Mice resistant to experimental autoimmune encephalomyelitis have increased thymic expression of myelin basic protein and increased MBP specific T cell tolerance

Liu, Hong-biao; MacKenzie-Graham, Allan; Kim, Sookhyun; Voskuhl, Rhonda R.

doi:10.1016/s0165-5728(01)00269-7

Cited by 35 publications

(22 citation statements)

References 36 publications

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“…We suggest that one or more of the mechanisms described earlier by others (31)(32)(33)(34)(35)(36)(37)(38)(39) and us (40,41) might contribute to incomplete tolerance to Rhsp65, particularly RCTD in the Lewis rat. However, the subsets of self Ag-specific T cells that evaded thymic tolerance in the studies based on various animal models of autoimmunity (31)(32)(33)(34)(35)(36)(37) were involved in induction of autoimmune disease, whereas in this study, RCTD-directed T cells that escaped tolerance induction revealed immunoregulatory properties. Further studies on thymic expression of Rhsp65 and the MHC binding of RCTD peptides would clarify the mechanisms involved in inefficient tolerance to this self protein.…”

Section: Discussionsupporting

confidence: 52%

The T Cells Specific for the Carboxyl-Terminal Determinants of Self (Rat) Heat-Shock Protein 65 Escape Tolerance Induction and Are Involved in Regulation of Autoimmune Arthritis

Durai

Gupta

Moudgil

2004

The Journal of Immunology

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Immunization of Lewis rats with heat-killed Mycobacterium tuberculosis H37Ra leads to development of polyarthritis (adjuvant-induced arthritis; AA) that shares several features with human rheumatoid arthritis (RA). Immune response to the 65-kDa mycobacterial heat-shock protein (Bhsp65) is believed to be involved in induction of AA as well as in experimental modulation of this disease. However, the understanding of several critical aspects of the pathogenesis of AA in the Lewis rat has severely been hampered by the lack of information both regarding the level as well as epitope specificity of tolerance to the mammalian self (rat) homologue of Bhsp65, 65-kDa rat heat-shock protein (Rhsp65), and about the functional attributes of the T cell repertoire specific for this self protein. In this study, we established that tolerance to Rhsp65 in the Lewis rat is incomplete, and that the residual T cells primed upon challenge with this self hsp65 are disease regulating in nature. We also have defined the T cell epitopes in the C-terminal region within Rhsp65 that contribute predominantly to the immune reactivity as well as the AA-protective effect of this self protein. Furthermore, the T cells primed by peptides comprising these C-terminal determinants can be efficiently restimulated by the naturally generated epitopes from endogenous Rhsp65, suggesting that self hsp65 might also be involved in natural remission from acute AA. These novel first experimental insights into the self hsp65-directed regulatory T cell repertoire in AA would help develop better immunotherapeutic approaches for autoimmune arthritis.

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Section: Discussionsupporting

confidence: 52%

The T Cells Specific for the Carboxyl-Terminal Determinants of Self (Rat) Heat-Shock Protein 65 Escape Tolerance Induction and Are Involved in Regulation of Autoimmune Arthritis

Durai

Gupta

Moudgil

2004

The Journal of Immunology

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“…However, despite extensive research on the pathogenesis of MS, no effective therapy is available to halt demyelination and/or stimulate remyelination. Several studies have implicated proinflammatory cytokines in the observed demyelination in MS patients [1][2][3][4][5][6][7]. Here we investigated if proinflammatory cytokines were capable of altering the expression of myelin-specific genes in human primary oligodendrocytes.…”

Section: Discussionmentioning

confidence: 96%

“…Pathologically, it can be identified by the presence of diffuse, discrete demyelinated areas, called plaques. Although the etiology of MS is not completely understood, studies of MS patients suggest that the observed demyelination in the CNS is a result of an autoimmune inflammation [1,2]. Consistently, demyelinated areas in the CNS of MS patients are associated with an inflammatory reaction orchestrated by activated T cells, macrophages, and endogenous glial cells (astroglia and microglia).…”

Section: Introductionmentioning

confidence: 97%

Redox regulation of cytokine-mediated inhibition of myelin gene expression in human primary oligodendrocytes

