LPA1 signaling drives Schwann cell dedifferentiation in experimental autoimmune neuritis.

BACKGROUND: Lysophosphatidic acid (LPA) is a pleiotropic lipid messenger that addresses at least six specific G-protein coupled receptors. Accumulating evidence indicates a significant involvement of LPA in immune cell regulation as well as Schwann cell physiology, with potential relevance for the pathophysiology of peripheral neuroinflammation. However, the role of LPA signaling in inflammatory neuropathies has remained completely undefined. Given the broad expression of LPA receptors on both Schwann cells and cells of the innate and adaptive immune system, we hypothesized that inhibition of LPA signaling may ameliorate the course of disease in experimental autoimmune neuritis (EAN). METHODS: We induced active EAN by inoculation of myelin protein 2 peptide (P255-78) in female Lewis rats. Animals received the orally available LPA receptor antagonist AM095, specifically targeting the LPA1 receptor subtype. AM095 was administered daily via oral gavage in a therapeutic regimen from 10 until 28 days post-immunization (dpi). Analyses were based on clinical testing, hemogram profiles, immunohistochemistry and morphometric assessment of myelination. RESULTS: Lewis rats treated with AM095 displayed a significant improvement in clinical scores, most notably during the remission phase. Cellular infiltration of sciatic nerve was only discretely affected by AM095. Hemogram profiles indicated no impact on circulating leukocytes. However, sciatic nerve immunohistochemistry revealed a reduction in the number of Schwann cells expressing the dedifferentiation marker Sox2 paralleled by a corresponding increase in differentiating Sox10-positive Schwann cells. In line with this, morphometric analysis of sciatic nerve semi-thin sections identified a significant increase in large-caliber myelinated axons at 28 dpi. Myelin thickness was unaffected by AM095. CONCLUSION: Thus, LPA1 signaling may present a novel therapeutic target for the treatment of inflammatory neuropathies, potentially affecting regenerative responses in the peripheral nerve by modulating Schwann cell differentiation.

Nuclear factor kappa B inhibitor suppresses experimental autoimmune neuritis in mice via declining macrophages polarization to M1 type.

Guillain-Barré syndrome (GBS) is an acute inflammatory and immune-mediated demyelinating disease of the peripheral nervous system (PNS). Macrophages play a central role in its animal model, experimental autoimmune neuritis (EAN), which has been well accepted. Additionally, nuclear factor (NF)-κB inhibitors have been used to treat cancers and have shown beneficial effects. Here, we investigated the therapeutic effect of M2 macrophage and the NF-κB pathway's correlation with macrophage activation in EAN in C57BL/6 mice. We demonstrate that M2 macrophage transfusion could alleviate the clinical symptoms of EAN by reducing the proportion of M1 macrophage in the peak period, inhibiting the phosphorylation of NF-κB p65. The NF-κB inhibitor (BAY-11-7082) could alleviate the clinical symptoms of EAN and shorten the duration of symptoms by reducing the proportion of M1 macrophages and the expression of proinflammatory cytokines. Consequently, BAY-11-7082 exhibits strong potential as a therapeutic strategy for ameliorating EAN by influencing the balance of M1/M2 macrophages and inflammatory cytokines.

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

BACKGROUND: Guillain-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). METHODS: EAN 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. RESULTS: Our 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. CONCLUSIONS: Our 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.

Ginsenoside Rd attenuates mouse experimental autoimmune neuritis by modulating monocyte subsets conversion.

Guillain-Barré Syndrome (GBS), characterized by peripheral nerve demyelination and axonal damage, is initiated and aggravated through various of immunopathogenesis. Ginsenoside Rd, main active components extracted from ginseng saponins, is known to exhibit immune-regulate functions in many immune-mediated diseases. However, the evidence of preventive effect of Ginsenoside Rd on GBS is lacking. Experimental autoimmune neuritis (EAN) mice, classic model of GBS, were established and treated with GSRd or vehicle. Clinical score and nerve tissue histomorphology were evaluated. Monocytes in peripheral blood and tissue were detected by flow cytometry analysis and immunofluorescence staining. For the in vitro study, GSRd and vehicle were added in the culture medium to assess their regulatory function on monocytes phenotype. In vivo data showed a protective role of GSRd on alleviating symptoms and tissue damage on Day 20 and 25. Administration of GSRd increased non-classical Ly6Clo monocytes in both peripheral blood and injured nerve tissue, and also switched tissue macrophages phenotype into resolution-phase. In vitro study indicated similar role of GSRd on monocytes differentiation status. Transcription factors like Nr4a1 were elevated after GSRd treatment. These findings revealed the protective role of GSRd against EAN, and potential preventive function on GBS patients.

