Scandinavian Journal of Rheumatology
ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20
Soluble Interfeukin-2 Receptors in Children with Juvenile Chronic Arthritis K. Fassbender, H. Michels, P. Vogt, A. Aeschlimann & W. Müller To cite this article: K. Fassbender, H. Michels, P. Vogt, A. Aeschlimann & W. Müller (1992) Soluble Interfeukin-2 Receptors in Children with Juvenile Chronic Arthritis, Scandinavian Journal of Rheumatology, 21:3, 120-123, DOI: 10.3109/03009749209095082 To link to this article: http://dx.doi.org/10.3109/03009749209095082
Published online: 12 Jul 2009.
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Date: 17 March 2016, At: 02:59
Soluble Interfeukin-2 Receptors in Children with Juvenile Chronic Arthritis K. Fassbender1.2.H. Michels3, P. Vogt’, A. Aeschlimann’ and W. Mliller’~2 ‘Department of Rheumatology, University Hospital, Felix-Platter-Spital, Basel, Switzerland; 2Hochrheininstitutof Rheumatism Research, Bad Sackingen, Germany; 3Pediatric Rheumatology Center, Garmisch-Partenkirchen,Germany
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Fassbender K., Michels H, Vogt P, Aeschlimann A, Miiller W. Soluble Interleukin-2 Receptors in Children with Juvenile Chronic Arthritis. Scand J Rheumatol 1992; 21: 120-23. Concentrations of interleukin-2 receptors were studied in sera of 81 patients with pauciarticular-, polyarticular-, and systemiconset juvenile chronic arthritis using a double antibody “sandwich” enzyme-linked immunosorbent technique. Serum concentrations were significantly increased in all subgroups when compared with the healthy controls. Higher concentrations were found in systemic onset disease than in pauci- or polyarticular onset disease. Serum levels were found to be increased in both inactive and active disease, showing maximal values in patients with systemic features. A correlation to C-reactive protein, alpha,-acid glycoprotein, and erythrocyte sedimentation was observed. Increased s L 2 R values suggest disease activity despite the absence of clinical symptoms.
Key words: soluble interleukin-2 receptor, juvenile chronic arthritis, acute-phase proteins
Juvenile chronic arthritis (JCA) describes a heterogeneous group of inflammatory rheumatic disorders in childhood, characterized by the presence of arthritis with or without extraarticular manifestations (1). Three major subgroups have been recognized on the basis of clinical features within the first 6 months of disease: pauciarticular-, polyarticular-, and systemic- onset JCA. Upon inflammatory stimuli, antigen-reactive Tcell populations proliferate dependent on sequential induction and expression of interleukin-2 and interleukin-2 receptors (2, 3). In addition to the surface expression of the interleukin-2 receptor, T-lymphocytes also release a soluble form of this glycoprotein (4) (sIL2R, 45000 Dalton) considered to be an early marker for immune stimulation (5). A rise in serum levels of sIL2R has been observed following acute bum injury (6), infections (7,s) hematologic cancers (9), and inflammatory rheumatic diseases such as rheumatoid arthritis (10,11, 12), systemic lupus erythematosus (13), or juvenile chronic arthritis (14). The aim of this study was to investigate the serum concentration of sIL2R in subtypes of JCA, and to assess its relation to clinical and laboratory parameters of disease activity.
