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. 1998 Sep 15;102(6):1173–1182. doi: 10.1172/JCI4235

Functional activation of lymphocyte CD44 in peripheral blood is a marker of autoimmune disease activity.

P Estess 1, H C DeGrendele 1, V Pascual 1, M H Siegelman 1
PMCID: PMC509100  PMID: 9739051

Abstract

Interactions between complementary receptors on leukocytes and endothelial cells play a central role in regulating extravasation from the blood and thereby affect both normal and pathologic inflammatory responses. CD44 on lymphocytes that has been "activated" to bind its principal ligand hyaluronate (HA) on endothelium can mediate the primary adhesion (rolling) of lymphocytes to vascular endothelial cells under conditions of physiologic shear stress, and this interaction is used for activated T cell extravasation into an inflamed site in vivo in mice (DeGrendele, H.C., P. Estess, L.J. Picker, and M.H. Siegelman. 1996. J. Exp. Med. 183:1119-1130. DeGrendele, H.D., P. Estess, and M.H. Siegelman. 1997. Science. 278:672-675. DeGrendele, H.C., P. Estess, and M.H. Siegelman. 1997. J. Immunol. 159: 2549-2553). Here, we have investigated the role of lymphocyte-borne-activated CD44 in the human and show that CD44-dependent primary adhesion is induced in human peripheral blood T cells through T cell receptor triggering. In addition, lymphocytes capable of CD44/HA-dependent rolling interactions can be found resident within inflamed tonsils. In analysis of peripheral bloods of patients from a pediatric rheumatology clinic, examining systemic lupus erythematosus, and a group of chronic arthropathies, expression of CD44-dependent primary adhesion strongly correlates with concurrent symptomatic disease, with 85% of samples from clinically active patients showing elevated levels of rolling activity (compared with only 4% of inactive patients). These rolling interactions are predominantly mediated by T cells. The results suggest that circulating T lymphocytes bearing activated CD44 are elevated under conditions of chronic inflammation and that these may represent a pathogenically important subpopulation of activated circulating cells that may provide a reliable marker for autoimmune or chronic inflammatory disease activity.

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Selected References

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  1. Abbassi O., Lane C. L., Krater S., Kishimoto T. K., Anderson D. C., McIntire L. V., Smith C. W. Canine neutrophil margination mediated by lectin adhesion molecule-1 in vitro. J Immunol. 1991 Oct 1;147(7):2107–2115. [PubMed] [Google Scholar]
  2. Alcocer-Varela J., Alarcón-Riquelme M., Laffón A., Sánchez-Madrid F., Alarcón-Segovia D. Activation markers on peripheral blood T cells from patients with active or inactive systemic lupus erythematosus. Correlation with proliferative responses and production of IL-2. J Autoimmun. 1991 Dec;4(6):935–945. doi: 10.1016/0896-8411(91)90056-i. [DOI] [PubMed] [Google Scholar]
  3. Ando D. G., Sercarz E. E., Hahn B. H. Mechanisms of T and B cell collaboration in the in vitro production of anti-DNA antibodies in the NZB/NZW F1 murine SLE model. J Immunol. 1987 May 15;138(10):3185–3190. [PubMed] [Google Scholar]
  4. Berlin C., Bargatze R. F., Campbell J. J., von Andrian U. H., Szabo M. C., Hasslen S. R., Nelson R. D., Berg E. L., Erlandsen S. L., Butcher E. C. alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell. 1995 Feb 10;80(3):413–422. doi: 10.1016/0092-8674(95)90491-3. [DOI] [PubMed] [Google Scholar]