T Cells from NOD-PerIg Mice Target Both Pancreatic and Neuronal Tissue.

It has become increasingly appreciated that autoimmune responses against neuronal components play an important role in type 1 diabetes (T1D) pathogenesis. In fact, a large proportion of islet-infiltrating B lymphocytes in the NOD mouse model of T1D produce Abs directed against the neuronal type III intermediate filament protein peripherin. NOD-PerIg mice are a previously developed BCR-transgenic model in which virtually all B lymphocytes express the H and L chain Ig molecules from the intra-islet-derived anti-peripherin-reactive hybridoma H280. NOD-PerIg mice have accelerated T1D development, and PerIg B lymphocytes actively proliferate within islets and expand cognitively interactive pathogenic T cells from a pool of naive precursors. We now report adoptively transferred T cells or whole splenocytes from NOD-PerIg mice expectedly induce T1D in NOD.scid recipients but, depending on the kinetics of disease development, can also elicit a peripheral neuritis (with secondary myositis). This neuritis was predominantly composed of CD4+ and CD8+ T cells. Ab depletion studies showed neuritis still developed in the absence of NOD-PerIg CD8+ T cells but required CD4+ T cells. Surprisingly, sciatic nerve-infiltrating CD4+ cells had an expansion of IFN-γ- and TNF-α- double-negative cells compared with those within both islets and spleen. Nerve and islet-infiltrating CD4+ T cells also differed by expression patterns of CD95, PD-1, and Tim-3. Further studies found transitory early B lymphocyte depletion delayed T1D onset in a portion of NOD-PerIg mice, allowing them to survive long enough to develop neuritis outside of the transfer setting. Together, this study presents a new model of peripherin-reactive B lymphocyte-dependent autoimmune neuritis.

M1 Macrophage Derived Exosomes Aggravate Experimental Autoimmune Neuritis via Modulating Th1 Response.

Guillain-Barré syndrome (GBS), an immune-mediated disorder affecting the peripheral nervous system, is the most common and severe acute paralytic neuropathy. GBS remains to be potentially life-threatening and disabling despite the increasing availability of current standard therapeutic regimens. Therefore, more targeted therapeutics are in urgent need. Macrophages have been implicated in both initiation and resolution of experimental autoimmune neuritis (EAN), the animal model of GBS, but the exact mechanisms remain to be elucidated. It has been increasingly appreciated that exosomes, a type of extracellular vesicles (EVs), are of importance for functions of macrophages. Nevertheless, the roles of macrophage derived exosomes in EAN/GBS remain unclear. Here we determined the effects of macrophage derived exosomes on the development of EAN in Lewis rats. M1 macrophage derived exosomes (M1 exosomes) were found to aggravate EAN via boosting Th1 and Th17 response, while M2 macrophage derived exosomes (M2 exosomes) showed potentials to mitigate disease severity via a mechanism bypassing Th1 and Th17 response. Besides, both M1 and M2 exosomes increased germinal center reactions in EAN. Further in vitro studies confirmed that M1 exosomes could directly promote IFN-γ production in T cells and M2 exosomes were not capable of inhibiting IFN-γ expression. Thus, our data identify a previously undescribed means that M1 macrophages amplify Th1 response via exosomes and provide novel insights into the crosstalk between macrophages and T cells as well.

The dynamic expression of canonical Wnt/ß-catenin signalling pathway in the pathologic process of experimental autoimmune neuritis.

