Skip to main content

Advertisement

SpringerLink
Log in

T and NK Cell Phenotypic Abnormalities in Systemic Sclerosis: a Cohort Study and a Comprehensive Literature Review

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Scleroderma (SSc) is a rare and heterogeneous immune-mediated disease involving the connective tissue and microvasculature whose pathogenesis remains unclear. Data concerning T and natural killer (NK) cell abnormalities and cytokine levels in the peripheral blood (PB) from patients with SSc are scarce, and the results are contradictory. The present study aimed to analyze the changes of T lymphocytes, NK cells, and T helper (Th)-related cytokines in the PB of patients with SSc in comparison to healthy individuals and its relation to disease subtype and stage, organ involvement, and nailfold capillaroscopic changes. A non-random convenience sample of 57 scleroderma patients was utilized. Fifty-five out of the 57 patients studied were women (97 %); 10 patients presented pre-scleroderma (pre-SSc) and 47 SSc: 34 limited cutaneous SSc (lcSSc) and 13 diffuse cutaneous SSc (dcSSc). Patients with SSc were classified in early (n = 7), intermediate (n = 10), and late (n = 30) disease. Blood samples were analyzed by flow cytometry for total T cells, CD4+ and CD8+ T cell subsets, total NK cells, and CD56+low and CD56+high NK cell subsets. T cells were further analyzed for the expression of the CD56 adhesion molecule and activation-related markers (HLA-DR, CD45RO). In addition, the serum levels of Th1-, Th2-, and Th17-related cytokines were measured by flow cytometry. Twenty-five healthy individuals recruited from the blood bank were used as controls. Patients had lower numbers of total lymphocytes and T cells comparing to healthy controls. Both CD4+ and CD8+ T cells were decreased, but differences were statistically significant only for CD8+ and CD8+ CD45RO+ T cells. These alterations were seen in patients with SSc but not in patients with pre-SSc, and, in general, they were more pronounced in patients with dcSSc than in patients with lcSSc, in patients with vascular involvement than in those without, as well as in patients having active and late nailfold capillaroscopic patterns. CD56+ T cells were also decreased in SSc patients, especially in those with active/late capillaroscopic patterns or with severe lung disease. Diminished numbers of circulating NK cells were also observed in patients with lcSSc and in those with early disease. No statistically significant changes were found in serum cytokine levels, as compared with controls. Patients with SSc had major alterations in circulating CD8+ and CD56+ T cells, as well as in NK cells, suggesting that these cells may play a relevant role in SSc pathogenesis, probably operating at different phases and/or at different organs. In addition, the serum levels of Th1, Th2, and Th17 cytokines did not provide useful information for evaluating T cell polarization in SSc.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Abraham DJ, Krieg T, Distler J, Distler O (2009) Overview of pathogenesis of systemic sclerosis. Rheumatology 48(Suppl 3):iii3–iii7. doi:10.1093/rheumatology/ken481

    CAS  PubMed  Google Scholar 

  2. Gabrielli A, Avvedimento EV, Krieg T (2011) Scleroderma. N Engl J Med 360:1989–2003. doi:10.1056/NEJMra0806188

    Article  Google Scholar 

  3. Pattanaik D, Brown M, Postlethwaite AE (2011) Vascular involvement in systemic sclerosis (scleroderma). J Inflamm Res 4:105–125. doi:10.2147/JIR.S18145

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Tamby MC, Chanseaud Y, Guillevin L, Mouthon L (2003) New insights into the pathogenesis of systemic sclerosis. Autoimmun Rev 2:152–157. doi:10.1016/S1568-9972(03)00004-1

    Article  CAS  PubMed  Google Scholar 

  5. Chizzolini C, Brembilla NC, Montanari E, Truchetet ME (2011) Fibrosis and immune dysregulation in systemic sclerosis. Autoimmun Rev 10:276–281. doi:10.1016/j.autrev.2010.09.016

    Article  CAS  PubMed  Google Scholar 

  6. Yazawa N, Fujimoto M, Tamaki K (2007) Recent advances on pathogenesis and therapies in systemic sclerosis. Clin Rev Allergy Immunol 33:107–112. doi:10.1007/s12016-007-8009-2

    Article  CAS  PubMed  Google Scholar 

  7. Wigley FM (2009) Vascular disease in scleroderma. Clin Rev Allergy Immunol 36:150–175. doi:10.1007/s12016-008-8106-x

    Article  PubMed  Google Scholar 

  8. Guillevin L (2010) A contemporary update on scleroderma. Clin Rev Allergy Immunol 40:75–77. doi:10.1007/s12016-010-8200-8