  5. Bombardier C., Gladman D. D., Urowitz M. B., Caron D., Chang C. H. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992 Jun;35(6):630–640. doi: 10.1002/art.1780350606. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Camp R. L., Scheynius A., Johansson C., Puré E. CD44 is necessary for optimal contact allergic responses but is not required for normal leukocyte extravasation. J Exp Med. 1993 Aug 1;178(2):497–507. doi: 10.1084/jem.178.2.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cannistra S. A., Kansas G. S., Niloff J., DeFranzo B., Kim Y., Ottensmeier C. Binding of ovarian cancer cells to peritoneal mesothelium in vitro is partly mediated by CD44H. Cancer Res. 1993 Aug 15;53(16):3830–3838. [PubMed] [Google Scholar]
  9. Carlos T. M., Harlan J. M. Leukocyte-endothelial adhesion molecules. Blood. 1994 Oct 1;84(7):2068–2101. [PubMed] [Google Scholar]
  10. Cassidy J. T., Levinson J. E., Bass J. C., Baum J., Brewer E. J., Jr, Fink C. W., Hanson V., Jacobs J. C., Masi A. T., Schaller J. G. A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum. 1986 Feb;29(2):274–281. doi: 10.1002/art.1780290216. [DOI] [PubMed] [Google Scholar]
  11. Clark R. A., Alon R., Springer T. A. CD44 and hyaluronan-dependent rolling interactions of lymphocytes on tonsillar stroma. J Cell Biol. 1996 Aug;134(4):1075–1087. doi: 10.1083/jcb.134.4.1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cush J. J., Lipsky P. E. Cellular basis for rheumatoid inflammation. Clin Orthop Relat Res. 1991 Apr;(265):9–22. [PubMed] [Google Scholar]
  13. Cush J. J., Lipsky P. E. Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum. 1988 Oct;31(10):1230–1238. doi: 10.1002/art.1780311003. [DOI] [PubMed] [Google Scholar]
  14. Dayal A. K., Kammer G. M. The T cell enigma in lupus. Arthritis Rheum. 1996 Jan;39(1):23–33. doi: 10.1002/art.1780390104. [DOI] [PubMed] [Google Scholar]
  15. DeGrendele H. C., Estess P., Picker L. J., Siegelman M. H. CD44 and its ligand hyaluronate mediate rolling under physiologic flow: a novel lymphocyte-endothelial cell primary adhesion pathway. J Exp Med. 1996 Mar 1;183(3):1119–1130. doi: 10.1084/jem.183.3.1119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. DeGrendele H. C., Estess P., Siegelman M. H. Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science. 1997 Oct 24;278(5338):672–675. doi: 10.1126/science.278.5338.672. [DOI] [PubMed] [Google Scholar]
  17. DeGrendele H. C., Kosfiszer M., Estess P., Siegelman M. H. CD44 activation and associated primary adhesion is inducible via T cell receptor stimulation. J Immunol. 1997 Sep 15;159(6):2549–2553. [PubMed] [Google Scholar]
  18. 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]
  19. Finck B. K., Linsley P. S., Wofsy D. Treatment of murine lupus with CTLA4Ig. Science. 1994 Aug 26;265(5176):1225–1227. doi: 10.1126/science.7520604. [DOI] [PubMed] [Google Scholar]
  20. Fink C. W. Proposal for the development of classification criteria for idiopathic arthritides of childhood. J Rheumatol. 1995 Aug;22(8):1566–1569. [PubMed] [Google Scholar]
  21. Gladman D. D. Indicators of disease activity, prognosis, and treatment of systemic lupus erythematosus. Curr Opin Rheumatol. 1994 Sep;6(5):487–492. doi: 10.1097/00002281-199409000-00006. [DOI] [PubMed] [Google Scholar]
  22. Haynes B. F., Hale L. P., Denning S. M., Le P. T., Singer K. H. The role of leukocyte adhesion molecules in cellular interactions: implications for the pathogenesis of inflammatory synovitis. Springer Semin Immunopathol. 1989;11(2):163–185. doi: 10.1007/BF00197187. [DOI] [PubMed] [Google Scholar]