Background: Guillain-Barré syndrome (GBS), an autoimmune disease and an acute inflammation disorder, is currently the most frequent cause of acute flaccid paralysis worldwide. EAN, an animal model of GBS, is a CD4+ T cell-mediated autoimmune disease of the PNS. Wnt/ß-catenin signals are critically important to several fundamental aspects of peripheral nerve development and play a crucial role in Schwann cell proliferation. Here, we investigate the role of Wnt/ß-catenin signalling cascades in EAN rats.Methods: 28 male Lewis rats weighing 170 ± 10 g were randomly divided into control group (n = 7) and EAN groups (Early group; Peak group and Recovery group. n = 7 per group). EAN rats were immunized with P257-81 peptide; weighed daily, and the neurologic signs of EAN were evaluated every day. The sciatic nerve was taken on the days 10, 17, and 30 p.i. for H&E staining, transmission electron microscopy and immunohistochemical staining; blood samples were collected weekly from caudal vein to detect IFN-γ, IL-4, TGF-ß1; and the sciatic nerve was taken to examinate the dynamics expression of Wnt/ß-catenin pathway molecules.Results: In our study, we chose tail-root injection to better model GBS. Moreover, we observed that IFN-γ levels paralleled clinical EAN, and the levels of TGF-ß1 and IL-4 gradually increased and peaked in the recovery phase. In addition, we have shown that canonical Wnt signalling is upregulated and reached a peak in the late recovery phase.Conclusion: Our findings suggest that Wnt/ß-catenin signalling is associated with the promotion of remyelination in EAN rats.

Autoantigen specific IL-2 activated CD4+CD25+T regulatory cells inhibit induction of experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) induced by peripheral nerve myelin (PNM) is self-limiting and re-immunization with PNM does not re-activate disease. This study showed inhibition of EAN by CD4+CD25+T cells both from sensitized hosts or from naïve hosts after ex-vivo activation by PNM and rIL-2. Transfer of naïve CD4+CD25+T cells has no effect on EAN, nor did naïve CD4+CD25+T cells activated with rIL-2 and renal tubular antigen. Culture of naive CD4+CD25+Treg with rIL-2 and PNM induced mRNA for the IFN-gamma receptor. We showed naïve CD4+CD25+T cells activated by specific auto-antigen and rIL-2 produced more potent antigen-specific Treg that may have therapeutic potential.

Th17 cells and their cytokines serve as potential therapeutic target in experimental autoimmune neuritis.

BACKGROUND: Accumulating evidence has pointed that T helper 17 cells and their cytokines are pathogenic in Guillain-Barré syndrome (GBS). However, little is known concerning the IL-17 expression change trend during the whole course of disease, and whether drugs specially targeting Th17 cells or their cytokines have potential effects on experimental autoimmune neuritis (EAN) is uncertain. METHODS: We explored the IL-17 and receptor-related orphan receptor-gamma-t (RORγt) expression change trends in EAN rats to identify the stage of effect of Th17 pathway in EAN, and further, we investigated the effect of RORγt inhibitors by assessing clinical score, histological staining, and IL-17 and RORγt expression change trends in serum and tissues. RESULTS: The expression level of IL-17 and RORγt in serum and tissues increased with the progression of the disease in the EAN group and decreased after the disease reaching its peak. RORγt-IN-1 treatment strikingly reduced the neurological deficits by ameliorating inflammatory cell infiltration, deceased the serum IL-17 and RORγt levels, and further downregulated the expression of IL-17 and RORγt mRNA in spleen, lymphnodes, and sciatic nerve. CONCLUSIONS: Th17 cells and their cytokines are closely associated with the onset of GBS and the novel RORγt inhibitors may be prospective strategies in treating GBS.

Induction of Regulatory Properties in the Intestinal Immune System by Dimethyl Fumarate in Lewis Rat Experimental Autoimmune Neuritis.

Objective: Dimethyl fumarate (DMF) exerts immunomodulatory and neuroprotective effects in the animal model of experimental autoimmune neuritis (EAN) in the Lewis rat. DMF has been shown to modulate gut microbiota in veterinary medicine, however the effects of oral DMF on the gut-associated lymphoid tissue (GALT) remain unknown. Methods: Lewis rats were treated orally twice daily with DMF up to day 10 after immunization with immunogenic P2 peptide. Histological, flow cytometric and RT-PCR analyses of the GALT (intraepithelial layer, lamina propria, and Peyer patches) in duodenum, jejunum, and ileum were performed ex vivo. Moreover, cell transfer experiments were used to examine the protective effects of GALT regulatory T cells of the Peyer patches. Results: In the upper layers of duodenum, DMF induced a reduction of the toll-like receptor 4 (TLR4) mRNA expression. This was combined by a decrease of the pro-inflammatory lamina propria IFN-γ mRNA expression. In the ileum, we detected an immunoregulatory phenotype characterized by an increase of FoxP3 mRNA expression and of the nuclear factor (erythroid-derived-2)- like 2 (Nrf2) downstream molecule heme oxygenase-1 (HO-1) mRNA. Finally, CD4+ CD25+ regulatory T cells were increased in the Peyer patches. In vivo, the protective effect of these regulatory cells was verified by cell transfer into recipient EAN rats. Conclusions: Our results identified a novel immunomodulatory effect of DMF through the different regions and layers of the small intestine, which led to an increase of regulatory T cells, exerting a protective role in experimental neuritis.

