Blood gammadelta T cells, Campylobacter jejuni, and GM1 titers in Guillain-Barré syndrome

The gammadelta T cells participate in microbial defense, are prevalent in intestinal epithelia, and are activated in autoimmune diseases. We studied whether peripheral blood gammadelta cells and gammadelta subsets are increased in Guillain-Barré syndrome (GBS) and whether elevations are associated with Campylobacter jejuni infection or GM1 elevations. In 20 GBS patients, we performed serial flow cytometry studies of blood gammadelta, Vdelta1, and Vdelta2 cells (+/- CD8+), C jejuni, and ganglioside titers. There was no significant difference in median gammadelta T-cell percentages between GBS patients and controls at onset and at convalescence. However, 5 patients had marked Vdelta1/CD8+ elevations. Elevated Vdelta1 or Vdelta1/CD8+ cells occurred in 3 of 6 patients with C jejuni or GM1 titer elevations. A minority of GBS patients have elevations of Vdelta1/CD8+ cells, possibly associated with elevated C jejuni or GM1 titers. The gammadelta T cells may have a cytotoxic (or suppressor) role in the disease.     

Infection and multiple sclerosis]

Multiple sclerosis is a putative autoimmune disease in which limited numbers of autoimmune T cells reactive to myelin basic protein or proteolipid protein would play critical roles in initiation or augmentation of the inflammatory processes. Owing to the recent immunological studies, it is now possible to discuss the possible link between infectious agents and the development of MS on the molecular terms. This article deals with key issues in this subject such as molecular mimicry between autoantigen and viral peptide, autoimmune T cell stimulation by bacterial superantigens, and regulatory network in MS. In addition to reviewing the current activity in other laboratories, I point out that there might be much more broader range of peptide ligands for autodestructive T cells causing MS. This postulate is based on our recent discovery for the presence of degenerate autoimmune T cells in animal model of MS (EAE). I also indicate the possibility that immune regulatory system could be destroyed by some infectious agents. These informations should have significant implications for management of MS patients.     

B-cell depletion abrogates T cell-mediated demyelination in an antibody-nondependent common marmoset experimental autoimmune encephalomyelitis model

CD20-positive B-cell depletion is a highly promising treatment for multiple sclerosis (MS), but the mechanisms underlying therapeutic effects are poorly understood. B cells are thought to contribute to MS pathogenesis by producing autoantibodies that amplify demyelination via opsonization of myelin. To analyze autoantibody-nondependent functions of B cells in an animal model of MS, we used a novel T cell-driven experimental autoimmune encephalomyelitis (EAE) model in marmoset monkeys (Callithrix jacchus). In this model, demyelination of brain and spinal cord white and gray matter and the ensuing neurological deficits are induced by immunization with peptide 34 to 56 of myelin/oligodendrocyte glycoprotein (MOG34-56) in incomplete Freund's adjuvant. Although autoantibodies do not have a detectable pathogeniccontribution in the model, depletion of B cells with monoclonal antibody 7D8, a human IgG1κ monoclonal antibody against human CD20, suppressed clinical and pathological EAE. In B cell-depleted monkeys, the activation of peptide-specific Th17-producing and cytotoxic T cells, which in previous studies were found to play an essential role in disease induction, was impaired. Thus, we demonstrate a critical antibody-nondependent role for B cells in EAE, that is, the activation of pathogenic T cells.     

γδ T cells: The overlooked T‐cell subset in demyelinating disease

γδ T cells represent a small subpopulation of T cells expressing a restricted repertoire of T‐cell receptors and, unlike αβ T cells, function more as cells of the innate immune system. These cells are found in skin and mucosal sites as well as secondary lymphoid tissues and frequently act as first line of defense sentinels. γδ T cells have been implicated in the pathogenesis of demyelinating disease, although little was known regarding their trafficking and effector functions. In this Mini‐Review, we highlight recent studies demonstrating that γδ T cells migrate rapidly to the CNS during experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. γδ T‐cell trafficking to the CNS is independent of β₂‐integrins and occurs well before onset of clinical signs of disease, peaking early during the acute phase of disease. γδ T‐cell‐mediated production of inflammatory cytokines, including interferon‐γ and tumor necrosis factor‐α, appears critical for EAE development, suggesting that these cells may set the stage for activation of other subsets of infiltrating effector cells. These data suggest that γδ T cells or subsets of γδ T cells may represent a new therapeutic target in demeylinating disease. © 2009 Wiley‐Liss, Inc.     

Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune‐mediated demyelinating diseases

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune‐mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN‐γ, a key pro‐inflammatory cytokine in MS and EAE, in the CNS. Several studies also demonstrate that PERK activation preserves oligodendrocyte viability and function, protecting mice against EAE. While evidence suggests activation of the ATF6α branch of the UPR in oligodendrocytes under normal and disease conditions, the effects of ATF6α activation on oligodendrocytes in immune‐mediated demyelinating diseases remain unknown. Herein, we showed that ATF6α deficiency had no effect on oligodendrocytes under normal conditions. Interestingly, we showed that ATF6α deficiency exacerbated ER stressed‐induced myelinating oligodendrocyte death and subsequent myelin loss in the developing CNS of IFN‐γ‐expressing mice. Moreover, we found that ATF6α deficiency increased EAE severity and aggravated EAE‐induced oligodendrocyte loss and demyelination, without affecting inflammation. Thus, these data suggest the protective effects of ATF6α activation on oligodendrocytes in immune‐mediated demyelinating diseases.     

The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: Effect of copolymer 1 on MOG-induced disease

Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) characterized by primary demyelination, is believed to result from an autoimmune attack against myelin components. In view of their ability to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS, the quantitatively major myelin proteins — myelin basic protein (MBP) and proteolipid protein (PLP) — have been extensively studied as the relevant primary antigens in MS, and therapeutic approaches have been targeted to counteract autoimmune reactivity to MBP and PLP. Accordingly, copolymer 1, a random synthetic amino acid copolymer cross-reactive with MBP and highly protective against the induction of EAE with MBP or PLP, is now being extensively tested in clinical studies as a therapeutic agent for MS. However, increasing evidence suggests that autoimmune reactivity against other CNS-specific myelin proteins could also be involved in the pathogenesis of MS. In this context, we have demonstrated that peripheral blood lymphocytes from patients with MS respond predominantly to myelin oligodendrocyte glycoprotein (MOG) rather than to MBP or PLP, suggesting an important role for cell reactivity against MOG in the pathogenesis of MS. We have demonstrated that T-cell reactivity to MOG can also be pathogenic by inducing neurological disease in H-2^u and H-2^b mice with the same peptide of MOG, pMOG 35–55. Most interestingly, the expression of the disease differed with the different MHC backgrounds. Induction of a differentially expressed disease in different strains of mice with the same myelin antigen makes this new model particularly relevant to MS, where different expression of the disease is seen in different patients. Therefore, notwithstanding the importance of the autoimmune reactivity to MBP and PLP in MS, the potentially pathogenic autoimmune reactivity to MOG must now also be taken into consideration in therapeutic approaches to MS. In this context, we have investigated the possible effect of copolymer 1 treatment on autoimmune reactivity to MOG and on the development of EAE induced by MOG. Copolymer 1 was found to inhibit the binding of MOG peptides to MHC molecules, as well as the proliferation of MOG-reactive T cells, in a dose-dependent manner. In parallel, injection of copolymer 1 concomitantly with the encephalitogenic MOG peptide exerted a strong protective effect against the development of EAE. These preliminary data on the effect of copolymer 1 on the autoimmune response to MOG in mice indicate that copolymer 1 may also be effective in cases of MS where the autoimmune response to MOG prevails, and should therefore be further investigated in this context.

     

