The quality and quantity of CD4+25+ regulatory T cells (Treg) in silicosis patients (SIL) were examined and compared with results from healthy donors (HD) because SIL often develop autoimmune diseases along with pulmonary disorders. Peripheral blood mononuclear cells from 57 SIL and 50 HD were analyzed for Treg. Treg frequency and clinical parameters were subjected to a factor analysis. Treg and CD4+25- T cells (Tneg) from five HD and five SIL, sorted by flow-cytometer, were used for functional assays of Treg, the expression pattern of Treg specific genes (FoxP3, GITR and CTLA-4) and activation-related genes (CD122 and CD123;. Although the actual frequency of Treg did not differ between SIL and HD, the age-corrected level was reduced in SIL. The factor analysis showed that Treg frequency was positively associated with the serum level of IL-2. The inhibitory effect of Treg on Tneg activation was decreased when the Treg:Tneg ratio was 1:¼ to ½. In addition, Treg dominancy of FoxP3 and CTLA-4 expression and Tneg dominancy of CD132 expression found in HD were lost in SIL. These results indicated that the Treg fraction in SIL may be substituted with chronically activated T cells due to recurrent exposure to silica, resulting in a reduction in the frequency and function of Treg. Since the reduction of Treg may precede the clinical manifestation, as silicosis may be a pre-clinical status for autoimmune diseases, control of Treg function using cell and/or gene therapy may be a good way to manage autoimmune disease.
UberC.L.McReynoldsR.A., 1982. Immunotoxicology of silica. Crit. Rev. Toxicol.10:303.
2.
SteenlandK.GoldsmithD.F., 1995. Silica exposure and autoimmune diseases. Am. J. Ind. Med.28:603.
3.
ShanklinD.R.SmalleyD.L., 1998. The immunopathology of siliconosis. History, clinical presentation and relation to silicosis and the chemistry of silicon and silicone. Immunol. Res.18:125.
4.
IannelloS.CamutoM.CantarellaS.CavaleriA.FerrieroP.LeanzaA.MilazzoP.BelfioreF., 2002. Rheumatoid syndrome associated with lung interstitial disorder in a dental technician exposed to ceramic silica dust. A case report and critical literature review. Clin. Rheumatol.21:76.
5.
TomokuniA.AikohT.MatsukiT.IsozakiY.OtsukiT.KitaS.UekiH.KusakaM.KishimotoT.UekiA., 1997. Elevated soluble Fas/APO-1 (CD95) levels in silicosis patients without clinical symptoms of autoimmune diseases or malignant tumours. Clin. Exp. Immunol.110:303.
6.
OtsukiT.SakaguchiH.TomokuniA.AikohT.MatsukiT.KawakamiY.KusakaM.UekiH.KitaS.UekiA., 1998. Soluble Fas mRNA is dominantly expressed in cases with silicosis. Immunology94:258.
7.
OtsukiT.IchiharaK.TomokuniA.SakaguchiH.AikohT.MatsukiT.IsozakiY.HyodohF.KusakaM.KitaS.UekiA., 1999. Evaluation of cases with silicosis using the parameters related to Fas-mediated apoptosis. Int. J. Mol. Med.4:407.
8.
TomokuniA.OtsukiT.IsozakiY.KitaS.UekiH.KusakaM.KishimotoT.UekiA., 1999. Serum levels of soluble Fas ligand in patients with silicosis. Clin. Ex. Immunol.118:441.
9.
OtsukiT.TomokuniA.SakaguchiH.AikohT.MatsukiT.IsozakiY.HyodohF.UekiH.KusakaM.KitaS.UekiA., 2000. Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients. Clin. Exp. Immunol.119:323.
10.
OtsukiT.SakaguchiH.TomokuniA.AikohT.MatsukiT.IsozakiY.HyodohF.KawakamiY.KusakaM.KitaS.UekiA., 2000. Detection of alternatively spliced variant messages of Fas gene and mutational screening of Fas and Fas ligand coding regions in peripheral blood mononuclear cells derived from silicosis patients. Immunol. Lett.72:137.
