-17A in sera were elevated in IFN-γ KO mice when compared with their WT counterparts. The proportions of major histocompatibility complex (MHC) II, macrosialin, and IL-12/IL-23p40 expressing cells, relative to total CE infiltrating cells were correspondingly higher in IFN-γ KO than in WT mice with EAN. However, IFN-γ deficiency reduced the production of NO by cultured macrophages in response to proinflammatory stimuli and induced a systemic Th2-oriented immune response. In conclusion, IFN-γ deficiency exacerbates EAN via upregulating Th17 cells despite a mitigated systemic Th1 immune response.     

A study of associated cell-mediated immune mechanisms in experimental autoimmune neuritis rats

The aims of this study are to investigate the optimal antigens used to induce acute or chronic EAN and the associated cell-mediated immune mechanisms. Lewis rats were grouped into EAN rats and control rats. EAN rats were immunized by injection into both hind footpads of inoculums containing 100 microg/200 microg of P2 peptide 57-81 and FCA, or 200 mug of P0 peptide 180-199 and FCA. Control rats were immunized by FCA. Clinical scores were compared at the maximum of disease. On the 14th day after immunization, we examined lymphocyte proliferation, fractions of CD4+ T cells within lymph node mononuclear cells (MNC), frequencies of CD4+CD25+ T cells within CD4+ T cells, supernatant productions of IFN-gamma, IL-4, IL-10 and TGF-beta1 secreted by lymphocytes. Histopathology of sciatic nerves was assessed. Our findings indicated: (1) 100 microg of P2 peptide 57-81 and 200 microg of P0 peptide 180-199 may induce an acute EAN and 200 microg of P2 peptide 57-81 may induce a chronic EAN; (2) Lewis rats were more sensitive to P2 peptide 57-81 than P0 peptide 180-199; (3) clinical disease had nothing to do with a change of relative CD4+ T cells number in lymph node MNC; (4) frequencies of CD4+CD25+ T cells and levels of TGF-beta1 secreted by lymphocytes negatively paralleled clinical EAN, while levels of IFN-gamma secreted by lymphocytes roughly paralleled clinical EAN at the acute phase; (5) sciatic nerve sections from the chronic EAN rats didn't show any inflammatory cells, but showed remaining segmental demyelination and axonal collapse at the chronic phase; (6) self-limitation of acute EAN may owe to the rising levels of IL-4 and IL-10, while a longer duration of chronic EAN may owe to the decreasing levels of IL-4 and IL-10.     

Induction of experimental autoimmune neuritis in CD4-8-C57BL/6J mice.

The C57BL/6J mice strain is known to be reputedly resistant to induction of experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome in humans. Here we describe the induction of EAN in mice of the C57BL/6J background by transfer into naive syngeneic recipients bovine peripheral nerve myelin (BPM)-primed donor lymph node cells that had been stimulated in vitro with the bovine peripheral nervous system (PNS) myelin P2 protein peptide 57-81 followed by challenge with BPM, Freund's complete adjuvant and pertussis toxin. EAN was more severe, both clinically and histologically, and accompanied by extensive infiltration of inflammatory cells and demyelination in peripheral nerves when examined on day 30 after transfer of primed T cells from CD4- 8- mice into identical naive hosts than after transfer of cells from primed wild type, CD4-/- or CD8-/- mice to corresponding recipient animals. EAN in CD4-8- mice was also associated with elevated numbers of P2 peptide-reactive interferon-y (TFN-gamma) secreting cells and alphabeta T cells were present in lymph nodes and spleens. The data suggest that PNS myelin activated T cells from an EAN-resistant mice strain are capable of homing to the PNS. The expanded CD4-8- alphabeta T cells may have helper and effector functions, related to initiation of EAN in the CD4-8- mice. Lack of CD4+ and CD8+ expressing cells does not prevent the initiation of an autoimmune disease.     

Dual role of B cells with accelerated onset but reduced disease activity in P0106–125-induced experimental autoimmune neuritis of IgH0/0 mice

The role of B cells in autoimmune-mediated diseases of the peripheral nervous system was studied in experimental autoimmune neuritis (EAN) in B cell deficient IgH^0/0 C57BL/6J mice having been immunized with P0_106–125 peptide. Compared to coisogenic IgH^+/+ mice, onset of EAN was accelerated [100% disease incidence at day 9 post immunization (p.i.) vs. day 15 p.i.]. At day 9 p.i., numbers of P0_106–125-specific interferon (IFN)-γ-producing CD4⁺ T cells were increased, while IL-10 mRNA and production were decreased in IgH^0/0 mice. Beyond day 9 p.i., declining disease activity and a significant reduction of maximal disease activity were correlated with significantly reduced numbers of IFN-γ-producing CD4⁺ T cells in IgH^0/0 mice as compared with IgH^+/+ mice. Correspondingly, neuropathology demonstrated only mild axonal damage, while demyelination and dying back axonopathy with spinal cord motor neuron apoptosis were absent. Thus, depending on the stage of EAN, B cells play a dual, i.e. suppressive and enhancing, role during induction and at height of EAN, respectively. The combined interaction of B cells as well as CD4⁺ and CD8⁺ T cells is required for the development of EAN.     