  23. Haynes B. F., Hale L. P., Patton K. L., Martin M. E., McCallum R. M. Measurement of an adhesion molecule as an indicator of inflammatory disease activity. Up-regulation of the receptor for hyaluronate (CD44) in rheumatoid arthritis. Arthritis Rheum. 1991 Nov;34(11):1434–1443. doi: 10.1002/art.1780341115. [DOI] [PubMed] [Google Scholar]
  24. Hemler M. E., Glass D., Coblyn J. S., Jacobson J. G. Very late activation antigens on rheumatoid synovial fluid T lymphocytes. Association with stages of T cell activation. J Clin Invest. 1986 Sep;78(3):696–702. doi: 10.1172/JCI112629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Iigo Y., Takashi T., Tamatani T., Miyasaka M., Higashida T., Yagita H., Okumura K., Tsukada W. ICAM-1-dependent pathway is critically involved in the pathogenesis of adjuvant arthritis in rats. J Immunol. 1991 Dec 15;147(12):4167–4171. [PubMed] [Google Scholar]
  26. Jalkanen S., Bargatze R. F., de los Toyos J., Butcher E. C. Lymphocyte recognition of high endothelium: antibodies to distinct epitopes of an 85-95-kD glycoprotein antigen differentially inhibit lymphocyte binding to lymph node, mucosal, or synovial endothelial cells. J Cell Biol. 1987 Aug;105(2):983–990. doi: 10.1083/jcb.105.2.983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Jasin H. E., Lightfoot E., Davis L. S., Rothlein R., Faanes R. B., Lipsky P. E. Amelioration of antigen-induced arthritis in rabbits treated with monoclonal antibodies to leukocyte adhesion molecules. Arthritis Rheum. 1992 May;35(5):541–549. doi: 10.1002/art.1780350508. [DOI] [PubMed] [Google Scholar]
  28. Jones D. A., Abbassi O., McIntire L. V., McEver R. P., Smith C. W. P-selectin mediates neutrophil rolling on histamine-stimulated endothelial cells. Biophys J. 1993 Oct;65(4):1560–1569. doi: 10.1016/S0006-3495(93)81195-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jones D. A., McIntire L. V., Smith C. W., Picker L. J. A two-step adhesion cascade for T cell/endothelial cell interactions under flow conditions. J Clin Invest. 1994 Dec;94(6):2443–2450. doi: 10.1172/JCI117612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kansas G. S. Selectins and their ligands: current concepts and controversies. Blood. 1996 Nov 1;88(9):3259–3287. [PubMed] [Google Scholar]
  31. Kansas G. S., Wood G. S., Dailey M. O. A family of cell-surface glycoproteins defined by a putative anti-endothelial cell receptor antibody in man. J Immunol. 1989 May 1;142(9):3050–3057. [PubMed] [Google Scholar]
  32. 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]
  33. Kitani A., Hara M., Hirose T., Norioka K., Hirose W., Kawagoe M., Nakamura H. Kinetic analysis of Ia expression on T cells in patients with systemic lupus erythematosus. J Clin Lab Immunol. 1986 Feb;19(2):59–63. [PubMed] [Google Scholar]
  34. Kitas G. D., Salmon M., Allan I. M., Bacon P. A. The T cell system in rheumatoid arthritis: activated or defective? Scand J Rheumatol Suppl. 1988;76:161–173. doi: 10.3109/03009748809102966. [DOI] [PubMed] [Google Scholar]
  35. Kotzin B. L. Systemic lupus erythematosus. Cell. 1996 May 3;85(3):303–306. doi: 10.1016/s0092-8674(00)81108-3. [DOI] [PubMed] [Google Scholar]
  36. Lawrence M. B., Springer T. A. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell. 1991 May 31;65(5):859–873. doi: 10.1016/0092-8674(91)90393-d. [DOI] [PubMed] [Google Scholar]
  37. Lesley J., Hyman R., Kincade P. W. CD44 and its interaction with extracellular matrix. Adv Immunol. 1993;54:271–335. doi: 10.1016/s0065-2776(08)60537-4. [DOI] [PubMed] [Google Scholar]
  38. Mackay C. R. T-cell memory: the connection between function, phenotype and migration pathways. Immunol Today. 1991 Jun;12(6):189–192. doi: 10.1016/0167-5699(91)90051-T. [DOI] [PubMed] [Google Scholar]
