Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 May 1;99(9):2165–2172. doi: 10.1172/JCI119389

Homing of mucosal leukocytes to joints. Distinct endothelial ligands in synovium mediate leukocyte-subtype specific adhesion.

M Salmi 1, P Rajala 1, S Jalkanen 1
PMCID: PMC508046  PMID: 9151788

Abstract

Inflammation and infection of the gut can be followed by reactive arthritis at a distant joint. Leukocyte recruitment into synovium is essential for this process, but nothing is known about the endothelial adhesion molecules in synovial membrane which direct the homing of activated, gut-derived leukocytes to joints. Here we analyzed the expression of the known endothelial adhesion molecules in inflamed synovium and their function in binding of mucosal leukocytes. Intercellular adhesion molecule-1 (ICAM-1/CD54) and vascular adhesion protein-1 (VAP-1) were most prominently expressed in synovial vessels. All other adhesion molecules were found at lower levels in inflamed synovia, except mucosal addressin which was absent. Binding of macrophages isolated from lamina propria of the gut to synovial endothelium was almost entirely P-selectin-dependent. In contrast, small intestinal lymphocytes and immunoblasts both relied mainly on VAP-1 in recognition of synovial vessels. Thus, endothelial P-selectin and VAP-1 mediate binding of mucosal effector cells to synovium in a leukocyte subtype-selective manner. Antiadhesive therapy against these inducible molecules should ablate the pathogenetic cascade leading to inappropriate homing of leukocytes to joints in arthritis.

Full Text

The Full Text of this article is available as a PDF (566.3 KB).