K. Fassbender, Max-Planck-Institute, Clinic, Kraepelin Str. 10, D-8000 - Munich 40, Germany Received 22 July 1991 Accepted 9 December 1991
120
Patients and methods Study groups
The study groups consisted of 81 children (57 females and 24 males) with pauci- (n = 53), polyarticular (n = 6) and systemic onset (n = 22) juvenile chronic arthritis (JCA), consecutively admitted to the Rheumatic Children’s Hospital (GarmischPartenkirchen, FRG) between 2/1989 and 10/1990 and meeting the standard criteria for diagnosis (15). Their demographic characteristics are shown in Table I. Patients with spondylarthropathies, or those exhibiting a positive HLA B-27 were excluded. Clinical and laboratory parameters were assessed in a blinded fashion. Active disease was defined by symptoms of active arthritis (swelling, or if swelling was not present, limitation of motion, accompagnied by pain or tenderness) with or without presence of systemic features such as fever, rash, lymphadenopathy, pericarditis, leucocytosis. As controls, 16 healthy children were investigated (Table I). Patients with JCA were treated with nonsteroidal antiinflammatory drugs (n = 66), prednisone (n = 17), azathioprine (n = 26), aurothiomalate (n = 7), methotrexate (n = 17), chloroquine (n = 21), or gamma-globulins (n = 1) in varying doses and combinations. Prednisone was given to 12 patients with systemic onset disease and to 5 patients with pauciarticular onset disease.
Soluble interleukin-2 receptors in JCA Table 1. Clinical characteristics of study population ~~
~~~
Clinical diagnosis (number)
Healthy controls (16) Pauciarticular onset JW (53) Polyarticular onset JCA (6) Systemic onset JCA (22)
~~
Median age (range)
7 (3-15) 9 11-21] 14.7 (3-23) 5.5 (2-14)
Wm
Median duration (years) of disease (range)
8/8
Disease course*
Disease activity** inactivelactive (-$active
Pauci
Poly
39 1 0
14 5 8
NA
NA
42/11 4 (0.5-14) 6/0 6.5(1-8) 9113 2 (0.5-14)
its)
Systemic NA
1 9/34/0
0
1/
!i/o
I/ 8/13
14
Downloaded by [RMIT University Library] at 02:59 17 March 2016
JCA" = juvenile chronic arthritis, NA = not applicable * Pauci = pauciarticular, poly = polyarticular ** active (-s) = active disease without systemic features active ( t s ) = active disease with systemic features
Quantification of acute phase proteins and erythrocyte sedimentation rate (ESR). Serum concentrations of C-reactive protein were measured by an enzyme- immunoassay (EMIT, C-reactive protein assay, Merck Diagnostica, Zurich, Switzerland). Serum levels of alpha,-acid glycoprotein were assessed by rocket immunoelectrophoresis as described by Laurel1 (16). ESR was measured according to the Westergren method with values recorded after one hour.
sIL2R measurement sIG2R in serum was measured by means of an enzyme-immunoassay according to the method employed by Rubin et al. (4). Reagents were purchased from T-cell Sciences, Cambridge MA, USA, and the procedure was performed as recommended by the manufacturer. Briefly, the murine monoclonal anti-sIL2R antibody was adsorbed onto a plastic well and the sIL2R in the specimen 4000,
.
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*
rir
.
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-
DISEASE ACT1 IITY
PAUCI ARTICULAR ONSET JCA
POLYAlTlCULM OWSET JCA
SYmrlC OlSET JCA
(53)
(61
(221
INACTIVE
Fig. 1. Serum concentrations of soluble interleukin-2 receptor (sIL2R) in sera of healthy controls, and patients with pauciarticular, polyarticular, and systemic onset juvenile chronic arthritis (JCA).
ACTIVE
(+I) (21)
66)
ACTIVE
( 47)
(131
Fig. 2. Serum concentrations of interleukin-2 receptor (sIG2R) in sera of patients with clinically inactive, active disease without (active) and with (active s) systemic features. Closed circles = pauci- and polyarticular onset disease; open circles = systemic onset disease.
