Abstract
BACKGROUND—Lack of CD28 expression on peripheral blood CD4+ and CD8+ T cells has been reported in patients with Wegener's granulomatosis (WG), suggesting a pathogenetic role of CD28- T cells in WG. METHODS—Ten patients with WG and six with sarcoidosis (disease control) were analysed. Fluorescence activated cell sorter (FACS) analysis was used to detect CD28 expression on T cells from peripheral venous blood and from bronchoalveolar lavage (BAL) fluid. T cells in biopsy specimens from granulomatous lesions of the upper respiratory tract were analysed for CD28 expression by double immunofluorescence staining. RESULTS—A significantly higher fraction of CD28- T cells was found in the CD4+ and CD8+ T cell compartment in BAL fluid (65.6 (5.4)% and 76.3 (4.1)%, respectively) than in blood (13.4 (6.2)% and 42.9 (6.2)%; p<0.001) in patients with WG but not in those with acute sarcoidosis (6.7 (2.2)% and 53.4 (7.3)% in BAL fluid v 4.1(2.5)% and 52.0 (9.4)% in blood). The total number of CD4+/CD28- T cells but not of CD8+/CD28- T cells was also significantly higher in BAL fluid than in blood in patients with WG (p<0.05). Patients with WG had a significantly higher fraction of CD28- T cells in the CD4+ and CD8+ T cell compartment in BAL fluid than patients with acute sarcoidosis (65.6 (5.4)% v 6.7 (2.2)%; p<0.001; and 76.3 (4.1)% v 53.4 (7.3)%; p<0.05). The total number of CD4+/CD28- and CD8+/CD28- T cells was also significantly higher in patients with WG than in those with sarcoidosis (p<0.01). An abundance of CD28- T cells was found in granulomatous lesions by double immunofluorescence staining in patients with WG. CONCLUSIONS—Our data indicate enrichment of CD28- T cells in BAL fluid and suggest recruitment of CD28- T cells into granulomatous lesions in WG. Further analysis of the phenotype and function of T cell subsets in WG is needed to better understand leucocyte homing in WG and to find new therapeutic targets.
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- Agostini C., Adami F., Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol. 2000 Jan;12(1):71–76. doi: 10.1097/00002281-200001000-00012. [DOI] [PubMed] [Google Scholar]
- Borthwick N. J., Lowdell M., Salmon M., Akbar A. N. Loss of CD28 expression on CD8(+) T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. Int Immunol. 2000 Jul;12(7):1005–1013. doi: 10.1093/intimm/12.7.1005. [DOI] [PubMed] [Google Scholar]
- Campbell J. J., Haraldsen G., Pan J., Rottman J., Qin S., Ponath P., Andrew D. P., Warnke R., Ruffing N., Kassam N. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature. 1999 Aug 19;400(6746):776–780. doi: 10.1038/23495. [DOI] [PubMed] [Google Scholar]
- Csernok E., Müller A., Gross W. L. Immunopathology of ANCA-associated vasculitis. Intern Med. 1999 Oct;38(10):759–765. [PubMed] [Google Scholar]
- Csernok E., Trabandt A., Müller A., Wang G. C., Moosig F., Paulsen J., Schnabel A., Gross W. L. Cytokine profiles in Wegener's granulomatosis: predominance of type 1 (Th1) in the granulomatous inflammation. Arthritis Rheum. 1999 Apr;42(4):742–750. doi: 10.1002/1529-0131(199904)42:4<742::AID-ANR18>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
- DeRemee R. A. Sarcoidosis and Wegener's granulomatosis: a comparative analysis. Sarcoidosis. 1994 Mar;11(1):7–18. [PubMed] [Google Scholar]
- Giscombe R., Nityanand S., Lewin N., Grunewald J., Lefvert A. K. Expanded T cell populations in patients with Wegener's granulomatosis: characteristics and correlates with disease activity. J Clin Immunol. 1998 Nov;18(6):404–413. doi: 10.1023/a:1023230722874. [DOI] [PubMed] [Google Scholar]
- Jennette J. C., Falk R. J., Andrassy K., Bacon P. A., Churg J., Gross W. L., Hagen E. C., Hoffman G. S., Hunder G. G., Kallenberg C. G. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994 Feb;37(2):187–192. doi: 10.1002/art.1780370206. [DOI] [PubMed] [Google Scholar]
- Leavitt R. Y., Fauci A. S., Bloch D. A., Michel B. A., Hunder G. G., Arend W. P., Calabrese L. H., Fries J. F., Lie J. T., Lightfoot R. W., Jr The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum. 1990 Aug;33(8):1101–1107. doi: 10.1002/art.1780330807. [DOI] [PubMed] [Google Scholar]
- Luqmani R. A., Bacon P. A., Moots R. J., Janssen B. A., Pall A., Emery P., Savage C., Adu D. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994 Nov;87(11):671–678. [PubMed] [Google Scholar]
