Elevated levels of circulating CD44 in patients with systemic sclerosis: association with a milder subset

K. Komura, S. Sato, M. Fujimoto1, M. Hasegawa and K. Takehara

Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa and
1 Department of Regenerative Medicine, Research Institute, International Medical Center of Japan, Tokyo, Japan


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To determine serum levels of soluble CD44 (sCD44), one of the adhesion molecules that regulate the migration of leucocytes, and clinical associations of these levels in patients with systemic sclerosis (SSc).

Methods. Serum sCD44 levels were examined by enzyme-linked immunosorbent assay.

Results. Serum sCD44 levels were elevated in SSc patients compared with normal controls. Serum sCD44 levels were higher in patients with limited cutaneous SSc than in those with diffuse cutaneous SSc. Patients with elevated sCD44 levels had pulmonary fibrosis less frequently than those with normal sCD44 levels. Serum sCD44 levels remained elevated during the follow-up in almost all patients with elevated levels at their first visit, whereas they remained normal in all patients with normal levels.

Conclusion. Elevated sCD44 levels were associated with a relatively mild subset of SSc. These results suggest that CD44 could be a potential therapeutic target in SSc.

KEY WORDS: Soluble CD44, Limited cutaneous systemic sclerosis, Pulmonary fibrosis, Longitudinal study.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis and vascular changes in the skin and other visceral organs. Although the pathogenesis of SSc remains unclear, numerous recent studies have suggested that some cytokines or growth factors regulate the induction and development of fibrosis and vascular changes by stimulating the synthesis of extracellular matrix components and regulating the function of leucocytes [1, 2]. These cytokines and growth factors are produced partly by leucocytes infiltrating inflammatory sites in patients with SSc [13].

The migration of leucocytes into inflammatory sites is fundamentally regulated by the expression of a series of adhesion molecules [3]. The selectin family, including L-selectin, E-selectin and P-selectin, assists leucocytes in rolling on the endothelium. Members of the immunoglobulin (Ig) superfamily—intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesion molecule-1 (VCAM-1)—mediate the firm adhesion of leucocytes to the endothelium followed by transendothelial migration [4, 5]. Transendothelial migration involves the function of platelet-endothelial cell adhesion molecule (PECAM, CD31) [6]. Abnormal expression of adhesion molecules appears to be a hallmark of SSc, as it has been reported that the soluble forms of various adhesion molecules, including L-selectin, E-selectin, ICAM-1 and VCAM-1, are significantly elevated in sera from patients with SSc. In addition, elevated serum levels of these soluble adhesion molecules correlate with the disease severity or some clinical features in patients with SSc: soluble E-selectin (sE-selectin) and soluble VCAM-1 (sVCAM-1) correlate with disease severity and pulmonary fibrosis [7, 8] and sE-selectin, sVCAM-1 and soluble ICAM-1 (sICAM-1) correlate with renal crisis [9]. We recently reported that, unlike these molecules, which reflect the severity of SSc, sCD31 at elevated levels was associated with limited cutaneous SSc (lSSc), a milder subset of SSc [10].

Homing cell adhesion molecule (H-CAM, CD44), a member of the proteoglycan link protein family, also plays an essential role in mediating the rolling of lymphocytes on vascular endothelial cells [11, 12]. Three isoform categories of the CD44 molecule, a polymorphic glycoprotein, have been identified: an isoform of 80–90 kDa, the so-called CD44 standard form (CD44std), which is widely expressed on all subsets of leucocytes, erythrocytes, many types of epithelium and mesenchymal elements, such as fibroblasts, smooth muscle cells and glial cells of the central nervous system; a medium-sized category of 110–160 kDa, which is weakly expressed on epithelial cells and highly expressed in some carcinomas; and a category which includes large isoforms of 250 kDa covalently modified by the addition of chondroitin sulphate. During lymphocyte migration, CD44 on lymphocytes binds its principal ligand, hyaluronan, on the endothelial cells. Increased CD44 expression on lymphocytes has been shown on the inflammatory infiltrating cells in human and mouse arthritis [13, 14]. In addition, the number of circulating T lymphocytes bearing activated CD44 is elevated in patients with rheumatoid arthritis and systemic lupus erythematosus (SLE) [15]. CD44 also exists in a soluble form. Elevated levels of soluble CD44 (sCD44) are demonstrated in sera from patients with any of several cancers [1618], although they have not been demonstrated in patients with connective tissue diseases.