    Article  Google Scholar 

  9. Varga J, Abraham D (2007) Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 117:557–567. doi:10.1172/JCI31139

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Ho YY, Lagares D, Tager AM, Kapoor M (2014) Fibrosis—a lethal component of systemic sclerosis. Nat Rev Rheumatol 10:390–402. doi:10.1038/nrrheum.2014.53

    Article  CAS  PubMed  Google Scholar 

  11. Scharffetter K, Lankat-Buttgereit B, Krieg T (1988) Localization of collagen mRNA in normal and scleroderma skin by in-situ hybridization. Eur J Clin Investig 18:9–17

    Article  CAS  Google Scholar 

  12. Sakkas LI, Platsoucas CD (2004) Is systemic sclerosis an antigen-driven T cell disease? Arthritis Rheum 50:1721–1733. doi:10.1002/art.20315

    Article  CAS  PubMed  Google Scholar 

  13. Jimenez SA, Derk CT (2004) Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med 140:37–50. doi:10.7326/0003-4819-140-2-200401200-00013

    Article  CAS  PubMed  Google Scholar 

  14. Boin F, Rosen A (2007) Autoimmunity in systemic sclerosis: current concepts. Curr Rheumatol Rep 9:165–172

    Article  CAS  PubMed  Google Scholar 

  15. Matucci-Cerinic M, Kahaleh B, Wigley FM (2013) Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum 65:1953–1962. doi:10.1002/art.37988

    Article  CAS  PubMed  Google Scholar 

  16. Fuschiotti P (2011) (2011) CD8+ T cells in systemic sclerosis. Immunol Res 50:188–194. doi:10.1007/s12026-011-8222-1

    Article  CAS  PubMed  Google Scholar 

  17. O’Reilly S, Hügle T, van Laar JM (2012) T cells in systemic sclerosis: a reappraisal. Rheumatology 51:1540–1549. doi:10.1093/rheumatology/kes090

    Article  PubMed  CAS  Google Scholar 

  18. Steen VD (2005) Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 35:35–42. doi:10.1016/j.semarthrit.2005.03.005

    Article  CAS  PubMed  Google Scholar 

  19. Arnett FC (2006) Is scleroderma an autoantibody mediated disease? Curr Opin Rheumatol 18:579–581

    Article  CAS  PubMed  Google Scholar 

  20. Sato S, Fujimoto M, Hasegawa M, Takehara K (2004) Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum 50:1918–1927. doi:10.1002/art.20274

    Article  PubMed  Google Scholar 

  21. Lafyatis R, O'Hara C, Feghali-Bostwick CA, Matteson E (2007) B cell infiltration in systemic sclerosis-associated interstitial lung disease. Arthritis Rheum 56:3167–3168. doi:10.1002/art.22847

    Article  PubMed  Google Scholar 

  22. Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, Fraticelli P, Sambo P, Funaro A, Kazlauskas A, Avvedimento EV, Gabrielli A (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354:2667–2676. doi:10.1056/NEJMoa052955

    Article  CAS  PubMed  Google Scholar 

  23. Francois A, Chatelus E, Wachsmann D, Sibilia J, Bahram S, Alsaleh G, Gottenberg J-E (2013) B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis. Arthitis Res Ther 15:R168. doi:10.1186/ar4352

    Article  CAS  Google Scholar 

  24. Sato S, Hayakawa I, Hasegawa M, Fujimoto M, Takehara K (2003) Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis. J Investig Dermatol 120:542–547

    Article  CAS  PubMed  Google Scholar 

  25. Roumm AD, Whiteside TL, Medsger TA, Rodnan GP (1984) Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum 27:645–653

    Article  CAS  PubMed  Google Scholar 

  26. Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P (1992) Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 166:255–263

    Article  CAS  PubMed  Google Scholar 

  27. Chizzolini C (2007) Update on pathophysiology of scleroderma with special reference to immunoinflammatory events. Ann Med 39:42–53. doi:10.1080/07853890601098152

    Article  CAS  PubMed  Google Scholar 

  28. Whiteside TL, Buckingham RB, Prince RK, Rodnan GP (1984) Products of activated mononuclear cells modulate accumulation of collagen by normal dermal and scleroderma fibroblasts in culture. J Lab Clin Med 104:355–369

