Central Nervous System Antigens Research Articles

Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen.

In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelitis (EAE) in the absence of B cells, when mice endogenously contained MOG-recognizing T cells. Adoptive transfer studies corroborated that anti-MOG Ab triggered activation and expansion of peripheral MOG-specific T cells in an Fc-dependent manner, subsequently causing EAE. To evaluate the underlying mechanism, anti-MOG Ab were added to a co-culture of myeloid APC and MOG-specific T cells. At otherwise undetected concentrations, anti-MOG Ab enabled Fc-mediated APC recognition of intact MOG; internalized, processed and presented MOG activated naïve T cells to differentiate in an encephalitogenic manner. In a series of translational experiments, anti-MOG Ab from two patients with an acute flare of CNS inflammation likewise facilitated detection of human MOG. Jointly, these observations highlight Ab-mediated opsonization of endogenous CNS auto-antigen as a novel disease- and/or relapse-triggering mechanism in CNS demyelinating disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1559-8) contains supplementary material, which is available to authorized users.

ACAID as a potential therapeutic approach to modulate inflammation in neurodegenerative diseases

The progressive loss of neurons and inflammation characterizes neurodegenerative diseases. Although the etiology, progression and outcome of different neurodegenerative diseases are varied, they share chronic inflammation maintained largely by central nervous system (CNS)-derived antigens recognized by T cells. Inflammation can be beneficial by recruiting immune cells to kill pathogens or to clear cell debris resulting from the primary insult. However, chronic inflammation exacerbates and perpetuates tissue damage. An increasing number of therapies that attempt to modulate neuroinflammation have been developed. However, so far none has succeeded in decreasing the secondary damage associated with chronic inflammation. A potential strategy to modulate the immune system is related to the induction of tolerance to CNS antigens. In this line, it is our hypothesis that this could be accomplished by using anterior chamber associated immune deviation (ACAID) as a strategy. Thus, we review current knowledge regarding some neurodegenerative diseases and the associated immune response that causes inflammation. In addition, we discuss further our hypothesis of the possible usefulness of ACAID as a therapeutic strategy to ameliorate damage to the CNS.

Role of T cell-glial cell interactions in creating and amplifying central nervous system inflammation and multiple sclerosis disease symptoms.

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System (CNS) that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons and axons. Historically, MS has been thought of as a T cell-mediated autoimmune disease of CNS white matter. However, recent studies have identified gray matter lesions in MS patients, suggesting that CNS antigens other than myelin proteins may be involved during the MS disease process. We have recently found that T cells targeting astrocyte-specific antigens can drive unique aspects of inflammatory CNS autoimmunity, including the targeting of gray matter and white matter of the brain and inducing heterogeneous clinical disease courses. In addition to being a target of T cells, astrocytes play a critical role in propagating the inflammatory response within the CNS induced NF-κB signaling. Here, we will discuss the pathophysiology of CNS inflammation mediated by T cell—glial cell interactions and its contributions to CNS autoimmunity.

Mouse models of multiple sclerosis: lost in translation?

Multiple sclerosis (MS) is a chronic neurological disorder of the central nervous system (CNS) leading to progressive accumulation of neurological deficits arising from recurrent episodes of inflammation, demyelination and neuronal degeneration. While the aetiology of the disease is unknown MS is widely considered to be the result of aberrant T cell and antibody responses to CNS antigens giving rise to the common concept that MS is an autoimmune disease or that there is an autoimmune component in the pathogenesis. This idea has lead to the development of experimental autoimmune encephalomyelitis (EAE) mouse models of MS in which immunisation with CNS antigens induces neurological and pathological signs of disease in mice. In addition to EAE models, injection with neurotropic viruses has been used to examine how infections are implicated in the disease process and how they may generate autoimmune responses in the CNS. Viral models are also crucial to investigate the impact of blocking trafficking of immune responses into the CNS since an emerging side-effect of current immunotherapeutic approaches in MS is the reactivation of viruses within the CNS. To investigate myelin damage and repair in the absence of the adaptive immune response, toxin-induced demyelination using cuprizone, ethidium bromide and lysolecithin, which rapidly leads to remyelination when the toxins are withdrawn, is also reviewed. Mice also lend themselves to the vast array of transgenic technologies to probe specific pathways as well as the use of humanised transgenic mice to examine the impact of human molecules. Despite the vast array of mouse models EAE is the most frequently exploited paradigm used to develop therapeutic approaches. However, despite over one thousand compounds used in the treatment of EAE few have become licenced for treatment of MS so far. Thus, this review also debates the reasons for these failures in mouse models as well as discusses how mouse models can be better utilised to provide more powerful preclinical tools to develop rational therapies for multiple sclerosis.

