The double-edged sword of autoimmunity: lessons from multiple sclerosis

The relationship between immune responses to self-antigens and autoimmune disease is unclear. In contrast to its animal model experimental autoimmune encephalomyelitis (EAE), which is driven by T cell responses to myelin antigens, the target antigen of the intrathecal immune response in multiple sclerosis (MS) has not been identified. Although the immune response in MS contributes significantly to tissue destruction, the action of immunocompetent cells within the central nervous system (CNS) may also hold therapeutic potential. Thus, treatment of MS patients with glatiramer acetate triggers a protective immune response. Here we review the immunopathogenesis of MS and some recent findings on the mechanism of glatiramer acetate (GA).     

Vaccines for multiple sclerosis: progress to date

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS, characterized pathologically by a perivascular infiltrate consisting predominantly of T cells and macrophages. Although its aetiology remains unknown, several lines of evidence support the hypothesis that autoimmune mechanisms play a major role in the development of the disease. Several widely used disease-modifying agents are approved for the treatment of MS. However, these agents are only partially effective and their ability to attenuate the more progressive phases of the disease is not clear at this time. Therefore, there is a need to develop improved treatment options for MS.This article reviews the role of several novel, selective vaccine strategies that are currently under investigation, including: (i) T-cell vaccination (TCV); (ii) T-cell receptor (TCR) peptide vaccination; (iii) DNA vaccination; and (iv) altered peptide ligand (APL) vaccination. The administration of attenuated autoreactive T cells induces regulatory networks to specifically suppress pathogenic T cells in MS, a strategy named TCV. The concept of TCV was based on the experience of vaccination against aetiological agents of infectious diseases in which individuals are purposely exposed to an attenuated microbial pathogen, which then instructs the immune system to recognize and neutralize it in its virulent form. In regard to TCV, attenuated, pathogenic T cells are similarly used to instruct the immune system to recognize and neutralize disease-inducing T cells. In experimental allergic encephalomyelitis (EAE), an animal model for MS, pathogenic T cells use a strikingly limited number of variable-region elements (V region) to form TCR specific for defined autoantigens. Thus, vaccination with peptides directed against these TCR structures may induce immunoregulatory mechanisms, thereby preventing EAE. However, unlike EAE, myelin-reactive T cells derived from MS patients utilize a broad range of different V regions, challenging the clinical utility of this approach. Subsequently, the demonstration that injection of plasmid DNA encoding a reporter gene into skeletal muscle results in expression of the encoded proteins, as well as in the induction of immune responses in animal models of autoimmunity, was explored as another strategy to re-establish self-tolerance. This approach has promise for the treatment of MS and, therefore, warrants further investigation. APLs are molecules in which the native encephalitogenic peptides are modified by substitution(s) of one or a few amino acids critical for contact with the TCR. Depending on the substitution(s) at the TCR contact residues of the cognate peptide, an APL can induce immune responses that can protect against or reverse EAE. However, the heterogeneity of the immune response in MS patients requires further study to determine which patients are most likely to benefit from APL therapy.Other potential approaches for vaccines in MS include vaccination against axonal growth inhibitors associated with myelin, use of dendritic cells pulsed with specific antigens, and active vaccination against proinflammatory cytokines. Overall, vaccines for MS represent promising approaches for the treatment of this devastating disease, as well as other autoimmune diseases.     