+
121
K. Fassbender et al.
+
Table It. Serum concentrations (mean SEM) of soluble interleukin-2 receptor and acute phase proteins in children with juvenile chronic arthritis and healthy controls ~
Clinical diagnosis
Soluble interleukin-2 receptor (Unitdml)
C-reactive protein (mgll)
Alpha,-acid glycoprotein (gal
Erythrocyte sedimentation rate (mmlh)
Healthy controls (n = 16) Pauciarticular onset JCA* (n = 53) Polyarticular onset JCA (n = 6) Systemic onset JCA In = 22)
560.17f53.70 1055.23?61.54afb 1216.97f292.25a 1880.98+172.46a
n.d.** 6.6+1.4b 1O.5f3.Ec 83.1f12.1
n.d. 1.13+0.07b 1.21f0.1gC 1.96f0.13
n.d. 13.81 f2.73' 21.20+6.62' 44.05k4.61
* JCA = juvenile chronic arthritis ** n.d. = not determined a p < 0.001 compared with healthy controls, ' p < 0.001 compared with systemic onset JCA,
Downloaded by [RMIT University Library] at 02:59 17 March 2016
p < 0.05 compared with systemic onset JCA
was bound to it. A second murine monoclonal anti-sIL-2R antibody conjugated to horseradish peroxidase was bound to a different site. The enzyme-substrate reaction resulted in a color formation, which was measured at 490 nm. Final values were expressed in units/ml; the reference is defined by the manufacturer to be the amount of sIL-2R present in the supernatant of a standard preparation of phytohemagglutininstimulated peripheral lymphocytes.
Statistical analysis Results are presented as mean k standard error of mean (SEM). Data were compared by the Kruskal Wallis Test and thereafter by the t-test. Results
Clinical parameters Patients with pauciarticular onset JCA exhibited inactive (n = 9) and active disease (n = 34), but none had systemic features. Children with polyarticular onset JCA had inactive (n = 1) and active disease (n = 5 ) , none of them had systemic disease. Systemic onset JCA patients had inactive disease (n = l), active disease without systemic
features (n = 8), and active disease with a severe systemic disease (n = 13). Systemic features at the time of blood sampling included fever (n = S), hepatosplenomegaly (n = 8), pericardial effusion (n = 7), and rash (n = 5 ) .
Concentrations of sIL-2R Levels of sIG2R in JCA were 1287.42 k 74.18 U/ml (mean SEM). This was significantly higher than the values in the control group (560.17 k 53.70 U/ml; p < 0.001). Table I1 shows the results in subtypes of JCR. Table I11 presents the result in relation to disease activity. The individual values in subtypes and disease activity are presented in Fig. 1 and 2, respectively. Children with JCA exhibiting clinically inactive diseases had significantly higher levels of sIL-2R than the controls (p < 0.001). Levels in active disease without systemic features were significantly increased compared to inactive disease (p < 0.01), however lower than in systemic disease (p < 0.001).
*
ESR and acute phase proteins Tables I1 and I11 show the values of acute phase parameters in relation to the subtypes of disease and disease activity. Levels of sIL-2R in serum
Table 111. Concentrations (mean ? SEM) of soluble interleukin-2 receptor and acute-phase proteins in children with juvenile rheumatoid arthritis in relation to disease activity Parameter
Soluble interleukin-2 receptor (Unitdml) C-reactive protein (mgll) Alpha-acid glycoprotein (glt) Erythrocyte sedimentation rate (mmlh)
* active = active disease without systemic features
**
a
active its)= active disease with systemic features p < 0.01 compared with inactive disease p < 0.001 compared with systemic disease p < 0.05 compared with inactive disease
122
Disease activity Inactive
Active*
Active (ts)**
880.58k61.75 3.4+ 1.3 0.90t0.06 8.24f 1.14
1214.1Of53.70"' 16.9t3.4C*b 1,34k0.08a*h 20.69k2.30"'
2171.1 3f884.36 104.0k16.8 2.14+0.13 51.15k4.91
Soluble interleukin-2 receptors in JCA
correlated with serum concentrations of CRP (r = 0.564; p < O.OOl), AGP (r = 0.580; p C O.OOl), and ESR (r = 0.487; p = 0.487; p 4 0.001).
