The immunology of multiple sclerosis

Current Allergy and Asthma Reports, 2007

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) leading to demyelination, axonal damage, and progressive neurologic disability. The development of MS is influenced by environmental factors, particularly the Epstein-Barr virus (EBV), and genetic factors, which include specific HLA types, particularly DRB1*1501-DQA1*0102-DQB1*0602, and a predisposition to autoimmunity in general. MS patients have increased circulating T-cell and antibody reactivity to myelin proteins and gangliosides. It is proposed that the role of EBV is to infect autoreactive B cells that then seed the CNS and promote the survival of autoreactive T cells there. It is also proposed that the clinical attacks of relapsing-remitting MS are orchestrated by myelinreactive T cells entering the white matter of the CNS from the blood, and that the progressive disability in primary and secondary progressive MS is caused by the action of autoantibodies produced in the CNS by meningeal lymphoid follicles with germinal centers.

Journal of Neuroimmunology, 1992

Elevated numbers of B cells--plasma cells secreting antibodies to measles and mumps virus, and to myelin associated glycoprotein (MAG), one of several putative myelin autoantigens--have previously been reported in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS), while it is unknown if corresponding T cell reactivities occur. We have defined the T cell reactivities to measles and mumps virus and to MAG in an immunospot assay which is based on the detection of secretion of interferon-gamma (IFN-y) by single cells upon stimulation with specific antigen in short term cultures. Patients with MS had higher numbers of MAG-reactive T cells in blood compared to controls, while no differences were observed for measles or mumps virus-reactive T cells. In CSF, elevated numbers of MAG-reactive T cells and also of measles-and mumps-reactive T cells were found in patients with MS compared to other neurological diseases. A strong accumulation of antigen-reactive T cells was observed in the MS patients' CSF compared to blood. The magnitude of these T cell reactivities did not correlate with clinical MS variables. The T cell repertoire in MS thus includes, besides myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein, also MAG and, in addition, measles and mumps virus. It is not clear whether these T cell reactivities accumulated in the CSF have importance for the pathogenesis of MS or reflect phenomena secondary to myelin damage, or result from both these alternatives.

Scandinavian Journal of Immunology, 2007

During the last few years, the concept of multiple sclerosis (MS) as a pure inflammatory disease mediated by myelin reactive T cells has been challenged. Neither the specificity nor the mechanisms triggering or perpetuating the immune response are understood. Genetic studies have so far not identified therapeutic targets outside the HLA complex, but epidemiological and immunological studies have suggested putative pathogenetic factors which may be important in therapy or prevention, including the Epstein-Barr virus and vitamin D. Advances in the treatment of MS have been reached by manipulating the immune response where the pathogenesis of MS intersects experimental autoimmune encephalomyelitis, most recently by blocking T-cell migration through the blood-brain barrier. Antigen-specific approaches are effective in experimental models driven by a focused immune response against defined autoantigens, but MS may not fit into this concept. Novel candidate autoantigens which are not constitutively expressed in the brain, such as protein a-B crystallin or IgG V-region idiotopes, as well as evidence of pathogenetic heterogeneity and complexity, suggest that treating MS by tolerizing the immune system against an universal MS antigen may be a fata morgana. Further characterization of MS subtypes may lead to individualized treatment. However, shared immunological features, such as intrathecal production of oligoclonal IgG, suggest that potential therapeutic targets may be shared by most MS patients.