The role of costimulation in autoimmune demyelination

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated, autoimmune disorder characterized by central nervous system (CNS) inflammation and demyelination, features reminiscent of the human disease, multiple sclerosis (MS). In addition to the signal the encephalitogenic T cell receives through the T cell receptor (TCR), a second signal, termed costimulation, is required for complete T cell activation. The B7 family of cell surface molecules expressed on antigen presenting cells (APC) is capable of providing this second signal to T cells via two receptors, CD28 and CTLA-4. Our studies have shown that costimulation provided by B7 molecules to its ligand CD28 is important in the initiation of the autoimmune response in EAE. Further, it appears the costimulation provided by B7-1 is important in disease development, while B7-2 may play an important regulatory role. We and others later showed that B7/CTLA-4 interaction plays a critical role in down-regulating the immune response. Previous work has shown that activated T cells and T cells of a memory phenotype are less dependent on costimulation than naive T cells. T cells reactive with myelin components that are involved in the pathogenesis of EAE and possibly MS would be expected to have been activated as part of the disease process. Building upon our prior work in the EAE model, we have tested the hypothesis that myelin-reactive T cells, which are relevant to the pathogenesis of CNS inflammatory demyelination, can be distinguished from naive myelin-reactive T cells by a lack of dependence upon costimulation for activation and that the costimulatory requirements of these myelin-reactive T cells change during the course of disease. Our studies in the EAE model have also addressed the mechanisms of extrathymic (peripheral) T cell tolerance following intravenous (i.v. ) administration of high dose antigen. It is believed that TCR signaling in the absence of costimulation is a vital component of peripheral tolerance mechanisms. However, recent evidence suggests that peripheral tolerance of antigen-specific T cells induced in vivo may require CTLA-4 engagement of the tolerized T cells. We have begun to examine the molecular mechanisms of tolerance induction following intravenous and intraperitoneal administration of myelin antigens in the EAE model and test the hypothesis that tolerance induction is dependent on the B7:CD28/CTLA-4 pathway. The results from our studies will enhance our understanding of the role that myelin-reactive T cells may play in the pathogenesis of MS. We have determined that MBP-reactive T cells in MS patients are less dependent upon CD28 costimulation than in normal controls, suggesting that these T cells were previously primed in vivo. Characterization of these CD28-independent myelin-specific T cells will have broad implications for a variety of immunologically based therapies in diseases such as MS.     

Glatiramer acetate for treatment of MS: regulatory B cells join the cast of players

Glatiramer acetate (GA, copolymer-1, Copaxone®) is a Food and Drug Administration-approved drug for the treatment of relapsing–remitting multiple sclerosis (MS). However, its mechanism of action remains ill-defined. The available evidence indicates that GA induces antigen-presenting cells with anti-inflammatory properties and promotes the generation of immunoregulatory T cells that suppress pathogenic T cells. A new study by Kala et al. (2010) now shows that B lymphocytes, which are best known for their antibody-secreting properties, contribute to the beneficial effects of GA against experimental autoimmune encephalomyelitis (EAE), the animal model of MS. This commentary discusses these new findings in the context of the pathogenesis of MS and EAE, the emerging immunoregulatory role of B cells in autoimmunity, and the relevance of B cells as targets for immunotherapy in MS.     

A protective effect of early pregnancy factor on experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein

Experimental autoimmune encephalomyelitis (EAE) is an organ-specific autoimmune disease characterised by inflammation and demyelination of the central nervous system and is the best available animal model of multiple sclerosis (MS). Since previous studies have shown that EAE is less severe or is delayed in onset during pregnancy and that administration of the pregnancy hormone early pregnancy factor (EPF) down-regulates EAE, experiments in the present study were designed to explore further the role of EPF in EAE. By using the rosette inhibition test, the standard bioassay for EPF and, by semi-quantitative RT-PCR techniques, we have now shown that inflammatory cells from the spinal cord of rats with EAE can produce and secrete EPF, with production being greatest during recovery from disease. Administration of EPF to rats with EAE resulted in a significant increase in the expression of IL-4 and IL-10 mRNA and a significant decrease in IFN-gamma mRNA expression in spinal cord inflammatory cells. Encephalitogenic MBP-specific T cell lines were prepared from popliteal lymph nodes of rats with EAE. Proliferation assays using these cells demonstrated the ability of exogenous EPF to down-regulate the responses of T lymphocytes to MBP.     

