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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Research article

Effects of conventional immunosuppressive treatment on CD244+ (CD28null) and FOXP3+ T cells in the inflamed muscle of patients with polymyositis and dermatomyositis

Authors: Jayesh M. Pandya, Ingela Loell, Mohammad Shahadat Hossain, Mei Zong, Helene Alexanderson, Sukanya Raghavan, Ingrid E. Lundberg, Vivianne Malmström

Published in: Arthritis Research & Therapy | Issue 1/2016

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Abstract

Background

T-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment. Here, we investigated to what extent persistent T cells in affected muscle were FOXP3+, a marker for regulatory T cells (Tregs), or CD244+, a marker for CD28null T cells, and whether their presence correlated to clinical outcome. The sensitivity of CD28null T cells towards glucocorticoid and Treg-mediated immunosuppression was also investigated.

Methods

Muscle biopsies from 16 newly diagnosed or untreated patients with PM/DM were investigated by immunohistochemistry for expression of CD3, FOXP3 and CD244 before and after treatment with glucocorticoids and immunosuppressive agents. For clinical evaluation, serum levels of creatine kinase, muscle performance (FI and MMT8), disease activity (MITAX) and disability (HAQ) were measured. In vitro suppressive effects of glucocorticoids and Tregs on T-cell activation were measured by CD69 upregulation.

Results

Before treatment, CD244+ cells were present at higher proportions compared to FOXP3+ cells in the inflamed muscle. Following treatment, FOXP3+ cell numbers decreased while CD244+ cells persisted. Patients with impaired muscle function (<75 % FI) post-treatment had higher levels of CD244+ cells in the follow-up biopsy compared to those with FI >75 %. MITAX and HAQ correlated with the number of CD244+ cells post-treatment. CD4+CD28null T cells displayed lower sensitivity towards both glucocorticoid and Treg-mediated immunosuppression in vitro compared to their CD28+ counterparts.