To determine whether serum levels of sCD44 reflect disease severity and clinical features in SSc patients, we examined serum levels of sCD44 and related these results to clinical features. In addition, we performed a retrospective longitudinal study of sCD44 levels in some of these SSc patients.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Serum samples
Serum samples were obtained from 59 Japanese patients with SSc (54 females and five males). All patients fulfilled the criteria for SSc proposed by the American College of Rheumatology (ACR) [19]. The patients were between 9 and 76 yr old (mean age 43 yr). They were grouped according to the classification system proposed by LeRoy et al. [20]: 30 patients (29 females and one male) had limited cutaneous SSc (lSSc) and 29 patients (25 females and four males) had diffuse cutaneous SSc (dSSc). The disease duration of patients with lSSc and dSSc was 11.6±11.0 and 5.1±7.2 yr respectively. At the first visit, four patients had been treated with low-dose steroids (prednisolone 5–20 mg/day) and low-dose D-penicillamine (100–500 mg/day) and one patient had been treated with low-dose steroids (prednisolone 5 mg/day). None of the SSc patients had received immunosuppressive therapy and none had a recent history of infection or other inflammatory diseases. As the disease control, we examined serum samples from 25 patients with SLE and polymyositis/dermatomyositis (PM/DM) that fulfilled the ACR criteria [21] and the Bohan and Peter criteria [22], respectively. Twenty-five age- and sex-matched healthy Japanese persons were used as normal controls.

For a retrospective longitudinal study, patients from whom serum samples were taken more than three times were analysed. The samples included 66 samples from 18 SSc patients (17 females and one male) out of 59 SSc patients. These patients were classified into 10 patients (all females) with lSSc and eight patients (seven females and one male) with dSSc. They were between 9 and 71 yr old (mean age 54 yr). The disease duration at their first visit was 6.9±9.6 yr. These patients had been followed up for 2.2±1.2 yr (0.4–3.9 yr) with 3.6±1.0 (3–7) different time points. At their first visit, none of the patients had been treated with steroids or D-penicillamine. All eight dSSc patients received low-dose steroids (prednisolone 5–20 mg/day) and four dSSc patients received low-dose D-penicillamine (100–300 mg/day) after their first visit. Treatment with steroids or D-penicillamine was not started in any lSSc patient and none of the SSc patients received immunosuppressive therapy throughout the follow-up period. Fresh venous blood samples were centrifuged shortly after clot formation. All samples were stored at -70°C prior to use.

Clinical assessment
Complete medical histories, physical examinations and laboratory tests were conducted for all patients at their first visit, with limited evaluations during follow-up visits. Organ system involvement was defined as described previously [23, 24]: lung=bibasilar fibrosis on chest radiography; oesophagus=hypomotility shown by barium radiography; joint=inflammatory polyarthralgias or arthritis; heart=pericarditis, congestive heart failure, or arrhythmias requiring treatment; kidney=malignant hypertension and rapidly progressive renal failure without another explanation; muscle = proximal muscle weakness and elevated serum creatine kinase. Pulmonary functions, comprising vital capacity (VC) and diffusion capacity for carbon monoxide (DLco), were also tested. When DLco and VC were <75 and <80% respectively of the predicted normal values, they were considered to be abnormal. The protocol was approved by the Kanazawa University School of Medicine and Kanazawa University Hospital, and informed consent was obtained from all patients.

ELISA
Specific enzyme-linked immunosorbent assay (ELISA) kits were used to measure serum sCD44std levels (Bender Medsystems, Vienna, Austria), according to the manufacturer's protocol. This ELISA system can detect all circulating CD44 isoforms. Each sample was tested in duplicate. The detection limit of this assay was 0.023 ng/ml.

