Interleukin-10, Interleukin- 16 and Interferon-Γ in Serum of Patients with Rheumatoid Arthritis and Correlation with Disease Activity

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provided by Directory of Open Access Journals The Egyptian Journal of Hospital Medicine Vol., 20: 46 – 57 September 2005 I.S.S.N: 12084 1687 –2002

Interleukin-10, Interleukin- 16 and Interferon-γ in serum of patients with rheumatoid arthritis and correlation with disease activity

Eman.M.Abdel Rahman, Hamdia.Ezzat, Maha M Abdel Mohsen, Karema Yosef Clinical pathology& Internal Medicine Departments, Faculty of Medicine for girls, Al Azhar University Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory disease of unknown etiology. The rheumatoid synovium is characterized by infiltration of T cells, macrophage, B cells, and proliferating fibroblasts which aggressively invade cartilage and bone, thus destroying joints' ability to function. In rheumatoid arthritis (RA) both an imbalance between excessive production of the proinflamatory and ant-inflammatory cytokines and skewing of the T cell to a T helper like response. Cytokines have been shown to play a modulatory role in the pathogenesis of RA. The imunoregulatory cytokine IL-10 increases autoantibody production by B cell stimulates its survival, proliferation and differentiation. Moreover IL-10 inhibits the generation of proinflamatory cytokines and proliferation of T helper lymphocyte. Interleukin 16 might play a role in the pathogenesis of chronic inflammation in RA. It has a proinflammatory properties by promoting recruitment of T cells into the rheumatoid synovium. Also IFN-γ is of interest because of the role it plays in the initiation and perpetuation of T helper cell . Serum level of IL-10, IL-16, and IFN-γ were determined in patients with rheumatoid arthritis in relation to disease activity. All patients with RA (n=30) showed highly significant increase in ESR, CRP, IL-10, IL- 16, IFNγ compared to control group (p<0.01). Positive correlation were found between IL-10 and each IL-16 and IFN-γ (p<0.001) (r=0.63, 0.55) respectively, and highly significant correlation between IL-16 and IFNγ (p<0.001) (r=0.89)were determined. Results showed positive correlation between ESR and each IL-10, IL-16, IFNγ (p<0.001) (r=0.67, 0.87, 0.75) respectively. And highly significant correlation between CRP and each IL- 10, IL-16, IFNγ (p<0.001) (r=0.0.71, 0.83, 0.73) which indicate relation between increase level of cytokine with disease activity. These data suggest that there is increased production of IL-10, IL-16, and IFN-γ in patients with rheumatoid arthritis, and that it is correlated with the disease activity. These cytokines are interesting for further research and novel therapeutic approach in this inflammatory disease.

Introduction

Rheumatoid arthritis (RA) is inflam- In RA, the cytokines resulting from matory disease of unknown etiology chara-- this cellular infiltration greatly influence the cterized by destruction of joints (Verhoef et outcome of disease. Macrophage generally al;2001). Activation and infiltration of express higher levels of cytokines than immunologic cells, including macrophage lymphocyte in RA, while the lymphocyte and lymphocytes, are prominent features of contribution to inflammatory and/or joint chronic inflammation in rheumatoid destructive process may be more indirect arthritis (Scola et al;2002). (Panayi et al;1992).

