Abstract
OBJECTIVE—To quantify the fraction of gut mucosal lymphocytes expressing the T helper type 1 (Th1) cytokines, interferon γ (IFNγ) and interleukin (IL)2, and the Th2 cytokines, IL4 and IL10, at the single cell level in patients with spondyloarthropathy (SpA) in comparison with healthy controls. METHODS—An improved extraction protocol was used for the enrichment of intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) from colonic and ileal biopsy specimens obtained from patients with SpA (n=20) and healthy controls (n=13). After stimulation with phorbol ester/ionomycin, expression of the intracellular cytokines IFNγ, IL2, IL4, and IL10 was determined in CD3+, CD3+CD8+ and CD3+CD8− T cells by flow cytometry. RESULTS—In colonic LPLs, a significant decrease in IFNγ-producing CD3+ cells was observed (p=0.02) in patients with SpA. In the CD3+CD8− subset, the proportion of cells producing IFNγ and IL2 was decreased in patients with SpA (p=0.021 and p=0.027 respectively). In ileal LPLs, the percentage of IL10-producing CD3+CD8− cells was significantly increased (p=0.046). CONCLUSION—An impaired Th1 cytokine profile is observed in gut mucosal lymphocytes from patients with SpA. This adds to the existing evidence that the gut mucosal immune apparatus is involved in the pathogenesis of SpA.
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- Anderson S. J., Coleclough C. Regulation of CD4 and CD8 expression on mouse T cells. Active removal from the cell surface by two mechanisms. J Immunol. 1993 Nov 15;151(10):5123–5134. [PubMed] [Google Scholar]
- Braun J., Yin Z., Spiller I., Siegert S., Rudwaleit M., Liu L., Radbruch A., Sieper J. Low secretion of tumor necrosis factor alpha, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis. Arthritis Rheum. 1999 Oct;42(10):2039–2044. doi: 10.1002/1529-0131(199910)42:10<2039::AID-ANR3>3.0.CO;2-6. [DOI] [PubMed] [Google Scholar]
- Cerf-Bensussan N., Jarry A., Brousse N., Lisowska-Grospierre B., Guy-Grand D., Griscelli C. A monoclonal antibody (HML-1) defining a novel membrane molecule present on human intestinal lymphocytes. Eur J Immunol. 1987 Sep;17(9):1279–1285. doi: 10.1002/eji.1830170910. [DOI] [PubMed] [Google Scholar]
- Claudepierre P., Rymer J. C., Chevalier X. IL-10 plasma levels correlate with disease activity in spondyloarthropathy. J Rheumatol. 1997 Aug;24(8):1659–1661. [PubMed] [Google Scholar]
- De Keyser F., Elewaut D., De Vos M., De Vlam K., Cuvelier C., Mielants H., Veys E. M. Bowel inflammation and the spondyloarthropathies. Rheum Dis Clin North Am. 1998 Nov;24(4):785-813, ix-x. doi: 10.1016/s0889-857x(05)70042-9. [DOI] [PubMed] [Google Scholar]
- De Vos M., Mielants H., Cuvelier C., Elewaut A., Veys E. Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology. 1996 Jun;110(6):1696–1703. doi: 10.1053/gast.1996.v110.pm8964393. [DOI] [PubMed] [Google Scholar]
- Dougados M., van der Linden S., Juhlin R., Huitfeldt B., Amor B., Calin A., Cats A., Dijkmans B., Olivieri I., Pasero G. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum. 1991 Oct;34(10):1218–1227. doi: 10.1002/art.1780341003. [DOI] [PubMed] [Google Scholar]
- Elewaut D., Van Damme N., De Keyser F., Baeten D., De Paepe P., Van Vlierberghe H., Mielants H., Cuvelier C., Verbruggen G., Veys E. M. Altered expression of alpha E beta 7 integrin on intra-epithelial and lamina propria lymphocytes in patients with Crohn's disease. Acta Gastroenterol Belg. 1998 Jul-Sep;61(3):288–294. [PubMed] [Google Scholar]
- Jarry A., Cerf-Bensussan N., Brousse N., Selz F., Guy-Grand D. Subsets of CD3+ (T cell receptor alpha/beta or gamma/delta) and CD3- lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Eur J Immunol. 1990 May;20(5):1097–1103. doi: 10.1002/eji.1830200523. [DOI] [PubMed] [Google Scholar]
- Jung T., Lack G., Schauer U., Uberück W., Renz H., Gelfand E. W., Rieger C. H. Decreased frequency of interferon-gamma- and interleukin-2-producing cells in patients with atopic diseases measured at the single cell level. J Allergy Clin Immunol. 1995 Oct;96(4):515–527. doi: 10.1016/s0091-6749(95)70296-2. [DOI] [PubMed] [Google Scholar]