Statistical analysis
Statistical analysis was performed using the Mann–Whitney U-test to compare sCD44 levels, Fisher's exact probability test to compare frequencies and Bonferroni's test for multiple comparisons. Spearman's rank correlation coefficient was used to examine the relationship between pairs of continuous variables. A P value less than 0.05 was considered statistically significant. All data are shown as mean±S.D.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Serum sCD44 levels in SSc
Serum sCD44 levels were significantly higher in patients with SSc (1.55 ± 0.45 ng/ml) than in normal controls (1.21±0.25 ng/ml, P<0.001), patients with SLE (1.35±0.23 ng/ml, P<0.05) and patients with PM/DM (1.34±0.29 ng/ml, P<0.05) (Fig. 1Go). Serum sCD44 levels were similar between patients with SLE or PM/DM and normal controls. In patients with some malignancies, sCD44 levels are reported to increase [1618], although there were no patients with SSc who had malignant diseases, including lymphoma, leukaemia, gastric cancer and colon cancer. Also, no significant difference was observed between PM/DM patients with and without malignancy (data not shown). sCD44 levels in both lSSc (1.67 ± 0.41 ng/ml) and dSSc (1.43 ± 0.46 ng/ml) patients were both significantly higher than those in normal controls (P < 0.0001 and P < 0.03 respectively). Furthermore, serum sCD44 levels were significantly elevated in patients with lSSc when compared with those with dSSc (P < 0.05).



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FIG. 1. Serum levels of sCD44 in patients with lSSc, dSSc, SLE and PM/DM, and normal controls (Control). Serum sCD44 levels were determined by a specific ELISA. Bars indicate the mean value in each group. The broken line indicates the cut-off value (mean+2 S.D. of the control samples).

 
When values higher than the mean±2 S.D. (1.732 ng/ml) of the control serum samples were considered to be elevated, sCD44 levels were elevated in 29% (17/59) of SSc patients, 40% (12/30) of lSSc patients and 17% (5/29) of dSSc patients. The frequency of pulmonary fibrosis and decreased VC as a percentage (%VC) in SSc patients with elevated sCD44 levels was lower than in those with normal sCD44 levels (18 vs 48%, P < 0.05 and 18 vs 42%, P < 0.05 respectively) (Table 1Go). Furthermore, sCD44 levels correlated positively with %VC in patients with SSc (P<0.003, r=0.458; Fig. 2AGo). As patients with lSSc have been reported to exhibit a lower frequency of pulmonary fibrosis compared with those with dSSc [20], the correlation of sCD44 levels with better pulmonary function may be related to the association of elevated sCD44 levels with lSSc. However, sCD44 levels also correlated positively with %VC in lSSc patients alone (P < 0.01, r = 0.419; Fig. 2BGo). Correlation of organ involvement other than pulmonary fibrosis with sCD44 elevation was not observed in patients with lSSc (data not shown). In patients with dSSc, no significant association of elevated sCD44 levels with clinical features, including pulmonary fibrosis and lung function, was detected (data not shown). All five patients receiving treatment exhibited dSSc with normal sCD44 levels; four patients were treated with low-dose steroids and D-penicillamine and one patient with low-dose steroids only. However, the remaining 24 patients with dSSc and the lSSc patients did not receive treatment. Serum levels of sCD44 did not correlate with serum sCD31 levels, which were also elevated in patients with lSSc (data not shown) [10]. Thus, elevated sCD44 levels were associated with lSSc and a lower frequency and severity of pulmonary fibrosis.


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TABLE 1. Clinical and laboratory data of patients with SSc with elevated and normal serum sCD44 levels

 


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FIG. 2. The correlation of %VC with serum levels of sCD44 in patients with SSc (A) and those with lSSc (B). Serum sCD44 levels were determined with a specific ELISA.

 

Longitudinal study of sCD44 level
To assess changes in serum sCD44 level over time, 66 serum samples from 18 patients with SSc were analysed (Fig. 3Go). In Figure 3Go, closed symbols show dSSc patients while open symbols show lSSc patients. At their first visit, none of patients had been treated with steroids or D-penicillamine. Seven of eight patients (three patients with dSSc and four with lSSc) with elevated sCD44 levels at their first visit had stable or slightly increased levels during the follow-up period (Fig. 3AGo). In the one remaining dSSc patient, the sCD44 level decreased to the normal range during the follow-up. There was no clinical difference between patients showing stable or slightly increased sCD44 levels and a patient showing decreased sCD44 levels during follow-up. All four dSSc patients received low-dose steroids and two of four dSSc patients received low-dose D-penicillamine, and no lSSc patients received steroids or D-penicillamine. The dSSc patient showing decreased sCD44 levels during follow-up received low-dose steroids and D-penicillamine. In all SSc patients (four patients with dSSc and six with lSSc) with normal sCD44 levels at their first visit, sCD44 levels remained normal throughout the follow-up period (Fig. 3BGo). All four dSSc patients received low-dose steroids while two of four dSSc patients received low-dose D-penicillamine. In our longitudinal study, one of the patients had worsening skin sclerosis and developed new organ involvement during the observation period.



