Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients.
OBJECTIVE
Pulmonary fibrosis is a major cause of death in scleroderma patients. Previous studies have shown an increase in CD8+ T cells in the lungs of scleroderma patients. In the present study, we sought to determine whether activated CD8+ T cells contribute to pulmonary fibrosis in scleroderma patients through the production and activation of profibrotic mediators.


METHODS
CD8+ cells were isolated from bronchoalveolar lavage fluid obtained from 19 scleroderma patients and 7 healthy subjects. The phenotype of these cells was determined using DNA array technology. Expression of selected genes was confirmed in real-time polymerase chain reaction and enzyme-linked immunosorbent assay experiments.


RESULTS
Hierarchical clustering of gene expression profiles revealed 2 groups of subjects. Group 1 consisted of 11 patients (8 with and 3 without lung inflammation). Group 2 consisted of 15 subjects (7 healthy controls and 2 patients with and 6 without lung inflammation). Gene expression in group 1 indicated T cell activation, a type 2 phenotype, production of profibrotic factors and matrix metalloproteinases, and reduced activation-induced cell death. Increased expression of beta6 integrin messenger RNA by CD8+ T cells in group 1 suggested the possibility that these T cells might induce cell-contact-dependent activation of latent transforming growth factor beta (TGFbeta).


CONCLUSIONS
A subset of scleroderma patients at higher risk of progressive lung disease have activated, long-lived CD8+ T cells in their lungs that could promote fibrosis directly, through production of profibrotic factors such as interleukin-4 and oncostatin M, as well as indirectly, through activation of TGFbeta.
Luzina
Irina G
IG
Research Service, Veterans Affairs Maryland Health Care System, Baltimore VA Medical Center, Room 3C-125, 10 North Greene Street, Baltimore, MD 21201, USA.
Atamas
Sergei P
SP
Wise
Robert
R
Wigley
Fredrick M
FM
Choi
Jung
J
Xiao
Hui Qing
HQ
White
Barbara
B
D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics; D002470:Cell Survival / Q000276:immunology; D016000:Cluster Analysis; D036342:Ephrins / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D016023:Integrins / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics
D015815:Cell Adhesion Molecules; D036342:Ephrins; D016023:Integrins; D016212:Transforming Growth Factor beta