- Jung T., Schauer U., Heusser C., Neumann C., Rieger C. Detection of intracellular cytokines by flow cytometry. J Immunol Methods. 1993 Feb 26;159(1-2):197–207. doi: 10.1016/0022-1759(93)90158-4. [DOI] [PubMed] [Google Scholar]
- Kruschwitz M., Fritzsche G., Schwarting R., Micklem K., Mason D. Y., Falini B., Stein H. Ber-ACT8: new monoclonal antibody to the mucosa lymphocyte antigen. J Clin Pathol. 1991 Aug;44(8):636–645. doi: 10.1136/jcp.44.8.636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Markowitz J., Daum F., Cohen S. A., Glassman M., Holmes R. D., Piccoli D., Rossi T. M., Treem W. R., Ulshen M. H., Winter H. S. Immunology of inflammatory bowel disease: summary of the proceedings of the Subcommittee on Immunosuppressive Use in IBD. J Pediatr Gastroenterol Nutr. 1991 May;12(4):411–423. [PubMed] [Google Scholar]
- Mielants H., Veys E. M., Cuvelier C., De Vos M., Goemaere S., De Clercq L., Schatteman L., Gyselbrecht L., Elewaut D. The evolution of spondyloarthropathies in relation to gut histology. III. Relation between gut and joint. J Rheumatol. 1995 Dec;22(12):2279–2284. [PubMed] [Google Scholar]
- Morita Y., Yamamura M., Kawashima M., Harada S., Tsuji K., Shibuya K., Maruyama K., Makino H. Flow cytometric single-cell analysis of cytokine production by CD4+ T cells in synovial tissue and peripheral blood from patients with rheumatoid arthritis. Arthritis Rheum. 1998 Sep;41(9):1669–1676. doi: 10.1002/1529-0131(199809)41:9<1669::AID-ART19>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
- Mosmann T. R., Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
- Pirmez C., Yamamura M., Uyemura K., Paes-Oliveira M., Conceiço-Silva F., Modlin R. L. Cytokine patterns in the pathogenesis of human leishmaniasis. J Clin Invest. 1993 Apr;91(4):1390–1395. doi: 10.1172/JCI116341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Prussin C., Metcalfe D. D. Detection of intracytoplasmic cytokine using flow cytometry and directly conjugated anti-cytokine antibodies. J Immunol Methods. 1995 Dec 15;188(1):117–128. doi: 10.1016/0022-1759(95)00209-x. [DOI] [PubMed] [Google Scholar]
- Schieferdecker H. L., Ullrich R., Hirseland H., Zeitz M. T cell differentiation antigens on lymphocytes in the human intestinal lamina propria. J Immunol. 1992 Oct 15;149(8):2816–2822. [PubMed] [Google Scholar]
- Sieling P. A., Wang X. H., Gately M. K., Oliveros J. L., McHugh T., Barnes P. F., Wolf S. F., Golkar L., Yamamura M., Yogi Y. IL-12 regulates T helper type 1 cytokine responses in human infectious disease. J Immunol. 1994 Oct 15;153(8):3639–3647. [PubMed] [Google Scholar]
- Sieper J., Braun J. Pathogenesis of spondylarthropathies. Persistent bacterial antigen, autoimmunity, or both? Arthritis Rheum. 1995 Nov;38(11):1547–1554. doi: 10.1002/art.1780381105. [DOI] [PubMed] [Google Scholar]
- Simon A. K., Seipelt E., Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8562–8566. doi: 10.1073/pnas.91.18.8562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Van Damme N., Baeten D., De Vos M., Demetter P., Elewaut D., Mielants H., Verbruggen G., Cuvelier C., Veys E. M., De Keyser F. Chemical agents and enzymes used for the extraction of gut lymphocytes influence flow cytometric detection of T cell surface markers. J Immunol Methods. 2000 Mar 6;236(1-2):27–35. doi: 10.1016/s0022-1759(99)00243-4. [DOI] [PubMed] [Google Scholar]
- Van den Bosch F., Kruithof E., Baeten D., De Keyser F., Mielants H., Veys E. M. Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha (infliximab) in spondyloarthropathy: an open pilot study. Ann Rheum Dis. 2000 Jun;59(6):428–433. doi: 10.1136/ard.59.6.428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wright V. Seronegative polyarthritis: a unified concept. Arthritis Rheum. 1978 Jul-Aug;21(6):619–633. doi: 10.1002/art.1780210603. [DOI] [PubMed] [Google Scholar]
- Yin Z., Braun J., Neure L., Wu P., Liu L., Eggens U., Sieper J. Crucial role of interleukin-10/interleukin-12 balance in the regulation of the type 2 T helper cytokine response in reactive arthritis. Arthritis Rheum. 1997 Oct;40(10):1788–1797. doi: 10.1002/art.1780401010. [DOI] [PubMed] [Google Scholar]