11.
OtsukiT.TakataA.HyodohF.UekiA.MatsuoY.KusakaM., 2002. Dysregulation of Fas-mediated apoptotic pathway in silicosis patientsRec. Res. Develop. Immunol.4:703.
12.
CohenP.L.EisenbergR.A., 1992. The lpr and gld genes in systemic autoimmunity: Life and death in the Fas lane. Immunol. Today13:427.
13.
NagataS.GolsteinP., 1995. The Fas death factor. Science267:1449.
14.
NagataS.1996. Fas-induced apoptosis and diseases caused by its abnormality. Genes Cells1:873.
15.
Rieux-LaucatF.FischerA.DeistF.L., 2003. Cell-death signaling and human disease. Cur. Opin. Immunol.15:325.
16.
PrasadK.V.PrabhakarB.S., 2003. Apoptosis and autoimmune disorders. Autoimmunity36:323.
17.
UekiH.KohdaM.NobutohT.YamaguchiM.OmoriK.MiyashitaY.HashimotoT.KomaiA.TomokuniA.UekiA., 2001. Antidesmoglein autoantibodies in silicosis patients with no bullous diseases. Dermatology202:16.
18.
UekiA.IsozakiY.TomokuniA.OtsukiT.HydohF.SakaguchiH.TanakaS.KusakaM., Is the anti-topoisomerase I autoantibody response associated with a distinct amino acid sequence in the HLA-DQbetal domain?Arthritis Rheum. 44:491.
19.
UekiA.IsozakiY.TomokuniA.HatayamaT.UekiH.KusakaM.ShiwaM.ArikuniH.TakeshitaT.MorimotoK., 2002. Intramolecular epitope spreading among anti-caspase-8 autoantibodies in patients with silicosis, systemic sclerosis and systemic lupus erythematosus, as well as in healthy individuals. Clin. Exp. Immunol.129:556.
20.
UekiA.IsozakiY.KusakaM., 2005. Anti-caspase-8 autoantibody response in silicosis patients is associated with HLA-DRB1, DQB1 and DPB1 alleles. J. Occup. Health247:61.
21.
Takata-TomokuniA.UekiA.ShiwaM.IsozakiY.HatayamaT.KatsuyamaH.HyodohF.FujimotoW.UekiH.KusakaM.ArikuniH.OtsukiT., 2005. Detection, epitope-mapping and function of anti-Fas autoantibody in patients with silicosis. Immunology116:21.
22.
SakaguchiS.TodaM.AsanoM.ItohM.MorseS.S.SakaguchiN., 1996. T cell-mediated maintenance of natural self-tolerance: Its breakdown as a possible cause of various autoimmune diseases. J. Autoimmun.9:211.
23.
SakaguchiS.SakaguchiN.ShimizuJ.YamazakiS.SakihamaT.ItohM.KuniyasuY.NomuraT.TodaM.TakahashiT., 2001. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: Their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev.182:18.
24.
GorbachevA.V.FairchildR.L., 2001. Regulatory role of CD4+ T cells during the development of contact hypersensitivity responses. Immunol. Res.24:69.
25.
de LafailleM.A. CurottoLafailleJ.J., 2002. CD4(+) regulatory T cells in autoimmunity and allergy. Curr. Opin. Immunol.14:771.
26.
WoodK.J.SakaguchiS., 2003. Regulatory T cells in transplantation tolerance. Nat. Rev. Immunol.3:199.
27.
CatonA.J.CozzoC.LarkinJ.3rdLermanM. A.BoesteanuA.JordanM.S., 2004. CD4(+) CD25(+) regulatory T cell selection. Ann. N.Y. Acad. Sci.1029:101.
28.
SakaguchiS.2004. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol.22:531.
29.
SakaguchiS.2005. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol.6:345.
30.
KaufmannS.H.1996. γ/δ and other unconventional T lymphocytes: What do they see and what do they do?Proc. Natl. Acad. Sci. U.S.A.93:2272.