46 Eman.M.Abdel Rahman et al

Two subsets of T cells are recognized lymphocyte, usually T-lymphocytes by their ability to produce different types of (Boehm et al;1997). IFN- γ can down-regu- cytokines. Th1 cell activity characterized late parameters of joint destruction such as by IFN-γ production participates in macro- IL-1, matrix metalloproteinase and prolife- phage activation and thereby causes joint ration of fibroblast- like synoviocytes (FLS) destruction (Verhoef et al;2001) (Moller et al;2003). Th2 cells selectively produces IL-4, IL-5, IL-6, IL-10 and IL-13, these cytokines Aim of the work mediate transformation of B- lymphocytes Is to determine the level of IL-10, IL- into antibody producing plasma cells 16, and IFNγ in serum of patients with (Libula et al;1995).The balance between T1 rheumatoid arthritis and assessing their role and T2 cells regulates the production of with disease activity. pro- and anti-inflammatory cytokines (Verhoef et al;2001) Patients and methods Systemic clinical signs of rheumatoid, Subjects: such as the acute phase response (ESR, and Our study included 30 patients with CRP) in turn depend on the balance betw- rheumatoid arthritis and 10 healthy een these pro- and anti-inflammatory cytok- controls. All patients were selected from ines (Littman et al;1995). patients attending internal medicine depart- Interleukin-10(IL-10) one of the ment, Al Zahraa university hospital cytokines which had been shown to exert a Subjects were divided into 2 groups: number of immunoregulatory and anti- Group I: (RA group): 30 patients were inflammatory effect in RA (Cush et fulfilling The 1988 Revised American al;1995). The immunoregulatory cytokine Rheumatism Association (ARA) IL-10 increases autoantibody production by criteria for adults RA (Arnett, et al B cells from RA patients (Reparon-Schujt 1988)) 22 were female and 8 were et al;1998 and 2001)). males. A side from this immunostimulatory Their Age ranged from 17-50 years function, IL-10 inhibits the activation and with a mean of (28.3± 9.7). effectors functions of T cells, macrophage, Duration of disease ranged between and monocytes (Lard et al;2003).As an 2.5 and 9 years with mean (5.2 ±2). anti-inflammatory cytokine IL-10 has been Morning stiffness ranged between 18 shown to inhibit the synthesis of IL-1α, IL- and 90 minute, with mean (19 ± 2). 1B, and TNF- α, IL-6, IL-8, IL-12, and IL- Articular index score (AIS) ranged 18. IL-10 also inhibits the synthesis of between 22 and 27 with mean (24.8 ± gelatinase and collagenase (Oberholzer et 1.7) al;2002). Group II: (Control group): 10 healthy age Interleukin -16 (IL-16) also known as and sex matched volunteers; they were lymphocyte chemoattractant factor, is selected from medical and paramedical generally considered to play a decisive role staff of the hospital, 2 males and 8 in most immune and inflammatory respo- females. Their Age ranged between 19- nses (Kaufmann et al;2001) in rheumatoid 51 years with mean (31.7 ±9.7). arthritis the presence of IL-16 has been described in synovial tissues from patients All patients and controls were submitted with RA. However the functional activity of to the following: this T cell derived cytokine in the pathog- 1- Complete history taking and full clinical enesis of RA is not completely understood examination (Blaschke et al;2001). 2-Routine laboratory investigations Interferon- gamma (IFN- γ) is a including: secretary product of activated T-cell of the  Complete blood picture by automated Th1 subset and natural killer cells (NK). blood counter. INF-γ is produced in response to specific  Assessment of ESR in the first hour and non-specific immunologic activation of according to Westergen method (1921)