DIAZEPAM EFFECTS ON IMMUNE CELLS ACTIVELY INVOLVED DURING THE DEVELOPMENT OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS.

DIAZEPAM EFFECTS ON IMMUNE CELLS ACTIVELY INVOLVED DURING THE DEVELOPMENT OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS.

Re-circulating Phagocytes Loaded with CNS Debris: A Potential Marker of Neurodegeneration in Parkinsons Disease?

Diagnosis and monitoring of diseases by measurement of biochemical markers has most commonly been performed on samples of peripheral blood. However, no such markers are available for clinical use in the major diseases of the central nervous system (CNS). In Parkinson's disease circulating biomarkers would find clinical utility in early diagnosis and also monitoring of disease progression. Of particular interest is early diagnosis as this would create .a window of opportunity for treatment with neuroprotective drugs. We have developed a novel strategy for monitoring disease activity in the CNS based on the recognition that tissue injuries incite inflammation and recruitment of phagocytes that engulf debris. We postulated that some of these debris laden phagocytes may return to the peripheral blood and their cargo of CNS proteins could be measured. If CNS antigens can be measured in PBMCs it may be an indicator of active neurodegeneration as the debris engulfed by phagocytes is completely degraded within days. To make this approach more specific to Parkinson's disease we probed PBMC lysates for neuromelanin as a marker of degeneration within the substancia nigra. We performed a proof of principle study in ten subjects with early PD and ten age and sex matched controls. The biomarkers neuromelanin, Tau protein, UCH-L1 and HPCAL-1 were measured in PBMC lysates from these two groups. Neuromelanin and Tau protein mean levels were elevated in PD compared with controls and was extremely statistically significant in both cases. UCH-L1 and HPCAL-1 mean levels were elevated in PD over controls and were not quite significant in both cases. These results suggest that this is a promising new approach for diagnosis and monitoring of PD and potentially other CNS diseases.

Chemotactic signaling and beyond: link between interleukin-16 and axonal degeneration in multiple sclerosis.

Multiple sclerosis (MS) is a progressive inflammatory, and chronic demyelinating, neurodegenerative disease of central nervous system (CNS). Autoimmune responses to myelin and other CNS antigens mediated by cluster of differentiation 4 (CD4+) T cells are critical for initiation and progression of disease. Migration of autoimmune T cells from the peripheral lymph organs into CNS parenchyma leads to inflammation, demyelination and damage of axonal cytoskeleton, which manifest in decreased impulse conduction velocity of motor and sensory nerves. Myelin and axonal pathology causes motor, sensory and autonomic nerve dysfunction, including optic nerve damage leading to double or distorted vision; paresis and paralysis of extremities, painful sensations, and bladder sphincter dysfunction, manifested as bladder incontinence. Gray matter pathology in cortical and subcortical regions, including cerebellum and hippocampus underlies cognitive and behavioral dysfunction consisting of memory deficits, depression, and ataxic gait and tremor.

B-Cell Receptors of Primary Central Nervous System Lymphoma Recognize Antigens in the Brain