    CAS  PubMed  Google Scholar 

  29. Fleischmajer R, Perlish JS, Reeves JR (1977) Cellular infiltrates in scleroderma skin. Arthritis Rheum 20:975–984

    Article  CAS  PubMed  Google Scholar 

  30. Hussein MR, Hassan HI, Hofny ERM, Elkholy M, Fatehy NA, Abd Elmoniem AEA, Ezz El-Din AM, Afifi OA, Rashed HG (2005) Alterations of mononuclear inflammatory cells, CD4/CD8+ T cells, interleukin 1beta, and tumour necrosis factor alpha in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis. J Clin Pathol 58:178–184. doi:10.1136/jcp.2004.019224

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Kalogerou A, Gelou E, Mountantonakis S, Settas L, Zafiriou E, Sakkas L (2005) Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis 64:1233–1235. doi:10.1136/ard.2004.027094

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Artlett CM (2005) Immunology of systemic sclerosis. Front Biosci 10:1707–1719. doi:10.2741/1654

    Article  CAS  PubMed  Google Scholar 

  33. Fuschiotti P, Larregina AT, Ho J, Feghali-Bostwick C, Medsger TA (2013) Interleukin-13-producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis. Arthritis Rheum 65:236–246

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Giacomelli R, Matucci-Cerinic M, Cipriani P, Ghersetich I, Lattanzio R, Pavan A, Pignone A, Cagnoni ML, Lotti T, Tonietti G (1998) Circulating Vdelta1+ T cells are activated and accumulate in the skin of systemic sclerosis patients. Arthritis Rheum 41:327–334. doi:10.1002/art.37706

    Article  CAS  PubMed  Google Scholar 

  35. Riccieri V, Parisi G, Spadaro A, Scrivo R, Barone F, Moretti T, Bernardini G, Strom R, Taccari E, Valesini G (2005) Reduced circulating natural killer T cells and gamma/delta T cells in patients with systemic sclerosis. J Rheumatol 32:283–286

    CAS  PubMed  Google Scholar 

  36. Giovannetti A, Rosato E, Renzi C, Maselli A, Gambardella L, Giammarioli AM, Palange P, Paoletti P, Pisarri S, Salsano F, Malorni W, Pierdominici M (2010) Analyses of T cell phenotype and function reveal an altered T cell homeostasis in systemic sclerosis. Correlations with disease severity and phenotypes. Clin Immunol 137:122–133. doi:10.1016/j.clim.2010.06.004

    Article  CAS  PubMed  Google Scholar 

  37. Radstake TRDJ, van Bon L, Broen J, Wenink M, Santegoets K, Deng Y, Hussaini A, Simms R, Cruikshank WW, Lafyatis R (2009) Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFbeta expression. PLoS One 4, e5981. doi:10.1371/journal.pone.0005981

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Wells AU, Lorimer S, Majumdar S, Harrison NK, Corrin B, Black CM, Jeffery PK, du Bois RM (1995) Fibrosing alveolitis in systemic sclerosis: increase in memory T-cells in lung interstitium. Eur Respir J 8:266–271

    Article  CAS  PubMed  Google Scholar 

  39. Domagała-Kulawik J, Hoser G, Doboszyńska A, Kawiak J, Droszcz W (1998) Interstitial lung disease in systemic sclerosis: comparison of BALF lymphocyte phenotype and DLCO impairment. Respir Med 92:1295–1301

    Article  PubMed  Google Scholar 

  40. Yurovsky VV, Wigley FM, Wise RA, White B (1996) Skewing of the CD8+ T-cell repertoire in the lungs of patients with systemic sclerosis. Hum Immunol 48:84–97

    Article  CAS  PubMed  Google Scholar 

  41. Ingegnoli F, Trabattoni D, Saresella M, Fantini F, Clerici M (2003) Distinct immune profiles characterize patients with diffuse or limited systemic sclerosis. Clin Immunol 108:21–28. doi:10.1016/S1521-6616(03)00062-7

    Article  CAS  PubMed  Google Scholar 

  42. Gambichler T, Tigges C, Burkert B, Höxtermann S, Altmeyer P, Kreuter A (2010) Absolute count of T and B lymphocyte subsets is decreased in systemic sclerosis. Eur J Med Res 15:44–46. doi:10.1186/2047-783X-15-1-44

    Article  PubMed Central  PubMed  Google Scholar 

  43. Gorla R, Airò P, Malagoli A, Carella G, Prati E, Brugnoni D, Franceschini F, Cattaneo R (1994) CD4+ and CD8+ subsets: naive and memory cells in the peripheral blood of patients with systemic sclerosis. Clin Rheumatol 13:83–87

    Article  CAS  PubMed  Google Scholar 

  44. Fiocco U, Rosada M, Cozzi L, Ortolani C, De Silvestro G, Ruffatti A, Cozzi E, Gallo C, Todesco S (1993) Early phenotypic activation of circulating helper memory T cells in scleroderma: correlation with disease activity. Ann Rheum Dis 52:272–277

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Ercole LP, Malvezzi M, Boaretti AC, Utiyama SR, Rachid A (2003) Analysis of lymphocyte subpopulations in systemic sclerosis. J Investig Allergol Clin Immunol 13:87–93

    PubMed  Google Scholar 

  46. Fuschiotti P, Medsger TA, Morel PA (2009) Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin-13 associated with increased skin fibrosis. Arthritis Rheum 60:1119–1128. doi:10.1002/art.24432

    Article  CAS  PubMed  Google Scholar 

  47. Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22:633–640. doi:10.1016/S1471-4906(01)02060-9

    Article  CAS  PubMed  Google Scholar 

  48. Schleinitz N, Vély F, Harlé JR, Vivier E (2010) Natural killer cells in human autoimmune diseases. Immunology 131:451–458. doi:10.1111/j.1365-2567.2010.03360.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Poggi A, Zocchi MR (2014) NK cell autoreactivity and autoimmune diseases. Front Immunol 5:27. doi:10.3389/fimmu.2014.00027

    PubMed Central  PubMed  Google Scholar 

  50. Horikawa M, Hasegawa M, Komura K, Hayakawa I, Yanaba K, Matsushita T, Takehara K, Sato S (2005) Abnormal natural killer cell function in systemic sclerosis: altered cytokine production and defective killing activity. J Investig Dermatol 125:731–737. doi:10.1111/j.0022-202X.2005.23767

    Article  CAS  PubMed  Google Scholar 

  51. López-Cacho JM, Gallardo S, Posada M, Aguerri M, Calzada D, Mayayo T, González-Rodríguez ML, Rabasco AM, Lahoz C, Cárdaba B (2014) Association of immunological cell profiles with specific clinical phenotypes of scleroderma disease. BioMed Res Int 2014:148293. doi:10.1155/2014/148293

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  52. Wanchu A, Singh VK, Yadav VS, Biswas S, Misra R, Agarwal SS (1995) Lack of natural killer cell augmentation in vitro by human interferon gamma in a subset of patients with systemic sclerosis. Pathobiol J Immunopathol Mol Cell Biol 63:288–292

    Article  CAS  Google Scholar 

  53. Momot T, Koch S, Hunzelmann N, Krieg T, Ulbricht K, Schmidt RE, Witte T (2004) Association of killer cell immunoglobulin-like receptors with scleroderma. Arthritis Rheum 50:1561–1565. doi:10.1002/art.20216

    Article  CAS  PubMed  Google Scholar 

  54. Wan YY, Flavell RA (2009) How diverse—CD4 effector T cells and their functions. J Mol Cell Biol 1:20–36. doi:10.1093/jmcb/mjp001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Wynn TA (2004) Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 4:583–594. doi:10.1038/nri1412

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Shabgah AG, Fattahi E, Shahneh FZ (2014) Interleukin-17 in human inflammatory diseases. Postepy Dermatol Alergol 31:256–261. doi:10.5114/pdia.2014.40954

    Article  PubMed Central  PubMed  Google Scholar 

  57. Raphael I, Nalawade S, Eagar TN, Forsthuber TG (2014) T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. doi:10.1016/j.cyto.2014.09.011

    PubMed  Google Scholar 

  58. O’Connor W, Esplugues E, Huber S (2014) The role of TH17-associated cytokines in health and disease. J Immunol Res 2014:936270. doi:10.1155/2014/936270

    Article  PubMed Central  PubMed  Google Scholar 

  59. Parel Y, Aurrand-Lions M, Scheja A, Dayer J-M, Roosnek E, Chizzolini C (2007) Presence of CD4 + CD8+ double-positive T cells with very high interleukin-4 production potential in lesional skin of patients with systemic sclerosis. Arthritis Rheum 56:3459–3467. doi:10.1002/art.22927