47 Interleukin-10, Interleukin- 16 and Interferon-γ……..

 Latex rheumatoid factor (MS) duration in minutes, articular index  C-reactive protein (CRP level) scor (AIS) (joint tenderness) it is measured  Fasting blood sugar, liver function tests using The Ritchia articular index (Ritichia, and kidney function tests, using et al, 1968), ESR in the first hours hemog- Bohringer Mannheim Company photo- lobin percentage (Hb%) and radiological metric kits West Germany on Hitachi examination of the affected joints. 911 auto analyzer. 3- Specific laboratory investigations Statistical analysis including: Results were tabulated and 1. Serum IL-10 by ELISA statistically analyzed through Compaq (II) Serum IL-16 by ELISA computer. The value were given as mean 2. Serum INF-γ by ELISA ±SD. Comparison of the values were  For this purpose blood samples from performed using the unpaired student T test patients and control were taken at the and one tailed P value is considered morning to avoid the influence of the significant when it is <0.05. time of the day on lymphocyte responses and cytokines. About 5cc of Results venous blood was drawn and centri- fuged for about 10 minutes and serum Baseline clinical and laboratory was separated, taken and stored at-20c° characteristic of the studied groups is until time of analysis. provided in table(1). Cytokines concentration were mea- Table (1) show the criteria of RA sured in serum using a commercially (Age, duration of disease, morning stiff, available monoclonal antibody based tender joint, swollen joint count, articular sandwich ELISA kit (Biosourse Europe index score (AIS). S.A) for human IL-10,IL-16 and INF- γ. Table(2) and fig(1,2,3) show that Briefly, standards, samples, and controls There was highly significant increase in tested sera were pipetted into wells pre- ESR, CRP in patients with RA compared to coated with murin monoclonal antibodies control group (P<0.001) .Also there was raised against each parameter followed by highly significant increase in serum IL-10, addition of horse radish peroxidase IL-16, IFNγ in patients with RA compared antibodies to each parameter. After an to control group (P<0.001). incubation period allowing the formation of Table (3) shows correlation between a sandwich, coated Mab1+Mab2 HRP. serum IL-10 and each Hb, ESR, CRP, IL- The microtiter plate was washed to 16, IFNγ in group I (30 patients with RA). remove unbound enzyme labeled antibo- There was highly significant correlation dies. Bound enzyme labeled antibodies between S. IL10 and each of ESR, CRP, IL- were measured through a chromogenic 16, IFNγ (p=<0.001) (r=0.67, 0.71, 0.63, reaction. Chromogenic solution (TMB+ 0.55) respectively. Also there was negative H2O2) was added and incubated. The significant correlation between S.IL-10 and reaction stopped with the addition of stop Hb (p=<0.001) (r=0.74). Fig 4 show solution(H2SO4) and the microtiter plate positive correlation between IL-10 and IL- was then read at 450nm wave length. The 16 among group 1. level of IL-10, IL-16 and INF γ were Fig 5 show positive correlation calculated from standard curve corresp- between IL-10 and IFNγ among group 1 onding to the measured optical densities. Table (4) show correlation between The results expressed as pg/ml. serum IL-16 and each Hb, ESR, CRP, IFNγ All RA patients met the American in group I (30 patients with RA). There was College of Rheumatology (ACR) 1987 highly significant correlation between S. revised criteria for the classification of RA IL16 and each of ESR, CRP, IFNγ (Arnett et al; 1988). The disease activity (p=<0.001) (r=0.87, 0.83, 0.89,) respect- comprised assessment of morning stiffness ively. Also there was negative significant

48 Eman.M.Abdel Rahman et al

correlation between S.IL-16 and Hb group I (30 patients with RA). There was (p=<0.001) (r=0.89). highly significant correlation between IFNγ Fig 6 show positive correlation and each of ESR, CRP, (p=<0.001) (r=0.75, between IL-16 and IFNγ among group 1. 0.73) respectively. And also there was Table (5) show correlation between negative correlation between IFNγ and Hb serums IFNγ and each Hb, ESR, CRP, in (p=<0.001) (r=0.80).

Table (1): Clinical and biochemical data for 30 patients with rheumatoid arthritis (group 1) and 10 control subject

parameter Group I patients with RA Group II control N=30 mean ±SD N=10 mean ±SD Age (years) 28.3 ± 9.7 31.1 ±9.7

Duration of disease 5.2 ± 2 _____ (years) Morning stiff 19 ± 3.2 ______(minuets) Tender joint 9.4 ± 2 ______

Swollen joint count 3.6 ± 1.4 ______

AIS 14.8 ±1.7 ______

Hemoglobin 10.5 ± 1.1 12.5 ± 4.7 (g/dl) ESR 60 ± 30 15± 4 (mm/h) CRP 34.1 ± 12.6 1.8 ± 0.4 (mg/l) IL-10 27.9 ± 5.6 2.27 ± 0.3 (pg/ml) IL-16 60.7 ± 41.4 3.2 ± 0.6 (pg/ml) IFN-γ 83.5 ± 16.8 12.6± 2.8 (pg./ml)

Table 2:Mean values of laboratory variables in patients with RA(group I) as compared to control group (group II). parameter Group I Group II mean P value T value significance mean ±SD ±SD Hemoglobin 10.5 ±1.1 12.5 ±4.7 <0.01 7.9 HS (g/dl) ESR 60± 30 15±4 <0.01 3.8 HS (mm/h) CRP 34.1 ±12.6 1.8 ±0.4 <0.01 1 HS (mg/l) IL-10 27.9 ±5.6 2.27 ±0.3 <0.01 9.2 HS (pg/ml) IL-16 60.7± 41.4 3.2 ±0.6 <0.01 1.2 HS (pg/ml) IFN-γ 83.5 ±16.8 12.6±2.8 <0.01 1.1 HS (pg./ml)