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Discussion
In this study, patients with inactive disease showed significantly increased serum levels of sIL-2R compared to healthy controls. Active disease without systemic features gave higher levels than inactive disease, whereas disease with systemic manifestations exhibited the highest values. The elevated concentrations of sIL-2R in inactive disease suggest an immunoactivation even in clinically inappearent instances. The highest values of systemic disease point to maximal immunostimulation. The results show significant differences between concentrations of sIL-2R in subgroups of JCA. Pauci- and polyarticular onset disease show lower values than systemic onset disease. Different concentrations of sIG2R in subtypes of JCA may be explained by the different distribution of disease activity within each subtype. It therefore seems that values of sIL2R are not indicative for a certain subtype of JCA. Although interleukin-2 receptors have not been observed on the surface of isolated T-cells in active JCA (17), elevated levels of sIL-2R in patients with JCA have been reported previously (14). A significant difference between levels of sIL-2R in systemic onset and oligo-, or polyarticular onset disease has not, to our knowledge, been described. A strong correlation of sIL-2R and the laboratory indicators of acute-phase reaction was found. This may be explained by the central role of inflammatory cytokines such as IL-1 in the induction of the hepatic acute-phase protein synthesis (18) as well as in the expression of interleukin-2 receptor at the T-cell surface (19). Previous studies have described a number of immunoregulatory disorders in patients with JCA (17,20,21). Of great interest is the observation of decreased interleukin-2 production in JCA (21). Since sIG2R binds this cytokine, it may be involved in the debilitated immune system. In conclusion, all subtypes of JCA showed increased levels of sIL-2R. Elevated values were also found in inactive disease and reflect immuneactivation even in clinically inactive JCA. Maximal values were observed in active disease with systemic features, indicating the highest immuneactivation . References 1. Ansell BM. Chronic arthritis in childhood. Ann Rheum Dis 1978; 37: 107-20.
2. Cantrell DA, Smith KA. Transient expression of interleukin-2 receptors. Consequences for T cell growth. J Exp Med 1983; 158: 1895-911. 3. Robb RJ, Greene WC. Direct demonstration of the identify of T-cell growth factor binding protein and the Tac antigen. J Exp Med 1983; 158: 1332-7. 4. Rubin LA, Kurman CC, Fritz ME et al. Soluble interleukin-2 receptors are released from activated human lymphoid cells in vitro. J Immunol 1985; 135: 3172-7. 5. Robb JR, Munck RA, Smith KA. T-cell growth factor receptors: Quantification, specificity and biological relevance. J Exp Med 1981; 154: 1455-74. 6. Theodorczyk-Injeyan JA, Sparkes BG, Mills GB, Falk RE, Peters WJ. Increase of serum interleukin-2 receptor levels in thermal injured patients. Clin Immunol Immunopathol 1989; 51: 205-13. 7. Boutin B, Matsuguchi L, Lebon P, Ponsot G, Arthuis M, Nelson DL. Soluble interleukin-2 receptors in acute and subacute encephalitis. Ann Neurol 1987; 658-61. 8. Griffin DE, Ward BJ, Jauregui E, Johnson RT, Vaisberg A. Immune activation in measles. N Engl J Med 1989; 320: 1667-72. 9. Pizzolo G , Chilosi M, Semenzato G . The soluble interleukin-2. receptor in hematological disorders. Br J Haematol 1987; 67: 377-80. 10. Symons JA, Wood NC, Di Giovine FS, Duff GW. Soluble interleukin-2 receptors in rheumatoid arthritis: correlation with disease activity, IL1 and IL-2 inhibition. J Immunol 1988; 141: 2612-8. 11. Herzog C, Aeschlimann A, Seibel M, Muller W. Soluble serum interleukin-2 receptors as a new marker for active rheumatoid arthritis? (abstract) Clin Exp Rheumatol 1987; 5: 234. 