    Article  CAS  PubMed  Google Scholar 

  60. Atamas SP, Yurovsky VV, Wise R, Wigley FM, Goter Robinson CJ, Henry P, Alms WJ, White B (1999) Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis. Arthritis Rheum 42:1168–1178

    Article  CAS  PubMed  Google Scholar 

  61. Medsger TA, Ivanco DE, Kardava L, Morel PA, Lucas MR, Fuschiotti P (2011) GATA-3 up-regulation in CD8+ T cells as a biomarker of immune dysfunction in systemic sclerosis, resulting in excessive interleukin-13 production. Arthritis Rheum 63:1738–1747. doi:10.1002/art.30489

    Article  PubMed  Google Scholar 

  62. Brembilla NC, Chizzolini C (2012) T cell abnormalities in systemic sclerosis with a focus on Th17 cells. Eur Cytokine Netw 23:128–139. doi:10.1684/ecn.2013.0325

    CAS  PubMed  Google Scholar 

  63. Nakashima T, Jinnin M, Yamane K, Honda N, Kajihara I, Makino T, Masuguchi S, Fukushima S, Okamoto Y, Hasegawa M, Fujimoto M, Ihn H (2012) Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J Immunol 188:3573–3583. doi:10.4049/jimmunol.1100591

    Article  CAS  PubMed  Google Scholar 

  64. Brembilla NC, Montanari E, Truchetet M-E, Raschi E, Meroni P, Chizzolini C (2013) Th17 cells favor inflammatory responses while inhibiting type I collagen deposition by dermal fibroblasts: differential effects in healthy and systemic sclerosis fibroblasts. Arthritis Res Ther 15:R151. doi:10.1186/ar4334

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  65. Truchetet M-E, Brembilla NC, Montanari E, Allanore Y, Chizzolini C (2011) Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res Ther 13:R166. doi:10.1186/ar3486

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Radstake TRDJ, van Bon L, Broen J, Hussiani A, Hesselstrand R, Wuttge DM, Deng Y, Simms R, Lubberts E, Lafyatis R (2009) The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenotypes. PLoS One 4, e5903. doi:10.1371/journal.pone.0005903

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Fenoglio D, Battaglia F, Parodi A, Stringara S, Negrini S, Panico N, Rizzi M, Kalli F, Conteduca G, Ghio M, De Palma R, Indiveri F, Filaci G (2011) Alteration of Th17 and Treg cell subpopulations co-exist in patients affected with systemic sclerosis. Clin Immunol Orlando Fla 139:249–257. doi:10.1016/j.clim.2011.01.013

    Article  CAS  Google Scholar 

  68. Yang X, Yang J, Xing X, Wan L, Li M (2014) Increased frequency of Th17 cells in systemic sclerosis is related to disease activity and collagen overproduction. Arthritis Res Ther 16:R4. doi:10.1186/ar4430

    Article  PubMed Central  PubMed  Google Scholar 

  69. Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, Takabayashi K, Iwamoto I (2000) Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 43:2455–2563. doi:10.1002/1529-0131(200011)43:11<2455::AID-ANR12>3.0.CO;2-K

    Article  CAS  PubMed  Google Scholar 

  70. Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA (2011) Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheum 63:783–794. doi:10.1002/art.30159

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Truchetet M-E, Brembilla N-C, Montanari E, Lonati P, Raschi E, Zeni S, Fontao L, Meroni P-L, Chizzolini C (2013) Interleukin-17A+ cell counts are increased in systemic sclerosis skin and their number is inversely correlated with the extent of skin involvement. Arthritis Rheum 65:1347–1356

    Article  CAS  PubMed  Google Scholar 

  72. Murata M, Fujimoto M, Matsushita T, Hamaguchi Y, Hasegawa M, Takehara K, Komura K, Sato S (2008) Clinical association of serum interleukin-17 levels in systemic sclerosis: is systemic sclerosis a Th17 disease? J Dermatol Sci 50:240–242. doi:10.1016/j.jdermsci.2008.01.001

    Article  CAS  PubMed  Google Scholar 

  73. Gourh P, Arnett FC, Assassi S, Tan FK, Huang M, Diekman L, Mayes MD, Reveille JD, Agarwal SK (2009) Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Res Ther 11:R147. doi:10.1186/ar2821

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee (1980) Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23:581–590

    Article  Google Scholar 

  75. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 65:2737–2747. doi:10.1002/art.38098

