Th17 Signature, Autoimmunity, and Differentially Expressed Genes in Cardiomyopathy and Heart Failure - European Medical Journal

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Th17 Signature, Autoimmunity, and Differentially Expressed Genes in Cardiomyopathy and Heart Failure

2 Mins
Cardiology
Authors:
Jennifer Myers,1 Clayton Sandel,1 Leslie Cooper,2 Stavros Stavrakis,3 DeLisa Fairweather,2 Kaity White,4 Lori Garman,4 Graham Wiley,4 Courtney Montgomery,4 Patrick Gaffney,4 *Madeleine Cunningham1

1. University of Oklahoma Health Sciences Center, Microbiology and Immunology, Oklahoma City, Oklahoma, USA
2. Mayo Clinic, Cardiovascular Medicine, Jacksonville, Florida, USA
3. University of Oklahoma Health Sciences Center, Cardiology, Oklahoma City, Oklahoma, USA
4. Oklahoma Medical Research Foundation, Genetics, Oklahoma City, Oklahoma, USA
*Correspondence to [email protected]

Disclosure:

Dr Myers reports grants from the National Heart, Lung, and Blood Institute, and the American Heart association during the conduct of the study. Mr Sandel and Dr Fairweather report grants from the National Heart, Lung, and Blood Institute. Dr Cunningham reports grants from the National Heart, Lung, and Blood Institute, American Heart Association, during the conduct of the study; personal fees and other from Moleculera Labs, outside the submitted work. In addition, Dr Cunningham has patents 10228376 and 9804171 with royalties paid to Moleculera labs and the Board of Regents of the University of Oklahoma and the National Institute of Health. All other authors have declared no conflicts of interest.

Citation:
EMJ Cardio. ;7[1]:74-75. Abstract Review No. AR2.
Keywords:
Antibodies, autoimmunity, cardiomyopathy, heart failure (HF), inflammation, myocarditis, T cells, transcriptome

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND

Myocarditis is a common precursor to dilated cardiomyopathy (DCM) and together they are the cause of approximately half of all heart transplants, constituting a major cause of sudden death in young adults.1 Frequently initiated by viral infection of cardiomyocytes, approximately one third of those with acute myocarditis develop a chronic autoimmune syndrome leading to DCM and heart failure (HF).2,3 The pathogenesis and treatment of the progressive disease is not well established; therefore, uncovering the molecular basis of why patients do not recover normal ejection fraction within a year following onset of the disease is needed to develop new biomarkers and therapies. Cardiac myosin released from the damaged heart is a damage-associated molecular pattern that binds to toll-like receptor 2 (TLR2)4,5 and TLR8,5 promoting a Th17 pathogenesis in chronic autoimmune DCM and inducing anti-heart autoimmunity.6 Previous studies have demonstrated elevated anti-heart and anti-human cardiac myosin IgG antibodies in myocarditis/DCM and their cross-reactivity with the beta-adrenergic receptor.6-9 The purpose of this study was therefore to identify new biomarkers in early stages of HF in individuals who did not recover ejection fraction over a year and who were candidates for current immunotherapies.

METHODS

Patients with myocarditis and HF (N=41) within 6 months of onset were enrolled and monitored for 12 months. Serum autoantibodies and cytokines were detected by ELISA, and fluorescence-activated cell sorting analysis was performed on peripheral blood mononuclear cells. The Mann-Whitney U test was used for statistical analysis. For gene expression studies, blood from 10 DCM patients and 19 healthy controls were collected for RNA sequencing and transcriptomic analysis by Ingenuity Pathway Analysis (IPA®) and Reactome.

RESULTS

The results of the study correlate anti-human cardiac myosin autoantibodies with poor outcomes and demonstratedthat they functionally act on cardiomyocytes to activate protein kinase A. Concomitantly, a Th17 immunophenotype was significantly elevated in the blood as well as in cardiac biopsies.6 CD4+IL17+ T cells (p=0.0008), TGF-β (a Th17-promoting cytokine (p<0.0001), IL-6 (p<0.0001), IL-23 (p=0.0001), granulocyte-macrophage colony-stimulating factor (GMCSF) (p=0.0336), and GMCSF-secreting CD4+ T cells (p=0.0006) were significantly elevated in the blood.6 A Th17 immunophenotype was significantly associated with HF in males (p=0.029).6 Persistent HF (New York Heart Association [NYHA] functional classification III and IV) and non-recovery of left ventricular function were associated with significantly higher percentages of IL-17A-producing T cells at baseline, 6 and 12 months after onset, and IL-17A (p=0.019) and Th17-promoting cytokines IL-6 (p=0.0001) and TGF-β (p=0.0076).6 Regulatory T cells were significantly decreased (p=0.0006) and correlated with elevated Th17 cytokines in HF.⁶ Overrepresentation analysis of differentially expressed genes (adjusted p<0.05) in blood of DCM (>1 year) patients was carried out and revealed significant (false discovery rate=1.52E-13) enrichment of neutrophil degranulation (48 genes) in IL-8, GMCSF, IL-17A, and other pathways. Neutrophil involvement is a feature of the IL-17A pathways which promote fibrosis.

CONCLUSION

In conclusion, the study illustrated a strong Th17 signature (Figure 1) in more severe HF early in the disease with anticardiac myosin autoantibodies highly elevated in non-recovery of left ventricular function. Additionally, a strong correlation with neutrophil degranulation pathways in the later disease was observed, which could become biomarkers of fibrosis progression and disease severity in patients with HF. HF identified with a Th17 signature might be treated with immunomodulatory therapies such as anti-IL-17A.

Figure 1: Diagram of the pathogenic mechanisms in the Th17 signature of myocarditis and dilated cardiomyopathy: an immunophenotype in myocarditis, dilated cardiomyopathy, and heart failure.FOXP3+: Forkhead box P3+; GM-CSF: granulocyte-macrophage colony-stimulating factor; TGF-β: transforming growth factor beta; TLR2: toll-like receptor 2.
Adapted from Myers JM et al.6

References
Cooper LT, Knowlton KU, “Myocarditis”, Mann DI et al. (eds), Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine (2015) 10th edition, Philadelphia: Elsevier Saunders, pp. 1589-602. Caforio AL et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(33):2636-48. Myers JM et al. Autoimmune myocarditis, valvulitis, and cardiomyopathy. Curr Protoc Immunol. 2013;15.14:1-57. Li Y et al. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J Immunol. 2006;177(11):8234-40. Zhang P et al. Cutting edge: Cardiac myosin activates innate immune responses through TLRs. J Immunol. 2009;183(1):27-31. Myers JM et al. Cardiac myosin-Th17 responses promote heart failure in human myocarditis. JCI Insight. 2016;1(9):e85851. Mascaro-Blanco A et al. Consequences of unlockingthe cardiac myosin molecule in human myocarditis and cardiomyopathies. Autoimmunity. 2008;41(6):442-53. Caforio AL et al. Clinical implications of anti-cardiac immunity in dilated cardiomyopathy. Ernst Schering Res Found Workshop. 2006;(55):169-93. Jahns R et al. Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure. Circulation. 1999;99(5):649-54.

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