T cell recognition of myelin proteolipid protein and myelin proteolipid protein peptides in the peripheral blood of multiple sclerosis and control subjects

Trotter, John L.; Pelfrey, Clara M.; Trotter, Amy; Selvidge, Jacqueline A.; Gushleff, Kelly C; Mohanakumar, T.; McFarland, Henry F.

doi:10.1016/s0165-5728(97)00260-9

Cited by 62 publications

(51 citation statements)

References 56 publications

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“…The association of PLP95-116 with HLA-DR2 + MS was later confirmed by Trotter et al (10). Using whole PLP molecules, they further defined PLP95-117 as an immunodominant epitope for HLA-DR2 + MS. More recently, we reported evidence for transient or continuous activation/expansion of PLP95-116-specific T-cell clones in an HLA-DR2 + (DRB1*1501/DRB1*1502 + ) MS patient (19).…”

Section: Discussionmentioning

confidence: 80%

HLA-DR2–restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice

et al. 2000

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IntroductionMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is histologically characterized by focal mononuclear cell infiltration with a varying extent of demyelination (1, 2). It is postulated that autoimmune T cells recognizing myelin autoantigens such as myelin basic protein (MBP) or proteolipid protein (PLP) play a central role in the pathogenesis of MS. This postulate is based on substantial evidence such as increased frequency of activated MBP-or PLP-specific T cells in peripheral blood and cerebrospinal fluid of MS patients (3-6), and significant complementarity-determining region 3 (CDR3) homology between T-cell infiltrates within MS plaques and MBP-or PLP-specific T-cell clones generated from MS patients (7,8). Moreover, previous studies have identified the peptides MBP84-102 and PLP95-116 as immunodominant and possible encephalitogenic epitopes in MS patients with the HLA-DR2 haplotype (9, 10). However, the role of such autoreactive T cells remains unclear. In fact, it is possible that some (but not all) autoreactive T cells may protect against CNS tissue damage by producing neurotrophic factors (11-13).To address the issue regarding the function of autoimmune T cells, we have introduced HLA-DR2 (DRB1*1502) transgenic mice that are able to mount a T-cell response to DR2-related epitopes in the context of HLA-DR2 molecules. To explore the potential pathogenicity of PLP95-116 in HLA-DR2 + MS, we challenged the HLA-DR2 (DRB1*1502) transgenic mice with PLP95-116 and generated 2 peptide-specific T-cell lines (TCLs) from the mice. These TCLs were HLA-DR2-restricted and produced T-helper type 1 (Th1) cytokine in response to the peptide in the presence of mouse or human antigen-presenting cells (APCs) expressing HLA-DR2 (DRB1*1502) molecules. It was remarkable that transfer of 1 of the TCLs induced atypical autoimmune encephalitis involving the deep cere- In multiple sclerosis (MS) patients who carry the Class II major histocompatibility (MHC) type HLA-DR2, T cells specific for amino acids 95-116 in the proteolipid protein (PLP) are activated and clonally expanded. However, it remains unclear whether these autoreactive T cells play a pathogenic role or, rather, protect against the central nervous system (CNS) damage. We have addressed this issue, using mice transgenic for the human MHC class II region carrying the HLA-DR2 (DRB1*1502) haplotype. After stimulating cultured lymph node cells repeatedly with PLP95-116, we generated 2 HLA-DR2-restricted, PLP95-116-specific T-cell lines (TCLs) from the transgenic mice immunized with this portion of PLP. The TCLs were CD4 + and produced T-helper 1 (Th1) cytokines in response to the peptide. These TCLs were adoptively transferred into RAG-2 -/-mice expressing HLA-DR2 (DRB1*1502) molecules. Mice receiving 1 of the TCLs developed a neurological disorder manifested ataxic movement without apparent paresis on day 3, 4, or 5 after cell transfer. Histological examination revealed inflammatory foci primarily restricted to th...

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Section: Discussionmentioning

confidence: 80%

HLA-DR2–restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice

et al. 2000

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“…T cell autoreactivity to myelin components is common in MS patients (18,19), but CNS-reactive T cell lines can also be grown from blood samples of healthy donors (20,21). Self-tolerance to myelin Ags is incomplete, and mammals readily develop experimental autoimmune encephalitis (EAE) following immunization with CNS Ags emulsified in CFA plus transient impairment of the blood-brain barrier (BBB) with pertussis toxin (PT) (22).…”

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confidence: 99%

Type I Diabetes and Multiple Sclerosis Patients Target Islet Plus Central Nervous System Autoantigens; Nonimmunized Nonobese Diabetic Mice Can Develop Autoimmune Encephalitis

Winer

Astsaturov

Cheung

et al. 2001

The Journal of Immunology

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Type I diabetes and multiple sclerosis (MS) are distinct autoimmune diseases where T cells target either islet or CNS self-proteins. Unexpectedly, we found that autoreactive T cells in diabetic patients, relatives with high diabetes risk, nonobese diabetic (NOD) mice, and MS patients routinely target classical islet as well as CNS autoantigens. The pathogenic potential of CNS autoreactivity was testable in NOD mice. Pertussis holotoxin, without additional Ags or adjuvants, allowed development of an NOD mouse-specific, autoimmune encephalitis with variable primary-progressive, monophasic, and relapsing-remitting courses. T cells from diabetic donors transferred CNS disease to pertussis toxin-pretreated NOD.scid mice, with accumulation of CD3/IFN-γ transcripts in the brain. Diabetes and MS appear more closely related than previously perceived. NOD mouse-specific, autoimmune encephalitis provides a new MS model to identify factors that determine alternative disease outcomes in hosts with similar autoreactive T cell repertoires.

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“…The acylation sites Cys 108 and Cys 140 are within the encephalitogenic PLP epitopes PLP 104 -117 and PLP 139 -151 , respectively (1,4,9,10). Reactivity to these epitopes is also found in some patients with multiple sclerosis (MS) (11)(12)(13)(14)(15). However, the contribution that the thioacyl side chains make to the immunogenicity and encephalitogenicity of PLP has not been studied.…”

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confidence: 99%

Thiopalmitoylation of Myelin Proteolipid Protein Epitopes Enhances Immunogenicity and Encephalitogenicity

Greer

Denis

Sobel

et al. 2001

The Journal of Immunology

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Proteolipid protein (PLP) is the most abundant protein of CNS myelin, and is posttranslationally acylated by covalent attachment of long chain fatty acids to cysteine residues via a thioester linkage. Two of the acylation sites are within epitopes of PLP that are encephalitogenic in SJL/J mice (PLP104–117 and PLP139–151) and against which increased immune responses have been detected in some multiple sclerosis patients. It is known that attachment of certain types of lipid side chains to peptides can result in their enhanced immunogenicity. The aim of this study was to determine whether thioacylated PLP peptides, as occur in the native protein, are more immunogenic than their nonacylated counterparts, and whether thioacylation influences the development of autoreactivity and experimental autoimmune encephalomyelitis. The results show that in comparison with nonacylated peptides, thioacylated PLP lipopeptides can induce greater T cell and Ab responses to both the acylated and nonacylated peptides. They also enhanced the development and chronicity of experimental autoimmune encephalomyelitis. Synthetic peptides in which the fatty acid was attached via an amide linkage at the N terminus were not encephalitogenic, and they induced greater proportions of CD8+ cells in initial in vitro stimulation. Therefore, the lability and the site of the linkage between the peptide and fatty acid may be important for induction of encephalitogenic CD4+ T cells. These results suggest that immune responses induced by endogenous thioacylated lipopeptides may contribute to the immunopathogenesis of chronic experimental demyelinating diseases and multiple sclerosis.

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T cell recognition of myelin proteolipid protein and myelin proteolipid protein peptides in the peripheral blood of multiple sclerosis and control subjects

Cited by 62 publications

References 56 publications

HLA-DR2–restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice

HLA-DR2–restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice

Type I Diabetes and Multiple Sclerosis Patients Target Islet Plus Central Nervous System Autoantigens; Nonimmunized Nonobese Diabetic Mice Can Develop Autoimmune Encephalitis

Thiopalmitoylation of Myelin Proteolipid Protein Epitopes Enhances Immunogenicity and Encephalitogenicity

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