Conclusions

Poor outcome in patients with myositis following immunosuppressive therapy was linked to persistence of CD244+ (CD28null) T cells in muscle tissue, suggesting their resistance against immunosuppression. A relative loss of regulatory T cells could also contribute to poor clinical outcome given their recently ascribed role in muscle tissue regeneration.
Literature
1.
Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol. 1984;16(2):193–208.CrossRefPubMed
2.
Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol. 1984;16(2):209–15.CrossRefPubMed
3.
Goebels N, Michaelis D, Engelhardt M, Huber S, Bender A, Pongratz D, et al. Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis. J Clin Invest. 1996;97(12):2905–10.CrossRefPubMedPubMedCentral
4.
Zong M, Lundberg IE. Pathogenesis, classification and treatment of inflammatory myopathies. Nat Rev Rheumatol. 2011;7(5):297–306.CrossRefPubMed
5.
Lundberg IE, Vencovsky J, Alexanderson H. Therapy of myositis: biological and physical. Curr Opin Rheumatol. 2014;26(6):704–11.CrossRefPubMed
6.
Bunch TW, Worthington JW, Combs JJ, Ilstrup DM, Engel AG. Azathioprine with prednisone for polymyositis. A controlled, clinical trial. Ann Intern Med. 1980;92(3):365–9.CrossRefPubMed
7.
Lundberg I, Kratz AK, Alexanderson H, Patarroyo M. Decreased expression of interleukin-1alpha, interleukin-1beta, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis. Arthritis Rheum. 2000;43(2):336–48.CrossRefPubMed
8.
Korotkova M, Helmers SB, Loell I, Alexanderson H, Grundtman C, Dorph C, et al. Effects of immunosuppressive treatment on microsomal prostaglandin E synthase 1 and cyclooxygenases expression in muscle tissue of patients with polymyositis or dermatomyositis. Ann Rheum Dis. 2008;67(11):1596–602.CrossRefPubMedPubMedCentral
9.
Schirmer M, Vallejo AN, Weyand CM, Goronzy JJ. Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4 + CD28- T cells from rheumatoid arthritis patients. J Immunol. 1998;161(2):1018–25.PubMed
10.
Posnett DN, Edinger JW, Manavalan JS, Irwin C, Marodon G. Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28– cytotoxic effector clones. Int Immunol. 1999;11(2):229–41.CrossRefPubMed
11.
Vallejo AN, Schirmer M, Weyand CM, Goronzy JJ. Clonality and longevity of CD4 + CD28null T cells are associated with defects in apoptotic pathways. J Immunol. 2000;165(11):6301–7.CrossRefPubMed
12.
Kovalcsik E, Antunes RF, Baruah P, Kaski JC, Dumitriu IE. Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4(+)CD28null T cells resistant to apoptosis in acute coronary syndrome. Circulation. 2015;131(8):709–20.CrossRefPubMed
13.
Namekawa T, Snyder MR, Yen JH, Goehring BE, Leibson PJ, Weyand CM, et al. Killer cell activating receptors function as costimulatory molecules on CD4 + CD28null T cells clonally expanded in rheumatoid arthritis. J Immunol. 2000;165(2):1138–45.CrossRefPubMed
14.
Fasth AE, Cao D, van Vollenhoven R, Trollmo C, Malmstrom V. CD28nullCD4+ T cells—characterization of an effector memory T-cell population in patients with rheumatoid arthritis. Scand J Immunol. 2004;60(1-2):199–208.CrossRefPubMed
15.
Fasth AE, Bjorkstrom NK, Anthoni M, Malmberg KJ, Malmstrom V. Activating NK-cell receptors co-stimulate CD4(+)CD28(-) T cells in patients with rheumatoid arthritis. Eur J Immunol. 2010;40(2):378–87.CrossRefPubMed
16.
Thome JJ, Yudanin N, Ohmura Y, Kubota M, Grinshpun B, Sathaliyawala T, et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell. 2014;159(4):814–28.CrossRefPubMedPubMedCentral
17.
Fagnoni FF, Vescovini R, Mazzola M, Bologna G, Nigro E, Lavagetto G, et al. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology. 1996;88(4):501–7.CrossRefPubMedPubMedCentral
18.
Martens PB, Goronzy JJ, Schaid D, Weyand CM. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum. 1997;40(6):1106–14.CrossRefPubMed
19.
Markovic-Plese S, Cortese I, Wandinger KP, McFarland HF, Martin R. CD4 + CD28- costimulation-independent T cells in multiple sclerosis. J Clin Invest. 2001;108(8):1185–94.CrossRefPubMedPubMedCentral
20.
Garcia de Tena J, Manzano L, Leal JC, San Antonio E, Sualdea V, Alvarez-Mon M. Active Crohn's disease patients show a distinctive expansion of circulating memory CD4+CD45RO+CD28null T cells. J Clin Immunol. 2004;24(2):185–96.CrossRefPubMed
21.
Thewissen M, Somers V, Venken K, Linsen L, van Paassen P, Geusens P, et al. Analyses of immunosenescent markers in patients with autoimmune disease. Clin Immunol. 2007;123(2):209–18.CrossRefPubMed
22.
Liuzzo G, Goronzy JJ, Yang H, Kopecky SL, Holmes DR, Frye RL, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation. 2000;101(25):2883–8.CrossRefPubMed
23.
Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.CrossRefPubMed
24.
Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.CrossRefPubMed
25.
Castiglioni A, Corna G, Rigamonti E, Basso V, Vezzoli M, Monno A, et al. FOXP3+ T cells recruited to sites of sterile skeletal muscle injury regulate the fate of satellite cells and guide effective tissue regeneration. PLoS One. 2015;10(6):e0128094.CrossRefPubMedPubMedCentral
26.
Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, et al. A special population of regulatory T cells potentiates muscle repair. Cell. 2013;155(6):1282–95.CrossRefPubMedPubMedCentral
