Skip to main content
NCBI home page
Thorax logoLink to Thorax
. 1994 Jun;49(6):577–585. doi: 10.1136/thx.49.6.577

Clonal analysis of lung and blood T cells in patients with sarcoidosis.

M J Garlepp 1, A H Rose 1, J E Dench 1, B W Robinson 1
PMCID: PMC474948  PMID: 8016795

Abstract

BACKGROUND--Sarcoidosis is a disease characterised by clinical "anergy" to delayed type hypersensitivity antigens and the formation of non-caseating granulomas, which frequently manifests in the lungs as a T lymphocyte/mononuclear cell alveolitis. Although there is an increased proportion of T cells in bronchoalveolar lavage (BAL) samples from these patients, and these T cells often show evidence of activation and spontaneous secretion of cytokines such as interleukin 2 (IL-2) and interferon gamma (IFN gamma)--a pattern similar to delayed type hypersensitivity reactions--it is unclear whether both cytokines are produced by the majority of T cells derived from the lungs of patients with sarcoidosis or whether unique subpopulations of T cells produce each cytokine. In this study the properties of T cells cloned from BAL fluid samples of patients with sarcoidosis have been analysed. METHODS--T cells were cloned by limiting dilution using IL-2, phytohaemagglutinin, and irradiated feeder cells. Cloning efficiencies were compared and phytohaemagglutinin induced clonal production of IL-2, IFN gamma, and IL-4 was determined by bioassay (IL-2 and IFN gamma) or ELISA (IL-4). RESULTS--T cells derived from the BAL fluid of patients with sarcoidosis cloned less efficiently than those from blood of the same individuals. Lung derived clones (CD4+ or CD8+) produced IFN gamma more frequently and to a higher titre than blood derived clones, whereas IL-2 production by CD4+ clones derived from BAL fluid was less than that from blood derived clones. Interestingly, IL-4 production by clones from both sites was similar. Analysis of the co-production of IL-2, IFN gamma, and IL-4 by these BAL fluid clones did not demonstrate a predominant "Th1"-like population which has been suggested to underlie delayed type hypersensitivity reactions. CONCLUSIONS--The reduced cloning efficiency of T cells from the lung compared with the blood in sarcoidosis is consistent with, although probably more pronounced than, previous observations in normal lungs and shows that T cell hyporesponsiveness is not overcome in the lungs of patients with sarcoidosis. Furthermore, major differences exist between the cytokine producing potential of T cells derived from the lung and the blood in sarcoidosis, and these parallel the differences in the properties of blood and lung T cells seen in healthy individuals.

