Invariant Natural Killer T-cell anergy to endogenous myelin acetyl-glycolipids in multiple sclerosis

Gately, Carol M.; Podbielska, Maria; Counihan, Timothy J.; Hennessy, Michael; Leahy, Teresa; Moran, Anthony P.; Hogan, Edward L.; O’Keeffe, Joan

doi:10.1016/j.jneuroim.2013.02.020

Cited by 18 publications

(25 citation statements)

References 38 publications

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“…Hyporesponsivness or anergy of lymphocytes from patients with MS who are in remission has previously been reported with poor proliferative capacity that was broken with CD28 stimulation, whereas regulatory T cells had unaltered suppressive function except for lower IL‐7 receptors (CD127). In our studies, using PA‐GC and FMC‐7 as stimulatory ligands, iNKT cells from patients with MS failed to respond in vitro to stimulation, which was in marked contrast to the broad range of Th1, Th2 and Th17 cell cytokines produced by healthy controls . This hyporesponsivess of the iNKT cell population was also observed in response to α ‐GalCer stimulation and importantly, in our study this anergic glycolipid response as measured by an expansion in cell number was specific to the iNKT cell population .…”

Section: Lipid Antigens and Inkt Cells In Multiple Sclerosismentioning

confidence: 46%

“…Recent progress in identifying the nature of lipid recognition for iNKT cells in immunity and in determining the functional consequences of the lipid–CD1d interaction during iNKT cell activation opens new avenues towards understanding the pathogenesis of demyelination in MS. The list of relevant lipids and glycolipids including self‐antigenic ligands for iNKT cells continues to grow and includes in humans, the myelin‐derived PA‐GC . These advances lead to a number of outstanding questions pertinent to the functional roles of iNKT cells in autoimmune diseases such as MS, and include the following.…”

Section: Discussionmentioning

confidence: 99%

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Invariant natural killer T cells and their ligands: focus on multiple sclerosis

2015

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SummaryInvariant natural killer T (iNKT) cells are an innate population of T cells identified by the expression of an invariant T-cell receptor and reactivity to lipid-based antigens complexed with CD1d. They account for a small percentage of lymphocytes, but are extremely potent and play central roles in immunity to infection, in some cancers, and in autoimmunity. The list of relevant stimulatory lipids and glycolipid antigens now includes a range of endogenous self-antigens including the myelin-derived acetylated galactosylceramides. Recent progress in studies to identify the nature of lipid recognition for iNKT cells in autoimmune diseases like multiple sclerosis is likely to foster the development of therapeutic strategies aimed at harnessing iNKT cell activity.

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Section: Lipid Antigens and Inkt Cells In Multiple Sclerosismentioning

confidence: 46%

Section: Discussionmentioning

confidence: 99%

Invariant natural killer T cells and their ligands: focus on multiple sclerosis

2015

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“…We postulate that for innate reactivity NKT cells regulation are relevant as for instance by treatment with the glycosphingolipid α-GalCer that elicits a NKT-cell-mediated suppressive effect on the effector function of encephalitogenic T cells [199] while for adaptive immune response CD4 + and CD8 + regulatory T cells can suppress EAE and their induction or enhancement influence remyelination regulation. Circulating lymphocytes in MS [200,201] are hyporesponsive to specific antigens. Importantly, these antigens are certain GLs that have been identified as exogenous but are almost certainly endogenous as well.…”

Section: Antigen-based Immune-interventionmentioning

confidence: 99%

“…Anergy of MS circulating lymphocytes to the exogenous α-GalCer ligand [200] or to the endogenous polyacetylated-GalCers (FMCs) [201] has been observed [12,13,14] (Figure 1C). In healthy individuals iNKT cells expanded upon stimulation with α-GalCer or acetyl-β-GalCers accompanied by robust cytokine secretion [200,201] including secretion of cytokines associated with Th1 cells (IFN-γ), Th17 cells (IL-17, TNF-α) and both pro-inflammatory (IL-1β, IL-6, TNF-α) and anti-inflammatory responses (IL-10) while the anergy of human MS circulating lymphocytes is consistent with previous iNKT cell usage and probably reflects saturation of the iTCR by GL antigen. This suggests that lymphocyte reactivity and especially that involving inflammation, should be explored in regard to the failure or severe limitation of remyelination, the process that should repair inflammatory demyelination.…”

Section: Antigen-based Immune-interventionmentioning

confidence: 99%

Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination

et al. 2013

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Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination—with emphasis upon myelin composition/architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

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“…2). Since CD1b is expressed by cells in areas of demyelination in multiple sclerosis, it has been proposed that gangliosides and probably other self-lipids derived from myelin debris, such as fast-migrating cerebrosides, may be presented by astrocytes and microglia, and thus propel a vicious cycle of chronic inflammation (Gately et al 2013; Shamshiev et al 1999). Involvement of CD1d-restricted iNKT cells in multiple sclerosis is more complicated and seems immunoregulatory rather than exacerbatory (Hogan et al 2013).…”

Section: Endogenous Lipids Presented By Cd1 Moleculesmentioning

confidence: 99%

CD1: A Singed Cat of the Three Antigen Presentation Systems

Kaczmarek

Paściak

Szymczak-Kulus

et al. 2017

Arch. Immunol. Ther. Exp.

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Contrary to general view that the MHC Class I and II are the kapellmeisters of recognition and response to antigens, there is another big player in that part of immunity, represented by CD1 glycoproteins. In contrast to MHC Class I or II, which present peptides, CD1 molecules present lipids. Humans express five CD1 proteins (CD1a-e), four of which (CD1a-d) are trafficked to the cell surface, where they may display lipid antigens to T-cell receptors. This interaction may lead to both non-cognate and cognate T cell help to B cells, the latter eliciting anti-lipid antibody response. All CD1 proteins can bind a broad range of structurally different exogenous and endogenous lipids, but each shows a preference to one or more lipid classes. This unorthodox binding behavior is the result of elaborate architectures of CD1 binding clefts and distinct intracellular trafficking routes. Together, these features make CD1 system a versatile player in immune response, sitting at the crossroads of innate and adaptive immunity. While CD1 system may be involved in numerous infectious, inflammatory, and autoimmune diseases, its involvement may lead to opposite outcomes depending on different pathologies. Despite these ambiguities and complexity, CD1 system draws growing attention and continues to show glimmers of therapeutic potential. In this review, we summarize the current knowledge about CD1 proteins, their structures, lipid-binding profiles, and roles in immunity, and evaluate the role of CD1 proteins in eliciting humoral immune response.

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Invariant Natural Killer T-cell anergy to endogenous myelin acetyl-glycolipids in multiple sclerosis

Cited by 18 publications

References 38 publications

Invariant natural killer T cells and their ligands: focus on multiple sclerosis

Invariant natural killer T cells and their ligands: focus on multiple sclerosis

Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination

CD1: A Singed Cat of the Three Antigen Presentation Systems

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