Cytokines in neuroinflammatory disease: role of myelin autoreactive T cell production of interferon-gamma

Many cytokines must be considered as effector and immunoregulatory molecules in neuroinflammatory diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). We have studied the potential role of interferon-gamma (IFN-γ) in the pathogenesis of these diseases, since this cytokine has a number of important effects such as macrophage activation, induction of MHC class I and class I antigens, and T cell homing. An immunospot assay that allows enumeration of single cells secreting IFN-γ after short-term culture in vitro of mononuclear cell suspensions has been used. In EAE, increased numbers of IFN-γ-secreting cells (IFN-γ-sc) appear in the central nervous system shortly before onset of clinical signs. Such cells also increased during pharmacologically induced relapse of EAE. In later stages of EAE, memory T cells that produced IFN-γ in response to presented antigen, recognized multiple regions of the myelin basic protein (MBP), showing that (i) myelin autoreactive T cells have the functional ability to produce this cytokine, (ii) the concept of immunodominance as to autoantigen peptide reactivity is non-absolute and time-dependent. In multiple sclerosis (MS) there are increased numbers of IFN-γ-sc among the CSF cells. Also, there are increased numbers of memory T cells, strongly enriched to the cerebrospinal fluid, which upon recognition of several myelin antigens and several MBP peptide stretches, produce IFN-γ. Taken together, the data are consistent with a role for IFN-γ as a key mediator in inflammatory demyelinating diseases.     

Agonists for the peroxisome proliferator-activated receptor-alpha and the retinoid X receptor inhibit inflammatory responses of microglia

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). In the present study we investigated the effects of PPAR-alpha agonists on primary mouse microglia, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha agonists ciprofibrate, fenofibrate, gemfibrozil, and WY 14,643 each inhibited NO production by cytokine-stimulated microglia in a dose-dependent manner. However, fenofibrate and WY 14,643 were more potent inhibitors than gemfibrozil and ciprofibrate. In LPS-stimulated microglia, only fenofibrate and WY 14,643 significantly suppressed NO production. Additionally, PPAR-alpha agonists inhibited the secretion of the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, and IL-12 p40 and the chemokine MCP-1 by LPS-stimulated microglia. Retinoid X receptors (RXRs) physically interact with PPAR-alpha receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, the RXR agonist 9-cis retinoic acid (9-cis RA) inhibited NO production by LPS-stimulated microglia. Furthermore, a combination of 9-cis RA and the PPAR-alpha agonist fenofibrate cooperatively inhibited NO production by these cells. A combination of these agonists also selectively inhibited the expression of proinflammatory cytokines including IL-1beta, TNF-alpha, and IL-6 by LPS-stimulated microglia. Collectively, these results raise the possibility that PPAR-alpha and RXR agonists might have benefit as a therapy in MS, where activated microglia are believed to contribute to disease pathology.     

Study of Herpesvirus saimiri immortalization of gammadelta T cells derived from peripheral blood and CSF of multiple sclerosis patients

Human gammadelta T cells are an integral part of the innate immune system and have been difficult to study owing primarily to their relatively low abundance and their fastidious culture properties associated with short in vitro lifespan. Their increased presence within multiple sclerosis (MS) white matter plaques compared to peripheral blood (PB) suggests a specific interaction with central nervous system (CNS) tissues. This fact, together with their innate ability to lyse human oligodendrocytes in culture implicate them possibly in the pathogenesis of MS. To further investigate their potential role in MS, we studied whether gammadelta T cells could be effectively immortalized using Herpesvirus saimiri (HVS), so that they could be studied in longer-term cultures. Effective culture conditions were established resulting in efficient HVS growth transformation of multiple PB and CSF gammadelta T cell lines and clones that could exist in IL-2-dependent culture for periods in excess of 2 years. Phenotypic and functional comparison studies with parental nontransformed gammadelta T cells were performed to characterize the changes that possibly induced by viral transformation. Using panels of transformed gammadelta T cell clones representing discrete gammadelta TcR subtypes, there was no apparent correlation between intracytoplasmic cytokine expression or tumor cell cytotoxicity with a specific TcR. All transformed gammadelta T cells analyzed, regardless of their compartment of origin, strongly expressed intracytoplasmic IFN-gamma and TNF-alpha, but little IL-2 or anti-inflammatory IL-4 or IL-10. These results indicate that HVS transformation of gammadelta T cells can be used to generate lines and clones from both the CSF and PB compartments for further study and elucidation of their potential role in MS pathogenesis.     