Jana

Pahan

2005

Free Radical Biology and Medicine

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Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS) of unknown etiology. Several studies have shown that demyelination in MS is caused by proinflammatory mediators which are released by perivascular infiltrates and/or activated glial cells. To understand if proinflammatory mediators such as IL (interleukin)-1β and TNF (tumor necrosis factor)-α are capable of modulating the expression of myelin-specific genes, we investigated the effect of these cytokines on the expression of myelin basic protein (MBP), 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP) in human primary oligodendrocytes. Interestingly, both IL-1β and TNF-α markedly inhibited the expression of MOG, CNPase, and PLP but not MBP, the effect that was blocked by antioxidants such as N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). Consistently, oxidants and prooxidants like H 2 O 2 and diamide also markedly inhibited the expression of MOG, CNPase, and PLP. Furthermore, both IL-1β and TNF-α induced the production of H 2 O 2 . Taken together, these studies suggest that proinflammatory cytokines inhibit the expression of myelin genes in human primary oligodendrocytes through the alteration of cellular redox.

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“…Moreover, recent analyses using mutant mice lacking MBP (29,30) and mice with proteolipid protein-induced EAE (31,32) have revealed that thymic expression of myelin autoantigens deletes T cells responding to the immunodominant epitope of the autoantigen and inversely correlates with the susceptibility to EAE. Other studies also demonstrated that increased thymic expression of autoantigens correlates with resistance to autoimmune diseases (33,34). Investigations of MBP expression in the thymus of DA and Lewis rats are currently underway in our laboratory.…”

Section: Discussionmentioning

confidence: 82%

Characterization of the Antigen Specificity and TCR Repertoire, and TCR-Based DNA Vaccine Therapy in Myelin Basic Protein-Induced Autoimmune Encephalomyelitis in DA Rats

Miyakoshi

Yoon

Jee

et al. 2003

The Journal of Immunology

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Like Lewis rats, DA rats are an experimental autoimmune encephalomyelitis (EAE)-susceptible strain and develop severe EAE upon immunization with myelin basic protein (MBP). However, there are several differences between the two strains. In the present study we induced acute EAE in DA rats by immunization with MBP and MBP peptides and examined the Ag specificity and TCR repertoire of encephalitogenic T cells. It was found that although immunization with MBP and a peptide corresponding to its 62–75 sequence (MBP62–75) induced clinical EAE, the responses of lymph node T cells isolated from MBP-immunized rats to MBP62–75 was marginal, indicating that this peptide contains major encephalitogenic, but not immunodominant, epitopes. The TCR analysis by CDR3 spectratyping of spinal cord T cells revealed that Vβ10 and Vβ15 spectratype expansion was always found in MBP62–75-immunized symptomatic rats. On the basis of these findings, we examined the encephalitogenicity of Vβ10- and Vβ15-positive T cells. First, the adoptive transfer experiments revealed that Vβ10-positive T line cells derived from MBP62–75-immunized rats induced clinical EAE in recipients. Second, administration of DNA vaccines encoding Vβ10 and Vβ15, alone or in combination, ameliorated MBP62–75-induced EAE. Collectively, it was strongly suggested that Vβ10- and Vβ15-positive T cells are encephalitogenic. Analyses of the Ag specificity and T cell repertoire of pathogenic T cells performed in this study provide useful information for designing specific immunotherapies against autoimmune diseases.

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Mice resistant to experimental autoimmune encephalomyelitis have increased thymic expression of myelin basic protein and increased MBP specific T cell tolerance

Cited by 35 publications

References 36 publications

The T Cells Specific for the Carboxyl-Terminal Determinants of Self (Rat) Heat-Shock Protein 65 Escape Tolerance Induction and Are Involved in Regulation of Autoimmune Arthritis

The T Cells Specific for the Carboxyl-Terminal Determinants of Self (Rat) Heat-Shock Protein 65 Escape Tolerance Induction and Are Involved in Regulation of Autoimmune Arthritis

Redox regulation of cytokine-mediated inhibition of myelin gene expression in human primary oligodendrocytes

Characterization of the Antigen Specificity and TCR Repertoire, and TCR-Based DNA Vaccine Therapy in Myelin Basic Protein-Induced Autoimmune Encephalomyelitis in DA Rats

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