    Article  PubMed Central  PubMed  Google Scholar 

  76. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, Rowell N, Wollheim F (1988) Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatology 15:202–205

    CAS  Google Scholar 

  77. LeRoy EC, Medsger TA (2001) Criteria for the classification of early systemic sclerosis. J Rheumatol 28:1573–1576

    CAS  PubMed  Google Scholar 

  78. Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C, Miniati I, Tarner IH, Randone SB, Cutolo M, Allanore Y, Distler O, Valentini G, Czirjak L, Müller-Ladner U, Furst DE, Tyndall A, Matucci-Cerinic M, EUSTAR Group (2011) Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis 70:476–481. doi:10.1136/ard.2010.136929

    Article  CAS  PubMed  Google Scholar 

  79. Fine LG, Denton CP, Korn J, de Crombrugghe B, Black CM (1996) Systemic sclerosis: current pathogenetic concepts and future prospects for targeted therapy. Lancet 347:1453–1458

    Article  Google Scholar 

  80. Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, Goulet J-R, Rich E, Grodzicky T, Raymond Y, Senécal J-L (2008) Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 58:3902–3912. doi:10.1002/art.24038

    Article  PubMed  Google Scholar 

  81. Medsger TA Jr, Steen VD (1996) Classification, prognosis. In: Clements PJ, Furst DE (eds) Systemic sclerosis. Williams and Wilkins, Baltimore, pp 51–79

    Google Scholar 

  82. Lonzetti LS, Joyal F, Raynauld JP, Roussin A, Goulet JR, Rich E, Choquette D, Raymond Y, Senécal JL (2001) Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 44:735–736

    Article  CAS  PubMed  Google Scholar 

  83. Medsger TA, Silman AJ, Steen VD, Black CM, Akesson A, Bacon PA, Harris CA, Jablonska S, Jayson MI, Jimenez SA, Krieg T, Leroy EC, Maddison PJ, Russell ML, Schachter RK, Wollheim FA, Zacharaie H (1999) A disease severity scale for systemic sclerosis: development and testing. J Rheumatol 26:2159–2167

    PubMed  Google Scholar 

  84. Medsger TA, Bombardieri S, Czirjak L, Scorza R, Della Rossa A, Bencivelli W (2003) Assessment of disease severity and prognosis. Clin Exp Rheumatol 21(Suppl 29):S42–S46

    PubMed  Google Scholar 

  85. Cutolo M, Sulli A, Smith V (2010) Assessing microvascular changes in systemic sclerosis diagnosis and management. Nat Rev Rheumatol 6:578–587. doi:10.1038/nrrheum.2010.104

    Article  PubMed  Google Scholar 

  86. Lima M, Teixeira MA, Queirós ML, Leite M, Santos AH, Justiça B, Orfão A (2001) Immunophenotypic characterization of normal blood CD56+lo versus CD56+hi NK-cell subsets and its impact on the understanding of their tissue distribution and functional properties. Blood Cells Mol Dis 27:731–743

    Article  CAS  PubMed  Google Scholar 

  87. Kelly-Rogers J, Madrigal-Estebas L, O'Connor T, Doherty DG (2006) Activation-induced expression of CD56 by T cells is associated with a reprogramming of cytolytic activity and cytokine secretion profile in vitro. Hum Immunol 67:863–873

    Article  CAS  PubMed  Google Scholar 

  88. Ko HS, Fu SM, Wincheste R Jr, Yu DT, Kunkel HG (1979) Ia determinants on stimulated human T lymphocytes. Occurrence on mitogen- and antigen-activated T cells. J Exp Med 150:246–255

    Article  CAS  PubMed  Google Scholar 

  89. Kristensson K, Dohlsten M, Fischer H, Ericsson PO, Hedlund G, Sjögren HO, Carlsson R (1990) Phenotypical and functional differentiation of CD4+ CD45RA+ human T cells following polyclonal activation. Scand J Immunol 32:243–253

    Article  CAS  PubMed  Google Scholar 

  90. Merkenschlager M, Beverley PC (1989) Evidence for differential expression of CD45 isoforms by precursors for memory-dependent and independent cytotoxic responses: human CD8 memory CTLp selectively express CD45RO (UCHL1). Int Immunol 1:450–459

    Article  CAS  PubMed  Google Scholar 

  91. Wetzig T, Petri JB, Mittag M, Haustein UF (1998) Serum levels of soluble Fas/APO-1 receptor are increased in systemic sclerosis. Arch Dermatol Res 290:187–190

    Article  CAS  PubMed  Google Scholar 

  92. Majone F, Olivieri S, Cozzi F, Montaldi A, Tonello M, Visentin MS, Ciprian L, Ruffatti A (2009) Increased apoptosis in circulating lymphocyte cultures of anti-RNA polymerase III positive patients with systemic sclerosis. Rheumatol Int 29:891–895. doi:10.1007/s00296-008-0799-x

    Article  CAS  PubMed  Google Scholar 

  93. Kessel A, Rosner I, Rozenbaum M, Zisman D, Sagiv A, Shmuel Z, Sabo E, Toubi E (2004) Increased CD8+ T cell apoptosis in scleroderma is associated with low levels of NF-kappa B. J Clin Immunol 24:30–36

    Article  CAS  PubMed  Google Scholar 

  94. Stummvoll GH, Aringer M, Smolen JS, Köller M, Kiener HP, Steiner CW, Bohle B, Knobler R, Graninger WB (2000) Derangement of apoptosis-related lymphocyte homeostasis in systemic sclerosis. Rheumatology 39:1341–1350. doi:10.1093/rheumatology/39.12.1341

    Article  CAS  PubMed  Google Scholar 

  95. Degiannis D, Seibold JR, Czarnecki M, Raskova J, Raska K (1990) Soluble and cellular markers of immune activation in patients with systemic sclerosis. Clin Immunol Immunopathol 56:259–270

    Article  CAS  PubMed  Google Scholar 

  96. Kahan A, Kahan A, Picard F, Menkès CJ, Amor B (1991) Abnormalities of T lymphocyte subsets in systemic sclerosis demonstrated with anti-CD45RA and anti-CD29 monoclonal antibodies. Ann Rheum Dis 50:354–358

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Dalkiliç E, Dilek K, Güllülü M, Yavuz M, Karakoç Y, Yurtkuran M, Budak F, Göral G (1999) Lymphocyte phenotypes in systemic sclerosis. Ann Rheum Dis 58:719–720

    Article  PubMed Central  PubMed  Google Scholar 

  98. Koreck A, Surányi A, Szöny BJ, Farkas A, Bata-Csörgö Z, Kemény L, Dobozy A (2002) CD3+CD56+ NK T cells are significantly decreased in the peripheral blood of patients with psoriasis. Clin Exp Immunol 127:176–182

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Kahaleh B (2008) The microvascular endothelium in scleroderma. Rheumatology 47(Suppl 5):v14–v15. doi:10.1093/rheumatology/ken279

    Article  CAS  PubMed  Google Scholar 

  100. De Palma R, D’Aiuto E, Vettori S, Cuoppolo P, Abbate G, Valentini G (2010) Peripheral T cells from patients with early systemic sclerosis kill autologous fibroblasts in co-culture: is T-cell response aimed to play a protective role? Rheumatology 49:1257–1266. doi:10.1093/rheumatology/keq094

    Article  PubMed  CAS  Google Scholar 

  101. Sgonc R, Gruschwitz MS, Boeck G, Sepp N, Gruber J, Wick G (2000) Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 43:2550–2562. doi:10.1002/1529-0131(200011)43:11<2550::AID-ANR24>3.0.CO;2-H

    Article  CAS  PubMed  Google Scholar 

  102. Baraut J, Michel L, Verrecchia F, Farge D (2010) Relationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis. Autoimmun Rev 10:65–73. doi:10.1016/j.autrev.2010.08.003

    Article  CAS  PubMed  Google Scholar 

  103. Stelmaszczyk-Emmel A, Zawadzka-Krajewska A, Kopatys A, Demkow U (2013) Th1, Th2, Th17, and regulatory cytokines in children with different clinical forms of allergy. Adv Exp Med Biol 788:321–328. doi:10.1007/978-94-007-6627-3_43

    Article  CAS  PubMed  Google Scholar 

  104. Feghali CA, Wright TM (1997) Cytokines in acute and chronic inflammation. Front Biosci 2:d12–d26

    CAS  PubMed  Google Scholar 

  105. Jason J, Archibald LK, Nwanyanwu OC, Byrd MG, Kazembe PN, Dobbie H, Jarvis WR (2001) Comparison of serum and cell-specific cytokines in humans. Clin Diagn Lab Immunol 8:1097–1103. doi:10.1128/CDLI.8.6.1097-1103.2001