Full text

PDF
577

Selected References

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

  1. Asano M., Minagawa T., Ohmichi M., Hiraga Y. Detection of endogenous cytokines in sera or in lymph nodes obtained from patients with sarcoidosis. Clin Exp Immunol. 1991 Apr;84(1):92–96. doi: 10.1111/j.1365-2249.1991.tb08129.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Becker S., Harris D. T., Koren H. S. Characterization of normal human lung lymphocytes and interleukin-2-induced lung T cell lines. Am J Respir Cell Mol Biol. 1990 Nov;3(5):441–448. doi: 10.1165/ajrcmb/3.5.441. [DOI] [PubMed] [Google Scholar]
  3. Costabel U., Bross K. J., Rühle K. H., Löhr G. W., Matthys H. Ia-like antigens on T-cells and their subpopulations in pulmonary sarcoidosis and in hypersensitivity pneumonitis. Analysis of bronchoalveolar and blood lymphocytes. Am Rev Respir Dis. 1985 Mar;131(3):337–342. doi: 10.1164/arrd.1985.131.3.337. [DOI] [PubMed] [Google Scholar]
  4. Crystal R. G., Bitterman P. B., Rennard S. I., Hance A. J., Keogh B. A. Interstitial lung diseases of unknown cause. Disorders characterized by chronic inflammation of the lower respiratory tract (first of two parts). N Engl J Med. 1984 Jan 19;310(3):154–166. doi: 10.1056/NEJM198401193100304. [DOI] [PubMed] [Google Scholar]
  5. Del Prete G. F., De Carli M., Mastromauro C., Biagiotti R., Macchia D., Falagiani P., Ricci M., Romagnani S. Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest. 1991 Jul;88(1):346–350. doi: 10.1172/JCI115300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Du Bois R. M., Kirby M., Balbi B., Saltini C., Crystal R. G. T-lymphocytes that accumulate in the lung in sarcoidosis have evidence of recent stimulation of the T-cell antigen receptor. Am Rev Respir Dis. 1992 May;145(5):1205–1211. doi: 10.1164/ajrccm/145.5.1205. [DOI] [PubMed] [Google Scholar]
  7. Garlepp M. J., Rose A. H., Bowman R. V., Mavaddat N., Dench J., Holt B. J., Baron-Hay M., Holt P. G., Robinson B. W. A clonal analysis of lung T cells derived by bronchoalveolar lavage of healthy individuals. Immunology. 1992 Sep;77(1):31–37. [PMC free article] [PubMed] [Google Scholar]
  8. Holt P. G., Kees U. R., Shon-Hegrad M. A., Rose A., Ford J., Bilyk N., Bowman R., Robinson B. W. Limiting-dilution analysis of T cells extracted from solid human lung tissue: comparison of precursor frequencies for proliferative responses and lymphokine production between lung and blood T cells from individual donors. Immunology. 1988 Aug;64(4):649–654. [PMC free article] [PubMed] [Google Scholar]
  9. Hunninghake G. W., Bedell G. N., Zavala D. C., Monick M., Brady M. Role of interleukin-2 release by lung T-cells in active pulmonary sarcoidosis. Am Rev Respir Dis. 1983 Oct;128(4):634–638. doi: 10.1164/arrd.1983.128.4.634. [DOI] [PubMed] [Google Scholar]
  10. Hunninghake G. W., Crystal R. G. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med. 1981 Aug 20;305(8):429–434. doi: 10.1056/NEJM198108203050804. [DOI] [PubMed] [Google Scholar]
  11. Hunninghake G. W., Gadek J. E., Young R. C., Jr, Kawanami O., Ferrans V. J., Crystal R. G. Maintenance of granuloma formation in pulmonary sarcoidosis by T lymphocytes within the lung. N Engl J Med. 1980 Mar 13;302(11):594–598. doi: 10.1056/NEJM198003133021102. [DOI] [PubMed] [Google Scholar]
  12. Kay A. B., Ying S., Varney V., Gaga M., Durham S. R., Moqbel R., Wardlaw A. J., Hamid Q. Messenger RNA expression of the cytokine gene cluster, interleukin 3 (IL-3), IL-4, IL-5, and granulocyte/macrophage colony-stimulating factor, in allergen-induced late-phase cutaneous reactions in atopic subjects. J Exp Med. 1991 Mar 1;173(3):775–778. doi: 10.1084/jem.173.3.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lecossier D., Valeyre D., Loiseau A., Battesti J. P., Soler P., Hance A. J. T-lymphocytes recovered by bronchoalveolar lavage from normal subjects and patients with sarcoidosis are refractory to proliferative signals. Am Rev Respir Dis. 1988 Mar;137(3):592–599. doi: 10.1164/ajrccm/137.3.592. [DOI] [PubMed] [Google Scholar]
  14. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  15. Paliard X., de Waal Malefijt R., Yssel H., Blanchard D., Chrétien I., Abrams J., de Vries J., Spits H. Simultaneous production of IL-2, IL-4, and IFN-gamma by activated human CD4+ and CD8+ T cell clones. J Immunol. 1988 Aug 1;141(3):849–855. [PubMed] [Google Scholar]
  16. Patel S. S., Duby A. D., Thiele D. L., Lipsky P. E. Phenotypic and functional characterization of human T cell clones. J Immunol. 1988 Dec 1;141(11):3726–3736. [PubMed] [Google Scholar]
  17. Pinkston P., Bitterman P. B., Crystal R. G. Spontaneous release of interleukin-2 by lung T lymphocytes in active pulmonary sarcoidosis. N Engl J Med. 1983 Apr 7;308(14):793–800. doi: 10.1056/NEJM198304073081401. [DOI] [PubMed] [Google Scholar]
  18. Robinson B. W., James A., Rose A. H., Sterrett G. F., Musk A. W. Bronchoalveolar lavage sampling of airway and alveolar cells. Br J Dis Chest. 1988 Jan;82(1):45–55. doi: 10.1016/0007-0971(88)90007-1. [DOI] [PubMed] [Google Scholar]
  19. Robinson B. W., McLemore T. L., Crystal R. G. Gamma interferon is spontaneously released by alveolar macrophages and lung T lymphocytes in patients with pulmonary sarcoidosis. J Clin Invest. 1985 May;75(5):1488–1495. doi: 10.1172/JCI111852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Robinson B. W., Rose A. H., Thompson P. J., Hey A. Comparison of bronchoalveolar lavage helper/suppressor T-cell ratios in sarcoidosis versus other interstitial lung diseases. Aust N Z J Med. 1987 Feb;17(1):9–15. doi: 10.1111/j.1445-5994.1987.tb05041.x. [DOI] [PubMed] [Google Scholar]
  21. Robinson D. S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
  22. Robinson D. S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
  23. Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol Today. 1991 Aug;12(8):256–257. doi: 10.1016/0167-5699(91)90120-I. [DOI] [PubMed] [Google Scholar]
  24. Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11;254(5029):279–282. doi: 10.1126/science.254.5029.279. [DOI] [PubMed] [Google Scholar]
  25. Semenzato G., Agostini C., Trentin L., Zambello R., Chilosi M., Cipriani A., Ossi E., Angi M. R., Morittu L., Pizzolo G. Evidence of cells bearing interleukin-2 receptor at sites of disease activity in sarcoid patients. Clin Exp Immunol. 1984 Aug;57(2):331–337. [PMC free article] [PubMed] [Google Scholar]
  26. Spiteri M. A., Clarke S. W., Poulter L. W. Alveolar macrophages that suppress T-cell responses may be crucial to the pathogenetic outcome of pulmonary sarcoidosis. Eur Respir J. 1992 Apr;5(4):394–403. [PubMed] [Google Scholar]
  27. Yamamura M., Uyemura K., Deans R. J., Weinberg K., Rea T. H., Bloom B. R., Modlin R. L. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. doi: 10.1126/science.254.5029.277. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES