Journal of Clinical Immunology

, Volume 31, Issue 2, pp 155–166

CD8+ T Cells in Facioscapulohumeral Muscular Dystrophy Patients with Inflammatory Features at Muscle MRI

  • Giovanni Frisullo
  • Roberto Frusciante
  • Viviana Nociti
  • Giorgio Tasca
  • Rosaria Renna
  • Raffaele Iorio
  • Agata Katia Patanella
  • Elisabetta Iannaccone
  • Alessandro Marti
  • Monica Rossi
  • Assunta Bianco
  • Mauro Monforte
  • Pietro Attilio Tonali
  • Massimiliano Mirabella
  • Anna Paola Batocchi
  • Enzo Ricci
Article

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8+ T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8+pSTAT1+, CD8+T-bet+ T cells and CD14+pSTAT1+, CD14+T-bet+ cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8+pSTAT1+, CD8+T-bet+ and CD14+pSTAT1+ cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8+ T cells, may favour FSHD progression by promoting active phases of muscle inflammation.

Keywords

T-bet pSTAT1 cytokines FSHD muscle MRI CD8 T cells inflammation 

References

  1. 1.
    Steinman L. Four easy pieces: interconnections between tissue injury, intermediary metabolism, autoimmunity, and chronic degeneration. Proc Am Thorac Soc. 2006;3:484–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Spencer MJ, Tidball JG. Do immune cells promote the pathology of dystrophin-deficient myopathies. Neuromuscul Disord. 2001;11:556–64.PubMedCrossRefGoogle Scholar
  3. 3.
    Moser H, Dubye P, Fatemi A. Progress in X-linked adrenoleukodystrophy. Curr Opin Neurol. 2004;17:263–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Ranes J, Stoller K. Review of alpha 1-antitrypsin deficiency. Semin Respir Crit Care Med. 2005;26:154–66.PubMedCrossRefGoogle Scholar
  5. 5.
    Pescatori M, Broccolini A, Minetti C, Bertini E, Bruno C, D’amico A, et al. Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression. FASEB J. 2007;21:1210–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Nagaraju K, Rawat R, Veszelovszky E, Thapliyal R, Kesari A, Sparks S, et al. Dysferlin deficiency enhances monocyte phagocytosis: a model for the inflammatory onset of limb-girdle muscular dystrophy 2B. Am J Pathol. 2008;172:774–85.PubMedCrossRefGoogle Scholar
  7. 7.
    van Deutekom JC, Wijmenga C, van Tienhoven EA, Gruter AM, Hewitt JE, Padberg GW, et al. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet. 1993;2:2037–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Tawil R, Van Der Maarel SM. Facioscapulohumeral muscular dystrophy. Muscle Nerve. 2006;34:1–15.PubMedCrossRefGoogle Scholar
  9. 9.
    Tupler R, Perini G, Pellegrino MA, Green MR. Profound misregulation of muscle-specific gene expression in facioscapulohumeral muscular dystrophy. Proc Natl Acad Sci USA. 1999;96:12650–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Munsat TL, Piper D, Cancilla P, Mednick J. Inflammatory myopathy with facioscapulohumeral distribution. Neurology. 1972;22:335–47.PubMedGoogle Scholar
  11. 11.
    Figarella-Branger D, Pellissier JF, Serratrice G, Pouget J, Bianco N. Immunocytochemical study of the inflammatory forms of facioscapulohumeral myopathies and correlation with other types of myositis. Ann Pathol. 1989;9:100–8.PubMedGoogle Scholar
  12. 12.
    Arahata K, Ishihara T, Fukunaga H, Orimo S, Lee JH, Goto K, et al. Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Muscle Nerve. 1995;2:S56–66.PubMedCrossRefGoogle Scholar
  13. 13.
    Tawil R, McDermott MP, Pandya S, King W, Kissel J, Mendell JR, et al. A pilot trial of prednisone in facioscapulohumeral muscular dystrophy FSH-DY group. Neurology. 1997;48:46–9.PubMedGoogle Scholar
  14. 14.
    Mercuri E, Talim B, Moghadaszadeh B, Petit N, Brockington M, Counsell S, et al. Clinical and imaging findings in six cases of congenital muscular dystrophy with rigid spine syndrome linked to chromosome 1p (RSMD1). Neuromuscul Disord. 2002;12:631–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Sookhoo S, Mackinnon I, Bushby K, Chinnery PF, Birchall D. MRI for the demonstration of subclinical muscle involvement in muscular dystrophy. Clin Radiol. 2007;62:160–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Olsen DB, Gideon P, Jeppesen TD, Vissing J. Leg muscle involvement in facioscapulohumeral muscular dystrophy assessed by MRI. J Neurol. 2006;253:1437–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Kan HE, Scheenen TW, Wohlgemuth M, Klomp DW, van Loosbroek-Wagenmans I, Padberg GW, et al. Quantitative MR imaging of individual muscle involvement in facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2009;19:357–62.PubMedCrossRefGoogle Scholar
  18. 18.
    May DA, Disler DG, Jones EA, Balkissoon AA, Manaster BJ. Abnormal signal intensity in skeletal muscle at MR imaging: patterns, pearls, and pitfalls. Radiographics. 2000;20:S295–315.PubMedGoogle Scholar
  19. 19.
    Kamath S, Venkatanarasimha N, Walsh MA, Hughes PM. MRI appearance of muscle denervation. Skeletal Radiol. 2008;37:397–404.PubMedCrossRefGoogle Scholar
  20. 20.
    Ricci E, Galluzzi G, Deidda G, Cacurri S, Colantoni L, Merico B, et al. Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann Neurol. 1999;45:751–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Lynöe N, Sandlund M, Dahlqvist G, Jacobsson L. Informed consent: study of quality of information given to participants in a clinical trial. BMJ. 1991;303:610–3.PubMedCrossRefGoogle Scholar
