Identification of novel mimicry epitopes for cardiac myosin heavy chain-α that induce autoimmune myocarditis in A/J mice

Massilamany, Chandirasegaran; Gangaplara, Arunakumar; Steffen, David; Reddy, Jay

doi:10.1016/j.cellimm.2011.08.013

Cited by 60 publications

(120 citation statements)

References 63 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…After ascertaining the inflammatory changes, the total number of inflammatory foci was determined by sections with the largest number of foci or by adding nonoverlapping foci across sections, as reported previously. 26 The disease severity was Myocarditis Induced by ANT 1 The American Journal of Pathology -ajp.amjpathol.orgassessed as follows: heart: 0 foci, normal; 1 to 5 foci, mild multifocal; 6 to 25 foci, moderate multifocal to coalescing; and 26 or more foci, diffuse 24,27 ; and liver: 0 to 6 foci, background; and >6 foci, multiple scattered.…”

Section: Histologymentioning

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%

“…24 Four to six longitudinal tissue layers were cut from each heart, and up to two layers were also cut from noncardiac tissues (namely, brain and liver). Two to six serial histological sections were then cut to a 5 mm thickness from each layer, skipping 25 mm between sections.…”

Section: Histologymentioning

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%

“…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%

See 4 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Histologymentioning

confidence: 99%

Section: -40ereactive T Cellsmentioning

confidence: 99%

Section: Histologymentioning

confidence: 99%

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

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

show abstract

Branched chain α‐ketoacid dehydrogenase kinase 111–130, a T cell epitope that induces both autoimmune myocarditis and hepatitis in A/J mice

Krishnan

Massilamany

Basavalingappa

et al. 2017

Immunity Inflam & Disease

Self Cite

View full text Add to dashboard Cite

IntroductionOrgan‐specific autoimmune diseases are believed to result from immune responses generated against self‐antigens specific to each organ. However, when such responses target antigens expressed promiscuously in multiple tissues, then the immune‐mediated damage may be wide spread.MethodsIn this report, we describe a mitochondrial protein, branched chain α‐ketoacid dehydrogenase kinase (BCKDk) that can act as a target autoantigen in the development of autoimmune inflammatory reactions in both heart and liver.ResultsWe demonstrate that BCKDk protein contains at least nine immunodominant epitopes, three of which, BCKDk 71–90, BCKDk 111–130 and BCKDk 141–160, were found to induce varying degrees of myocarditis in immunized mice. One of these, BCKDk 111–130, could also induce hepatitis without affecting lungs, kidneys, skeletal muscles, and brain. In immunogenicity testing, all three peptides induced antigen‐specific T cell responses, as verified by proliferation assay and/or major histocompatibility complex class II/IAk dextramer staining. Finally, the disease‐inducing abilities of BCKDk peptides were correlated with the production of interferon‐γ, and the activated T cells could transfer disease to naive recipients.ConclusionsThe disease induced by BCKDk peptides could serve as a useful model to study the autoimmune events of inflammatory heart and liver diseases.

show abstract

An overview of the immune mechanisms of viral myocarditis

Lasrado

Reddy

2020

Reviews in Medical Virology

Self Cite

View full text Add to dashboard Cite

Viral myocarditis has been identified as a major cause of dilated cardiomyopathy (DCM) that can lead to heart failure. Historically, Coxsackieviruses and adenoviruses have been commonly suspected in myocarditis/DCM patients in North America and Europe. However, this notion is changing as other viruses such as Parvovirus B19 and human herpesvirus-6 are increasingly reported as causes of myocarditis in the United States, with the most recent example being the severe acute respiratory syndrome coronavirus 2, causing the Coronavirus Disease-19. The mouse model of Coxsackievirus B3 (CVB3)-induced myocarditis, which may involve mediation of autoimmunity, is routinely used in the study of immune pathogenesis of viral infections as triggers of DCM. In this review, we discuss the immune mechanisms underlying the development of viral myocarditis with an emphasis on autoimmunity in the development of post-infectious myocarditis induced with CVB3.

show abstract

Identification of novel mimicry epitopes for cardiac myosin heavy chain-α that induce autoimmune myocarditis in A/J mice

Cited by 60 publications

References 63 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

Branched chain α‐ketoacid dehydrogenase kinase 111–130, a T cell epitope that induces both autoimmune myocarditis and hepatitis in A/J mice

An overview of the immune mechanisms of viral myocarditis

Contact Info

Product

Resources

About