Selected References

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

  1. Aho R., Jalkanen S., Kalimo H. CD44-hyaluronate interaction mediates in vitro lymphocyte binding to the white matter of the central nervous system. J Neuropathol Exp Neurol. 1994 May;53(3):295–302. doi: 10.1097/00005072-199405000-00011. [DOI] [PubMed] [Google Scholar]
  2. Airas L., Salmi M., Jalkanen S. Lymphocyte-vascular adhesion protein-2 is a novel 70-kDa molecule involved in lymphocyte adhesion to vascular endothelium. J Immunol. 1993 Oct 15;151(8):4228–4238. [PubMed] [Google Scholar]
  3. Aruffo A., Stamenkovic I., Melnick M., Underhill C. B., Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990 Jun 29;61(7):1303–1313. doi: 10.1016/0092-8674(90)90694-a. [DOI] [PubMed] [Google Scholar]
  4. Butcher E. C., Picker L. J. Lymphocyte homing and homeostasis. Science. 1996 Apr 5;272(5258):60–66. doi: 10.1126/science.272.5258.60. [DOI] [PubMed] [Google Scholar]
  5. Carlos T. M., Harlan J. M. Leukocyte-endothelial adhesion molecules. Blood. 1994 Oct 1;84(7):2068–2101. [PubMed] [Google Scholar]
  6. Coffman R. L., Weissman I. L. B220: a B cell-specific member of th T200 glycoprotein family. Nature. 1981 Feb 19;289(5799):681–683. doi: 10.1038/289681a0. [DOI] [PubMed] [Google Scholar]
  7. Fischer C., Thiele H. G., Hamann A. Lymphocyte-endothelial interactions in inflamed synovia: involvement of several adhesion molecules and integrin epitopes. Scand J Immunol. 1993 Aug;38(2):158–166. doi: 10.1111/j.1365-3083.1993.tb01708.x. [DOI] [PubMed] [Google Scholar]
  8. Grober J. S., Bowen B. L., Ebling H., Athey B., Thompson C. B., Fox D. A., Stoolman L. M. Monocyte-endothelial adhesion in chronic rheumatoid arthritis. In situ detection of selectin and integrin-dependent interactions. J Clin Invest. 1993 Jun;91(6):2609–2619. doi: 10.1172/JCI116500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Issekutz T. B. Leukocyte adhesion and the anti-inflammatory effects of leukocyte integrin blockade. Agents Actions Suppl. 1995;46:85–96. doi: 10.1007/978-3-0348-7276-8_9. [DOI] [PubMed] [Google Scholar]
  10. Jalkanen S. T., Butcher E. C. In vitro analysis of the homing properties of human lymphocytes: developmental regulation of functional receptors for high endothelial venules. Blood. 1985 Sep;66(3):577–582. [PubMed] [Google Scholar]
  11. Jalkanen S., Steere A. C., Fox R. I., Butcher E. C. A distinct endothelial cell recognition system that controls lymphocyte traffic into inflamed synovium. Science. 1986 Aug 1;233(4763):556–558. doi: 10.1126/science.3726548. [DOI] [PubMed] [Google Scholar]
  12. Kavanaugh A. F., Davis L. S., Nichols L. A., Norris S. H., Rothlein R., Scharschmidt L. A., Lipsky P. E. Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1. Arthritis Rheum. 1994 Jul;37(7):992–999. doi: 10.1002/art.1780370703. [DOI] [PubMed] [Google Scholar]
  13. Koch A. E., Burrows J. C., Haines G. K., Carlos T. M., Harlan J. M., Leibovich S. J. Immunolocalization of endothelial and leukocyte adhesion molecules in human rheumatoid and osteoarthritic synovial tissues. Lab Invest. 1991 Mar;64(3):313–320. [PubMed] [Google Scholar]
  14. Leirisalo-Repo M., Suoranta H. Ten-year follow-up study of patients with Yersinia arthritis. Arthritis Rheum. 1988 Apr;31(4):533–537. doi: 10.1002/art.1780310410. [DOI] [PubMed] [Google Scholar]
  15. Leirisalo-Repo M., Turunen U., Stenman S., Helenius P., Seppälä K. High frequency of silent inflammatory bowel disease in spondylarthropathy. Arthritis Rheum. 1994 Jan;37(1):23–31. doi: 10.1002/art.1780370105. [DOI] [PubMed] [Google Scholar]
  16. Luscinskas F. W., Ding H., Lichtman A. H. P-selectin and vascular cell adhesion molecule 1 mediate rolling and arrest, respectively, of CD4+ T lymphocytes on tumor necrosis factor alpha-activated vascular endothelium under flow. J Exp Med. 1995 Mar 1;181(3):1179–1186. doi: 10.1084/jem.181.3.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. MacDermott R. P., Bragdon M. J., Jenkins K. M., Franklin G. O., Shedlofsky S., Kodner I. J. Human intestinal mononuclear cells. II. Demonstration of a naturally occurring subclass of T cells which respond in the allogeneic mixed leukocyte reaction but do not effect cell-mediated lympholysis. Gastroenterology. 1981 Apr;80(4):748–757. [PubMed] [Google Scholar]
  18. McEver R. P., Moore K. L., Cummings R. D. Leukocyte trafficking mediated by selectin-carbohydrate interactions. J Biol Chem. 1995 May 12;270(19):11025–11028. doi: 10.1074/jbc.270.19.11025. [DOI] [PubMed] [Google Scholar]
  19. Michie S. A., Streeter P. R., Bolt P. A., Butcher E. C., Picker L. J. The human peripheral lymph node vascular addressin. An inducible endothelial antigen involved in lymphocyte homing. Am J Pathol. 1993 Dec;143(6):1688–1698. [PMC free article] [PubMed] [Google Scholar]
  20. Mielants H., Veys E. M., Cuvelier C., De Vos M., Goemaere S., Maertens M., Joos R. Gut inflammation in children with late onset pauciarticular juvenile chronic arthritis and evolution to adult spondyloarthropathy--a prospective study. J Rheumatol. 1993 Sep;20(9):1567–1572. [PubMed] [Google Scholar]