INTRODUCTIONThe pathobiology mediating the development of primary central nervous system lymphoma (PCNSL) and its exclusive manifestation in the brain and spinal cord is still poorly understood. The monoclonal B-cell receptor expressed in PCNSL cells have a germinal center typology, suggesting previous antigen contact and antigen-based selection during B-cell development. Furthermore, sequence analysis of B-cell receptors in various patients revealed a bias in the immunoglobulin repertoire in PCNSL, potentially indicating that distinct epitopes might elicit such an immune response. Nevertheless, the nature of potential antigens containing such epitopes is unknown. Here, we provide the first evidence that such antigens may be located within the central nervous system itself, which might contribute to the specific organ tropism of PCNSL. METHODSCryopreserved tissue of five randomly chosen PCNSL cases and three control cases with mantle cell lymphoma were used for this study. The variable heavy and light chains of the B-cell receptors were amplified from extracted RNA and cloned in IgG1 expression vectors. Recombinant B-cell receptors were expressed and purified as soluble human immunoglobulins. To explore the potential recognition of central nervous system antigens, murine cryo- and paraffin-embedded brain tissue sections were immunostained using these PCNSL or mantle cell lymphoma-derived immunoglobulins as primary antibodies. RESULTSFour out of five recombinant B-cell receptors from PCNSL but none of the MCL-derived control immunoglobulins recognized distinct anatomical structures in the brain which resulted in unambiguous immunostaining especially in regions with high neuronal density. The staining of brain tissue was associated with neuronal cells in all four positive cases. Staining was stronger in the cerebellum and the hippocampus compared to other areas of the brain and staining intensity varied broadly among the four positive cases. In the cerebellum, all four positive B-cell receptors recognized the cytoplasm of Purkinje cells, the largest neurons in the brain (therefore, staining could be readily identified). Two of the B-cell receptors also recognized the Purkinje cell’s dendrites. Three of the PCNSL-derived immunoglobulins also stained the granule cells, the most frequent neuronal cell type in the brain. Two of those stained in the cytoplasm and one showed a patchy but strong staining pattern in the nucleus of these cells. All of these stainings including negative controls were reproduced multiple times in independent experiments. CONCLUSIONB-cell receptors of primary central nervous system lymphomas recognize neuronal structures in the brain in an individually case-dependent pattern. This might point towards an important role of antigen recognition in the pathobiology and specific organ tropism of this lymphoma. DisclosuresNo relevant conflicts of interest to declare.

Cross-talk between the inflammatory response, sympathetic activation and pulmonary infection in the ischemic stroke.

The immune system response and inflammation play a key role in brain injury during and after a stroke. The acute immune response is responsible for secondary brain tissue damage immediately after the stroke, followed by immunosuppression due to sympathetic nervous system activation. The latter increases risk of infection complications, such as pneumonia. The pneumonia-related inflammatory state can release a bystander autoimmune response against central nervous system antigens, thereby initiating a vicious circle. The aim of this review is to summarize the relationship between ischemic stroke, sympathetic nervous system activation and pulmonary infection.

T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases.

Neuroinflammation is involved in several neurodegenerative disorders and emerging evidence indicates that it constitutes a critical process that is required for the progression of neurodegeneration. Microglial activation constitutes a central event in neuroinflammation. Furthermore, microglia can not only be activated with an inflammatory and neurotoxic phenotype (M1-like phenotype), but they also can acquire a neurosupportive functional phenotype (M2-like phenotype) characterised by the production of anti-inflammatory mediators and neurotrophic factors. Importantly, during the past decade, several studies have shown that CD4+ T-cells infiltrate the central nervous system (CNS) in many neurodegenerative disorders, in which their participation has a critical influence on the outcome of microglial activation and consequent neurodegeneration. In this review, we focus on the analysis of the interplay of the different sub-populations of CD4+ T-cells infiltrating the CNS and how they participate in regulating the outcome of neuroinflammation and neurodegeneration in the context of Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and multiple sclerosis. In this regard, encephalitogenic inflammatory CD4+ T-cells, such as Th1, Th17, GM-CSF-producer CD4+ T-cells and γδT-cells, strongly contribute to chronic neuroinflammation, thus perpetuating neurodegenerative processes. In contrast, encephalitogenic or meningeal Tregs and Th2 cells decrease inflammatory functions in microglial cells and promote a neurosupportive microenvironment. Moreover, whereas some neurodegenerative disorders such as multiple sclerosis, Parkinson’s disease and Alzheimer’s disease involve the participation of inflammatory CD4+ T-cells 'naturally', the physiopathology of other neurodegenerative diseases, such as amyotrophic lateral sclerosis, is associated with the participation of anti-inflammatory CD4+ T-cells that delay the neurodegenerative process. Thus, current evidence supports the hypothesis that the involvement of CD4+ T-cells against CNS antigens constitutes a key component in regulating the progression of the neurodegenerative process.

