The Immune System in Duchenne Muscular Dystrophy: Friend or Foe

Overview

Journal Rare Dis

Date 2015 Oct 21

PMID 26481612

Citations 37

Authors

S Armando Villalta

Amy S Rosenberg

Jeffrey A Bluestone

Affiliations

Soon will be listed here.

Abstract

Duchenne muscular dystrophy (DMD) is a genetic disease caused by mutations in the X-linked dystrophin gene, resulting in reduced or absent protein production, subsequently leading to the structural instability of the dystroglycan complex (DGC), muscle degeneration, and early death in males. Thus, current treatments have been targeting the genetic defect either by bypassing the mutation through exon skipping or replacing the defective gene through gene therapy and stem cell approaches. However, what has been an underappreciated mediator of muscle pathology and, ultimately, of muscle degeneration and fibrotic replacement, is the prominent inflammatory response. Of potentially critical importance, however, is the fact that the elements mediating the inflammatory response also play an essential role in tissue repair. In this opinion piece, we highlight the detrimental and supportive immune parameters that occur as a consequence of the genetic disorder and discuss how changes to immunity can potentially ameliorate the disease intensity and be employed in conjunction with efforts to correct the genetic disorder.

Citing Articles

Type-2 innate signals are dispensable for skeletal muscle regeneration and pathology linked to Duchenne muscular dystrophy.

Messing M, Theret M, Hughes M, Wu J, Syed O, Li F EMBO Rep. 2025; 26(5):1406-1421.

PMID: 39900735 PMC: 11894123. DOI: 10.1038/s44319-025-00383-y.

Determination of qPCR reference genes suitable for normalizing gene expression in a novel model of Duchenne muscular dystrophy, the D2-mdx mouse.

Boccanegra B, Lenti R, Mantuano P, Conte E, Tulimiero L, Piercy R PLoS One. 2024; 19(11):e0310714.

PMID: 39535998 PMC: 11560031. DOI: 10.1371/journal.pone.0310714.

Benfotiamine improves dystrophic pathology and exercise capacity in mdx mice by reducing inflammation and fibrosis.

Coles C, Woodman K, Gibbs E, Crosbie R, White J, Lamande S Hum Mol Genet. 2024; 33(15):1339-1355.

PMID: 38710523 PMC: 11262745. DOI: 10.1093/hmg/ddae066.

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?.

Dowling P, Trollet C, Negroni E, Swandulla D, Ohlendieck K Proteomes. 2024; 12(1).

PMID: 38250815 PMC: 10801633. DOI: 10.3390/proteomes12010004.

Association between blood eosinophil count and Duchenne muscular dystrophy severity and prognosis: a retrospective cohort study.

Jiang Z, Liao H, Wu L, Hu W, Yang L, Chen B Ital J Pediatr. 2023; 49(1):83.

PMID: 37443128 PMC: 10347798. DOI: 10.1186/s13052-023-01483-y.

References

Radley H, Davies M, Grounds M . Reduced muscle necrosis and long-term benefits in dystrophic mdx mice after cV1q (blockade of TNF) treatment. Neuromuscul Disord. 2008; 18(3):227-38. DOI: 10.1016/j.nmd.2007.11.002. View

Bulfield G, Siller W, Wight P, Moore K . X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci U S A. 1984; 81(4):1189-92. PMC: 344791. DOI: 10.1073/pnas.81.4.1189. View

Fife B, Bluestone J . Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008; 224:166-82. DOI: 10.1111/j.1600-065X.2008.00662.x. View

Birnbaum M, Mendoza J, Sethi D, Dong S, Glanville J, Dobbins J . Deconstructing the peptide-MHC specificity of T cell recognition. Cell. 2014; 157(5):1073-87. PMC: 4071348. DOI: 10.1016/j.cell.2014.03.047. View

Ermolova N, Martinez L, Vetrone S, Jordan M, Roos K, Sweeney H . Long-term administration of the TNF blocking drug Remicade (cV1q) to mdx mice reduces skeletal and cardiac muscle fibrosis, but negatively impacts cardiac function. Neuromuscul Disord. 2014; 24(7):583-95. PMC: 4122520. DOI: 10.1016/j.nmd.2014.04.006. View