12. Keystone EC, Snow KM, Bombardier C, Chang C-H, Nelson DL, Rubin LA. Elevated soluble interleukin-2 receptor levels in the sera and synovial fluids of patients with rheumatoid arthritis. Arthritis Rheum 1988; 31: 844-9. 13. Wolfe RE, Brelsford WG. Soluble interleukin-2 receptors in systemic lupus erythematosus. Arthritis Rheum 1988; 31: 729-35. 14. Barron KS, Montalvo JF, Saadeh CK, Orson FM. Soluble interleukin-2 receptors (IL-2R) in children with juvenile rheumatoid arthritis (JRA). (abstract). Arthritis Rheum 1988 (suppl.) 31: B109. 15. Wood PHN. Special meeting on nomenclature and classification of arthritis. In: Munthe E. ed. The care of rheumatic children. Vol. 3, Basel: EULAR, 1978: 47-50. 16. Laurel1 CB. Quantitative estimation of proteins by electrophoresis in agarosegel containing antibodies. Anal Biochem 1966; 15: 45-52. 17. Oedum N, Morling N, Platz P, et al. Increased prevalence of late stage T cell activation antigen (VLA-1) in active chronic arthritis. Ann Rheum Dis 1987; 46: 846-52. 18. Dinarello CA. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med 1984; 311: 1413-8. 19. Kaye J, Gillis S, Mitzel SB et al. Growth of a cloned helper T-cell line induced by a monoclonal antibody specific for the antigen receptor. Interleukin-1 is required for the expression of receptors for interleukin-2. J Immunol 1984; 33: 1339. 20. Barron KS, Decunto CL, Montalovo JF, Orson FM, Lewis DE. Abnormalities of immunoregulation in juvenile rheumatoid arthritis. J Rheumatol 1989; 16: 940-8. 21. Martini A, Ravelli A, Notarangelo LD et al. Enhanced interleukin-1 and depressed interleukin-2 production in juvenile arthritis. J Rheumatol 1986; 13: 598-603.
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ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20
Soluble Interfeukin-2 Receptors in Children with Juvenile Chronic Arthritis K. Fassbender, H. Michels, P. Vogt, A. Aeschlimann & W. Müller To cite this article: K. Fassbender, H. Michels, P. Vogt, A. Aeschlimann & W. Müller (1992) Soluble Interfeukin-2 Receptors in Children with Juvenile Chronic Arthritis, Scandinavian Journal of Rheumatology, 21:3, 120-123, DOI: 10.3109/03009749209095082 To link to this article: http://dx.doi.org/10.3109/03009749209095082
Published online: 12 Jul 2009.
Submit your article to this journal
Article views: 3
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=irhe20 Download by: [RMIT University Library]
Date: 17 March 2016, At: 02:59
Soluble Interfeukin-2 Receptors in Children with Juvenile Chronic Arthritis K. Fassbender1.2.H. Michels3, P. Vogt’, A. Aeschlimann’ and W. Mliller’~2 ‘Department of Rheumatology, University Hospital, Felix-Platter-Spital, Basel, Switzerland; 2Hochrheininstitutof Rheumatism Research, Bad Sackingen, Germany; 3Pediatric Rheumatology Center, Garmisch-Partenkirchen,Germany
Downloaded by [RMIT University Library] at 02:59 17 March 2016
Fassbender K., Michels H, Vogt P, Aeschlimann A, Miiller W. Soluble Interleukin-2 Receptors in Children with Juvenile Chronic Arthritis. Scand J Rheumatol 1992; 21: 120-23. Concentrations of interleukin-2 receptors were studied in sera of 81 patients with pauciarticular-, polyarticular-, and systemiconset juvenile chronic arthritis using a double antibody “sandwich” enzyme-linked immunosorbent technique. Serum concentrations were significantly increased in all subgroups when compared with the healthy controls. Higher concentrations were found in systemic onset disease than in pauci- or polyarticular onset disease. Serum levels were found to be increased in both inactive and active disease, showing maximal values in patients with systemic features. A correlation to C-reactive protein, alpha,-acid glycoprotein, and erythrocyte sedimentation was observed. Increased s L 2 R values suggest disease activity despite the absence of clinical symptoms.