49 Interleukin-10, Interleukin- 16 and Interferon-γ……..

Table (3): Correlation between IL-10 and each hemoglobin level, erythrocyte sedimentation rate, C reactive protein, IL-16, and IFNγ in (group I) 30 patients with RA

parameter R value P value significance Hemoglobin - 0.74 <0.001 HS (g/dl) IL-10 ESR 0.67 <0.001 HS (pg./ ml) (mm/h) CRP 0.71 <0.001 HS (mg/l) IL-16 0.63 <0.001 HS (pg/ml) IFN-γ 0.55 <0.001 HS (pg./ml)

Table 4): Correlation between IL-16and each of hemoglobin level, erythrocyte sedimentation rate, C reactive protein, and IFNγ in 30 patients (group I) with RA

parameter R value P value significance Hemoglobin - 0.89 <0.001 HS (g/dl) IL-16 ESR 0.87 <0.001 HS (pg./ ml) (mm/h) CRP 0.83 <0.001 HS (mg/l) IFN-γ 0.89 <0.001 HS (pg./ml)

Table (5): Correlation between IFNγ and each hemoglobin level, erythrocyte sedimentation rate, C reactive protein in (group I) 30 patients with RA

parameter R value P value significance Hemoglobin - 0.80 <0.001 HS (g/dl) ESR 0.75 <0.001 HS IFN-γ (mm/h) (pg./ ml) CRP 0.73 <0.001 HS (mg/l)

50 Eman.M.Abdel Rahman et al

mean

IL-10 (pg/ml) 15

0 mean mean 27.96666667 2.27

Fig(1) Mean values of IL-10 in rheumatoid arthritis group and control group

40 IL-16 (pg/ml) 30

0 1 2 3.15 60.69333333 متسلسلة1 mean

Fig (2) Mean values of IL-16 in patients with rheumatoid arthritis and control group.

51 Interleukin-10, Interleukin- 16 and Interferon-γ……..

50 IFN 40

0 1 2

Series1 83.56666667 12.6 mean

Fig (3) Mean values of IFNγ in patients with rheumatoid arthritis and control group

r=0.63

200

180

160

140

120

100 (pg/ml)

16 80 IL- 60

0 1 2 IL-10 (pg/ml)

Fig (4) Positive correlation between IL-10 and IL-16 among group 1

52 Eman.M.Abdel Rahman et al

r=0.55

140

120

100

80 IFN 60

0 0 10 20 30 40 50 60 70

IL-10 (pg/ml)

Fig (5) Positive correlation between IL-10 and IFNγ among group 1

r=0.89

140

120

100

80 (pg/ml)

