Skip to main content
NCBI home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2005 Aug;64(8):1165–1173. doi: 10.1136/ard.2004.030338

Up regulated expression of tumour necrosis factor α converting enzyme in peripheral monocytes of patients with early systemic sclerosis

T Bohgaki 1, Y Amasaki 1, N Nishimura 1, M Bohgaki 1, Y Yamashita 1, M Nishio 1, K Sawada 1, S Jodo 1, T Atsumi 1, T Koike 1
PMCID: PMC1755608  PMID: 16014681

Abstract

Background: Systemic sclerosis (SSc) is accompanied by abnormalities in humoral and cellular immune systems.

Objective: To determine the genes specifically expressed in the immune system in SSc by analysis of the gene expression profile of peripheral blood mononuclear cells (PBMC) from patients with SSc, including those treated with haematopoietic stem cell transplantation (HSCT). Additionally, to investigate the clinical significance of the up regulation of tumour necrosis factor α (TNFα) converting enzyme (TACE).

Methods: PBMC from patients with SSc (n = 23) and other autoimmune diseases (systemic lupus erythematosus (SLE, n = 16), rheumatoid arthritis (RA, n = 29)), and from disease-free controls (n = 36) were examined. Complementary DNA arrays were used to evaluate gene expression of PBMC, in combination with real time quantitative polymerase chain reactions. TACE protein expression in PBMC was examined by fluorescence activated cell sorter (FACS).

Results: In patients with SSc 118 genes were down regulated after HSCT. Subsequent comparative analysis of SSc without HSCT and healthy controls indicated SSc-specific up regulation for three genes: monocyte chemoattractant protein-3 (p = 0.0015), macrophage inflammatory protein 3α (p = 0.0339), and TACE (p = 0.0251). In the FACS analysis, TACE protein was mainly expressed on CD14+ monocytes both in patients with SSc and controls. TACE expression on CD14+ cells was significantly increased in patients with early SSc (p = 0.0096), but not in those with chronic SSc, SLE, or RA. TACE protein levels in SSc monocytes correlated with the intracellular CD68 levels (p = 0.0016).

Conclusions: Up regulation of TACE expression was a unique profile in early SSc, and may affect the function of TNFα and other immunoregulatory molecules.

Full Text

The Full Text of this article is available as a PDF (198.6 KB).

Figure 1.

Figure 1

Open in a new tab

 Quantitative analysis of up regulated genes in PBMC from patients with SSc, assessed using real time PCR. cDNA specimen from patients with SSc (n = 9) and disease-free volunteers (n = 6) were analysed for six genes species (TACE, interleukin (IL) 1ß, MIP-3α, MIP-1ß, MCP-3, and a regulator of G-protein signalling (RGS)-1), indicated from the cDNA array study (table 3). *p<0.05.

Figure 2.

Figure 2

Open in a new tab

 Changes of mRNA expression levels of IL1ß, MIP-1ß, MCP-3, MIP3-α, RGS-1, and TACE in patients with SSc before and after HSCT using cDNA array. RNA specimens were obtained from individual patients before (<1 month before mobilisation) and 6 months after HSCT. Relative expression levels of mRNA were determined using cDNA arrays performed simultaneously. The expression levels of each cDNA transcript were displayed as a relative mRNA expression index compared with the levels of internal GAPDH gene expression, as described in "Patients and methods".

Figure 3.

Figure 3

Open in a new tab

 Expression of TACE protein in PBMC of healthy controls and patients. (A, left panel) A small population was detected in a high fluorescence intensity. (A, right panel) Solid line, cells stained with anti-TACE monoclonal Ab; dotted line, cells stained with isotype matched control mouse IgG1 Ab. (B) Expression of TACE protein in PBMC subsets from a healthy control. (C) Representative cell surface expression of TACE protein on monocytes from patients with autoimmune diseases and controls. Solid line, cells stained with anti-TACE monoclonal Ab; dotted line, cells stained with mIgG1 Ab. Results are representative of three independent experiments.

Figure 4.

Figure 4

Open in a new tab

 (A) Comparison of cell surface TACE expression by monocytes of patients with early SSc, chronic SSc, RA, SLE, and healthy controls. Cell surface expression levels of TACE were evaluated using FACS, gating on monocytes by forward and side light scatter and on CD14+ cells. The levels of TACE protein expression were represented by the MFI. mIgG1 Ab-PE staining was performed in all measurements, and showed identical levels of background staining. *p<0.05, (p = 0.0065 (Kruskal-Wallis H statistics)). (B) Comparison of TACE positive cells in PBMC of patients with early SSc, chronic SSc, RA, SLE, and healthy controls evaluated using FACS. TACE positive cells were defined on gate R1 in fig 3B. *p<0.05.

Figure 5.

Figure 5

Open in a new tab

 Correlation of TACE protein expression levels and maturation/activation markers on monocytes, and serum CRP levels in patients with SSc. Correlation of TACE protein levels with intracellular CD68 expression, cell surface CD69 expression, cell surface CD71 expression, and serum C reactive protein (CRP) levels are displayed. Cells were stained with anti-TACE-PE monoclonal antibody, or with FITC-anti-CD68, CD69, and CD71, in the presence of anti-CD14-FITC. Intracellular or cell surface levels of each marker were measured by FACS, gating on the monocytes as described above. The expression levels of individual proteins, represented by the MFI, were plotted on the horizontal axis (CD68, CD69, and CD71) and on the vertical axis (TACE), respectively. Serum CRP levels were measured by a latex agglutination test. *p<0.05.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abraham D. J., Shiwen X., Black C. M., Sa S., Xu Y., Leask A. Tumor necrosis factor alpha suppresses the induction of connective tissue growth factor by transforming growth factor-beta in normal and scleroderma fibroblasts. J Biol Chem. 2000 May 19;275(20):15220–15225. doi: 10.1074/jbc.275.20.15220. [DOI] [PubMed] [Google Scholar]
  2. Allavena P., Piemonti L., Longoni D., Bernasconi S., Stoppacciaro A., Ruco L., Mantovani A. IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur J Immunol. 1998 Jan;28(1):359–369. doi: 10.1002/(SICI)1521-4141(199801)28:01<359::AID-IMMU359>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
  3. Anderegg U., Saalbach A., Haustein U. F. Chemokine release from activated human dermal microvascular endothelial cells--implications for the pathophysiology of scleroderma? Arch Dermatol Res. 2000 Jul;292(7):341–347. doi: 10.1007/s004030000134. [DOI] [PubMed] [Google Scholar]
  4. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  5. Atamas Sergei P., White Barbara. The role of chemokines in the pathogenesis of scleroderma. Curr Opin Rheumatol. 2003 Nov;15(6):772–777. doi: 10.1097/00002281-200311000-00015. [DOI] [PubMed] [Google Scholar]
  6. Binks M., Passweg J. R., Furst D., McSweeney P., Sullivan K., Besenthal C., Finke J., Peter H. H., van Laar J., Breedveld F. C. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis. 2001 Jun;60(6):577–584. doi: 10.1136/ard.60.6.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Black R. A., Rauch C. T., Kozlosky C. J., Peschon J. J., Slack J. L., Wolfson M. F., Castner B. J., Stocking K. L., Reddy P., Srinivasan S. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997 Feb 20;385(6618):729–733. doi: 10.1038/385729a0. [DOI] [PubMed] [Google Scholar]
  8. Bolster M. B., Ludwicka A., Sutherland S. E., Strange C., Silver R. M. Cytokine concentrations in bronchoalveolar lavage fluid of patients with systemic sclerosis. Arthritis Rheum. 1997 Apr;40(4):743–751. doi: 10.1002/art.1780400422. [DOI] [PubMed] [Google Scholar]
  9. Burt R. K., Traynor A. E., Craig R., Marmont A. M. The promise of hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant. 2003 Apr;31(7):521–524. doi: 10.1038/sj.bmt.1703868. [DOI] [PubMed] [Google Scholar]
  10. Clements P. J., Furst D. E., Campion D. S., Bohan A., Harris R., Levy J., Paulus H. E. Muscle disease in progressive systemic sclerosis: diagnostic and therapeutic considerations. Arthritis Rheum. 1978 Jan-Feb;21(1):62–71. doi: 10.1002/art.1780210111. [DOI] [PubMed] [Google Scholar]
  11. Contin Cécile, Pitard Vincent, Itai Toshimitsu, Nagata Shigekazu, Moreau Jean-François, Déchanet-Merville Julie. Membrane-anchored CD40 is processed by the tumor necrosis factor-alpha-converting enzyme. Implications for CD40 signaling. J Biol Chem. 2003 Jun 16;278(35):32801–32809. doi: 10.1074/jbc.M209993200. [DOI] [PubMed] [Google Scholar]
  12. Conway J. G., Andrews R. C., Beaudet B., Bickett D. M., Boncek V., Brodie T. A., Clark R. L., Crumrine R. C., Leenitzer M. A., McDougald D. L. Inhibition of tumor necrosis factor-alpha (TNF-alpha) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-alpha-converting enzyme and matrix metalloproteinases. J Pharmacol Exp Ther. 2001 Sep;298(3):900–908. [PubMed] [Google Scholar]
  13. Della Rossa A., Valentini G., Bombardieri S., Bencivelli W., Silman A. J., D'Angelo S., Cerinic M. M., Belch J. F., Black C. M., Becvar R. European multicentre study to define disease activity criteria for systemic sclerosis. I. Clinical and epidemiological features of 290 patients from 19 centres. Ann Rheum Dis. 2001 Jun;60(6):585–591. doi: 10.1136/ard.60.6.585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ermert M., Pantazis C., Duncker H-R, Grimminger F., Seeger W., Ermert L. In situ localization of TNFalpha/beta, TACE and TNF receptors TNF-R1 and TNF-R2 in control and LPS-treated lung tissue. Cytokine. 2003 May;22(3-4):89–100. doi: 10.1016/s1043-4666(03)00117-0. [DOI] [PubMed] [Google Scholar]
  15. Farge D., Passweg J., van Laar J. M., Marjanovic Z., Besenthal C., Finke J., Peter H. H., Breedveld F. C., Fibbe W. E., Black C. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis. 2004 Aug;63(8):974–981. doi: 10.1136/ard.2003.011205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Furst D. E., Clements P. J. Hypothesis for the pathogenesis of systemic sclerosis. J Rheumatol Suppl. 1997 May;48:53–57. [PubMed] [Google Scholar]
  17. Galindo M., Santiago B., Rivero M., Rullas J., Alcami J., Pablos J. L. Chemokine expression by systemic sclerosis fibroblasts: abnormal regulation of monocyte chemoattractant protein 1 expression. Arthritis Rheum. 2001 Jun;44(6):1382–1386. doi: 10.1002/1529-0131(200106)44:6<1382::AID-ART231>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  18. Grell M., Douni E., Wajant H., Löhden M., Clauss M., Maxeiner B., Georgopoulos S., Lesslauer W., Kollias G., Pfizenmaier K. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell. 1995 Dec 1;83(5):793–802. doi: 10.1016/0092-8674(95)90192-2. [DOI] [PubMed] [Google Scholar]
  19. Grell M., Wajant H., Zimmermann G., Scheurich P. The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):570–575. doi: 10.1073/pnas.95.2.570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gruschwitz M. S., Albrecht M., Vieth G., Haustein U. F. In situ expression and serum levels of tumor necrosis factor-alpha receptors in patients with early stages of systemic sclerosis. J Rheumatol. 1997 Oct;24(10):1936–1943. [PubMed] [Google Scholar]
  21. Gruschwitz M. S., Vieth G. Up-regulation of class II major histocompatibility complex and intercellular adhesion molecule 1 expression on scleroderma fibroblasts and endothelial cells by interferon-gamma and tumor necrosis factor alpha in the early disease stage. Arthritis Rheum. 1997 Mar;40(3):540–550. doi: 10.1002/art.1780400321. [DOI] [PubMed] [Google Scholar]
  22. Hochberg M. C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725–1725. doi: 10.1002/art.1780400928. [DOI] [PubMed] [Google Scholar]
  23. Holmes A., Abraham D. J., Sa S., Shiwen X., Black C. M., Leask A. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem. 2001 Jan 4;276(14):10594–10601. doi: 10.1074/jbc.M010149200. [DOI] [PubMed] [Google Scholar]
  24. Kräling B. M., Maul G. G., Jimenez S. A. Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology. 1995;63(1):48–56. doi: 10.1159/000163933. [DOI] [PubMed] [Google Scholar]
  25. LeRoy E. C., Black C., Fleischmajer R., Jablonska S., Krieg T., Medsger T. A., Jr, Rowell N., Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb;15(2):202–205. [PubMed] [Google Scholar]