  39. Mato T., Masuko K., Misaki Y., Hirose N., Ito K., Takemoto Y., Izawa K., Yamamori S., Kato T., Nishioka K. Correlation of clonal T cell expansion with disease activity in systemic lupus erythematosus. Int Immunol. 1997 Apr;9(4):547–554. doi: 10.1093/intimm/9.4.547. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Mohamadzadeh M., DeGrendele H., Arizpe H., Estess P., Siegelman M. Proinflammatory stimuli regulate endothelial hyaluronan expression and CD44/HA-dependent primary adhesion. J Clin Invest. 1998 Jan 1;101(1):97–108. doi: 10.1172/JCI1604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Mohan C., Shi Y., Laman J. D., Datta S. K. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol. 1995 Feb 1;154(3):1470–1480. [PubMed] [Google Scholar]
  43. Morimoto C., Hafler D. A., Weiner H. L., Letvin N. L., Hagan M., Daley J., Schlossman S. F. Selective loss of the suppressor-inducer T-cell subset in progressive multiple sclerosis. Analysis with anti-2H4 monoclonal antibody. N Engl J Med. 1987 Jan 8;316(2):67–72. doi: 10.1056/NEJM198701083160202. [DOI] [PubMed] [Google Scholar]
  44. Morimoto C., Steinberg A. D., Letvin N. L., Hagan M., Takeuchi T., Daley J., Levine H., Schlossman S. F. A defect of immunoregulatory T cell subsets in systemic lupus erythematosus patients demonstrated with anti-2H4 antibody. J Clin Invest. 1987 Mar;79(3):762–768. doi: 10.1172/JCI112882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Murakami M., Kumagai S., Sugita M., Iwai K., Imura H. In vitro induction of IgG anti-DNA antibody from high density B cells of systemic lupus erythematosus patients by an HLA DR-restricted T cell clone. Clin Exp Immunol. 1992 Nov;90(2):245–250. doi: 10.1111/j.1365-2249.1992.tb07936.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Murakami S., Miyake K., June C. H., Kincade P. W., Hodes R. J. IL-5 induces a Pgp-1 (CD44) bright B cell subpopulation that is highly enriched in proliferative and Ig secretory activity and binds to hyaluronate. J Immunol. 1990 Dec 1;145(11):3618–3627. [PubMed] [Google Scholar]
  47. Panayi G. S., Lanchbury J. S., Kingsley G. H. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum. 1992 Jul;35(7):729–735. doi: 10.1002/art.1780350702. [DOI] [PubMed] [Google Scholar]
  48. Potocnik A. J., Kinne R., Menninger H., Zacher J., Emmrich F., Kroczek R. A. Expression of activation antigens on T cells in rheumatoid arthritis patients. Scand J Immunol. 1990 Feb;31(2):213–224. doi: 10.1111/j.1365-3083.1990.tb02762.x. [DOI] [PubMed] [Google Scholar]
  49. Rajagopalan S., Zordan T., Tsokos G. C., Datta S. K. Pathogenic anti-DNA autoantibody-inducing T helper cell lines from patients with active lupus nephritis: isolation of CD4-8- T helper cell lines that express the gamma delta T-cell antigen receptor. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7020–7024. doi: 10.1073/pnas.87.18.7020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ravelli A., Viola S., Ruperto N., Corsi B., Ballardini G., Martini A. Correlation between conventional disease activity measures in juvenile chronic arthritis. Ann Rheum Dis. 1997 Mar;56(3):197–200. doi: 10.1136/ard.56.3.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Raziuddin S., Nur M. A., al-Wabel A. A. Increased circulating HLA-DR+ CD4+ T cells in systemic lupus erythematosus: alterations associated with prednisolone therapy. Scand J Immunol. 1990 Feb;31(2):139–145. doi: 10.1111/j.1365-3083.1990.tb02753.x. [DOI] [PubMed] [Google Scholar]