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FIG. 3. Serial changes in serum sCD44 level during the follow-up period in SSc patients with an elevated sCD44 level at their first visit (A) and those with a normal sCD44 level at their first visit (B). Serum sCD44 level was determined with a specific ELISA. Open symbols, patients with lSSc; closed symbols, patients with dSSc. Dashed lines indicate the cut-off value.

 


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This is the first report of elevated serum sCD44 levels in connective tissue diseases. In this study, sCD44 levels were increased in SSc patients but not in SLE patients and PM/DM patients. Remarkably, sCD44 levels were elevated in lSSc, a milder subset of SSc [20]. Moreover, elevated sCD44 levels were also associated with the lower prevalence of pulmonary involvement and better pulmonary function in patients with SSc, which was also observed in lSSc patients alone. The results of this study suggest that sCD44 may be a factor that prevents the development of skin sclerosis and pulmonary fibrosis in patients with SSc.

Elevation of sCD44 correlated with a milder subset of SSc. Furthermore, the longitudinal study revealed that sCD44 levels did not reflect the disease activity, as sCD44 levels in SSc patients were stable during the follow-up. By contrast, the other markers, such as von Willebrand factor, sICAM-1 and sVCAM-1, correlate with disease severity [79, 25]. Therefore, sCD44 differs from other markers in its clinical significance. SSc fibroblasts express intrinsically elevated levels of surface ICAM-1 and release a high level of sICAM-1 in vitro [26]. Because fibroblasts express CD44 on the cell surface [27], they may be a major source of sCD44. However, CD44 expression by SSc fibroblasts has been reported to be similar to that of normal fibroblasts [27] and CD44 shedding by SSc fibroblasts is unknown. It is unlikely that sCD44 levels reflected the amount or activation of fibroblasts, as elevated sCD44 levels were seen in a milder subset and sCD44 levels were stable longitudinally. Thus, there are differences in various aspects between sCD44 and other markers; the reason for this remains unknown. Nonetheless, our study suggests that sCD44 would be a novel predicting marker of a milder subset of SSc patients.

Our previous study revealed that elevated serum levels of sCD31, an adhesion molecule that functions during transendothelial migration, were also associated with lSSc [10]. Furthermore, elevated serum sCD31 levels, like elevated sCD44, correlated with the lower frequency of pulmonary involvement. Because a soluble chimera made of the first Ig domain of CD31 fused to the Fc portion of IgG blocks transendothelial migration both in vitro and in vivo [28] and sCD31 itself can inhibit CD31-mediated adhesive interactions [29], sCD31 may also play a protective role in SSc. However, our finding that sCD44 levels did not correlate with sCD31 levels suggests that sCD44 functions in a different way from sCD31. Nonetheless, soluble forms of these adhesion molecules are likely to act against the development of the disease.