Key words: soluble interleukin-2 receptor, juvenile chronic arthritis, acute-phase proteins
Juvenile chronic arthritis (JCA) describes a heterogeneous group of inflammatory rheumatic disorders in childhood, characterized by the presence of arthritis with or without extraarticular manifestations (1). Three major subgroups have been recognized on the basis of clinical features within the first 6 months of disease: pauciarticular-, polyarticular-, and systemic- onset JCA. Upon inflammatory stimuli, antigen-reactive Tcell populations proliferate dependent on sequential induction and expression of interleukin-2 and interleukin-2 receptors (2, 3). In addition to the surface expression of the interleukin-2 receptor, T-lymphocytes also release a soluble form of this glycoprotein (4) (sIL2R, 45000 Dalton) considered to be an early marker for immune stimulation (5). A rise in serum levels of sIL2R has been observed following acute bum injury (6), infections (7,s) hematologic cancers (9), and inflammatory rheumatic diseases such as rheumatoid arthritis (10,11, 12), systemic lupus erythematosus (13), or juvenile chronic arthritis (14). The aim of this study was to investigate the serum concentration of sIL2R in subtypes of JCA, and to assess its relation to clinical and laboratory parameters of disease activity.
K. Fassbender, Max-Planck-Institute, Clinic, Kraepelin Str. 10, D-8000 - Munich 40, Germany Received 22 July 1991 Accepted 9 December 1991
120
Patients and methods Study groups
The study groups consisted of 81 children (57 females and 24 males) with pauci- (n = 53), polyarticular (n = 6) and systemic onset (n = 22) juvenile chronic arthritis (JCA), consecutively admitted to the Rheumatic Children’s Hospital (GarmischPartenkirchen, FRG) between 2/1989 and 10/1990 and meeting the standard criteria for diagnosis (15). Their demographic characteristics are shown in Table I. Patients with spondylarthropathies, or those exhibiting a positive HLA B-27 were excluded. Clinical and laboratory parameters were assessed in a blinded fashion. Active disease was defined by symptoms of active arthritis (swelling, or if swelling was not present, limitation of motion, accompagnied by pain or tenderness) with or without presence of systemic features such as fever, rash, lymphadenopathy, pericarditis, leucocytosis. As controls, 16 healthy children were investigated (Table I). Patients with JCA were treated with nonsteroidal antiinflammatory drugs (n = 66), prednisone (n = 17), azathioprine (n = 26), aurothiomalate (n = 7), methotrexate (n = 17), chloroquine (n = 21), or gamma-globulins (n = 1) in varying doses and combinations. Prednisone was given to 12 patients with systemic onset disease and to 5 patients with pauciarticular onset disease.
Soluble interleukin-2 receptors in JCA Table 1. Clinical characteristics of study population ~~
~~~
Clinical diagnosis (number)
Healthy controls (16) Pauciarticular onset JW (53) Polyarticular onset JCA (6) Systemic onset JCA (22)
~~
Median age (range)
7 (3-15) 9 11-21] 14.7 (3-23) 5.5 (2-14)
Wm
Median duration (years) of disease (range)
8/8
Disease course*
Disease activity** inactivelactive (-$active
Pauci
Poly
39 1 0
14 5 8
NA
NA
42/11 4 (0.5-14) 6/0 6.5(1-8) 9113 2 (0.5-14)
its)
Systemic NA
1 9/34/0
0
1/
!i/o
I/ 8/13
14
Downloaded by [RMIT University Library] at 02:59 17 March 2016
JCA" = juvenile chronic arthritis, NA = not applicable * Pauci = pauciarticular, poly = polyarticular ** active (-s) = active disease without systemic features active ( t s ) = active disease with systemic features
Quantification of acute phase proteins and erythrocyte sedimentation rate (ESR). Serum concentrations of C-reactive protein were measured by an enzyme- immunoassay (EMIT, C-reactive protein assay, Merck Diagnostica, Zurich, Switzerland). Serum levels of alpha,-acid glycoprotein were assessed by rocket immunoelectrophoresis as described by Laurel1 (16). ESR was measured according to the Westergren method with values recorded after one hour.