The role of CD1-mediated presentation of myelin lipids in experimental autoimmune encephalomyelitis and multiple sclerosis pathologenesis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by the destruction of the myelin sheath surrounding axons. On the basis of data from the animal model, experimental autoimmune encephalomyelitis (EAE) and the detection of myelin-reactive cells in MS patients, this destruction is thought to be due to an autoimmune T-cell-mediated response to myelin antigens. Until recently, the characterization of T-cell recognition of myelin antigens has necessarily focused on the response to myelin proteins. However, the discovery of CD1-mediated presentation of lipids and glycolipids to a variety of T-cell populations has greatly expanded the repertoire of antigens to which T cells can respond. Studies in the EAE model suggest a role for myelin lipids in disease pathogenesis. Recent characterization of the expression and function of CD1 and the responding T-cell populations does support a role for this pathway in the disease process. Furthermore, data suggest that it may be possible to modulate the disease course by targeting this pathway. Characterization of CD1-mediated presentation of lipids to T cells has only recently been investigated in MS, with most attention focusing on the expression of group I CD1 proteins in MS lesions. In light of data from the animal model, further characterization of the expression and function of group I and group II CD1 proteins is warranted, and could lead to the development of effective therapies to treat MS.     

Role of the innate immune system in autoimmune inflammatory demyelination

Considerable research has been devoted to the role of the adaptive immune system in the pathogenesis of autoimmune inflammatory demyelination (AID). AID is thought to occur spontaneously in patients with multiple sclerosis (MS), a common cause of neurological disability. AID is also observed in the best characterized animal model of MS, experimental autoimmune encephalomyelitis (EAE). The adaptive immune system recognizes and responds to antigens via highly specific T-cell receptors. Myelin-reactive T-cells may initiate pathological immune responses that lead to central nervous system damage in MS and EAE. By contrast, the innate immune system recognizes evolutionarily conserved structures that are common to invading pathogens with high efficiency for rapid recognition and elimination of viruses, bacteria, and fungi. This recognition is mediated by pattern-recognition receptors such as Toll-like receptors (TLRs) expressed on cells of the innate immune system (dendritic cells and CNS-resident cells, such as microglia) that have the potential to activate autoimmune responses by inducing the production of inflammatory cytokines and chemokines. Conversely, the innate immune system can also regulate autoimmune inflammation by inducing the production of immunoregulatory molecules such as type I interferons, which are currently used in the treatment of MS. We review the evidence that TLRs can exacerbate or regulate AID and discuss the therapeutic potential of targeting either process.     

The role of myelin oligodendrocyte glycoprotein in autoimmune demyelination: a target for multiple sclerosis therapy?

Introduction: Myelin oligodendrocyte glycoprotein (MOG) is a myelin antigen at the outer surface of the central nervous system (CNS) myelin sheath, which may trigger T-cell as well as B-cell responses. It therefore constitutes a pivotal target for autoimmune responses, which result in inflammation and also demyelination in the CNS. In particular, it is a major target for auto-antibodies in experimental autoimmune encephalomyelitis (EAE), which mimics many aspects of multiple sclerosis (MS). B-cell responses toward MOG and anti-MOG antibodies have also been demonstrated in patients with demyelinating diseases, such as MS and acute disseminating encephalomyelitis (ADEM). Co-transfer of such anti-MOG antibodies in experimental models results in a distinct lesion pattern with antibody and complement-mediated demyelination, which is also hallmark of some lesion subtypes in MS.

Areas covered: A comprehensive literature search on MOG, B cells, MS, and ADEM was performed to outline the role of MOG in autoimmune demyelination in animal models and its relevance for human disease.

Expert opinion: Although the definite role of MOG in the pathogenesis of MS still remains to be clarified, innovative therapeutic strategies targeting B cells may reduce pathogenic immune responses against myelin auto-antigens including anti-myelin auto-antibodies.     

Chemokines and chemokine receptors: potential therapeutic targets in multiple sclerosis

Multiple sclerosis (MS) is a common inflammatory and demyelinating disease of the central nervous system (CNS), which causes progressive neurological disability. The disease is characterised pathologically by destruction of the myelin sheaths, which surround nerve fibres in the CNS. It is believed that this tissue damage in the brain and spinal cord of MS patients is caused by an inflammatory response that is initiated when autoreactive T cells, specific for myelin antigens, cross the blood-brain barrier and detect their antigen within the CNS. As a result, most therapies to date have been immunosuppressive and/or anti-inflammatory in nature, targeting the processes involved in activation and migration of leukocytes and promotion of the immune response. Over the last decade, a family of chemotactic cytokines called chemokines, have been found to be involved in the trafficking of leukocytes in both the normal and pathological states. The expression of these chemokines and their receptors is increased during the acute phase of MS and also in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). As a result, these chemokines have become an emerging focus for research into novel therapeutics for EAE and ultimately MS. This review will briefly describe the structure and function of chemokines and their receptors, before discussing the latest advances in developing pharmacological agents to block the effects of chemokines involved in promoting the inflammatory response in EAE and MS.     