Clinical and Applied Immunology Reviews, 2005

Multiple sclerosis (MS) remains a leading cause of neurologic disability among young adults. Clinical manifestations of the disease result from immune-mediated demyelination of the central nervous system. Most patients experience new symptoms in a relapsing-remitting pattern, although the course is highly variable from person to person and even in the same individual over time. Recent neuropathological studies reveal that in addition to the surrounding myelin sheath, nerve axons themselves are targets of injury in MS lesions. Characterization of the inflammatory infiltrates present in MS brain and spinal cord tissue shows that active lesions can be segregated into 1 of 4 subtypes, with each individual having only a single pattern of involvement. Studies in animal models demonstrate that a number of myelin proteins can become immune system targets resulting in demyelination, and these models have also served to define multiple immunological mechanisms of disease. Translational studies using peripheral blood samples have characterized differences in the various myelin protein-reactive immune responses of MS patients and controls, and these investigations have validated some, but not all, of the disease mechanisms uncovered in animals. Adaptive and innate immunity both appear to contribute to disease pathogenesis within the target tissue of the central nervous system. Immunomodulatory therapies have been developed that partially arrest disease relapses and progression. Studies to dissect how these agents work have shed light on underlying disease

Frontiers in Immunology

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by destruction of the myelin sheath structure. The loss of myelin leads to damage of a neuron’s axon and cell body, which is identified as brain lesions on magnetic resonance image (MRI). The pathogenesis of MS remains largely unknown. However, immune mechanisms, especially those linked to the aberrant lymphocyte activity, are mainly responsible for neuronal damage. Th1 and Th17 populations of lymphocytes were primarily associated with MS pathogenesis. These lymphocytes are essential for differentiation of encephalitogenic CD8+ T cell and Th17 lymphocyte crossing the blood brain barrier and targeting myelin sheath in the CNS. B-lymphocytes could also contribute to MS pathogenesis by producing anti-myelin basic protein antibodies. In later studies, aberrant function of Treg and Th9 cells was identified as contributing to MS. This review summarizes the aberrant function and coun...

Nature Reviews Neuroscience, 2002

Multiple sclerosis (MS) is one of the most common chronic and disabling disorders of the central nervous system (CNS), affecting 0.05-0.15% of Caucasians 1 . The disease usually begins in young adulthood and affects women more frequently than men. In 80-90% of cases, MS starts with a relapsing-remitting course (RR-MS). Over time, the number of relapses decreases, but most patients develop progressive neurological deficits that occur independently of relapses (the so-called secondary progressive phase). In 10-20% of patients, MS begins with a primary progressive course (PP-MS) without acute relapses. In general, the progression rate in RR-MS is comparable to that of PP-MS as soon as the patients enter the secondary progressive phase 2 . Imaging studies have revealed differences between RR-MS and PP-MS. In patients that suffer from RR-MS, acute CNS lesions with spontaneous resolution are frequently detected, even in the absence of clinical attacks 3 . These lesions are usually located in areas of white matter, and are often characterized by a disturbance of the blood-brain barrier, local oedema and demyelination -features that are compatible with an inflammatory process. By contrast, when progressing to the secondary phase and in patients with PP-MS, such inflammatory activity is much less conspicuous 3 . Global brain atrophy, however, is more dominant in the progressive stage and seems to correlate with disability 4,5 . These findings indicate that early in the disease, ongoing inflammatory activity is present in most patients and is responsible for the relapsing-remitting course, whereas a distinct process might be operative in the progressive phase of the disease, when inflammatory activity diminishes despite faster evolution of disability.

PLOS ONE

Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS). It is a major cause of neurological disability in young adults, particularly women. What triggers the destruction of myelin sheaths covering nerve fibres is unknown. Both genetic and infectious agents have been implicated. Of the infectious agents, Epstein-Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence. However, the presence of EBV in the CNS and demonstration of the underlying mechanism(s) linking EBV to the pathogenesis of MS remain to be elucidated. We aimed at understanding the contribution of EBV infection in the pathology of MS. We examined 1055 specimens (440 DNA samples and 615 brain tissues) from 101 MS and 21 non-MS cases for the presence of EBV using PCR and EBER-in situ hybridization (EBER-ISH). EBV was detected by PCR and/or EBER-ISH in 91/101 (90%) of MS cases compared to only 5/21 (24%) of non-MS cases with other neuropathologies. None of the samples were PCR positive for other common herpesviruses (HSV-1, CMV, HHV-6). By quantitative PCR, EBV viral load in MS brain was mainly low to moderate in most cases. However, in 18/101 (18%) of MS cases, widespread but scattered presence of EBV infected cells was noted in the affected tissues by EBER-ISH. Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed. Furthermore, using double-staining we how for the first time that astrocytes and microglia, in addition to B-cells can also be infected. To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis. Further studies are required to address the mechanism of EBV involvement in MS pathology.