sIL2R measurement sIG2R in serum was measured by means of an enzyme-immunoassay according to the method employed by Rubin et al. (4). Reagents were purchased from T-cell Sciences, Cambridge MA, USA, and the procedure was performed as recommended by the manufacturer. Briefly, the murine monoclonal anti-sIL2R antibody was adsorbed onto a plastic well and the sIL2R in the specimen 4000,
.
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*
rir
.
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I
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llEALTRY
connow
-
DISEASE ACT1 IITY
PAUCI ARTICULAR ONSET JCA
POLYAlTlCULM OWSET JCA
SYmrlC OlSET JCA
(53)
(61
(221
INACTIVE
Fig. 1. Serum concentrations of soluble interleukin-2 receptor (sIL2R) in sera of healthy controls, and patients with pauciarticular, polyarticular, and systemic onset juvenile chronic arthritis (JCA).
ACTIVE
(+I) (21)
66)
ACTIVE
( 47)
(131
Fig. 2. Serum concentrations of interleukin-2 receptor (sIG2R) in sera of patients with clinically inactive, active disease without (active) and with (active s) systemic features. Closed circles = pauci- and polyarticular onset disease; open circles = systemic onset disease.
+
121
K. Fassbender et al.
+
Table It. Serum concentrations (mean SEM) of soluble interleukin-2 receptor and acute phase proteins in children with juvenile chronic arthritis and healthy controls ~
Clinical diagnosis
Soluble interleukin-2 receptor (Unitdml)
C-reactive protein (mgll)
Alpha,-acid glycoprotein (gal
Erythrocyte sedimentation rate (mmlh)
Healthy controls (n = 16) Pauciarticular onset JCA* (n = 53) Polyarticular onset JCA (n = 6) Systemic onset JCA In = 22)
560.17f53.70 1055.23?61.54afb 1216.97f292.25a 1880.98+172.46a
n.d.** 6.6+1.4b 1O.5f3.Ec 83.1f12.1
n.d. 1.13+0.07b 1.21f0.1gC 1.96f0.13
n.d. 13.81 f2.73' 21.20+6.62' 44.05k4.61
* JCA = juvenile chronic arthritis ** n.d. = not determined a p < 0.001 compared with healthy controls, ' p < 0.001 compared with systemic onset JCA,
Downloaded by [RMIT University Library] at 02:59 17 March 2016
p < 0.05 compared with systemic onset JCA
was bound to it. A second murine monoclonal anti-sIL-2R antibody conjugated to horseradish peroxidase was bound to a different site. The enzyme-substrate reaction resulted in a color formation, which was measured at 490 nm. Final values were expressed in units/ml; the reference is defined by the manufacturer to be the amount of sIL-2R present in the supernatant of a standard preparation of phytohemagglutininstimulated peripheral lymphocytes.
Statistical analysis Results are presented as mean k standard error of mean (SEM). Data were compared by the Kruskal Wallis Test and thereafter by the t-test. Results
Clinical parameters Patients with pauciarticular onset JCA exhibited inactive (n = 9) and active disease (n = 34), but none had systemic features. Children with polyarticular onset JCA had inactive (n = 1) and active disease (n = 5 ) , none of them had systemic disease. Systemic onset JCA patients had inactive disease (n = l), active disease without systemic
features (n = 8), and active disease with a severe systemic disease (n = 13). Systemic features at the time of blood sampling included fever (n = S), hepatosplenomegaly (n = 8), pericardial effusion (n = 7), and rash (n = 5 ) .