Transcriptomes in rat sciatic nerves at different stages of experimental autoimmune neuritis determined by RNA sequencing.

Guillain-Barré syndrome (GBS) is characterized by acute immune-mediated peripheral neuropathy, which may result in rapidly progressive paralysis and fatal respiratory failure. As the underlying pathological mechanisms of GBS are unclear, we surveyed the transcriptome of rats with experimental autoimmune neuritis (EAN), a model of GBS. Briefly, sciatic nerves on both sides were collected from 8-10-week-old Lewis rats during early (10 days post-induction), peak (19 days) and late neuritis (30 days). Total RNA was sequenced to identify differentially expressed genes. Compared to control rats without induced neuritis, 33 genes were differentially expressed in the early phase (14 up-regulated and 19 down-regulated), with an adjusted P-value < 0·05 and |log2 fold-change| >1, as were 137 genes in the peak phase (126 up-regulated and 11 down-regulated) and 60 genes in the late phase (58 up-regulated and two down-regulated). Eleven of these genes were common to all stages, suggesting their crucial roles throughout the disease course. Analysis of protein-protein interactions revealed Fos, Ccl2, Itgax and C3 as node genes at different stages. Functional analysis of differentially expressed genes identified biological processes and pathways that are activated as neuritis progresses. This is the first genomewide gene expression study of peripheral nerves in experimental autoimmune neuritis model. Dynamic gene expression and significantly altered biological functions were detected in different phases of the disease, increasing our understanding of the molecular mechanisms underlying EAN and highlighting potential targets for its diagnosis and treatment.

Time Course of Axon and Myelin Degeneration in Peripheral Nerves in Experimental Autoimmune Neuritis Rats.

Experimental autoimmune neuritis (EAN) is an animal model for Guillain-Barré syndrome (GBS), which results in neurological symptoms and histopathological changes in peripheral nerves. In this model, the correlation between the progression of the disease and the histopathological changes is not clear. To further examine histopathological changes in peripheral nerves in EAN rats, sciatic nerves were sampled at onset (day 10), peak (day 16), and recovery (days 22 and 25) of neurological symptoms in P2(57-81)-peptide-administered rats. Axon and myelin degeneration was observed by light microscopy at onset, degeneration became severe at peak, and persisted at recovery. Densities of myelinated nerve fibers and myelin areas decreased from day 10 to a minimum on day 22. Slight axon and myelin degeneration, such as accumulation of vesicles in axons and focal myelin splitting and folding, was observed by transmission electron microscopy at onset; severe degeneration, such as axonal loss, myelin ovoid, and demyelination, increased at peak; and regenerative changes, such as remyelination and enlargement of Schwann cell cytoplasm, occurred at recovery. These results suggest that EAN rats have histopathological similarities to some types of GBS patients and that EAN rats are a useful model to understand the pathogenesis of GBS.

Sulfatides ameliorate experimental autoimmune neuritis by suppressing Th1/Th17 cells.

Sulfatides have immunomodulatory functions, and play protective roles in multiple autoimmune diseases. In the present study, we showed that sulfatides ameliorated experimental autoimmune neuritis in Lewis rats induced with bovine peripheral myelin, which was associated with decreased proportions of Th1 and Th17 cells. Furthermore, compared control group, cells from sulfatide-treated rats exhibited lower potential in proliferation and IL-17 secretion in the presence of BPM or ConA in vitro. Moreover, sulfatides also reduced the proportions of NK and NKT cells. In summary, our study indicated that sulfatides might become a new therapeutic agent in Guillain-Barré syndrome in the future.

Trapped in the epineurium: early entry into the endoneurium is restricted to neuritogenic T cells in experimental autoimmune neuritis.

