MOG transmembrane and cytoplasmic domains contain highly stimulatory T-cell epitopes in MS

Varrin‐Doyer, Michel; Shetty, Aparna; Spencer, Collin M.; Schulze-Topphoff, Ulf; Weber, Martin; Bernard, Claude Charles Andre; Forsthuber, Thomas G.; Cree, Bruce A.C.; Slavin, Anthony; Zamvil, Scott S.

doi:10.1212/nxi.0000000000000020

Cited by 25 publications

(25 citation statements)

References 14 publications

(18 reference statements)

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“…Within this category, a small proportion of patients show antibodies against MOG in the serum [ 58 ]. MOG is a transmembrane protein expressed on the surface of oligodendrocytes [ 59 ] and the outermost lamella of the myelin sheath. Although its exact function remains unclear, it is assumed to mediate the adhesion of neighboring myelinated fibers acting as an adhesive glue between them [ 60 ].…”

Section: Stratifying Human Demyelinating Disorders By the Involvemmentioning

confidence: 99%

The Role of Peripheral CNS‐Directed Antibodies in Promoting Inflammatory CNS Demyelination

Kinzel

Weber

2017

Brain Sciences

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In central nervous system (CNS) demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO) and related NMO-spectrum disorders (NMO-SD), a pathogenic role for antibodies is primarily projected into enhancing ongoing CNS inflammation by directly binding to target antigens within the CNS. This scenario is supported at least in part, by antibodies in conjunction with complement activation in the majority of MS lesions and by deposition of anti-aquaporin-4 (AQP-4) antibodies in areas of astrocyte loss in patients with classical NMO. A currently emerging subgroup of AQP-4 negative NMO-SD patients expresses antibodies against myelin oligodendrocyte glycoprotein (MOG), again suggestive of their direct binding to CNS myelin. However, both known entities of anti-CNS antibodies, anti-AQP-4- as well as anti-MOG antibodies, are predominantly found in the serum, which raises the questions why and how a humoral response against CNS antigens is raised in the periphery, and in a related manner, what pathogenic role these antibodies may exert outside the CNS. In this regard, recent experimental and clinical evidence suggests that peripheral CNS-specific antibodies may indirectly activate peripheral CNS-autoreactive T cells by opsonization of otherwise unrecognized traces of CNS antigen in peripheral compartments, presumably drained from the CNS by its newly recognized lymphatic system. In this review, we will summarize all currently available data on both possible roles of antibodies in CNS demyelinating disorders, first, directly enhancing damage within the CNS, and second, promoting a peripheral immune response against the CNS. By elaborating on the latter scenario, we will develop the hypothesis that peripheral CNS-recognizing antibodies may have a powerful role in initiating acute flares of CNS demyelinating disease and that these humoral responses may represent a therapeutic target in its own right.

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Section: Stratifying Human Demyelinating Disorders By the Involvemmentioning

confidence: 99%

The Role of Peripheral CNS‐Directed Antibodies in Promoting Inflammatory CNS Demyelination

Kinzel

Weber

2017

Brain Sciences

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“…This is far from the case for many autoimmune diseases. Considerable progress has been made in recent years in the identification of potential antigens in many autoimmune conditions [13][14][15][16][17][18][19][20]. However, pinning down the specificity of the T cells that cause these diseases is a complex process, further confused by the accumulation of different antigenic targets as the disease progresses, a process known as epitope spreading [21].…”

Section: Autoimmune Diseasementioning

confidence: 99%

Antigen-based immunotherapy (AIT) for autoimmune and allergic disease

MacLeod

Anderton

2015

Current Opinion in Pharmacology

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Autoimmune and allergic diseases are major causes of morbidity. Antigen-based immunotherapy (AIT) is immunologically the most satisfying means of specifically targeting only those T cells driving disease, thereby inducing antigen-specific immune tolerance, with the lowest adverse risk profile. AIT is highly effective in rodent models of T cell-driven inflammation and is now in clinical trials. The range of approaches to applying AIT in the clinic prevents a consensus on the molecular basis for this form of tolerance. In particular, there has been a paucity of information on how pre-activated effector and memory T cells respond to AIT. New, advanced murine models of AIT are beginning to deliver such information at the cellular, biochemical, transcriptional and epigenetic levels.

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“…26,27 There have been extensive studies of different fragments of MOG as autoimmune triggers. [28][29][30][31][32] The MOG epitopes 1-22, 61-80, 92-106 have been highlighted as target antigens and the 35-55 epitope has been found to induce highly specific antibodies reacting similar to the entire MOG protein. 33,34 Moreover, T-cell responses to MOG epitopes have been measured through biological assays in MS patients.…”

mentioning

confidence: 99%

“…33,34 Moreover, T-cell responses to MOG epitopes have been measured through biological assays in MS patients. 29,30 The MOG35-55 epitope (M 35 EVGWYRS 42 PFSRVVHLYRNGK 55 ), based on the mouse/rat MOG peptide sequence, is shown as strongly immunogenic in mice leading to the development of chronic EAE. 27,35 Our group has previously rationally designed and synthesized linear and cyclic peptide analogues of human MOG35-55 immunodominant epitope (hMOG35-55) with crucial TCR substitutions.…”

mentioning

confidence: 99%

Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35–55 epitope implicated in multiple sclerosis

Yannakakis

Tzoupis

Michailidou

et al. 2016

Journal of Molecular Graphics and Modelling

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Multiple Sclerosis (MS) is a common autoimmune disease whereby myelin is destroyed by the immune system. The disease is triggered by the stimulation of encephalitogenic T-cells via the formation of a trimolecular complex between the Human Leukocyte Antigen (HLA), an immunodominant epitope of myelin proteins and T-cell Receptor (TCR). Myelin Oligodendrocyte Glycoprotein (MOG) is located on the external surface of myelin and has been implicated in MS induction. The immunodominant 35-55 epitope of MOG is widely used for in vivo biological evaluation and immunological studies that are related with chronic Experimental Autoimmune Encephalomyelitis (EAE, animal model of MS), inflammatory diseases and MS. In this report, Molecular Dynamics (MD) simulations were used to explore the interactions of MOG35-55 at the receptor level. A detailed mapping of the developed interactions during the creation of the trimolecular complex is reported. This is the first attempt to gain an understanding of the molecular recognition of the MOG35-55 epitope by the HLA and TCR receptors. During the formation of the trimolecular complex, the residues Arg(41) and Arg(46) of MOG35-55 have been confirmed to serve as TCR anchors while Tyr(40) interacts with HLA. The present structural findings indicate that the Arg at positions 41 and 46 is a key residue for the stimulation of the encephalitogenic T-cells.

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MOG transmembrane and cytoplasmic domains contain highly stimulatory T-cell epitopes in MS

Cited by 25 publications

References 14 publications

The Role of Peripheral CNS‐Directed Antibodies in Promoting Inflammatory CNS Demyelination

The Role of Peripheral CNS‐Directed Antibodies in Promoting Inflammatory CNS Demyelination

Antigen-based immunotherapy (AIT) for autoimmune and allergic disease

Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35–55 epitope implicated in multiple sclerosis

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