Myelin peptides in multiple sclerosis

Grau-López, Laia; Raïch, D.; Ramo-Tello, Cristina; Naranjo-Gómez, Mar; Dávalos, Antonio; Pujol-Borrell, Ricardo; Borràs, Francesc E.; Martínez-Cáceres, Eva

doi:10.1016/j.autrev.2009.02.013

Cited by 29 publications

(18 citation statements)

References 33 publications

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Section: Introductionmentioning

confidence: 99%

“…Although the pathogenic mechanisms of MS remain unclear, some lines of evidence suggest a crucial role of autoreactive CD4 + T cells [1]. In fact, some groups have confirmed CD4 + T-cell reactivity to myelin antigens [2,3].In addition, a higher proportion of high-avidity myelin-specific CD4 + T cells was demonstrated in MS patients in comparison with controls, and their specificities were predominantly directed toward a group of immunodominant epitopes of myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG) [4]. Furthermore, our group has recently confirmed the reactivity to the aforementioned set of immunodominant peptides in peripheral blood T cells from MS patients compared with healthy controls (HCs) [5].…”

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confidence: 99%

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Stable antigen‐specific T‐cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

et al. 2012

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Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system. Current therapies decrease the frequency of relapses and limit, to some extent, but do not prevent disease progression. Hence, new therapeutic approaches that modify the natural course of MSneed to be identified. Tolerance induction to self‐antigens using monocyte‐derived dendritic cells (MDDCs) is a promising therapeutic strategy in autoimmunity. In this work, we sought to generate and characterize tolerogenic MDDCs (tolDCs) from relapsing‐remitting (RR) MSpatients, loaded with myelin peptides as specific antigen, with the aim of developing immunotherapeutics for MS. MDDCs were generated from both healthy‐blood donors and RR‐MSpatients, and MDDCmaturation was induced with a proinflammatory cytokine cocktail in the absence or presence of 1α,25‐dihydroxyvitamin‐D3, a tolerogenicity‐inducing agent. tolDCs were generated from monocytes of RR‐MSpatients as efficiently as from monocytes of healthy subjects. The RR‐MStolDCs expressed a stable semimature phenotype and an antiinflammatory profile as compared with untreated MDDCs. Importantly, myelin peptide‐loaded tolDCs induced stable antigen‐specific hyporesponsiveness in myelin‐reactive T cells from RR‐MS patients. These results suggest that myelin peptide‐loaded tolDCs may be a powerful tool for inducing myelin‐specific tolerance in RR‐MS patients.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Stable antigen‐specific T‐cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

et al. 2012

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“…Our knowledge about CNS-related autoantigens relevant for MS pathogenesis has remained limited. The role of peptides derived from various myelin proteins, including proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in both MS onset and induction of antigen-specific T-cell tolerance is still intensively discussed [22,23] and myelin-peptides or proteins or their respective specific immune responses have traditionally been a target of therapeutic approaches. However, it still remains unclear whether modification of myelin-(peptide)-specific immune responses are capable of impacting MS [24,25].…”