  22. 22.
    Brunn A, Schroder R, Deckert M. The inflammatory reaction pattern distinguishes primary dysferlinopathies from idiopathic inflammatory myopathies: an important role for the membrane attack complex. Acta Neuropathol. 2006;112:325–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Wang J, Fathman JW, Lugo-Villarino G, Scimone L, von Andrian U, Dorfman DM, et al. Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. J Clin Invest. 2006;116:414–21.PubMedCrossRefGoogle Scholar
  24. 24.
    Lighvani AA, Frucht DM, Jankovic D, Yamane H, Aliberti J, Hissong BD, et al. T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci USA. 2001;98:15137–42.PubMedCrossRefGoogle Scholar
  25. 25.
    Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, et al. T-bet is a STAT1-induced regulator of IL-12R receptor in naïve CD4+ cells. Nat Immunol. 2002;3:549–57.PubMedCrossRefGoogle Scholar
  26. 26.
    Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science. 2001;292:1907–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Yang Y, Ochando JC, Bromberg JS, Ding Y. Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNgamma/Stat1 signals. Blood. 2007;110:2494–500.PubMedCrossRefGoogle Scholar
  28. 28.
    Mayer KD, Mohrs K, Reiley W, Wittmer S, Kohlmeier JE, Pearl JE, et al. Cutting edge: T-bet and IL-27R are critical for in vivo IFN-gamma production by CD8 T cells during infection. J Immunol. 2008;180:693–7.PubMedGoogle Scholar
  29. 29.
    Sullivan BM, Juedes A, Szabo SJ, von Herrath M, Glimcher LH. Antigen-driven effector CD8 T cell function regulated by T-bet. Proc Natl Acad Sci USA. 2003;100:15818–23.PubMedCrossRefGoogle Scholar
  30. 30.
    Cruz-Guilloty F, Pipkin ME, Djuretic IM, Levanon D, Lotem J, Lichtenheld MG, et al. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med. 2009;206:51–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008;9:641–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol. 1998;161(9):4652–60.PubMedGoogle Scholar
  33. 33.
    Mangan JK, Rane SG, Kang AD, Amanullah A, Wong BC, Reddy EP. Mechanisms associated with IL-6-induced up-regulation of Jak3 and its role in monocytic differentiation. Blood. 2004;103:4093–101.PubMedCrossRefGoogle Scholar
  34. 34.
    Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, et al. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol. 2008;9:650–7.PubMedCrossRefGoogle Scholar
  35. 35.
    O’Garra A, Vieira P. T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol. 2007;7:425–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Corinti S, Albanesi C, la Sala A, Pastore S, Girolomoni G. Regulatory activity of autocrine IL-10 on dendritic cell functions. J Immunol. 2001;166:4312–8.PubMedGoogle Scholar
  37. 37.
    Hoentjen F, Sartor RB, Ozaki M, Jobin C. STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells. Blood. 2005;105:689–96.PubMedCrossRefGoogle Scholar
  38. 38.
    Williams L, Bradley L, Smith A, Foxwell B. Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol. 2004;172:567–76.PubMedGoogle Scholar
  39. 39.
    Murray PJ. Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol. 2006;6:379–86.PubMedCrossRefGoogle Scholar
  40. 40.
    Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol. 2007;8:1363–71.PubMedCrossRefGoogle Scholar
  41. 41.
    Janssen SP, Gayan-Ramirez G, Van den Bergh A, Herijgers P, Maes K, Verbeken E, et al. Interleukin-6 causes myocardial failure and skeletal muscle atrophy in rats. Circulation. 2005;111:996–1005.PubMedCrossRefGoogle Scholar
  42. 42.
    Haddad F, Zaldivar F, Cooper DM, Adams GR. IL-6-induced skeletal muscle atrophy. J Appl Physiol. 2005;98:911–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Schaap LA, Pluijm SM, Deeg DJ, Visser M. Inflammatory markers and loss of muscle mass (sarcopenia) and strength. Am J Med. 2006;119:9–17.CrossRefGoogle Scholar
  44. 44.
    Toth MJ, Ades PA, Tischler MD, Tracy RP, LeWinter MM. Immune activation is associated with reduced skeletal muscle mass and physical function in chronic heart failure. Int J Cardiol. 2006;109:179–87.PubMedCrossRefGoogle Scholar
  45. 45.
    Huey KA, McCusker RH, Kelley KW. Exaggerated expression of skeletal muscle-derived interleukin-6, but not TNFalpha, in mice lacking interleukin-10. J Neuroimmunol. 2008;199:56–62.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Giovanni Frisullo
    • 1
  • Roberto Frusciante
    • 1
  • Viviana Nociti
    • 1
    • 2
  • Giorgio Tasca
    • 1
  • Rosaria Renna
    • 1
  • Raffaele Iorio
    • 1
  • Agata Katia Patanella
    • 1
    • 2
  • Elisabetta Iannaccone
    • 1
  • Alessandro Marti
    • 1
  • Monica Rossi
    • 1
    • 2
  • Assunta Bianco
    • 1
  • Mauro Monforte
    • 1
  • Pietro Attilio Tonali
    • 1
    • 2
  • Massimiliano Mirabella
    • 1
    • 2
  • Anna Paola Batocchi
    • 1
  • Enzo Ricci
    • 1
    • 2
  1. 1.Institute of Neurology, Department of NeurosciencesCatholic University of RomeRomeItaly
  2. 2.Fondazione Don Carlo GnocchiMilanItaly

Personalised recommendations