16 60 IL-

0 IFN

Fig (6) Positive correlation between IL-16 and IFNγ among group 1

53 Interleukin-10, Interleukin- 16 and Interferon-γ……..

Discussion

Arthritis and joint destruction are the statistically higher in patients group with hallmarks of rheumatoid arthritis (RA). The mild disease compared to severe disease. progression of joint destruction varies Also our results show highly signif- considerably among patients with RA icant positive correlation between serum (Huizinga et al; 2000). IL-10 and each of ESR, CRP.This result Proinflammatory cytokines play a disagree with Cush et al;( 1995 ) who found significant pathogenic role in RA. Anti- no correlation was demonstrated between inflammatory cytokines can also be found IL-10 levels and most clinical measures of in the affected joints and it has been disease activity (age, disease duration, postulated that chronic synovitis may morning stiffness, patients and physician reflect an imbalance in pro- and anti- global assessment, swollen or tender joint inflammatory cytokine production in RA counts. Also they reported no significant (Weckmann et al; 1996). Consequently, the difference was noted between those patients potential effect of anti-inflammatory treated or not treated with prednisone. But cytokines such as IL-10 in RA is of great Verhoef et al; (2001) found negative interest (Mackay et al; 2003). correlations between IL-10 production and Various lines of research suggest an ESR, CRP, and strong negative correlation important role of IL-10 in the pathogenesis with radiographic joint damage as well as of joint destruction in RA. Other studies progression of joint damage. show that IL-10 inhibits the generation of In the present study serum level of IL- proinflammatory cytokines and the 10 show highly significant correlation with proliferation of Th1 lymphocytes. each serum level of IL-16 and IFNγ, this IL-16 is a T cell derived cytokine results show disagreements with the results originally identified and purified as of Verhoef et al; (2001) they reported no lymphocyte chemoattractant factor.IL-16 correlation between IL-10 and IFNγ. acts via the CD4 molecule as its receptor Lard et al; (2003) reported that IL- 10 and exert a broad spectrum of both pro- and genotype was not associated with the anti-inflammatory biologic activities incidence of RA, but instead ,correlated (Blaschke et al; 2001). with disease progression, as determined by Interferon- gamma (IFN- γ) is a extent of joint destruction. secretary product of activated T-cell of the Our results show highly significant Th1 subset and natural killer cells (NK). increase in serum IL-16 in patients with RA INF-γ is produced in response to specific compared to control group. And also show and non-specific immunologic activation of highly significant positive correlation betw- lymphocyte, usually T-lymphocytes een serum IL-16 and each of ESR, CRP. (Boehm et al; 1997). Our data show agreements with that In the present study plasma level of of Blaschke et al; (2001 ) who detect that IL-10, IL-16, and IFN-γ were measured in IL-16 was significantly high in sera and 30 patients with rheumatoid arthritis comp- synovial fluid of patients with RA in ared to 10 sex and age matched normal comparison to osteoarthritis and to normal subjects. control, also they reported the lack of Our results show highly significant significant correlation between IL-16 increase in serum IL-10 in patients with RA expression, clinical disease activity, and compared to control group. Our results local inflammatory activity suggesting a agree with Cush et al; (1995) who found regulatory rather a pro-inflammatory serum and synovial fluid (SF) contained function for IL-16 in the pathogenesis of significantly elevated IL-10 level compared chronic synovial inflammation in RA. to control group. On other hand Verhoef et These finding for IL-16 differ from al; (2001) found IL-10 production was cytokines with predominant proinflam-