Angiotensin IV is Induced in Experimental Autoimmune Encephalomyelitis but Fails to Influence the Disease

In multiple sclerosis (MS) and its corresponding animal models, over-activity of the renin-angiotensin system (RAS) has been reported and pharmacological RAS blockade exerts beneficial effects. The RAS generates a number of bioactive angiotensins, thereby primarily regulating the body’s sodium homeostasis and blood pressure. In this regard, angiotensin IV (AngIV), a metabolite of the RAS has been shown to modulate inflammatory responses. Here we studied potential implications of AngIV signalling in myelin oligodendrocyte glycoprotein (MOG) peptide induced murine experimental autoimmune encephalomyelitis (EAE), a close-to-MS animal model. Mass spectrometry revealed elevated plasma levels of AngIV in EAE. Expression of cognate AT₄ receptors was detected in macrophages and T cells as major drivers of pathology in EAE. Yet, AngIV did not modulate macrophage or T cell functions in vitro or displayed detectable effects on neuroantigen specific immune responses in vivo. The data argue against a major contribution of AngIV signalling in the immunopathogenesis of MOG-EAE.     

Biological markers for multiple sclerosis

Multiple sclerosis (MS) is the most common disabling neurological disease in young adults and is thought to result from an autoimmune attack against autoantigens within the myelin sheath. A characteristic feature of MS is the broad heterogeneity of clinical, histopathological and immunological phenotypes, which urges a more differentiated defining of patients by biological markers that reflect the underlying disease process and allow the prediction of disease courses and treatment responses. Here we review the current research on the identification of biomarkers for MS in cerebrospinal fluid and/or blood. We will focus on antibodies to myelin and non-myelin antigens, cells and soluble molecules of the immune system and the brain as biomarkers for 1) the diagnosis and prediction of clinical courses, 2) disease activity and 3) treatment response in MS.     

Section Review Central & Peripheral Nervous Systems: Recent developments in the treatment of encephalomyelitis

Multiple sclerosis (MS) is a form of chronic encephalomyelitis that results in demyelination of neuronal processes and subsequent neurological dysfunction. Demyelinated plaques are characterised by blood brain barrier compromise, infiltration of immune cells, and selective loss of myelin and oligodendrocyte function. Although there are genetic and environmental factors, autoimmunity is considered to be central to the pathogenesis of MS. Experimental allergic/autoimmune encephalomyelitis (EAE) is an excellent model of immune-mediated demyelination and has provided insight into the disease course of MS. Because EAE has a similar pathophysiology it has also been used as a testing ground for potential therapies of MS. Recent treatment strategies include modulation of antigen levels, prevention of T cell activation or function, modulation of cytokine activity, and promotion of oligodendrocyte regeneration and/or function. This review discusses the current experimental agents that have shown promise in the amelioration of EAE and/or MS.     

Induction of Experimental Autoimmune Encephalomyelitis With Recombinant Human Myelin Oligodendrocyte Glycoprotein in Incomplete Freund’s Adjuvant in Three Non-human Primate Species