  21. Mielants H., Veys E. M. The gut in the spondyloarthropathies. J Rheumatol. 1990 Jan;17(1):7–10. [PubMed] [Google Scholar]
  22. Mikecz K., Brennan F. R., Kim J. H., Glant T. T. Anti-CD44 treatment abrogates tissue oedema and leukocyte infiltration in murine arthritis. Nat Med. 1995 Jun;1(6):558–563. doi: 10.1038/nm0695-558. [DOI] [PubMed] [Google Scholar]
  23. Morales-Ducret J., Wayner E., Elices M. J., Alvaro-Gracia J. M., Zvaifler N. J., Firestein G. S. Alpha 4/beta 1 integrin (VLA-4) ligands in arthritis. Vascular cell adhesion molecule-1 expression in synovium and on fibroblast-like synoviocytes. J Immunol. 1992 Aug 15;149(4):1424–1431. [PubMed] [Google Scholar]
  24. Parham P. Monoclonal antibodies against two separate alloantigenic sites of HLA-B40. Immunogenetics. 1981;13(6):509–527. doi: 10.1007/BF00343719. [DOI] [PubMed] [Google Scholar]
  25. Picker L. J., Butcher E. C. Physiological and molecular mechanisms of lymphocyte homing. Annu Rev Immunol. 1992;10:561–591. doi: 10.1146/annurev.iy.10.040192.003021. [DOI] [PubMed] [Google Scholar]
  26. Randolph G. J., Furie M. B. Mononuclear phagocytes egress from an in vitro model of the vascular wall by migrating across endothelium in the basal to apical direction: role of intercellular adhesion molecule 1 and the CD11/CD18 integrins. J Exp Med. 1996 Feb 1;183(2):451–462. doi: 10.1084/jem.183.2.451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Salmi M., Andrew D. P., Butcher E. C., Jalkanen S. Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms. J Exp Med. 1995 Jan 1;181(1):137–149. doi: 10.1084/jem.181.1.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Salmi M., Granfors K., Leirisalo-Repo M., Hämäläinen M., MacDermott R., Leino R., Havia T., Jalkanen S. Selective endothelial binding of interleukin-2-dependent human T-cell lines derived from different tissues. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11436–11440. doi: 10.1073/pnas.89.23.11436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Salmi M., Jalkanen S. A 90-kilodalton endothelial cell molecule mediating lymphocyte binding in humans. Science. 1992 Sep 4;257(5075):1407–1409. doi: 10.1126/science.1529341. [DOI] [PubMed] [Google Scholar]
  30. Shyjan A. M., Bertagnolli M., Kenney C. J., Briskin M. J. Human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional similarities to the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but extreme divergence of mucin-like sequences. J Immunol. 1996 Apr 15;156(8):2851–2857. [PubMed] [Google Scholar]
  31. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  32. Starzl T. E., Weil R., 3rd, Koep L. J., McCalmon R. T., Jr, Terasaki P. I., Iwaki Y., Schröter G. P., Franks J. J., Subryan V., Halgrimson C. G. Thoracic duct fistula and renal transplantation. Ann Surg. 1979 Oct;190(4):474–486. doi: 10.1097/00000658-197910000-00007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Steere A. C., Duray P. H., Butcher E. C. Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis. Comparison with rheumatoid synovium and tonsillar lymphoid tissue. Arthritis Rheum. 1988 Apr;31(4):487–495. doi: 10.1002/art.1780310405. [DOI] [PubMed] [Google Scholar]
  34. Streeter P. R., Rouse B. T., Butcher E. C. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J Cell Biol. 1988 Nov;107(5):1853–1862. doi: 10.1083/jcb.107.5.1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Weller A., Isenmann S., Vestweber D. Cloning of the mouse endothelial selectins. Expression of both E- and P-selectin is inducible by tumor necrosis factor alpha. J Biol Chem. 1992 Jul 25;267(21):15176–15183. [PubMed] [Google Scholar]
  36. Wellicome S. M., Thornhill M. H., Pitzalis C., Thomas D. S., Lanchbury J. S., Panayi G. S., Haskard D. O. A monoclonal antibody that detects a novel antigen on endothelial cells that is induced by tumor necrosis factor, IL-1, or lipopolysaccharide. J Immunol. 1990 Apr 1;144(7):2558–2565. [PubMed] [Google Scholar]
  37. Wells A. F., Larsson E., Tengblad A., Fellström B., Tufveson G., Klareskog L., Laurent T. C. The localization of hyaluronan in normal and rejected human kidneys. Transplantation. 1990 Aug;50(2):240–243. doi: 10.1097/00007890-199008000-00014. [DOI] [PubMed] [Google Scholar]
  38. de Fougerolles A. R., Stacker S. A., Schwarting R., Springer T. A. Characterization of ICAM-2 and evidence for a third counter-receptor for LFA-1. J Exp Med. 1991 Jul 1;174(1):253–267. doi: 10.1084/jem.174.1.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. el-Gabalawy H., Gallatin M., Vazeux R., Peterman G., Wilkins J. Expression of ICAM-R (ICAM-3), a novel counter-receptor for LFA-1, in rheumatoid and nonrheumatoid synovium. Comparison with other adhesion molecules. Arthritis Rheum. 1994 Jun;37(6):846–854. doi: 10.1002/art.1780370612. [DOI] [PubMed] [Google Scholar]
  40. van Dinther-Janssen A. C., Horst E., Koopman G., Newmann W., Scheper R. J., Meijer C. J., Pals S. T. The VLA-4/VCAM-1 pathway is involved in lymphocyte adhesion to endothelium in rheumatoid synovium. J Immunol. 1991 Dec 15;147(12):4207–4210. [PubMed] [Google Scholar]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES