Quantitative Analysis of Peptides from Myelin Basic Protein Binding to the MHC Class II Protein, I-Au, Which Confers Susceptibility to Experimental Allergic Encephalomyelitis

Fugger, Lars; Liang, James; Gautam, Anand M.; Rothbard, Jonathan B.; McDevitt, Hugh O.

doi:10.1007/bf03401615

Cited by 56 publications

(58 citation statements)

References 24 publications

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“…The 50% inhibitory concentration (IC 50 ) for each peptide was calculated based on the concentrations of competitor peptides, which prevented 50% binding of the reference peptide (HEL 46-61), as described previously. 34,35 Cytokine Bead Array Analysis…”

Section: T-cell Proliferation Assaymentioning

confidence: 99%

“…31 Groups of mice were immunized with or without ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], and the animals were subjected for MRM imaging to measure end diastolic volume, end systolic volume, SV, EF, and left ventricular wall thickness. Expectedly, both SV and EF were significantly reduced in immunized animals on different days as compared to healthy group [day 30 to 35: SV, 11.33 AE 2.17 mL versus 25.67 AE 4.67 mL; EF, 30.17 AE 2.52% versus 65.67 AE 0.88% (P < 0.05); and day 46: SV, 9.00 AE 2.52 mL versus 29.00 AE 0.58 mL; EF, 24.00 AE 4.51% versus 60.00 AE 1.15% (P < 0.01)].…”

Section: Mrm Imaging Of Animals Immunized With Ant 1 21-40 Revealed Cmentioning

confidence: 99%

“…The presence of such a repertoire of cells has previously shown to be correlated with the lack of expression of autoantigens, like cardiac myosin and proteolipid protein in the thymus. 43,44 Splenocytes harvested from naïve mice were used to assess their reactivity to ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Using RNase 43-56 as a control peptide, we noted that the splenocytes did not respond to ANT 1 21-40 (Supplemental Figure S2), suggesting the absence of preexisting endogenously derived repertoire of ANT-reactive T cells in the naïve animals.…”

Section: -40ereactive T Cellsmentioning

confidence: 99%

“…In addition, by using AST as a biochemical readout of liver damage, we noted that serum from animals immunized with ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] showed elevated AST levels during the chronic phase of disease (beyond 30 days after immunization) as compared to naïve mice (Supplemental Figure S4). However, livers, but not brains, from animals that received CFA/PT with no peptide also showed relatively more inflammatory foci as compared to ANT 1 21-40eimmunized group (34.93 AE 2.82 versus 20.86 AE 3.58; P Z 0.039) ( Figure 7 and Table 4), suggesting that the occurrence of inflammation in livers from the ANT 1 21-40 group is not specific to antigen.…”

Section: Animals Immunized With Ant 1 21-40 Showed Inflammatory Lesiomentioning

confidence: 99%

“…One such model for cardiac autoimmunity is experimental autoimmune myocarditis (EAM), which involves induction of disease in susceptible rodent strains by immunizing animals with cardiac antigens or their peptide fragments. 23e25 In this study, we used the EAM model in A/J mice to demonstrate that ANT 1 possesses multiple immunodominant epitopes, and one of these, ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], was found to induce myocarditis in the immunized animals. Furthermore, myocarditogenicity of ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] was associated with the generation of T cells capable of producing predominantly IL-17A, and the antigen-sensitized T cells can transfer the disease to naïve recipients, suggesting that ANT 1 can be a potential autoantigen in the heart autoimmunity.…”

mentioning

confidence: 99%

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Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice

Basavalingappa

Massilamany

Krishnan

et al. 2016

The American Journal of Pathology

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Heart failure, a leading cause of death in humans, can emanate from myocarditis. Although most individuals with myocarditis recover spontaneously, some develop chronic dilated cardiomyopathy. Myocarditis may result from both infectious and noninfectious causes, including autoimmune responses to cardiac antigens. In support of this notion, intracellular cardiac antigens, like cardiac myosin heavy chain-a, cardiac troponin-I, and adenine nucleotide translocator 1 (ANT 1 ), have been identified as autoantigens in cardiac autoimmunity. Herein, we demonstrate that ANT 1 can induce autoimmune myocarditis in A/J mice by generating autoreactive T cells. We show that ANT 1 encompasses multiple immunodominant epitopes (namely, ANT 1 21-40, ANT 1 31-50, ANT 1 171-190, and ANT 1 181-200). Although all four peptides induce comparable T-cell responses, only ANT 1 21-40 was found to be a major myocarditogenic epitope in immunized animals. The myocarditis-inducing ability of ANT 1 21-40 was associated with the generation of T cells producing predominantly IL-17A, and the antigen-sensitized T cells could transfer the disease to naïve recipients. These data indicate that cardiac mitochondrial proteins can be target autoantigens in myocarditis, supporting the notion that the antigens released as a result of primary damage may contribute to the persistence of chronic inflammation through autoimmunity. Myocarditis can occur as a result of exposure to various infectious and noninfectious insults, but does not generally lead to a fatal outcome (ie, most affected individuals can recover spontaneously). However, a proportion of those affected can develop dilated cardiomyopathy (DCM). Estimates indicate that approximately half of DCM patients undergo heart transplantation because of a lack of alternative therapeutic options.1e3 Furthermore, several clinical studies suggest that DCM patients can have autoantibodies to several cardiac antigens, including adenine nucleotide translocator (ANT).4e6 Because DCM can arise as a sequel to myocarditis, it has been postulated that autoimmune response may be an underlying mechanism in its pathogenesis. 7ANT exists in multiple isoforms, all four of which are expressed in humans (ANT 1 , ANT 2 , ANT 3 , and ANT 4 ), but only three in mice (ANT 1 , ANT 2 , and ANT 4 ). ANT 1 is expressed in muscle tissues (heart and skeletal) and the brain, ANT 2 can be expressed in liver, kidney, and heart, and ANT 4 expression is restricted to the testes in mice.