The binding of CD44 to hyaluronan is critical during leucocyte migration into the inflammatory sites [11, 12]. Like other antibodies to adhesion molecules, such as ICAM-1 and VCAM-1, which regulate the migration of leucocytes into inflammatory sites, anti-CD44 monoclonal antibodies (mAbs) have been introduced for the treatment of autoimmune diseases in murine models [30]. IM7.8.1, an anti-CD44 mAb whose epitope lies outside the hyaluronan binding domain of CD44, suppresses the inflammatory symptoms in a murine model of rheumatoid arthritis [30]. Importantly, IM7.8.1 induces substantial CD44 shedding, which results in the elevation of serum sCD44 [30]. By contrast, administration of another anti-CD44 mAb, IRAWB14, which induces CD44-mediated hyaluronan binding activity, exacerbates the inflammatory symptoms of murine arthritis [30]. Furthermore, some other anti-CD44 mAbs have also been reported to modulate T-cell activation in vitro [31] and in vivo [14, 32]. However, while some anti-CD44 antibodies inhibit trafficking of leucocytes to sites of inflammation in organs, they essentially do not affect trafficking to lymph nodes, which consist mainly of naive cells. Therefore, CD44 may be considered to be a target for novel interventions for the treatment of autoimmune diseases, especially rheumatoid arthritis and SSc. In SSc patients, the expression of E-selectin and ICAM-1 by endothelial cells was increased [33]. These adhesion molecules are likely to be responsible for the adhesion of pathogenetic lymphocytes to activated endothelium and could be therapeutic targets in SSc patients. Similarly, CD44 could also be a therapeutic target, as expression of CD44 was increased in SSc lymphocytes [27]. In our longitudinal study, serum sCD44 levels were elevated throughout the follow-up in ~90% of SSc patients with elevated levels at their first visit, whereas sCD44 levels remained normal in all patients with normal levels at their first visit. These results suggest that the persistent elevation of serum sCD44 levels protects against the progression of SSc. Although the mechanisms for this protection are unknown, serum sCD44 may directly inhibit CD44-mediated leucocyte rolling by the binding of its receptor for hyaluronan, as other functional soluble adhesion molecules do [28, 29, 34, 35]. It is also possible that the loss of cell-surface CD44 on leucocytes by shedding prevents hyaluronan-dependent leucocyte–matrix interactions at the inflammatory sites. However, the effects of anti-CD44 mAbs on matrix–cell interactions and extracellular matrix biosynthesis remain unknown. Nonetheless, the results of this study suggest that the persistent administration of anti-CD44 reagents, such as IM7.8.1, is a potential therapy in patients with SSc.