BACKGROUND: Autoimmune polyneuropathies are acquired inflammatory disorders of the peripheral nervous system (PNS) characterized by inflammation, demyelination, and axonal degeneration. Although the pathogenesis has not been fully elucidated, T cells recognizing self-antigens are believed to initiate inflammation in a subgroup of patients. However, the route and time of T cell entry into the PNS have not yet been described in detail. In this study, we analyzed both kinetics as well as localization of retrovirally transfected green fluorescent protein (GFP)-expressing neuritogenic T lymphocytes in experimental autoimmune neuritis (EAN). METHODS: T lymphocytes obtained from rats following EAN induction by immunization with peripheral nerve protein peptide P255-78 were retrovirally engineered to express GFP. Non-specific T cells were negatively selected by in vitro restimulation, whereas GFP-expressing neuritogenic T cells (reactive to P255-78) were adoptively transferred into healthy rats (AT-EAN). Antigen-specific T cell tracking and localization was performed by flow cytometry and immunohistochemistry during the course of disease. RESULTS: After induction of autoimmune neuritis, P2-reactive T cells were detectable in the liver, spleen, lymph nodes, lung, peripheral blood, and the sciatic nerves with distinct kinetics. A significant number of GFP+ T cells appeared early in the lung with a peak at day four. In the peripheral nerves within the first days, GFP-negative T cells rapidly accumulated and exceeded the number of GFP-expressing cells, but did not enter the endoneurium. Very early after adoptive transfer, T cells are found in proximity to peripheral nerves and in the epineurium. However, only GFP-expressing neuritogenic T cells are able to enter the endoneurium from day five after transfer. CONCLUSIONS: Our findings suggest that neuritogenic T cells invade the PNS early in the course of disease. However, neuritogenic T cells cross the blood-nerve barrier with a certain delay without preference to dorsal roots. Further understanding of the pathophysiological role of autoagressive T cells may help to improve therapeutic strategies in immune-mediated neuropathies.

Myelin Protein Zero180-199 Peptide Induced Experimental Autoimmune Neuritis in C57BL/6 Mice.

Mouse models of peripheral demyelinating neuropathy play an important role in enabling the study of disease pathogenesis. Further, induction in transgenic mice allows for the precise interrogation of disease mechanisms, as well as the analysis of the efficacy and mechanisms of potential new therapies. Here we describe a method to successfully induce experimental autoimmune neuritis (EAN) using myelin protein zero (P0)180-199 peptide in combination with Freund's complete adjuvant and pertussis toxin in the C57BL/6 mouse strain. We also outline a sensitive paradigm of accurately assessing the extent of functional deficits occurring in murine EAN.

Beneficial or Harmful Role of Macrophages in Guillain-Barré Syndrome and Experimental Autoimmune Neuritis.

Guillain-Barré syndrome (GBS), an immune-mediated demyelinating peripheral neuropathy, is characterized by acute weakness of the extremities and areflexia or hyporeflexia. Experimental autoimmune neuritis (EAN) is a common animal model for GBS, which represents a CD4+ T cell-mediated inflammatory autoimmune demyelination of the peripheral nervous system (PNS), and is used to investigate the pathogenic mechanism of GBS. It has been found that macrophages play a critical role in the pathogenesis of both GBS and EAN. Macrophages have been primarily classified into two major phenotypes: proinflammatory macrophages (M1) and anti-inflammatory macrophages (M2). The two different macrophage subsets M1 and M2 may play a decisive role in initiation and development of GBS and EAN. However, recently, it has been indicated that the roles of macrophages in immune regulation and autoimmune diseases are more complex than those suggested by a simple M1-M2 dichotomy. Macrophages might exert either inflammatory or anti-inflammatory effect by secreting pro- or anti-inflammatory cytokines, and either inducing the activation of T cells to mediate immune response, resulting in inflammation and demyelination in the PNS, or promoting disease recovery. In this review, we summarize the dual roles of macrophages in GBS and EAN and explore the mechanism of macrophage polarization to provide a potential therapeutic approach for GBS in the future.

Decitabine induces regulatory T cells, inhibits the production of IFN-gamma and IL-17 and exerts preventive and therapeutic efficacy in rodent experimental autoimmune neuritis.

Guillain-Barré syndrome (GBS) is an immune-mediated acute disorder of the peripheral nervous system. Despite treatment, there is an associated mortality and severe disability in 9 to 17% of the cases. Decitabine (DAC) is a hypomethylating drug used in myelodisplastic syndrome, that has been shown to exert immunomodulatory effects. We have evaluated the effects of DAC in two rodent models of GBS, the Experimental Allergic Neuritis (EAN). Both prophylactic and therapeutic treatment with DAC ameliorated the clinical course of EAN, increasing the numbers of thymic regulatory T cells and reducing the production of proinflammmatory cytokines. Our data suggest the possible use of decitabine for the treatment of GBS.