54 Eman.M.Abdel Rahman et al

matory activity in RA, such as TNF-α, IL1- IFN-γ in patients with rheumatoid arthritis, B, and IL-6, also OKamoto et al; ( 1997) and that is correlated with disease activity. have described increased serum levels of These cytokines are interesting for further these macrophage derived cytokines and research and novel therapeutic approach in significant correlation between serum this inflammatory disease. cytokine concentration and disease activity in RA. References Kaufmann et al; ( 2001) found serum level of IL-16 in RA was increased significantly compared with non RA control, and 1. Arnett, F.C; Edworthy, S.M;Bloch, D.A; in RA patients and controls, there were no McShare, D.J; et al. (1988): The significant differences in cytokine level American Rheumatism Association 1987 with respect to age and sex. And also they revised criteria for the classification of reported that a level of IL-16 was correlated Rheumatoid arthritis. Arthritis Rheum 31:315-324 with ESR and C-reactive protein. 2. Bas, S; Kvien, T.K; Buchs, N; Fulpius, T; Our results show highly significant Gabay, C.(2003): Lower level of synovial increase in serum IFNγ in patients with RA fluid interferon- in HLA-B27-positive than compared to control group. And also show in HLA-B27-negative patients with highly significant positive correlation betw- Chlamydia trachomatis reactive arthritis. een serum IFNγ and each of ESR, CRP. Rheumatology 42:461-467 This result agree with Kanik et al; 3. Blaschke, S; Schulz, H; Schwarz, G; (1998) who found increased production of Blaschke, V;et al. (2001): Interleukin 16 IFNγ in RA patients with new onset syno- Expression in relation to disease Activity in vitis, in contrast to patients with chronic Rheumatoid Arthritis. The Journal of Rheumatology 28:1 RA who had increased IL-16 production. 4. Boehm, U; et al.(1997): Cellular responses Verhoef et al; (2001) reported no to interferon gamma. Annu Rev Immunol correlation between IFNγ with disease acti- 15:749. vity variables (ESR, CRP) or joint damage 5. Cush, J.J; Splawski, J.B; Thomas, R; and that may be due to use of medication, McFarlin, J.E; et al. (1995): Elevated and also found negative correlation between interleukin-10 levels in patients with IFNγ and age of RA patients. rheumatoid arthritis. Arthritis Rheum Scola et al; (2002) found that juvenile 38:96-104. RA (JRA) has generally been described as a 6. Huizinga, T.W.J; Keijser, V; Yanni, G; type I disease with increased level of IFNγ Hall, M; et al. (2000): Are differences in interleukin 10 production associated with and variably low IL-4 in study utilizing joint damage? Rheumatology 39:1180- synovial fluid, and also confirm continued 1188. expression of IFNγ/IL-4 ratio compared to 7. Kanik, K.S; Hagiwara, E; Yarboro, C.H; that of control tissue, but also they reported Schumacher, H.R; et al. (1998): Distinct no significant difference in the expression patterns of cytokine secretion characterizes of IL-10 in JRA from that controls, possibly new onset synovitis versus chronic indicating a loss of regulation in severe or Rheumatoid arthritis. The Journal of long standing disease. Rheumatology 25:16-22. Bas et al; (2003) found SF concentr- 8. Kaufmann, J; Franke, S; Kintsch-Engel, ations of IL-10 were significantly lower in R; et al. (2001): Correlation of circulating patients with reactive arthritis than RA interleukin 16 with proinflammatory cytokines in patients with rheumatoid patients. The SF level of IFNγ was not arthritis. Rheumatology 40:474-475. significantly different but the ratios of IFNγ 9. Lard, L. R; Gaalen, F .A; Schonkeren, J to IL-10 were significantly higher in .J; Pieterman, E. J; et al. (2003): patients with reactive arthritis. Association of the -2849 Interleukin -10 promoter polymorphism with autoantibody Conclusion production and joint destruction in These data suggest that there is rheumatoid arthritis. Arthritis & Rheum increased production of IL-10, IL-16, and vol.48, No7, July, pp 1841:48.

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10. Libula, R; Singer, S; and Mcvecitt, M. 16. Panayi, G.S; Lanchbury, J.S; Kingsley, (1995): Th1 and Th2 CD4+ T cell in the G.H. (1992): The importance of the T cell pathogenesis of organ specific autoimmune in initiating and maintaining the chronic disease. Immunology Today 16:32-36. synovitis of rheumatoid arthritis. Arthritis 11. Littman,B.H; Drury, C.E; Zimmerer, Rheum 35:729-35. R.O; Stack, C.B; Law, C.G. (1995): 17. Reparon-Schuijt, C.C; van Esch, W.J.E; Rheumatoid arthritis treated with tenidap van Kooten,M; et al. (2001): Secretion of and piroxicam. Clinical associations with ant-citrulline-containing peptide antibody cytokine modulation by tenidap. Arthritis by B lymphocytes in rheumatoid arthritis. Rheum 38: 29-37. Arthritis Rheum 44:41-7. 12. Mackay, K; Milicic, A; Lee, D; Tikly, M 18. Reparon-Schuijt, C.C; van Esch, W.J.E; ;et al. (2003): Rheumatoid arthritis susce- van Kooten,M; Levarht, E.W.N; et al. ptibility and interleukin 10 : a study of two (1998): Functional analysis of rheumatoid ethnically diverse populations. factor-producing B cells from the synovial Rheumatology 42:149-153. fluid of rheumatoid arthritis patients. 13. Moller, B; Paulukat, G; Nold, M; Arthritis Rheum 41:2211-20. Behrens, M;et al. (2003): Interferon- ind- 19. Scola, M.P; Thompson, S.D; Brunner, uces expression of interleukin-18 binding H.I; et al. (2002): Interferon-γ: Interleukin protein in fibroblast- like synoviocytes. 4 Ratios and Associated Type 1 Cytokine Rheumatology 42:442-445. Expression in Juvenile Rheumatoid 14. Oberholzer, A; Oberholzer, C; and Arthritis Synovial Tissue. The Journal of Moldamer, L. (2002): IL-10: A complex Rheumatology 29:369-78. role in the pathogenesis of sepsis syndr- 20. Verhoef, C.M; van Roon, J.A.G; Vianen, omes and its potential as an anti-inflam- M.A, et al. (2001): Interleukin-10, Not IL- matory drug. Crit. Care. Med 301 (supp 4 or Interferon-γ Production, Correlates 11):558-563. with Progression of Joint Destruction in 15. Okamoto, H; Yamamura, M; Morita, Y; Rheumatoid Arthritis. The Journal of Harada, S; et al. (1997): The synovial Rheumatology 28:1960-6. expression and serum levels of interleukin- 21. Weckmann, A.L; Alcocer-Varela, J; et 6, interleukin-11, leukemia inhibitory al.(1996): Cytokine inhibitors in autoim- factor, and oncostatin M in Rheumatoid mune disease. Semin Arthritis Rheum 26: arthritis. Arthritis Rheum 40:1096-105. 539-57.