The experimental autoimmune encephalitis (EAE) model is used for preclinical research into the pathogenesis of multiple sclerosis (MS), mostly in inbred, specific pathogen free (SPF)-raised laboratory mice. However, the naive state of the laboratory mouse immune system is considered a major hurdle in the translation of principles from the EAE model to the MS patient. Non-human primates (NHP) have an immune system harboring T- and B-cell memory against environmental antigens, similar as in humans. We sought to further refine existing NHP EAE models, which may help to bridge the gab between mouse EAE models and MS. We report here on new EAE models in three NHP species: rhesus monkeys (Macaca mulatta), cynomolgus monkeys (Macaca fascicularis) and common marmosets (Callithrix jacchus). EAE was induced with recombinant human myelin oligodendrocyte glycoprotein extracellular domain (1–125) (rhMOG) formulated in incomplete Freund’s adjuvant (IFA). IFA lacks the bacterial antigens that are present in complete Freund’s adjuvant (CFA), which are notorious for the induction of discomforting side effects. Clinically evident EAE could be induced in two out of five rhesus monkeys, six out of six cynomolgus monkeys and six out of six common marmosets. In each of these species, the presence of an early, high anti-rhMOG IgM response is correlated with EAE with an earlier onset and more severe disease course. Animals without an early high IgM response either did not develop disease (rhesus monkeys) or developed only mild signs of neurological deficit (marmoset and cynomolgus monkeys).     

Recombinant TCR Ligand Reverses Clinical Signs and CNS Damage of EAE Induced by Recombinant Human MOG

Increasing evidence suggests that in addition to T cell-dependent effector mechanisms, autoantibodies are also involved in the pathogenesis of MS, including demyelinating antibodies specific for myelin oligodendrocyte glycoprotein (MOG). Our previous studies have demonstrated that recombinant T cell receptor ligands (RTLs) are very effective for treating T cell-mediated experimental autoimmune encephalomyelitis (EAE). In order to expand the scope of RTL therapy in MS patients, it was of interest to study RTL treatment of EAE involving a demyelinating antibody component. Therefore, we evaluated the therapeutic effects of RTL551, specific for T cells reactive to mouse (m)MOG-35-55 peptide, on EAE induced with recombinant human (rh)MOG in C57BL/6 mice. We report that RTL551 therapy can reverse disease progression and reduce demyelination and axonal damage induced by rhMOG without suppressing the anti-MOG antibody response. This result suggests that T cell-mediated inflammation and associated blood–brain barrier dysfunction are the central contributors to EAE pathogenesis and that successful regulation of these key players restricts potential damage by demyelinating antibodies. The results of our study lend support for the use of RTL therapy for treatment of MS subjects whose disease includes inflammatory T cells as well as those with an additional antibody component.     

Genistein down-modulates pro-inflammatory cytokines and reverses clinical signs of experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is the most common non-traumatic, disabling neurological human inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) models MS and is characterized as a CD4+ T-helper type 1 (Th1) cell-mediated autoimmune disease. It is characterized by an influx of activated leukocytes into the CNS. Genistein, occurring abundantly in soy products, has apoptotic, antioxidant, and anti-inflammatory properties. In the present report, we investigated the use of genistein for the treatment of the murine model of MS. After induction of EAE with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG(35-55)), we observed that genistein treatment ameliorated significantly the clinical symptoms, modulating pro- and anti-inflammatory cytokines. Moreover, we analyzed the leukocyte rolling and adherence in the CNS by performing intravital microscopy. Genistein treatment resulted in decreased rolling and adhering of leukocytes as compared to the untreated group. Our data suggest that genistein might be a potential therapy for MS.     

Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis

Impaired remyelination is critical to neuroinflammation in multiple sclerosis (MS), which causes chronic and relapsing neurological impairments. Recent studies revealed that immunomodulatory activity of statins in an experimental autoimmune encephalomyelitis (EAE) model of MS are via depletion of isoprenoids (farnesyl-pyrophosphate and geranylgeranyl-pyrophosphate) rather than cholesterol in immune cells. In addition, we previously documented that lovastatin impedes demyelination and promotes myelin repair in treated EAE animals. To this end, we revealed the underlying mechanism of lovastatin-induced myelin repair in EAE using in vitro and in vivo approaches. Survival, proliferation (chondroitin sulfate proteoglycan-NG2(+) and late oligodendrocyte progenitor marker(+)), and terminal-differentiation (myelin basic protein(+)) of OPs was significantly increased in association with induction of a promyelinating milieu by lovastatin in mixed glial cultures stimulated with proinflammatory cytokines. Lovastatin-induced effects were reversed by cotreatment with mevalonolactone or geranylgeranyl-pyrophosphate, but not by farnesyl-pyrophosphate or cholesterol, suggesting that depletion of geranygeranyl-pyrophosphate is more critical than farnesyl-pyrophosphate in glial cells. These effects of lovastatin were mimicked by inhibitors of geranylgeranyl-transferase (geranylgeranyl transferase inhibitor-298) and downstream effectors {i.e., Rho-family functions (C3-exoenzyme) and Rho kinase [Y27632 (N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide dihydrochloride)]} but not by an inhibitor of farnesyl-transferase (farnesyl transferase inhibitor-277). Moreover, activities of Rho/Ras family GTPases were reduced by lovastatin in glial cells. Corresponding with these findings, EAE animals exhibiting demyelination (on peak clinical day; clinical scores >/=3.0) when treated with lovastatin and aforementioned agents validated these in vitro findings. Together, these data provide unprecedented evidence that-like immune cells-geranylgeranyl-pyrophosphate depletion and thus inhibition of Rho family functions in glial cells by lovastatin promotes myelin repair in ameliorating EAE.     

Crotalphine Attenuates Pain and Neuroinflammation Induced by Experimental Autoimmune Encephalomyelitis in Mice

Multiple sclerosis (MS) is a demyelinating disease of inflammatory and autoimmune origin, which induces sensory and progressive motor impairments, including pain. Cells of the immune system actively participate in the pathogenesis and progression of MS by inducing neuroinflammation, tissue damage, and demyelination. Crotalphine (CRO), a structural analogue to a peptide firstly identified in Crotalus durissus terrificus snake venom, induces analgesia by endogenous opioid release and type 2 cannabinoid receptor (CB2) activation. Since CB2 activation downregulates neuroinflammation and ameliorates symptoms in mice models of MS, it was presently investigated whether CRO has a beneficial effect in the experimental autoimmune encephalomyelitis (EAE). CRO was administered on the 5th day after immunization, in a single dose, or five doses starting at the peak of disease. CRO partially reverted EAE-induced mechanical hyperalgesia and decreased the severity of the clinical signs. In addition, CRO decreases the inflammatory infiltrate and glial cells activation followed by TNF-α and IL-17 downregulation in the spinal cord. Peripherally, CRO recovers the EAE-induced impairment in myelin thickness in the sciatic nerve. Therefore, CRO interferes with central and peripheral neuroinflammation, opening perspectives to MS control.     

Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease associated with chronic inflammatory demyelination of the central nervous system (CNS). Due to disease complexity and heterogeneity, its pathogenesis remains unknown and despite extensive studies, specific effective treatments have not yet been developed. The factors behind the initiation of the inflammatory reactions in CNS have not been identified until now. MS is considered as a complex disease depending on genetic as well as environmental factors. Experimental autoimmune encephalomyelitis (EAE) is the preferential experimental rodent model for MS. Histamine [2-(4-imidazole) ethylamine] is a ubiquitous inflammatory mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems which can modulate immune responses. Histamine functions are mediated through four G-protein coupled receptors that are named H1-H4 receptor. Histamine is implicated as an important factor in pathophysiology of MS and EAE. It has been shown that histamine can change the permeability of blood brain barrier, which leads to elevation of infiltrated cells in CNS and neuroinflammation. In contrast, there are evidence that show the protective role of histamine in MS and its animal model, EAE. In this review, we try to clarify the role of histamine in pathogenesis of MS, as well as we evaluate the efficacy of histamine receptors agonists and antagonists in treatment of this disease.     