Therapeutic Effect of CD4+CD25+ Regulatory T Cells Amplified In Vitro on Experimental Autoimmune Neuritis in Rats.

BACKGROUND/AIMS: This study aimed to explore whether the adoptive transfusion of autologous CD4+CD25+ regulatory T cells (CD4+CD25+ Tregs) has a therapeutic effect on Experimental autoimmune neuritis (EAN) model rats, and it provides new experimental and theoretical bases for the immunotherapy of Guillain-Barre syndrome (GBS). METHODS: CD4+CD25+ Tregs were sorted from the spleens of rats using immunomagnetic bead separation techniques combined with flow cytometry. Their in vitro inhibitory function was determined using a lymphocyte proliferation inhibition test, and their purity was confirmed by flow cytometry. Cells were stimulated using CD3/CD28 monoclonal antibodies and were cultured in culture medium containing interleukin 2 (IL-2), transforming growth factor-ß (TGF-ß) and rapamycin. After 15 days of amplification, CD4+CD25+ Tregs were collected and transfused into EAN model rats. Changes in the pathology and electron microscopical morphology of rat sciatic nerves in the normal group, untreated group, low-dose group (2 × 107) and high-dose group (4 × 107) were observed, and the expression of CD4+CD25+FOXP3 in peripheral blood in the four groups of rats was detected by flow cytometry. RESULTS: Compared with rats in the untreated group, rats in the treatment groups had significantly reduced infiltration of inflammatory cells in the sciatic nerve, as well as myelin and axonal damage. Additionally, the CD4+CD25+ Tregs levels in peripheral blood were significantly higher than those in the untreated group (P< 0. 05). Moreover, the therapeutic effect became more significant with an increase in the dose of adoptive transfusion. CONCLUSION: Adoptive transfusion of CD4+CD25+ Tregs into EAN model rats has significant therapeutic effects.

IL-10 Paradoxically Promotes Autoimmune Neuropathy through S1PR1-Dependent CD4+ T Cell Migration.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a debilitating condition caused by autoimmune demyelination of peripheral nerves. CIDP is associated with increased IL-10, a cytokine with well-described anti-inflammatory effects. However, the role of IL-10 in CIDP is unclear. In this study, we demonstrate that IL-10 paradoxically exacerbates autoimmunity against peripheral nerves. In IL-10-deficient mice, protection from neuropathy was associated with an accrual of highly activated CD4+ T cells in draining lymph nodes and absence of infiltrating immune cells in peripheral nerves. Accumulated CD4+ T cells in draining lymph nodes of IL-10-deficient mice expressed lower sphingosine-1-phosphate receptor 1 (S1pr1), a protein important in lymphocyte egress. Additionally, IL-10 stimulation in vitro induced S1pr1 expression in lymph node cells in a STAT3-dependent manner. Together, these results delineate a novel mechanism in which IL-10-induced STAT3 increases S1pr1 expression and CD4+ T cell migration to accelerate T cell-mediated destruction of peripheral nerves.

Tissue resident macrophages are sufficient for demyelination during peripheral nerve myelin induced experimental autoimmune neuritis?

The contribution of resident endoneurial tissue macrophages versus recruited monocyte derived macrophages to demyelination and disease during Experimental Autoimmune Neuritis (EAN) was investigated using passive transfer of peripheral nerve myelin (PNM) specific serum antibodies or adoptive co-transfer of PNM specific T and B cells from EAN donors to leukopenic and normal hosts. Passive transfer of PNM specific serum antibodies or adoptive co-transfer of myelin specific T and B cells into leukopenic recipients resulted in a moderate reduction in nerve conduction block or in the disease severity compared to the normal recipients. This was despite at least a 95% decrease in the number of circulating mononuclear cells during the development of nerve conduction block and disease and a 50% reduction in the number of infiltrating endoneurial macrophages in the nerve lesions of the leukopenic recipients. These observations suggest that during EAN in Lewis rats actively induced by immunization with peripheral nerve myelin, phagocytic macrophages originating from the resident endoneurial population may be sufficient to engage in demyelination initiated by anti-myelin antibodies in this model.