Sulfasalizine aggravates experimental autoimmune encephalomyelitis and causes an increase in the number of autoreactive T cells

Sulfasalazine (SASP; 5-(p-(2-pyridylsulfamoyl)phenylazo)salicylic acid) has beneficial effects on certain inflammatory diseases and has been proposed for clinical trials in multiple sclerosis (MS). We have explored the effects of SASP on actively induced experimental autoimmune encephalomyelitis (EAE) in Lewis rats. SASP was given orally at three different doses from the day of immunization to day 40 post-immunization (p.i.). All doses led to a clinically more protracted disease, increased numbers of T cells infiltrating into the central nervous system (CNS) and to increased numbers of interferon-γ-secreting cells (IFN-γ-sc) in the CNS. The effects of SASP treatment on T cell-mediated autoimmunity against CNS myelin and peptides of myelin basic protein (MBP) were measured by IFN-γ secretion and proliferation by lymph node mononuclear cells in response to these antigens. In SASP-treated rats, increased numbers of IFN-γ-sc appeared in response to myelin antigens, while the proliferative responses were decreased. We suggest that monitoring cell-mediated immunity with the IFN-γ-sc method may be relevant for the evaluation of new immunotherapeutic strategies in flammatory demyelinating diseases. Furthermore, our results demand caution as to clinical trials with SASP in MS.     

TGFβ regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte‐derived dendritic cells

Intracerebral levels of Transforming Growth Factor beta (TGFβ) rise rapidly during the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). We addressed the role of TGFβ responsiveness in EAE by targeting the TGFβ receptor in myeloid cells, determining that Tgfbr2 was specifically targeted in monocyte‐derived dendritic cells (moDCs) but not in CNS resident microglia by using bone‐marrow chimeric mice. TGFβ responsiveness in moDCs was necessary for the remission phase since LysM^CreTgfbr2^fl/fl mice developed a chronic form of EAE characterized by severe demyelination and extensive infiltration of activated moDCs in the CNS. Tgfbr2 deficiency resulted in increased moDC IL‐12 secretion that skewed T cells to produce IFN‐γ, which in turn enhanced the production of moDC‐derived reactive oxygen species that promote oxidative damage and demyelination. We identified SNPs in the human NOX2 (CYBB) gene that associated with the severity of MS, and significantly increased CYBB expression was recorded in PBMCs from both MS patients and from MS severity risk allele rs72619425‐A carrying individuals. We thus identify a novel myeloid cell‐T cell activation loop active in the CNS during chronic disease that could be therapeutically targeted. GLIA 2016;64:1925–1937     

Cytapheresis with a filter for selective removal of CD4+ T cells in experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a major animal model of human multiple sclerosis (MS). CD4+ T cells are thought to play a pivotal role in the pathogenesis of EAE and MS. In order to investigate the depletion of CD4+ T cells from the systemic circulation as an effective strategy for the treatment of MS, we performed extracorporeal CD4+ T cell adsorption, using a filter to which anti-CD4+ antibody is immobilized as a ligand, in adoptively transferred EAE. Rats treated with CD4+ T cell removal filter (CD4RF) exhibited milder clinical signs of EAE and earlier recovery than those receiving sham treatment. Moreover, the thymic cells from EAE rats treated with CD4RF exhibited a suppressed proliferative response and IFN-gamma production to myelin basic protein. These results suggest that depletion of CD4+ T cells from the systemic circulation by extracorporeal treatment is a potentially useful strategy for treatment of acute phase and relapsing MS.     

T cells, cytokines, and autoantigens in multiple sclerosis

In multiple sclerosis (MS), inflammatory demyelination in the central nervous system is thought to be initiated by T cells that recognize myelin antigens. T cells are the main regulators of acquired immunity and are involved in the pathogenesis of several organ-specific autoimmune diseases. This review provides an overview of recent studies on the role of T cells in autoimmune demyelination. Because autoreactive T cells are normally present in the mature repertoire of T cells in the blood and lymphoid organs of MS patients, but also in normal controls, particular attention is devoted to the mechanisms of activation and the functional phenotype of such T cells in patients with MS. The role of cytokines as effector molecules and the main candidate antigens are also discussed.     