Case of autoantibodies against N‐methyl‐D‐aspartate receptor+/antibodies against myelin‐oligodendrocyte glycoprotein+ multiphasic acute disseminated encephalomyelitis (ADEM)

Case of autoantibodies against N‐methyl‐D‐aspartate receptor+/antibodies against myelin‐oligodendrocyte glycoprotein+ multiphasic acute disseminated encephalomyelitis (<scp>ADEM</scp>)

Molecular targeted therapy against B cells in multiple sclerosis

AbstractB cells have been implicated in the pathology of multiple sclerosis (MS) since the initial observation in the 1940s and 50s of increased immunoglobulin concentrations in the cerebrospinal fluid of MS patients. Until recently, B cells have been considered to participate in MS pathology through the secretion of antibodies specific to central nervous system antigens. However, the successful targeting of B cells with anti‐CD20 monoclonal antibodies without affecting immunoglobulin levels suggests that B cells have antibody‐independent functions in immune regulation in MS. Furthermore, the recent identification of B cell‐rich follicle‐like structures in the meninges of patients with secondary progressive MS indicates that B cells also have pathogenic roles within the central nervous system, where they contribute to disease progression by inducing cortical injury. These observations suggest that B cells are key players in the pathogenesis of MS, and are therefore attractive targets for therapeutic intervention. In addition to CD20, several other molecules and pathways related to B cell function are being evaluated as therapeutic targets in other autoimmune diseases. Furthermore, based on the increased understanding of the molecular mechanisms underlying B cell effector function, particularly those involved in MS, therapeutic strategies for specifically inhibiting the pro‐inflammatory activity of B cells while preserving or even enhancing their role in protective immune response are under active investigation. Here, we review recent advances in molecular targeted therapies against B cells for MS, and discuss perspectives for future therapies targeting B cells and related molecules.

Tcells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation.

Paraneoplastic neurologic diseases (PND) involving immune responses directed toward intracellular antigens are poorly understood. Here, we examine immunity to the PND antigen Nova2, which is expressed exclusively in central nervous system (CNS) neurons. We hypothesized that ectopic expression of neuronal antigen in the periphery could incite PND. In our C57BL/6 mouse model, CNS antigen expression limits antigen-specific CD4+ and CD8+ T-cell expansion. Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells. CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo. Despite mediating cancer rejection, adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting. Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity. This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled. Since humoral immunity was not required for tumor rejection, B-cell targeting therapy, such as rituximab, may be a rational treatment option for PND that does not hamper tumor immunity.

Epstein-Barr virus and multiple sclerosis: potential opportunities for immunotherapy.

Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein–Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8+ T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8+ T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of αB-crystallin in EBV-infected B cells leading to a CD4+ T-cell response against oligodendrocyte-derived αB-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8+ T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production.

Current and future therapies targeting the immune system in multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The exact pathomechanism is unknown, but an aberrant immune response against CNS antigens, leading to inflammation in brain and spinal cord followed by demyelination, axonal damage and scar formation, seems to play a major role. Later in the disease course, inflammation decreases, while neurodegeneration proceeds. Approximately 80% of the patients initially show a relapsing-remitting disease course (RRMS), but the majority of them later develops a secondary progressive MS (SPMS). A minority suffers from primary progressive MS (PPMS). Primary goals of long-term MS therapy are to prevent relapses and disease progression. Assuming that MS is an autoimmune disease, most therapeutics aim to modulate or suppress the immune system. Until now many drugs have proven efficacy in RRMS, but none in PPMS. Interferon-β (IFN-β) and glatiramer acetate are known in RRMS therapy for years. Based on preclinical research and clinical trials, new treatment strategies have emerged and have been transferred from bench to bedside. The α4β-integrin-antagonist natalizumab was approved in 2005. Fingolimod, dimethyl fumarate and teriflunomide were the first oral drugs introduced in MS therapy. Recently alemtuzuab, another monoclonal antibody, was approved in Europe. Promising future perspectives are alemtuzumab, daclizumab, and laquinimod. Here, we review drug mechanisms in the therapy of MS. The mechanisms of action and the effect of the drugs on the immune system are summarized. We report recent results of clinical trials, highlight special features of different treatment strategies, and discuss future perspectives and ongoing clinical trials.

KIR4.1 Antibodies as Biomarkers in Multiple Sclerosis.

KIR4.1 Antibodies as Biomarkers in Multiple Sclerosis.

Immune privilege of the CNS is not the consequence of limited antigen sampling

Central nervous system (CNS) immune privilege is complex, and it is still not understood how CNS antigens are sampled by the peripheral immune system under steady state conditions. To compare antigen sampling from immune-privileged or nonprivileged tissues, we created transgenic mice with oligodendrocyte or gut epithelial cell expression of an EGFP-tagged fusion protein containing ovalbumin (OVA) antigenic peptides and tested peripheral anti-OVA peptide-specific sentinel OT-I and OT-II T cell activation. We report that oligodendrocyte or gut antigens are sampled similarly, as determined by comparable levels of OT-I T cell activation. However, activated T cells do not access the CNS under steady state conditions. These data show that afferent immunity is normally intact as there is no barrier at the antigen sampling level, but that efferent immunity is restricted. To understand how this one-sided surveillance contributes to CNS immune privilege will help us define mechanisms of CNS autoimmune disease initiation.