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اوترليىكيه 01 و اوترليىكيه 01و اوترفيرون جاما في مرض الرثيان المفصلي وعالقتها بالىشاط المرضى إيمان محمد عبد الرحمه*، حمدية عزت** ، مها محمد عبد المحسه**،كريمة يىسف* قسن الباطٌت العاهت*، الباثْلْجيا االكلٌيكيت**، كليت طب بٌاث جاهعت األزُر

ٌُاااا العد ااد هااي األااابام الوةخولاات لواارن الرثياااى الواألاالب ّلكااي األااابام الةقيقيااات لااايع هقهْ اااا بِاااا دخااأ انى، القاااد لاااْدة ى ال اااا الليوااّ ااات B ّ T ّ الويكرّالاااات حخ لاااا اللزاااا السليلااأ الواألااالب، الخاااْآ رلااأ ِاااْ ال لاااا الخركيبااأ ّالْ ياب لِذا اللزا ّكذلك حْثر لٔ دالت اللضا ف ّالوااصا ّقد حبايي ى ٌُااا دالت هي دم الخْازى بيي اإلًخات الوخسا اد هاي هسابباث االلخِاام ّهضااااث االلخِاام، الخلعب العزائر ال لْ ت هثا اًخرلياْكيي01 اّ ا ُاهاا الاب الخهاْ الورلأ للوااصاا ّكذلك الخأثير لٔ الجِاز الوٌا ب. ّ لعب اًخرليْكيي 01 اّ ا ُاها الب الخهْ الورلٔ الوسهي الب ُذٍ الةااالث ديااإ رى لااَ صألااائة هٌزااهت ل ااا T الخااب حااعثر لاأ األلزاايت السليليااَ كوااا اى اًخراليْ ى جاها لعب اّ ا هٌزها ضا لٔ ص ا T الوسا دة. ّقد حن حةليا هسخْٓ اًخرليْكيي 01 ّ اًخرلياْكيي )01( ّاًخرالياْ ى جاهاا الاب الورلٔ لخقيين ا جت ًزاط الورلٔ ّقد ِارث الٌخاائ ا حاااذ تاث االلات ردألاائيت الااب كااا هااي ااار ت الخرااايب ّباارّحيي C الٌزااظ ّاًخرليااْكيي 01 ّ اًخرليااْكيي 01 ّاًخراليْ ى جاها ّثبج ّجْا قت ا حباطيَ تاث االلت ردألائيت هرحاعت بايي كاا هاي اًخرليْكيي 01 ّاًخرليْكيي 01 اًخراليْ ى جاها كوا ْجد ضاا قات ا حباطيات بايي اًخرليْكيي 01ّ اًخراليْى جاهاا ّكاذلك بايي اار ت الخراايب ّكاا هاي اًخرلياْكيي 01 ّاًخرلْكيي 01 ّاًخراليْى جاها. ّّجْا قت ا حباطيت تاث االلت ادألائيت بيي برّحيي C الٌزظ ّكا هي اًخرليْكيي 01 ّاوترليىكيه 01 ّاًخراليرّى جاها هوا زير رلٔ ّجْا قت بيي ا حااذ هسخْٓ العزائر ال لْ ت ّا جت ًزاط الورن.