  52. Shimizu Y., Newman W., Tanaka Y., Shaw S. Lymphocyte interactions with endothelial cells. Immunol Today. 1992 Mar;13(3):106–112. doi: 10.1016/0167-5699(92)90151-V. [DOI] [PubMed] [Google Scholar]
  53. Shivakumar S., Tsokos G. C., Datta S. K. T cell receptor alpha/beta expressing double-negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J Immunol. 1989 Jul 1;143(1):103–112. [PubMed] [Google Scholar]
  54. Silverman E. D., Isacovics B., Petsche D., Laxer R. M. Synovial fluid cells in juvenile arthritis: evidence of selective T cell migration to inflamed tissue. Clin Exp Immunol. 1993 Jan;91(1):90–95. doi: 10.1111/j.1365-2249.1993.tb03360.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. 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]
  56. Spronk P. E., vd Gun B. T., Limburg P. C., Kallenberg C. G. B cell activation in clinically quiescent systemic lupus erythematosus (SLE) is related to immunoglobulin levels, but not to levels of anti-dsDNA, nor to concurrent T cell activation. Clin Exp Immunol. 1993 Jul;93(1):39–44. doi: 10.1111/j.1365-2249.1993.tb06494.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Tan E. M., Cohen A. S., Fries J. F., Masi A. T., McShane D. J., Rothfield N. F., Schaller J. G., Talal N., Winchester R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. doi: 10.1002/art.1780251101. [DOI] [PubMed] [Google Scholar]
  58. Tsokos G. C., Inghirami G., Pillemer S. R., Mavridis A., Magilavy D. B. Immunoregulatory aberrations in patients with polyarticular juvenile rheumatoid arthritis. Clin Immunol Immunopathol. 1988 Apr;47(1):62–74. doi: 10.1016/0090-1229(88)90145-6. [DOI] [PubMed] [Google Scholar]
  59. Van Boxel J. A., Paget S. A. Predominantly T-cell infiltrate in rheumatoid synovial membranes. N Engl J Med. 1975 Sep 11;293(11):517–520. doi: 10.1056/NEJM197509112931101. [DOI] [PubMed] [Google Scholar]
  60. Verdrengh M., Holmdahl R., Tarkowski A. Administration of antibodies to hyaluronanreceptor (CD44) delays the start and ameliorates the severity of collagen II arthritis. Scand J Immunol. 1995 Sep;42(3):353–358. doi: 10.1111/j.1365-3083.1995.tb03667.x. [DOI] [PubMed] [Google Scholar]
  61. Wofsy D., Seaman W. E. Reversal of advanced murine lupus in NZB/NZW F1 mice by treatment with monoclonal antibody to L3T4. J Immunol. 1987 May 15;138(10):3247–3253. [PubMed] [Google Scholar]
  62. Wofsy D., Seaman W. E. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J Exp Med. 1985 Feb 1;161(2):378–391. doi: 10.1084/jem.161.2.378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Yokoyama W. M., Koning F., Kehn P. J., Pereira G. M., Stingl G., Coligan J. E., Shevach E. M. Characterization of a cell surface-expressed disulfide-linked dimer involved in murine T cell activation. J Immunol. 1988 Jul 15;141(2):369–376. [PubMed] [Google Scholar]
  64. Youinou P., Pennec Y. L., Blaschek M. A., Gentric A., Jouquan J., Lamour A., Angelidis P. Activation of peripheral blood lymphocytes in patients with primary Sjögren's syndrome. Rheumatol Int. 1988;8(3):125–130. doi: 10.1007/BF00272434. [DOI] [PubMed] [Google Scholar]
  65. Yu D. T., Winchester R. J., Fu S. M., Gibofsky A., Ko H. S., Kunkel H. G. Peripheral blood Ia-positive T cells. Increases in certain diseases and after immunization. J Exp Med. 1980 Jan 1;151(1):91–100. doi: 10.1084/jem.151.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. de Belder A. N., Wik K. O. Preparation and properties of fluorescein-labelled hyaluronate. Carbohydr Res. 1975 Nov;44(2):251–257. doi: 10.1016/s0008-6215(00)84168-3. [DOI] [PubMed] [Google Scholar]

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