  26. LeRoy E. C., Mercurio S., Sherer G. K. Replication and phenotypic expression of control and scleroderma human fibroblasts: responses to growth factors. Proc Natl Acad Sci U S A. 1982 Feb;79(4):1286–1290. doi: 10.1073/pnas.79.4.1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Luzina Irina G., Atamas Sergei P., Wise Robert, Wigley Fredrick M., Choi Jung, Xiao Hui Qing, White Barbara. Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients. Arthritis Rheum. 2003 Aug;48(8):2262–2274. doi: 10.1002/art.11080. [DOI] [PubMed] [Google Scholar]
  28. Malinin N. L., Boldin M. P., Kovalenko A. V., Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997 Feb 6;385(6616):540–544. doi: 10.1038/385540a0. [DOI] [PubMed] [Google Scholar]
  29. Mezyk Renata, Bzowska Monika, Bereta Joanna. Structure and functions of tumor necrosis factor-alpha converting enzyme. Acta Biochim Pol. 2003;50(3):625–645. [PubMed] [Google Scholar]
  30. Minty A., Chalon P., Guillemot J. C., Kaghad M., Liauzun P., Magazin M., Miloux B., Minty C., Ramond P., Vita N. Molecular cloning of the MCP-3 chemokine gene and regulation of its expression. Eur Cytokine Netw. 1993 Mar-Apr;4(2):99–110. [PubMed] [Google Scholar]
  31. Mizui Y., Yamazaki K., Sagane K., Tanaka I. cDNA cloning of mouse tumor necrosis factor-alpha converting enzyme (TACE) and partial analysis of its promoter. Gene. 1999 Jun 11;233(1-2):67–74. doi: 10.1016/s0378-1119(99)00155-9. [DOI] [PubMed] [Google Scholar]
  32. Moss M. L., Jin S. L., Milla M. E., Bickett D. M., Burkhart W., Carter H. L., Chen W. J., Clay W. C., Didsbury J. R., Hassler D. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature. 1997 Feb 20;385(6618):733–736. doi: 10.1038/385733a0. [DOI] [PubMed] [Google Scholar]
  33. Nagasako Tomokazu, Sugiyama Toshiro, Mizushima Takuji, Miura Yosuke, Kato Mototsugu, Asaka Masahiro. Up-regulated Smad5 mediates apoptosis of gastric epithelial cells induced by Helicobacter pylori infection. J Biol Chem. 2002 Dec 6;278(7):4821–4825. doi: 10.1074/jbc.M211143200. [DOI] [PubMed] [Google Scholar]
  34. Ohta S., Harigai M., Tanaka M., Kawaguchi Y., Sugiura T., Takagi K., Fukasawa C., Hara M., Kamatani N. Tumor necrosis factor-alpha (TNF-alpha) converting enzyme contributes to production of TNF-alpha in synovial tissues from patients with rheumatoid arthritis. J Rheumatol. 2001 Aug;28(8):1756–1763. [PubMed] [Google Scholar]
  35. Ong Voon H., Evans Lowri A., Shiwen Xu, Fisher Ivan B., Rajkumar Vineeth, Abraham David J., Black Carol M., Denton Christopher P. Monocyte chemoattractant protein 3 as a mediator of fibrosis: Overexpression in systemic sclerosis and the type 1 tight-skin mouse. Arthritis Rheum. 2003 Jul;48(7):1979–1991. doi: 10.1002/art.11164. [DOI] [PubMed] [Google Scholar]
  36. Patel I. R., Attur M. G., Patel R. N., Stuchin S. A., Abagyan R. A., Abramson S. B., Amin A. R. TNF-alpha convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-alpha. J Immunol. 1998 May 1;160(9):4570–4579. [PubMed] [Google Scholar]
  37. Peschon J. J., Slack J. L., Reddy P., Stocking K. L., Sunnarborg S. W., Lee D. C., Russell W. E., Castner B. J., Johnson R. S., Fitzner J. N. An essential role for ectodomain shedding in mammalian development. Science. 1998 Nov 13;282(5392):1281–1284. doi: 10.1126/science.282.5392.1281. [DOI] [PubMed] [Google Scholar]
  38. Pimentel-Muiños F. X., Seed B. Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity. 1999 Dec;11(6):783–793. doi: 10.1016/s1074-7613(00)80152-1. [DOI] [PubMed] [Google Scholar]
  39. Prescott R. J., Freemont A. J., Jones C. J., Hoyland J., Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol. 1992 Mar;166(3):255–263. doi: 10.1002/path.1711660307. [DOI] [PubMed] [Google Scholar]
  40. Roberts N. K., Cabeen W. R., Jr, Moss J., Clements P. J., Furst D. E. The prevalence of conduction defects and cardiac arrhythmias in progressive systemic sclerosis. Ann Intern Med. 1981 Jan;94(1):38–40. doi: 10.7326/0003-4819-94-1-38. [DOI] [PubMed] [Google Scholar]