Acharyya S, Villalta S, Bakkar N, Bupha-Intr T, Janssen P, Carathers M . Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy. J Clin Invest. 2007; 117(4):889-901. PMC: 1821069. DOI: 10.1172/JCI30556. View

Burzyn D, Kuswanto W, Kolodin D, Shadrach J, Cerletti M, Jang Y . A special population of regulatory T cells potentiates muscle repair. Cell. 2013; 155(6):1282-95. PMC: 3894749. DOI: 10.1016/j.cell.2013.10.054. View

Villalta S, Deng B, Rinaldi C, Wehling-Henricks M, Tidball J . IFN-γ promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation. J Immunol. 2011; 187(10):5419-28. PMC: 3208069. DOI: 10.4049/jimmunol.1101267. View

Long S, Buckner J, Greenbaum C . IL-2 therapy in type 1 diabetes: "Trials" and tribulations. Clin Immunol. 2013; 149(3):324-31. DOI: 10.1016/j.clim.2013.02.005. View

10.

Vetrone S, Montecino-Rodriguez E, Kudryashova E, Kramerova I, Hoffman E, Liu S . Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta. J Clin Invest. 2009; 119(6):1583-94. PMC: 2689112. DOI: 10.1172/JCI37662. View

11.

Spencer M, Dorshkind K, Tidball J . Helper (CD4(+)) and cytotoxic (CD8(+)) T cells promote the pathology of dystrophin-deficient muscle. Clin Immunol. 2001; 98(2):235-43. DOI: 10.1006/clim.2000.4966. View

12.

Liu C, Ye P, Yen B, Miao C . In vivo expansion of regulatory T cells with IL-2/IL-2 mAb complexes prevents anti-factor VIII immune responses in hemophilia A mice treated with factor VIII plasmid-mediated gene therapy. Mol Ther. 2011; 19(8):1511-20. PMC: 3149174. DOI: 10.1038/mt.2011.61. View

13.

Zhou X, Bailey-Bucktrout S, Jeker L, Penaranda C, Martinez-Llordella M, Ashby M . Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009; 10(9):1000-7. PMC: 2729804. DOI: 10.1038/ni.1774. View

14.

Tokarz S, Duncan N, Rash S, Sadeghi A, Dewan A, Pillers D . Redefinition of dystrophin isoform distribution in mouse tissue by RT-PCR implies role in nonmuscle manifestations of duchenne muscular dystrophy. Mol Genet Metab. 1999; 65(4):272-81. DOI: 10.1006/mgme.1998.2763. View

15.

Frisullo G, Frusciante R, Nociti V, Tasca G, Renna R, Iorio R . CD8(+) T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI. J Clin Immunol. 2010; 31(2):155-66. DOI: 10.1007/s10875-010-9474-6. View

16.

Gussoni E, Pavlath G, Miller R, Panzara M, Powell M, Blau H . Specific T cell receptor gene rearrangements at the site of muscle degeneration in Duchenne muscular dystrophy. J Immunol. 1994; 153(10):4798-805. View

17.

Serra F, Quarta M, Canato M, Toniolo L, De Arcangelis V, Trotta A . Inflammation in muscular dystrophy and the beneficial effects of non-steroidal anti-inflammatory drugs. Muscle Nerve. 2012; 46(5):773-84. DOI: 10.1002/mus.23432. View

18.

Wehling-Henricks M, Sokolow S, Lee J, Myung K, Villalta S, Tidball J . Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy. Hum Mol Genet. 2008; 17(15):2280-92. PMC: 2574717. DOI: 10.1093/hmg/ddn129. View

19.

Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J . Administration of CD4+CD25highCD127- regulatory T cells preserves β-cell function in type 1 diabetes in children. Diabetes Care. 2012; 35(9):1817-20. PMC: 3425004. DOI: 10.2337/dc12-0038. View

20.

De Paepe B, De Bleecker J . Cytokines and chemokines as regulators of skeletal muscle inflammation: presenting the case of Duchenne muscular dystrophy. Mediators Inflamm. 2013; 2013:540370. PMC: 3835490. DOI: 10.1155/2013/540370. View