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Section: T-cell Proliferation Assaymentioning

confidence: 99%

Section: Mrm Imaging Of Animals Immunized With Ant 1 21-40 Revealed Cmentioning

confidence: 99%

Section: -40ereactive T Cellsmentioning

confidence: 99%

Section: Animals Immunized With Ant 1 21-40 Showed Inflammatory Lesiomentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice

Basavalingappa

Massilamany

Krishnan

et al. 2016

The American Journal of Pathology

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The structural basis of MHC control of collagen-induced arthritis; binding of the immunodominant type II collagen 256 – 270 glycopeptide to H-2Aq and H-2Ap molecules

et al. 1998

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The Aq major histocompatibility complex (MHC) class II molecule is associated with susceptibility to murine collagen-induced arthritis (CIA), whereas the closely related H-2Ap molecule is not. To understand the molecular basis for this difference, we have analyzed the ability of H-2Aq and H-2Ap molecules (referred to as Aq and Ap) to bind and present collagen type II (CII)-derived glycosylated and non-glycosylated peptides. T cell clones specific for the immunodominant CII 256-270 peptide and restricted to both Aq and Ap molecules were identified. When these clones were incubated with CII protein and either Aq- or Ap-expressing antigen-presenting cells (APC), only Aq-expressing APC were able to induce stimulation. With the use of A(beta) transgenic mice this could be shown to be solely dependent on the MHC class II molecule itself and to be independent of other MHC- or non-MHC genes. Peptide binding studies were performed using affinity-purified MHC class II molecules. The CII 256-270 peptide bound with lower affinity to the Ap molecule than to the Aq molecule. Using a set of alanine-substituted CII 256-270 peptides, MHC class II and T cell receptor (TCR) contacts were identified. Mainly the side chains of isoleucine 260 and phenylalanine 263 were used for binding both the Aq and Ap molecule, i.e. the peptide was orientated similarly in the binding clefts. The major TCR contact amino acids were lysine 264, which can be posttranslationally modified, and glutamic acid 266, which is the only amino acid in the heterologous peptide which differs from the mouse sequence. Glycosylation at positions 264 and 270 of the CII 256-270 peptide did not change the anchor positions used for binding to the Aq or Ap molecules. The autologous form of the peptide (with aspartic acid at position 266) bound with lower affinity to the Aq molecule as compared with the heterologous peptide. The variable affinity displayed by the immunodominant CII 256-270 peptide for different MHC class II molecules, the identification of MHC and TCR contacts and the significance of glycosylation of these have important implications for the understanding of the molecular basis for inherited MHC class II-associated susceptibility to CIA and in turn, for development of novel treatment strategies in this disease.

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Hierarchy in the ability of T cell epitopes to induce peripheral tolerance to antigens from myelin

Anderton

Wraith

1998

Eur. J. Immunol.

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Nasal administration of peptide antigens has been shown to induce T cell tolerance. We have investigated the potential for peptide therapy of the autoimmune response to myelin antigens in experimental autoimmune encephalomyelitis (EAE). Three major encephalitogenic epitopes were studied for their ability to induce nasal tolerance to myelin antigens. These included epitopes Ac1-9 and 89-101 of myelin basic protein (MBP) and 139-151 from proteolipid protein (PLP). Peptide Ac1-9 from MBP effectively suppressed responses to both MBP epitopes, following immunization with whole myelin (linked suppression). The N-terminal epitope failed, however, to modify the response to epitope 139-151 of PLP. The second MBP epitope (89-101) was poorly tolerogenic for the immune response to any naturally processed myelin epitope. By contrast, PLP[139-151] was able to induce bystander suppression of T cells responsive to both itself and the two epitopes from MBP. Furthermore, this epitope suppressed EAE induced with peptides derived from MBP and was capable of treating ongoing disease. The mechanism of bystander suppression, mediated by PLP[139-151], did not correlate with an overt switch from the T helper 1 to the T helper 2 phenotype. These results demonstrate how a complex autoimmune disease may be controlled by treatment with a single peptide epitope and reveal a hierarchy in the suppressive properties of different myelin antigens.

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Quantitative Analysis of Peptides from Myelin Basic Protein Binding to the MHC Class II Protein, I-Au, Which Confers Susceptibility to Experimental Allergic Encephalomyelitis

Abstract: The dominance of the natural determinant does not arise from a high-affinity interaction with the MHC class II molecule. This suggests that other mechanisms are operative and that the specific T cell for this peptide/MHC ligand is of high affinity.

Cited by 56 publications

References 24 publications

Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice

Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice

The structural basis of MHC control of collagen-induced arthritis; binding of the immunodominant type II collagen 256 – 270 glycopeptide to H-2Aq and H-2Ap molecules

Hierarchy in the ability of T cell epitopes to induce peripheral tolerance to antigens from myelin

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