Generation of autonomously pathogenic neo-autoreactive TH1 cells during the development of the determinant spreading cascade in murine autoimmune encephalomyelitis

Chronic progression of autoimmune disease is accompanied by the acquisition of autoreactivity to new self-determinants. Recent evidence indicates that this process, commonly referred to as determinant spreading, may be pathogenic for chronicity. Our studies on experimental autoimmune encephalomyelitis (EAE), a murine model widely used in multiple sclerosis (MS) studies, have shown that determinant spreading develops as a predictable sequential cascade of neo-autoimmunity during progression to chronic disease. By 7–8 weeks after immunization of (SWRxSJL)F₁ mice with the immunodominant myelin proteolipid protein determinant (PLP 139–151), splenocytes consistently respond to the immunodominant myelin basic protein determinant (MBP 87–99). In the present study, we directly address the pathogenicity of neo-autoimmunity resulting from endogenous self-priming during the course of disease. Our results indicate that T cells responding to the spreading MBP 87–99 determinant produce a proinflammatory cytokine profile consistent with type 1 helper T cells (Th1) cells. In addition, splenocytes activated to the spreading MBP 87–99 determinant consistently transfer acute EAE in naive recipients even when T cells reactive to the priming PLP 139–151 immunogen are eliminated by bromodeoxyuridine (BUdR)-mediated photolysis. Our data indicate that endogenous neo-autoantigen priming during chronic autoimmune disease generates type 1 helper T cells (Th1) cells that are autonomously pathogenic. These results provide further evidence supporting the view that determinant spreading is a pathogenic process that leads to chronic progression of autoimmune disease. © 1996 Wiley-Liss, Inc.     

The FcRgamma chain is not essential for induction of experimental allergic encephalomyelitis (EAE) or anti-myelin antibody-mediated exacerbation of EAE

Macrophages are considered essential mediators in multiple sclerosis (MS) pathogenesis, presumably through myelin phagocytosis and release of inflammatory mediators. Macrophages and microglia express activating Fcgamma receptors (FcgammaRI and FcgammaRIII), which depend on the FcRgamma chain for surface expression and signaling. In MS lesions, crosslinking of FcgammaR by immunoglobulins (IgG) directed against myelin may enhance myelin phagocytosis and inflammation. We studied the role of FcgammaR and anti-myelin antibodies in MOG35-55-induced experimental allergic encephalomyelitis (EAE) in C57BL/6 mice, a model of MS-like disease. Incidence and severity of EAE were similar in FcRy chain-/- (FcRgamma-/-) and wild-type (wt) mice, albeit with delayed onset in FcRgamma-/- mice. This demonstrates that the FcRy chain is not essential for induction of EAE, but that FcRgamma signaling may contribute to the preclinical phase. The role of FcgammaR in antibody-mediated demyelination was addressed by injection of anti-myelin antibodies (Z12 mAb) at onset of MOG35-55-induced EAE. Injection of Z12 mAb rapidly reduced survival time in both wt and FcRgamma-/- mice, demonstrating that antibody-mediated exacerbation of EAE is independent of the FcRgamma chain. Interestingly, Z12-induced exacerbation of inflammation and demyelination persisted longer in wt than FcRgamma-/- mice, suggesting that IgG-FcgammaR interactions may contribute to a sustained pathologic effect of anti-myelin antibodies in the CNS.     

The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-gamma

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), is mediated by autoantigen-specific T-helper1 (Th1) cells. IL-12, an inducer of Th1 cell development, exerts immunomodulatory effects in EAE. Programmed death-1 (PD-1) and PD-1 ligand (PD-L), new members of the B7 superfamily of costimulatory molecules, play a critical role in regulating EAE. Whether the interaction of IL-12 and the PD-1/PD-L pathway regulates EAE is unclear. We have previously shown that IL-12 suppresses EAE induced by MOG35-55 in C57BL/6 mice, but not in IFN-gamma-deficient mice, suggesting that IFN-gamma is required for the inhibitory effects of IL-12 on EAE. In the current study, PD-L1 expression is up-regulated following IL-12 treatment in wild-type mice, but not in IFN-(-deficient EAE mice. Similarly, IL-12 induces IFN-gamma and PD-L1 expression in cultured MOG-specific T cells from wild-type mice but not from IFN-gamma-deficient mice. Furthermore, PD-L1 expression increased specifically in CD11b+ antigen presenting cells (APCs) after IL-12 administration. These data suggest that one mechanism of IL-12 suppression of EAE is mediated by PD-1/PD-L signaling downstream of IFN-gamma induction in CD11b+ APCs. The regulation of PD-1/PD-L1 may have potential therapeutic effects for EAE and MS.