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Mosca M, Tani C, Vagnani S, Carli L, Bombardieri S (2014) The diagnosis and classification of undifferentiated connective tissue diseases. J Autoimmun 48–49:50–52

    Article  PubMed  Google Scholar 

  107. Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE (2015) Pathogenesis of systemic sclerosis. Front Immunol 6:272

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  108. Bhattacharyya S, Varga J (2015) Emerging roles of innate immune signaling and toll-like receptors in fibrosis and systemic sclerosis. Curr Rheumatol Rep 17(1):474

    Article  PubMed  CAS  Google Scholar 

  109. Maverakis E, Patel F, Kronenberg DG, Chung L, Fiorentino D, Allanore Y, Guiducci S, Hesselstrand R, Hummers LK, Duong C, Kahaleh B, Macgregor A, Matucci-Cerinic M, Wollheim FA, Mayes MD, Gershwin ME (2014) International consensus criteria for the diagnosis of Raynaud's phenomenon. J Autoimmun 48–49:60–65

    Article  PubMed  Google Scholar 

  110. van Bon L, Cossu M, Loof A, Gohar F, Wittkowski H, Vonk M, Roth J, van den Berg W, van Heerde W, Broen JC, Radstake TR (2014) Proteomic analysis of plasma identifies the toll-like receptor agonists S100A8/A9 as a novel possible marker for systemic sclerosis phenotype. Ann Rheum Dis 73(8):1585–1589

    Article  PubMed  CAS  Google Scholar 

  111. Tani C, Carli L, Vagnani S, Talarico R, Baldini C, Mosca M, Bombardieri S (2014) The diagnosis and classification of mixed connective tissue disease. J Autoimmun 48–49:46–49

    Article  PubMed  CAS  Google Scholar 

  112. Hudson M, Fritzler MJ (2014) Diagnostic criteria of systemic sclerosis. J Autoimmun 48–49:38–41

    Article  PubMed  CAS  Google Scholar 

  113. Khor CG, Chen XL, Lin TS, Lu CH, Hsieh SC (2014) Rituximab for refractory digital infarcts and ulcers in systemic sclerosis. Clin Rheumatol 33(7):1019–1020

    Article  PubMed  Google Scholar 

  114. Luo Y, Wang Y, Wang Q, Xiao R, Lu Q (2013) Systemic sclerosis: genetics and epigenetics. J Autoimmun 41:161–167

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are indebted to Mónica Santos for technical support concerning lymphocyte immunophenotyping. We also thanks to the medical doctors and technicians from the Laboratory of Cytometry, Clinical Haematology Department, Hospital de Santo António, Centro Hospitalar do Porto, for helping in implementing this study.

This work was supported in part by grants from the “Unidade de Imunologia Clínica.”

The authors thank the nurse Manuela Magalhães, for her collaboration in the study.

Conflict of Interest

'The authors declare that they have no competing interests.

Author Contributions

All authors provided substantial contributions to the work presented in this paper. IA, SVS, and ML wrote the manuscript. In addition, IA assisted the patients and collected the clinical data, and ML performed the immunophenotypic and statistical analysis. ARF did cytokine measurements and data analysis. CV supervised the project and reviewed the manuscript. All authors discussed the results and implications and approved the final version of the manuscript.

Author information

Authors and Affiliations

  1. Clinical Immunology Unit, Department of Medicine, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, s/n, 4099-001, Porto, Portugal

    Isabel Almeida, Sara Vieira Silva, Ivone Silva & Carlos Vasconcelos

  2. Laboratory of Cytometry, Department of Haematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Porto, Portugal

    Ana Raquel Fonseca & Margarida Lima

  3. Department of Vascular Surgery, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Porto, Portugal

    Ivone Silva

  4. Multidisciplinary Unit for Biomedical Investigation (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

    Isabel Almeida, Carlos Vasconcelos & Margarida Lima

Authors
  1. Isabel Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sara Vieira Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana Raquel Fonseca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ivone Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carlos Vasconcelos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Margarida Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Isabel Almeida.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 94.5 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Almeida, I., Silva, S.V., Fonseca, A.R. et al. T and NK Cell Phenotypic Abnormalities in Systemic Sclerosis: a Cohort Study and a Comprehensive Literature Review. Clinic Rev Allerg Immunol 49, 347–369 (2015). https://doi.org/10.1007/s12016-015-8505-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-015-8505-8

Keywords

Search

Navigation