  41. Saito Eriko, Fujimoto Manabu, Hasegawa Minoru, Komura Kazuhiro, Hamaguchi Yasuhito, Kaburagi Yuko, Nagaoka Tetsuya, Takehara Kazuhiko, Tedder Thomas F., Sato Shinichi. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest. 2002 Jun;109(11):1453–1462. doi: 10.1172/JCI15078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sakkas Lazaros I., Platsoucas Chris D. Is systemic sclerosis an antigen-driven T cell disease? Arthritis Rheum. 2004 Jun;50(6):1721–1733. doi: 10.1002/art.20315. [DOI] [PubMed] [Google Scholar]
  43. Sakkas Lazaros I., Xu Bin, Artlett Carol M., Lu Song, Jimenez Sergio A., Platsoucas Chris D. Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J Immunol. 2002 Apr 1;168(7):3649–3659. doi: 10.4049/jimmunol.168.7.3649. [DOI] [PubMed] [Google Scholar]
  44. Schmuth M., Neyer S., Rainer C., Grassegger A., Fritsch P., Romani N., Heufler C. Expression of the C-C chemokine MIP-3 alpha/CCL20 in human epidermis with impaired permeability barrier function. Exp Dermatol. 2002 Apr;11(2):135–142. doi: 10.1034/j.1600-0625.2002.110205.x. [DOI] [PubMed] [Google Scholar]
  45. Seifert T., Kieseier B. C., Ropele S., Strasser-Fuchs S., Quehenberger F., Fazekas F., Hartung H. P. TACE mRNA expression in peripheral mononudear cells precedes new lesions on MRI in multiple sclerosis. Mult Scler. 2002 Dec;8(6):447–451. doi: 10.1191/1352458502ms830oa. [DOI] [PubMed] [Google Scholar]
  46. Steen V. D. Scleroderma renal crisis. Rheum Dis Clin North Am. 1996 Nov;22(4):861–878. doi: 10.1016/s0889-857x(05)70305-7. [DOI] [PubMed] [Google Scholar]
  47. Tamby Mathieu C., Chanseaud Youri, Guillevin Loïc, Mouthon Luc. New insights into the pathogenesis of systemic sclerosis. Autoimmun Rev. 2003 May;2(3):152–157. doi: 10.1016/s1568-9972(03)00004-1. [DOI] [PubMed] [Google Scholar]
  48. Tartaglia L. A., Pennica D., Goeddel D. V. Ligand passing: the 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor. J Biol Chem. 1993 Sep 5;268(25):18542–18548. [PubMed] [Google Scholar]
  49. Tyndall A., Passweg J., Gratwohl A. Haemopoietic stem cell transplantation in the treatment of severe autoimmune diseases 2000. Ann Rheum Dis. 2001 Jul;60(7):702–707. doi: 10.1136/ard.60.7.702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Tyndall Alan, Koike Takao. High-dose immunoablative therapy with hematopoietic stem cell support in the treatment of severe autoimmune disease: current status and future direction. Intern Med. 2002 Aug;41(8):608–612. doi: 10.2169/internalmedicine.41.608. [DOI] [PubMed] [Google Scholar]
  51. Varga John. Scleroderma and Smads: dysfunctional Smad family dynamics culminating in fibrosis. Arthritis Rheum. 2002 Jul;46(7):1703–1713. doi: 10.1002/art.10413. [DOI] [PubMed] [Google Scholar]
  52. Warrick J. H., Bhalla M., Schabel S. I., Silver R. M. High resolution computed tomography in early scleroderma lung disease. J Rheumatol. 1991 Oct;18(10):1520–1528. [PubMed] [Google Scholar]
  53. Yamane Kenichi, Ihn Hironobu, Asano Yoshihide, Jinnin Masatoshi, Tamaki Kunihiko. Antagonistic effects of TNF-alpha on TGF-beta signaling through down-regulation of TGF-beta receptor type II in human dermal fibroblasts. J Immunol. 2003 Oct 1;171(7):3855–3862. doi: 10.4049/jimmunol.171.7.3855. [DOI] [PubMed] [Google Scholar]
  54. Zhou X., Tan F. K., Xiong M., Milewicz D. M., Feghali C. A., Fritzler M. J., Reveille J. D., Arnett F. C. Systemic sclerosis (scleroderma): specific autoantigen genes are selectively overexpressed in scleroderma fibroblasts. J Immunol. 2001 Dec 15;167(12):7126–7133. doi: 10.4049/jimmunol.167.12.7126. [DOI] [PubMed] [Google Scholar]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group

RESOURCES