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

Autoimmune diseases such as multiple sclerosis (MS) are characterized by the breakdown of immune tolerance to autoantigens. Targeting surface receptors on immune cells offers a unique strategy for reprogramming immune responses in autoimmune diseases. The B7 signaling pathway was targeted using adaptations of soluble antigen array (SAgA) technology achieved by covalently linking B7-binding peptides and disease causing autoantigen (proteolipid peptide (PLP)) to hyaluronic acid (HA). We hypothesized that co-delivery of a B7-binding peptide and autoantigen would suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Three independent B7-targeted SAgAs were created containing peptides to either inhibit or potentially stimulate the B7 signaling pathway. Surprisingly, all SAgAs were found to suppress EAE disease symptoms. Altered cytokine expression was observed in primary splenocytes isolated from SAgA-treated mice, indicating that SAgAs with different B7-binding peptides may suppress EAE through different immunological mechanisms. This antigen-specific immunotherapy using SAgAs can successfully suppress EAE through co-delivery of autoantigen and peptides targeting with the B7 signaling pathway.     

Adrenergic and Dopaminergic Modulation of Immunity in Multiple Sclerosis: Teaching Old Drugs New Tricks?

Multiple sclerosis (MS) is an autoimmune disorder of the CNS characterized by inflammation, demyelination and axonal loss. Classical evidence in experimental allergic encephalomyelitis, the animal model of MS, support the relevance of sympatoadrenergic as well as of dopaminergic mechanisms. In MS patients, dysregulation of adrenergic and dopaminergic pathways contribute to the disease in immune system cells as well as in glial cells. Available evidence is summarized and discussed also in the light of the novel role of dopamine, noradrenaline and adrenaline as transmitters in immune cells, providing a conceptual frame to exploit the potential of several dopaminergic and adrenergic agents, already in clinical use for non-immune indications and with a usually favourable risk-benefit profile, as add-on drugs to conventional immunomodulating therapies in MS.     

Towards Clinical Application of Mesenchymal Stem Cells for Treatment of Neurological Diseases of the Central Nervous System

The diagnosis of a neurological disease of the central nervous system (CNS) is often associated with the anticipation of an irreversible and untreatable disability. This is the case also of multiple sclerosis (MS) where approved treatments effectively modulate the autoimmune attack to myelin antigens, but poorly affect neurodegeneration and do not promote tissue repair. Thus, stem cell-based therapies are increasingly being considered a possible strategy for diseases of the CNS. Mesenchymal stem cells (MSC), the safety of which has been demonstrated in the last 20 years through clinical trials and case studies, are of particular interest in view not only of their neuroprotective, but also of their immunomodulatory properties. Here, we review the therapeutic features of MSC that make them relevant in the treatment of CNS illnesses and discuss the pioneer clinical experience with MSC-based therapy in neurological diseases.     

Regulation of self-reactive T cells by human immunoglobulins--implications for multiple sclerosis therapy

The intravenous administration of high doses of immunoglobulins pooled from the plasma of healthy donors (IVIg therapy) has beneficial effects in patients with a variety of autoimmune disorders. These clinical observations indicate that IVIg have potent antiinflammatory characteristics, and identification of the precise mode of action may open up perspectives for future therapeutic strategies. In certain tissue-specific autoimmune disorders like multiple sclerosis (MS), self-reactive T cells recognizing autoantigens play a significant role for disease pathogenesis, as these cells are able to initiate, maintain, and propagate the harmful immune attack in experimental animal models of disease. These findings render self-reactive T cells an important therapeutic target for autoimmune diseases. Here, we review the effects of IVIg on the homeostasis of T cells and discuss the possible therapeutic implications for multiple sclerosis. As supported by several experimental studies, IVIg regulate crucial steps of T cell-mediated immune responses. These effects involve the modulation of activation, proliferation, differentiation, apoptosis, and effector mechanisms of T cells. The pattern of IVIg-T cell interactions is complex, as IVIg may directly bind to regulatory structures on T cells, or modulate T cell functions indirectly via soluble or cellular components of the immune system.