Neutralizing antibodies to IL-18 ameliorate experimental autoimmune neuritis by counter-regulation of autoreactive Th1 responses to peripheral myelin antigen

Experimental autoimmune neuritis (EAN) is a demyelinating disease of the peripheral nervous system (PNS). This acute inflammatory disease is mediated by CD4+ T cells and bears significant similarities to the Guillain-Barré syndrome of humans. In the present study, we investigated the function of IL-18 in T cell-mediated autoimmunity of EAN in mice induced by P0 peptide 180-199 and Freund's complete adjuvant. Our data indicate that in 2 different therapeutic regimens, anti-IL-18 monoclonal antibody (mAb) effectively ameliorates the clinical and pathological signs of EAN. The suppression is associated with reduced inflammatory cell infiltration into the PNS and an insufficiency of autoreactive Th1 cells, as reflected by a reduced mononuclear cell proliferation and IFN-gamma-secretion in the spleen. Increased numbers of IL-4 expressing cells and decreased numbers of IFN-gamma and TNF-alpha expressing cells were found in the PNS. Our results suggest that shifting the Th1/Th2 balance towards Th2 cells may be one mechanism underlying EAN suppression by anti-IL-18 mAb. In addition, anti-IL-18 mAb treatment reduced anti-P0 peptide 180-199 autoantibody responses, which may also contribute to EAN suppression. We conclude that endogenous IL-18 plays a critical role in the pathogenesis of autoimmune demyelinating disease of the PNS and that IL-18 antagonists may provide a new therapy for these diseases.     

TNF-alpha receptor 1 deficiency enhances kainic acid-induced hippocampal injury in mice

The exact role of TNF-alpha in excitotoxic neurodegeneration of the brain is unclear. To address this issue, the kainic acid (KA)-induced hippocampal injury model, a well-characterized model of human neurodegenerative diseases, was used in TNF-alpha receptor 1 (TNFR1)-knockout (TNFR1-/-) mice in the present study. After nasal application of a single dose of 40 mg of KA per kilogram body weight, TNFR1-/- mice showed significantly more severe seizures than the wild-type mice. In addition, obvious neurodegeneration, enhanced microglia activation, and astrogliosis in the hippocampus, as well as increased locomotor activity, were found in TNFR1-/- mice compared with the wild-type controls 8 days after KA delivery. Moreover, CC chemokine receptor 3 expression on activated microglia was increased 3 days after KA treatment in TNFR1-/- mice, as measured by flow cytometry. These data suggest that TNF-alpha may play a protective role through TNFR1 signaling.     

Apolipoprotein E deficiency enhances the antigen-presenting capacity of Schwann cells

Apolipoprotein E (apoE) has immunomodulatory properties and has been implicated in the pathogenic mechanism of autoimmune diseases. Previously, the authors found that apoE deficiency increased the susceptibility to experimental autoimmune neuritis (EAN), an animal model for human Guillain-Barré syndrome. To further elucidate the mechanism behind apoE deficiency exacerbating EAN, the authors investigated the role of major target and important antigen-presenting cells of the peripheral nerve system, Schwann cells (SCs), in apoE knockout mice. Treatment of apoE deficient SCs with recombinant mouse interferon-gamma and lipopolysaccharide resulted in higher MHC-II and CD40 expression as compared with normal SCs derived from wild-type mice. The increased MHC-II and CD40 expression on SCs was accompanied by lower levels of intracellular IL-6 production within SCs of apoE deficiency, which is confirmed by the neutralization with anti IL-6 antibody. The increased antigen-presenting capacity of apoE deficient SCs was further explored by enhancement of T cell proliferation co-cultured with P0 peptide 180-199 specific T cells derived from EAN mice immunized with the P0 peptide. In conclusion, apoE may protect mice from EAN and probably also from chronic inflammatory demyelinating polyneuropathy by affecting the antigen-presenting function of SCs via influence of IL-6 production.     

Initiation and development of experimental autoimmune neuritis in Lewis rats is independent of the cytotoxic capacity of NKR-P1A+ cells

Natural killer (NK) cells are implicated in T cell-mediated autoimmune diseases. Experimental autoimmune neuritis (EAN) is a CD4+ T cell-mediated animal model of the Guillain-Barré syndrome in human. The role of NK cells in the initiation and development of EAN remains unclear. In the present study, we demonstrate that anti-NKR-P1A monoclonal antibody (mAb) treatment in vivo did not affect the initiation and development of clinical EAN in Lewis rats induced by immunization with peripheral nerve myelin P0 protein peptide 180-199 and Freund's complete adjuvant, as well as the proportion of NKR-P1A+ cells (including NK cells and NKT cells) in the spleen. Furthermore, inflammatory cell infiltrations and demyelination in the peripheral nervous system (PNS) and in vitro P0 peptide 180-199-specific splenocyte proliferation were not different in anti-NKR-P1A mAb-treated rats compared to the control antibody-treated rats. The cytotoxic activity of NKR-P1A+ cells, determined by NK cell-sensitive K562 cells as target cells, decreased markedly in anti-NKR-P1A mAb-treated rats, suggesting that decrease of the cytotoxic activities of NKR-P1A+ cells is not sufficient to alter clinical EAN, although NKR-P1A+ cells may participate in the pathogenesis of T cell-mediated autoimmune diseases, such as EAN, by the mechanisms that involve the release of cytokines.