27.
Fasth AE, Dastmalchi M, Rahbar A, Salomonsson S, Pandya JM, Lindroos E, et al. T cell infiltrates in the muscles of patients with dermatomyositis and polymyositis are dominated by CD28null T cells. J Immunol. 2009;183(7):4792–9.CrossRefPubMed
28.
Pandya JM, Fasth AE, Zong M, Arnardottir S, Dani L, Lindroos E, et al. Expanded T cell receptor Vbeta-restricted T cells from patients with sporadic inclusion body myositis are proinflammatory and cytotoxic CD28null T cells. Arthritis Rheum. 2010;62(11):3457–66.CrossRefPubMed
29.
Waschbisch A, Schwab N, Ruck T, Stenner MP, Wiendl H. FOXP3+ T regulatory cells in idiopathic inflammatory myopathies. J Neuroimmunol. 2010;225(1-2):137–42.CrossRefPubMed
30.
Thewissen M, Somers V, Hellings N, Fraussen J, Damoiseaux J, Stinissen P. CD4 + CD28null T cells in autoimmune disease: pathogenic features and decreased susceptibility to immunoregulation. J Immunol. 2007;179(10):6514–23.CrossRefPubMed
31.
Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292(8):403–7.CrossRefPubMed
32.
Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344–7.CrossRefPubMed
33.
Labirua-Iturburu A, Selva-O'Callaghan A, Vincze M, Danko K, Vencovsky J, Fisher B, et al. Anti-PL-7 (anti-threonyl-tRNA synthetase) antisynthetase syndrome: clinical manifestations in a series of patients from a European multicenter study (EUMYONET) and review of the literature. Medicine. 2012;91(4):206–11.CrossRefPubMed
34.
Henriksson KG, Sandstedt P. [Polymyositis]. Scand J Rheumatol Suppl. 1979;30:200–6.PubMed
35.
Dorph C, Nennesmo I, Lundberg IE. Percutaneous conchotome muscle biopsy. A useful diagnostic and assessment tool. J Rheumatol. 2001;28(7):1591–9.PubMed
36.
Raghavan S, Cao D, Widhe M, Roth K, Herrath J, Engstrom M, et al. FOXP3 expression in blood, synovial fluid and synovial tissue during inflammatory arthritis and intra-articular corticosteroid treatment. Ann Rheum Dis. 2009;68(12):1908–15.CrossRefPubMed
37.
Josefson A, Romanus E, Carlsson J. A Functional Index in myositis. J Rheumatol. 1996;23:1380–4.PubMed
38.
Hay EM, Bacon PA, Gordon C, Isenberg DA, Maddison P, Snaith ML, et al. The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q J Med. 1993;86(7):447–58.PubMed
39.
Rider LG, Koziol D, Giannini EH, Jain MS, Smith MR, Whitney-Mahoney K, et al. Validation of manual muscle testing and a subset of eight muscles for adult and juvenile idiopathic inflammatory myopathies. Arthritis Care Res (Hoboken). 2010;62(4):465–72.CrossRef
40.
Alexanderson H, Lundberg IE, Stenstrom CH. Development of the myositis activities profile—validity and reliability of a self-administered questionnaire to assess activity limitations in patients with polymyositis/dermatomyositis. J Rheumatol. 2002;29(11):2386–92.PubMed
41.
Munro BH. Statistical methods for health care research. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2005.
42.
Fasth AE, Snir O, Johansson AA, Nordmark B, Rahbar A, Af Klint E, et al. Skewed distribution of proinflammatory CD4+CD28null T cells in rheumatoid arthritis. Arthritis Res Ther. 2007;9(5):R87.CrossRefPubMedPubMedCentral
43.
Namekawa T, Wagner UG, Goronzy JJ. Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum. 1998;41:2108–16.CrossRefPubMed
44.
Tidball JG, Villalta SA. Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol. 2010;298(5):R1173–87.CrossRefPubMedPubMedCentral
45.
Pandya JM, Venalis P, Al-Khalili L, Hossain MS, Stache V, Lundberg IE, et al. CD4+ and CD8+ CD28null T cells are cytotoxic to autologous muscle cells in polymyositis patients. Arthritis Rheumatol. 2016. doi: 10.​1002/​art.​39650. [Epub ahead of print].
46.
Gold R, Buttgereit F, Toyka KV. Mechanism of action of glucocorticosteroid hormones: possible implications for therapy of neuroimmunological disorders. J Neuroimmunol. 2001;117(1-2):1–8.CrossRefPubMed
47.
Ashwell JD, Lu FW, Vacchio MS. Glucocorticoids in T cell development and function. Annu Rev Immunol. 2000;18:309–45.CrossRefPubMed
48.
49.
Effros RB. Replicative senescence: impact on T cell immunity in the elderly. Aging. 1998;10(2):152.PubMed
50.
51.
52.
Wust S, van den Brandt J, Tischner D, Kleiman A, Tuckermann JP, Gold R, et al. Peripheral T cells are the therapeutic targets of glucocorticoids in experimental autoimmune encephalomyelitis. J Immunol. 2008;180(12):8434–43.CrossRefPubMed
53.
Hodge G, Jersmann H, Tran HB, Holmes M, Reynolds PN, Hodge S. Lymphocyte senescence in COPD is associated with loss of glucocorticoid receptor expression by pro-inflammatory/cytotoxic lymphocytes. Respir Res. 2015;16:2.CrossRefPubMedPubMedCentral
54.
Weyand CM, Brandes JC, Schmidt D, Fulbright JW, Goronzy JJ. Functional properties of CD4+ CD28- T cells in the aging immune system. Mech Ageing Dev. 1998;102(2-3):131–47.CrossRefPubMed
Metadata
Title
Effects of conventional immunosuppressive treatment on CD244+ (CD28null) and FOXP3+ T cells in the inflamed muscle of patients with polymyositis and dermatomyositis
Authors
Jayesh M. Pandya
Ingela Loell
Mohammad Shahadat Hossain
Mei Zong
Helene Alexanderson
Sukanya Raghavan
Ingrid E. Lundberg
Vivianne Malmström
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-0974-5

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