Section: Chances and Pitfalls Of The Therapeutic Use Of Toldcsmentioning

confidence: 99%

Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis

2012

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Autoimmune diseases including multiple sclerosis (MS) are the result of an imbalanced immune tolerance network. Dendritic cells (DCs) are key players in both initiating immunity (immunogenic DCs) and regulating immune responses (tolerogenic DCs= IntroductionMultiple sclerosis (MS) is the prototype of a central nervous system (CNS) directed, antigen-driven, predominantly T-cell medi- Immunological tolerance induction, its maintenance by DCs and what goes wrong in MSThe major subtypes of human DCs are conventional myeloid (CD11c + ) DCs (mDCs) and type I interferon-secreting plasmacytoid (CD11c dim CD123 + ) DCs (pDCs). Depending on the antigen presented and the activation status of the DCs, both subsets can either exhibit immunogenic or tolerogenic features [9,10]. Immature DCs are located in the peripheral tissues where they constantly encounter/sample antigens. While TLR ligands and pro-inflammatory cytokines induce maturation into immunogenic DCs that migrate to secondary lymphoid organs where they prime naïve T cells, anti-inflammatory cytokines including IL-10 and TGF-β induce DCs with a more tolerogenic phenotype (tolDCs) [10]. The term tolDCs summarizes a heterogeneous group of different DC subsets (mDCs and pDCs) located in various tissues where they use different mechanisms to induce and maintain both central and peripheral tolerance. In the thymus, DCs eliminate autoreactive T cells by clonal deletion of high-affinity thymocytes or diversion into Treg cells [11]. Despite these central tolerance mechanisms, some low avidity autoreactive T cells escape into the periphery, where peripheral tolerance mechanisms are required to prevent spontaneous autoimmunity. Multiple peripheral tolerance mechanisms have been identified for myelin-specific T cells, most importantly Treg cells and tolerogenic DCs [5,12]. TolDCs keep autoreactive T cells under control by inducing anergy, apoptosis, phenotypic skewing, and/or Treg cells [13][14][15].In MS, both immunogenic and tolerogenic features of different DC subsets are disrupted [7,12]. Elevated numbers of mature mDCs have been found in the peripheral blood of MS patients, and the occurrence of both mDCs and pDCs in the CSF of MS patients suggests their active participation in disease pathogenesis [12]. Furthermore, alterations in phenotype and/or function of different DC subsets have been observed in MS [7,12]. pDCs for example show an imbalance in the ratio between tolerogenic and immunogenic subtypes generating a propensity to generate proinflammatory Th17 cell responses in MS [16]. The "dysfunctional state" of certain DC subsets in MS could be linked to the observation of dysfunctional Treg-cell responses in MS [5]. Therefore, therapies targeting DCs for MS aim to either diminish their immunogenic potential or enhance their tolerogenic features [7]. Chances and pitfalls of the therapeutic use of tolDCsSo far, most of our knowledge in using tolDCs to treat autoimmunity is derived from extensive work in animal models including experimental autoimmune encephalitis (EA...

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“…The Myelin-Reactive T-Cell Repertoire Earlier studies on the frequency of myelin-reactive T cells in MS are conflicting; some investigators report a significantly higher incidence of myelin-specific PBMC in individuals with MS compared with age-and gender-matched healthy controls (HC), while others report no significant difference (de Rosbo and Ben-Nun 1998; Diaz-Villoslada and others 1999; Moldovan and others 2003;Bielekova and others 2004;Moldovan and others 2005;Grau-López and others 2009). Many of the earlier studies that found no differences between patients and HC used proliferation as a measure of T-cell reactivity, and nonhuman myelin proteins for antigenic stimulation.…”

Section: Dysregulation Of Adaptive Immunity In Rrmsmentioning

confidence: 99%

Stage-Specific Immune Dysregulation in Multiple Sclerosis

Segal

2014

Journal of Interferon & Cytokine Research

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A large body of data indicates that multiple sclerosis (MS) is an autoimmune disease which is initiated by CD4 + T-helper 1 (Th1) and Th17 cells that are reactive against proteins in the myelin sheath. MS typically begins with a relapsing-remitting course, punctuated by clinical exacerbations associated with the development of focal inflammatory lesions in central nervous system white matter, followed by a secondary progressive (SP) phase, characterized by a gradual accumulation of neurological disability associated with widespread microglial activation and axonal loss. The molecular and cellular basis for this transition is unclear, and the role of inflammation during the SP stage is a subject of active debate. As of now, no immunological biomarkers have been identified in MS that are predictive of the clinical course or therapeutic responsiveness to diseasemodifying agents, or that correlate with new lesion development, cumulative lesion load, or degree of disability. The discovery of such biomarkers would greatly facilitate clinical management and provide power for smaller and shorter clinical trials. In this article, we discuss the literature on immunological biomarkers in MS with a focus on stage-specific differences and similarities.

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Myelin peptides in multiple sclerosis

Cited by 29 publications

References 33 publications

Stable antigen‐specific T‐cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

Stable antigen‐specific T‐cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis

Stage-Specific Immune Dysregulation in Multiple Sclerosis

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