31.
HaydayA.TigelaarR., 2003. Immunoregulation in the tissues by gammadelta T cells. Nat. Rev. Immunol.3:233.
32.
CottrezF.GrouxH., 2004. Specialization in tolerance: Innate CD(4+)CD(25+) versus acquired TR1 and TH3 regulatory T cells. Transplantation77:S12.
33.
BattagliaM.GianfraniC.GregoriS.RoncaroloM.G., 2004. IL-10-producing T regulatory type 1 cells and oral tolerance. Ann. N.Y. Acad. Sci.1029:142.
34.
JenkinsM.K.MillerR.A., 1992. Memory and anergy: Challenges to traditional models of T lymphocyte differentiation. FASEB J. 6:2428.
35.
TaniguchiM.NakayamaT., 2000. Recognition and function of Vα14 NKT cells. Semin. Immunol.12:543.
36.
TaniguchiM.HaradaM.KojoS.NakayamaT.WakaoH., 2003. The regulatory role of Vα14 NKT cells in innate and acquired immune response. Annu. Rev. Immunol.21:483.
37.
HorwitzD.A.ZhengS.G.GrayJ.D., 2003. The role of the combination of IL-2 and TGF-β or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets. J. Leukoc. Biol.74:471.
38.
CaoD.MalmstromV.Baecher-AllanC.HaflerD.KlareskogL.TrollmoC., 2003. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur. J. Immunol.33:215.
39.
PuthetiP.SoderstromM.LinkH.HuangY.M., 2003. Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis. J. Neuroimmunol.144:125.
40.
PuthetiP.PetterssonA.SoderstromM.LinkH.HuangY.M., 2004. Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J. Clin. Immunol.24:155.
41.
de KleerI.M.WedderburnL.R.TaamsL.S.A.PatelA.VarsaniH.KleinM.de JagerW.PugayungG.GiannoniF.RijkersG.AlbaniS.KuisW.PrakkenB., 2004. CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J. Immunol.172:6435.
42.
SomasundaramR.JacobL.SwobodaR.CaputoL.SongH.BasakS.MonosD.PerittD.MarincolaF.CaiD.BirebentB.BloomeE.KimJ.BerencsiK.MastrangeloM.HerlynD., 2002. Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25+ regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-β. Cancer Res. 62:5267.
43.
Guidelines for the Use of the ILO International Classification of Radiographs of Pneumoconioses Revised Edition 2000, ILO (International Labour Organization), Geneva, Switzerland.
44.
OtsukiT.YamadaO.KurebayashiJ.MoriyaT.SakaguchiH.KunisueH.YataK.UnoM.YawataY.UekiA., 2000. Estrogen receptors in human myeloma cells. Cancer Res. 60:1434.
45.
WuP.HyodohF.HatayamaT.SakaguchiH.HatadaS.MiuraY.Takata-TomokuniA.KatsuyamaH.OtsukiT., 2005. Induction of CD69 antigen expression in peripheral blood mononuclear cells on exposure to silica, but not by asbestos/chrysotile-A. Immunol. Lett.98:145.
46.
CorrigallV.M.ArastuM.KhanS.ShahC.FifeM.SmeetsT.TakP.P.PanayiG.S., 2001. Functional IL-2 receptor beta (CD122) and gamma (CD132) chains are expressed by fibroblast-like synoviocytes: Activation by IL-2 stimulates monocyte chemoattractant protein-1 production. J. Immunol.166:4141.
47.
PerolaO.RipattiA.PelkonenJ., 2000. T-lymphocyte subpopulations do not express identical combinations of interleukin-2 receptor chains in the early phase of their activation and proliferation. Scand. J. Immunol.52:123.
48.
NielsenO.H.KirmanI.JohnsonK.GiedlinM.CiardelliT., 1998. The circulating common gamma chain (CD132) in inflammatory bowel disease. Am. J. Gastroenterol.93:323.