What we know and do not know about fingolimod: Outline and interpretation of results from the Japanese fingolimod core and extension studies

AbstractMultiple sclerosis (MS) is an idiopathic demyelinating disease of the central nervous system (CNS). Autoreactive T cells that recognize undetermined CNS antigens are assumed to mediate the disease. Fingolimod or FTY720, a sphingosine 1‐phosphate receptor (S1PR) modulator, downmodulates S1PR on lymphocytes causing retention of circulating lymphocytes in the lymph nodes, including the CNS antigen‐autoreactive lymphocytes that invade the CNS. Fingolimod has recently been approved in several countries as a once‐daily, oral, disease‐modifying drug for relapsing–remitting MS. Recently, the Japanese fingolimod core and extension studies showed the efficacy of fingolimod in terms of brain magnetic resonance imaging criteria and clinical activities in Japanese patients with relapsing MS without longitudinally extensive spinal cord lesions (LESCL). These results were consistent with the effects of fingolimod in Caucasian MS patients. No new safety issues were observed except for severe exacerbations that occurred in four anti‐aquaporin‐4 antibody‐positive cases in whom LESCL were absent at the time of the entry. Thus, fingolimod is regarded as efficacious and safe for Asian MS patients, although Asian neuromyelitis optica cases in the early course of the disease should be excluded from fingolimod treatment.

Heterogeneous Nuclear Ribonucleoprotein K Autoantibodies in Patients who Suffered Severe Traumatic Brain Injury

The immune-inflammatory response as well as cerebral endothelial activation has been described after Traumatic Brain Injury (TBI). Although inflammation can have both beneficial and detrimental effects in TBI, the mechanisms underlying this dichotomy are mostly unknown. Moreover, emerging data indicates that chronic alterations produced after TBI are probably the result of systemic and persistent inflammation that activates immune response, culminating in the production of different specific auto antibodies against central nervous system antigens. In the previous study we demonstrated the production of anti-hnRNPK antibodies, belonging to Anti-Endothelial Cell Antibodies (AECA), in heart transplanted patients who developed Cardiac Allograft Vasculopathy (CAV). These antibodies could be produced in response to the vascular endothelial damage that is also present in TBI patients. In the current study we analyse the presence of AECA by Indirect Immunofluorescence assay (IFI) and anti-hnRNPK IgG antibodies by Enzyme-Linked Immunosorbent Assay (ELISA) in a cohort of 19 patients who suffered TBI. We detected a significant increase in the number of patients with AECA and anti-hnRNPK antibodies after TBI. Moreover, anti-hnRNPK antibody levels were also higher during follow-up, being the values obtained after TBI significantly higher than those detected at the time of trauma (p = 0.001). We also found that AECA and anti-hnRNPK antibodies were mostly present in the sera of patients with a worse outcome (p = 0.018 and p = 0.04 respectively). Taking into account, measuring these auto antibodies could be useful for evaluating endothelial injury and/or the outcome after TBI.

Glatiramer acetate ameliorates experimental autoimmune neuritis

Glatiramer acetate (GA) is one of the first-line disease-modifying medications that have been approved for the treatment of multiple sclerosis via immune modulatory mechanisms. However, it remains unclear whether the immunomodulation effect of GA is central nervous system (CNS) antigen specific. Here, we explored the mechanism of action of GA by subcutaneously injecting GA in experimental autoimmune neuritis (EAN) rats, an animal model for Guillain-Barré syndrome (GBS). Clinical, electrophysiological and histological findings showed that neurological deficits, demyelination and axonal injury of sciatic nerves were all significantly attenuated in Lewis rats when GA was administered before immunization with peripheral nervous system antigen P0. Our results further demonstrated that GA treatment inhibited either P0 or myelin basic protein (MBP) (CNS antigen)-stimulated auto-immune T-cell proliferation in vitro. GA administrated at 10 days after induction of EAN when neurological sign became apparent also ameliorated the severity of disease, inhibited T-cell response to P0 and MBP and induced shift of proinflammatory and immune modulatory cytokines. Collectively, our findings suggested that GA attenuated neurological deficits in EAN rats and that the immune modulatory mechanisms of GA were not CNS antigen specific.