    Notes
 
Correspondence to: S. Sato, Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. White B. Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am 1996;32:695–708.
  2. Furst DE, Clements PJ. Hypothesis for the pathogenesis of systemic sclerosis. J Rheumatol 1997;24(Suppl. 48):53–7.[ISI]
  3. Sato S. Abnormalities of adhesion molecules and chemokines in scleroderma. Curr Opin Rheumatol 1999;11:503–7.[Medline]
  4. Springer TA. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol 1995;57:827–72.[ISI][Medline]
  5. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 1991;67:1033–6.[ISI][Medline]
  6. DeLisser HM, Newman PJ, Albelda SM. Molecular and functional aspects of PECAM-1/CD31. Immunol Today 1994;15:490–5.[ISI][Medline]
  7. Ihn H, Sato S, Fujimoto M, Takehara K, Tamaki K. Increased serum levels of soluble vascular cell adhesion molecule-1 and E-selectin in patients with systemic sclerosis. Br J Rheumatol 1998;37:1188–92.[ISI][Medline]
  8. Denton CP, Bickerstaff MCM, Shiwen X et al. Serial circulating adhesion molecule levels reflect disease severity in systemic sclerosis. Br J Rheumatol 1995;34:1048–54.[ISI][Medline]
  9. Stratton RJ, Coghlan JG, Pearson JD et al. Different patterns of endothelial cell activation in renal and pulmonary vascular disease in scleroderma. Q J Med 1998;91:561–6.
  10. Sato S, Komura K, Hasegawa M, Fujimoto M, Takehara K. Clinical significance of soluble CD31 in patients with systemic sclerosis (SSc): Association with limited cutaneous SSc. J Rheumatol 2001;28:2460–5.[ISI][Medline]
  11. Drillenburg P, Pals ST. Cell adhesion receptors in lymphoma dissemination. Blood. 2000;95:1900–10.[Abstract/Free Full Text]
  12. DeGrendele HC, Estess P, Siegelman MH. Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 1997;278:672–5.[Abstract/Free Full Text]
  13. Haynes BF, Hale LP, Patton KL, Martin ME, McCallum RM. 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;34:1434–43.[ISI][Medline]
  14. Mikecz K, Brennan FR, Kim JH, Glant T. Anti-CD44 treatment abrogates tissue oedema and leukocyte infiltration in murine arthritis. Nature Med 1995;1:558–63.[ISI][Medline]
  15. Estess P, DeGrendele HC, Pascual V, Siegelman MH. Functional activation of lymphocyte CD44 in peripheral blood is a marker of autoimmune disease activity. J Clin Invest 1998;102:1173–82.[Abstract/Free Full Text]
  16. Guo YJ, Liu G, Wang X et al. Potential use of soluble CD44 in serum as indicator of tumor burden and metastasis in patients with gastric or colon cancer. Cancer Res 1994;54:422–6.[Abstract]
  17. Martin S, Jansen F, Bokelmann J, Kolb H. Soluble CD44 splice variants in metastasizing human breast cancer. Int J Cancer 1997;74:443–5.[ISI][Medline]
  18. De Rossi G, Marroni P, Paganuzzi M et al. Increased serum levels of soluble CD44 standard, but not of variant isoforms v5 and v6, in B cell chronic lymphocytic leukemia. Leukemia 1997;11:134–41.[ISI]
  19. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581–90.[ISI][Medline]
  20. LeRoy EC, Krieg T, Black C et al. Scleroderma (systemic sclerosis): classification, subsets, and pathogenesis. J Rheumatol 1988;15:202–5.[ISI][Medline]
  21. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.[ISI][Medline]
  22. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med 1975;292:344–7.[ISI][Medline]
  23. Steen VD, Powell DL, Medsger TAJ. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum 1988;31:196–203.[ISI][Medline]
  24. Sato S, Ihn H, Kikuchi K, Takehara K. Antihistone antibodies in systemic sclerosis: association with pulmonary fibrosis. Arthritis Rheum 1994;37:391–4.[ISI][Medline]
  25. Kahaleh MB, Osborn I, LeRoy EC. Increased factor 8/von Willebrand factor and von Willebrand activity in scleroderma and in Raynaud's phenomenon. Ann Intern Med 1981;94:482–4.[ISI][Medline]
  26. Shi-Wen X, Panesar M, Vancheeswaran R et al. Expression and shedding of intercellular adhesion molecule 1 and lymphocyte function-associated antigen 3 by normal and scleroderma fibroblasts. Effects of interferon-gamma, tumor necrosis factor alpha, and estrogen. Arthritis Rheum 1994;37:1689–97.[ISI][Medline]
  27. Koch EK, Kronfeld-Harrington LB, Szekanecz Z et al. In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Pathobiology 1993;61:239–46.[ISI][Medline]
  28. Liao F, Ali J, Greene T, Muller WA. Soluble domain 1 of platelet-endothelial cell adhesion molecule (PECAM) is sufficient to block transendothelial migration in vitro and in vivo. J Exp Med 1997;185:1349–57.[Abstract/Free Full Text]
  29. Goldberger A, Middleton KA, Oliver JA et al. Biosynthesis and processing of the cell adhesion molecule PECAM-1 includes production of a soluble form. J Biol Chem 1994;269:17183–91.[Abstract/Free Full Text]
  30. Mikecz K, Dennis K, Shi M, Kim JH. Modulation of hyaluronan receptor (CD44) function in vivo in a murine model of rheumatoid arthritis. Arthritis Rheum 1999;42:659–68.[ISI][Medline]
  31. Rothmann BL, Blue M-L, Kelley KA, Wunderlich D, Mierz DV, Aune TM. Human T cell activation by OKT3 is inhibited by a monoclonal antibody to CD44. J Immunol 1991;147:2493–9.[Abstract/Free Full Text]
  32. Verdrengh M, Holmdahl R, Tarkowski A. Administration of antibodies to hyaluronan receptor (CD44) delays the start and ameliorates the severity of collagen II arthritis. Scand J Immunol 1995;42:353–8.[ISI][Medline]
  33. Sollberg S, Peltonen J, Uitto J, Jimenez SA. Elevated expression of beta 1 and beta 2 integrins, intercellular adhesion molecule 1, and endothelial leukocyte adhesion molecule 1 in the skin of patients with systemic sclerosis of recent onset. Arthritis Rheum 1992;35:290–8.[ISI][Medline]
  34. Watson SR, Fennie C, Lasky LA. Neutrophil influx into an inflammatory site inhibited by a soluble homing receptor–IgG chimera. Nature 1991;349:164–7.[ISI][Medline]
  35. Gamble JR, Skinner MP, Berndt MC, Vadas MA. Prevention of activated neutrophil adhesion to endothelium by soluble adhesion protein GMP. Science 1990;249:414–7.[ISI][Medline]
Submitted 30 October 2001; Accepted 16 April 2002





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