Human Immunology, 1988

In the present report we describe the isolation and characterization of sta~4e, long-term, human T-lymphocyte clones specific for myelin basic protein (MBP) from multiple sclerosis (MS) patients. Isolation of these clones appeared passible only by seeding peripheral blood mononuclear cells into a limiting dilution microcMture system containing MBP, autdogeus irradiated cells and lntedeukin-2 (IL-2), thereby minimizing effects of putative suppr~sor cdl lmpulatio~s. All clones obtained were of the CD4 + phenotype. The majority was capable of MBP-sl~cific tytolysis, tested with Jt Chromium-la~ded autologous Epstein-Barr virus (EBV),transfe~ud B-cd~, c~ted ~oi~h MBP, as targets. A few other clones had natural killer (NIO function. All clonea produced lntedeukiu-2 (11.-2) upon adequate stimulation. ABBREVIATIONS MS multiple sclerosis CTL ¢ytotoxic T-lyrophocyte (H)MBP (human) myelin basic TT tetanus toxoid protein MoAb monodonal antibody EAE. experimental auto-immune PHA-M phytohemagglutlnln encephalomyelitis FCS fetal calf sermn 1L-2 interleukin-2 EBV Epstein-Barr virus PBMC peripheral blood mononuclear cells Fmtu the Departments of Neurology (W.E.J.W.

Clinical Immunology, 2016

Antibody-independent B cell functions play an important role in multiple sclerosis (MS) pathogenesis. In this study, B cell antigen presentation and costimulation in MS were studied. Peripheral blood B cells of MS patients showed increased expression of costimulatory CD86 and CD80 molecules compared with healthy controls (HC). In MS cerebrospinal fluid (CSF), 12-fold and 2-fold increases in CD86 + and CD80 + B cells, respectively, were evidenced compared with peripheral blood. Further, B cells from MS patients induced proinflammatory T cells in response to myelin basic protein (MBP). Immunomodulatory treatment restored B cell costimulatory molecule expression and caused significantly reduced B cell induced T cell responses. Together, these results demonstrate the potential of B cells from MS patients to induce autoreactive proinflammatory T cell responses. Immunomodulatory therapy abrogated this effect, emphasizing the importance of B cell antigen presentation and costimulation in MS pathology.

California Medicine, 1972

An animal model for acute multiple sclerosis (MSa) is experimental allergic encephalomyelitis (EAE). EAE is produced by intradermal injection of a protein component of central nervous system (CNS) myelin. Ultrastructural studies of EAE and of a peripheral nerve analog, experimental allergic neuritis (EAN), have revealed an orderly sequence of cellular events leading to the destruction and removal of myelin with sparing of axons (primary demyelination). Acute MS has not been studied electron microscopically, but the ultrastructural similarities between EAN and a case of acute Landry-Guillain-Barre syndrome, a primary demyelinating disease of the peripheral nervous system, suggest that a similar sequence of events might be found in acute MS. While the pathological findings support a cellmediated or delayed hypersensitivity response, there is also evidence for the pathogenetic role of circulating antibodies. Among such evidence is included the finding that sera from animals with EAE and humans with acute MS rapidly produce a reversible block of complex (polysynaptic) electrical activity when applied to CNS tissue cultures, which suggests a possible mechanism for transient symptoms in Ms. Epidemiological and other studies link MS with a viral cause, although no direct evidence that MS is caused by a virus exists. Viral and immunological mechanisrs are not mutually exclusive in considering pathogenetic possibilities for MS, for it can be postulated that a viral infection of the central nervous system acts as a triggering agent for a series of immune responses, including production of a bioelectric blocking antibody and demyelination mediated by sensitized cells, the combination of which ultimately produces the total clinical picture of MS.