Concentrations of sIL-2R Levels of sIG2R in JCA were 1287.42 k 74.18 U/ml (mean SEM). This was significantly higher than the values in the control group (560.17 k 53.70 U/ml; p < 0.001). Table I1 shows the results in subtypes of JCR. Table I11 presents the result in relation to disease activity. The individual values in subtypes and disease activity are presented in Fig. 1 and 2, respectively. Children with JCA exhibiting clinically inactive diseases had significantly higher levels of sIL-2R than the controls (p < 0.001). Levels in active disease without systemic features were significantly increased compared to inactive disease (p < 0.01), however lower than in systemic disease (p < 0.001).
*
ESR and acute phase proteins Tables I1 and I11 show the values of acute phase parameters in relation to the subtypes of disease and disease activity. Levels of sIL-2R in serum
Table 111. Concentrations (mean ? SEM) of soluble interleukin-2 receptor and acute-phase proteins in children with juvenile rheumatoid arthritis in relation to disease activity Parameter
Soluble interleukin-2 receptor (Unitdml) C-reactive protein (mgll) Alpha-acid glycoprotein (glt) Erythrocyte sedimentation rate (mmlh)
* active = active disease without systemic features
**
a
active its)= active disease with systemic features p < 0.01 compared with inactive disease p < 0.001 compared with systemic disease p < 0.05 compared with inactive disease
122
Disease activity Inactive
Active*
Active (ts)**
880.58k61.75 3.4+ 1.3 0.90t0.06 8.24f 1.14
1214.1Of53.70"' 16.9t3.4C*b 1,34k0.08a*h 20.69k2.30"'
2171.1 3f884.36 104.0k16.8 2.14+0.13 51.15k4.91
Soluble interleukin-2 receptors in JCA
correlated with serum concentrations of CRP (r = 0.564; p < O.OOl), AGP (r = 0.580; p C O.OOl), and ESR (r = 0.487; p = 0.487; p 4 0.001).
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Discussion
In this study, patients with inactive disease showed significantly increased serum levels of sIL-2R compared to healthy controls. Active disease without systemic features gave higher levels than inactive disease, whereas disease with systemic manifestations exhibited the highest values. The elevated concentrations of sIL-2R in inactive disease suggest an immunoactivation even in clinically inappearent instances. The highest values of systemic disease point to maximal immunostimulation. The results show significant differences between concentrations of sIL-2R in subgroups of JCA. Pauci- and polyarticular onset disease show lower values than systemic onset disease. Different concentrations of sIG2R in subtypes of JCA may be explained by the different distribution of disease activity within each subtype. It therefore seems that values of sIL2R are not indicative for a certain subtype of JCA. Although interleukin-2 receptors have not been observed on the surface of isolated T-cells in active JCA (17), elevated levels of sIL-2R in patients with JCA have been reported previously (14). A significant difference between levels of sIL-2R in systemic onset and oligo-, or polyarticular onset disease has not, to our knowledge, been described. A strong correlation of sIL-2R and the laboratory indicators of acute-phase reaction was found. This may be explained by the central role of inflammatory cytokines such as IL-1 in the induction of the hepatic acute-phase protein synthesis (18) as well as in the expression of interleukin-2 receptor at the T-cell surface (19). Previous studies have described a number of immunoregulatory disorders in patients with JCA (17,20,21). Of great interest is the observation of decreased interleukin-2 production in JCA (21). Since sIG2R binds this cytokine, it may be involved in the debilitated immune system. In conclusion, all subtypes of JCA showed increased levels of sIL-2R. Elevated values were also found in inactive disease and reflect immuneactivation even in clinically inactive JCA. Maximal values were observed in active disease with systemic features, indicating the highest immuneactivation . References 1. Ansell BM. Chronic arthritis in childhood. Ann Rheum Dis 1978; 37: 107-20.
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