- Lúdvíksson B. R., Sneller M. C., Chua K. S., Talar-Williams C., Langford C. A., Ehrhardt R. O., Fauci A. S., Strober W. Active Wegener's granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10. J Immunol. 1998 Apr 1;160(7):3602–3609. [PubMed] [Google Scholar]
- Martens P. B., Goronzy J. J., Schaid D., Weyand C. M. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum. 1997 Jun;40(6):1106–1114. doi: 10.1002/art.1780400615. [DOI] [PubMed] [Google Scholar]
- McGuirk P., Mahon B. P., Griffin F., Mills K. H. Compartmentalization of T cell responses following respiratory infection with Bordetella pertussis: hyporesponsiveness of lung T cells is associated with modulated expression of the co-stimulatory molecule CD28. Eur J Immunol. 1998 Jan;28(1):153–163. doi: 10.1002/(SICI)1521-4141(199801)28:01<153::AID-IMMU153>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
- Moosig F., Csernok E., Wang G., Gross W. L. Costimulatory molecules in Wegener's granulomatosis (WG): lack of expression of CD28 and preferential up-regulation of its ligands B7-1 (CD80) and B7-2 (CD86) on T cells. Clin Exp Immunol. 1998 Oct;114(1):113–118. doi: 10.1046/j.1365-2249.1998.00695.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morales J., Homey B., Vicari A. P., Hudak S., Oldham E., Hedrick J., Orozco R., Copeland N. G., Jenkins N. A., McEvoy L. M. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14470–14475. doi: 10.1073/pnas.96.25.14470. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Müller A., Trabandt A., Gloeckner-Hofmann K., Seitzer U., Csernok E., Schönermarck U., Feller A. C., Gross W. L. Localized Wegener's granulomatosis: predominance of CD26 and IFN-gamma expression. J Pathol. 2000 Sep;192(1):113–120. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH656>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
- Namekawa T., Snyder M. R., Yen J. H., Goehring B. E., Leibson P. J., Weyand C. M., Goronzy J. J. Killer cell activating receptors function as costimulatory molecules on CD4+CD28null T cells clonally expanded in rheumatoid arthritis. J Immunol. 2000 Jul 15;165(2):1138–1145. doi: 10.4049/jimmunol.165.2.1138. [DOI] [PubMed] [Google Scholar]
- Namekawa T., Wagner U. G., Goronzy J. J., Weyand C. M. Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum. 1998 Dec;41(12):2108–2116. doi: 10.1002/1529-0131(199812)41:12<2108::AID-ART5>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
- Roos M. T., van Lier R. A., Hamann D., Knol G. J., Verhoofstad I., van Baarle D., Miedema F., Schellekens P. T. Changes in the composition of circulating CD8+ T cell subsets during acute epstein-barr and human immunodeficiency virus infections in humans. J Infect Dis. 2000 Jul 24;182(2):451–458. doi: 10.1086/315737. [DOI] [PubMed] [Google Scholar]
- Schlesier M., Kaspar T., Gutfleisch J., Wolff-Vorbeck G., Peter H. H. Activated CD4+ and CD8+ T-cell subsets in Wegener's granulomatosis. Rheumatol Int. 1995;14(5):213–219. doi: 10.1007/BF00262300. [DOI] [PubMed] [Google Scholar]
- Schnabel A., Reuter M., Gloeckner K., Müller-Quernheim J., Gross W. L. Bronchoalveolar lavage cell profiles in Wegener's granulomatosis. Respir Med. 1999 Jul;93(7):498–506. doi: 10.1016/s0954-6111(99)90093-8. [DOI] [PubMed] [Google Scholar]
- Travis W. D. Pathology of pulmonary granulomatous vasculitis. Sarcoidosis Vasc Diffuse Lung Dis. 1996 Mar;13(1):14–27. [PubMed] [Google Scholar]
- Vallejo A. N., Nestel A. R., Schirmer M., Weyand C. M., Goronzy J. J. Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity. J Biol Chem. 1998 Apr 3;273(14):8119–8129. doi: 10.1074/jbc.273.14.8119. [DOI] [PubMed] [Google Scholar]
- Yang H., Rittner H., Weyand C. M., Goronzy J. J. Aberrations in the primary T-cell receptor repertoire as a predisposition for synovial inflammation in rheumatoid arthritis. J Investig Med. 1999 May;47(5):236–245. [PubMed] [Google Scholar]
- Yeung M. M., Melgar S., Baranov V., Oberg A., Danielsson A., Hammarström S., Hammarström M. L. Characterisation of mucosal lymphoid aggregates in ulcerative colitis: immune cell phenotype and TcR-gammadelta expression. Gut. 2000 Aug;47(2):215–227. doi: 10.1136/gut.47.2.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Groot K., Gross W. L., Herlyn K., Reinhold-Keller E. Development and validation of a disease extent index for Wegener's granulomatosis. Clin Nephrol. 2001 Jan;55(1):31–38. [PubMed] [Google Scholar]