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					EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009                     El-Damarany et al


  POSSIBLE ROLE OF INTERLEUKIN-6 AND C-REACTIVE PROTEIN IN
      PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

                                      By
             Eman El-Masry El-Damarany*, Aahmed M. Mahmoud*,
                Moustafa M. Mohammad*, and May M. Fawzi **
       Departments of *Medical Biochemistry, El-Minia Faculty of Medicine,
              and **Internal Medicine, Cairo Faculty of Medicine.

ABSTRACT:
        Systemic lupus erythematosus (SLE) is an autoimmune disease with a
complex pathogenesis. The significance of cytokines and acute phase reactants in the
pathogenesis of SLE has been debated; interleukin-6 (IL-6) has been shown to be a
key factor in regulating autoantibody-secreting B-cell activity in lupus and
contributing to disease activity. Other mediators as C-reactive protein (CRP) was
found to be high in several autoimmune diseases and played an important role in
maintenance of disease activity. IL-6 and CRP were determined by PCR and ELISA
respectively and their relation to the different disease parameters as auto-antibodies,
complement levels and disease activity were studied. Sixty SLE patients and thirty
age and sex-matched controls were included in this study. The results were correlated
to anti-double-stranded-DNA (ds-DNA) antibodies, anti-nuclear antibodies (ANA),
and C3 & C4 and disease activity. IL-6 (gene expression as well as its serum level)
and CRP were higher in SLE patients than in healthy controls. They correlated
significantly with each other. Also a positive relation was found between levels of
both IL-6 and CRP with anti-DNA and with C3 & C4. CRP levels correlated to
photosensitivity. Both IL-6 and CRP levels correlated to the presence of arthritis, but
no relation was found with the presence of lupus nephritis, neurological
manifestations, arthralgia or serositis. SLAM score correlated to the presence of malar
rash. Our results confirm earlier reports that SLE patients have increased serum levels
of IL-6. CRP levels were also found to be high with a statistically significant
correlation between them. Both correlated significantly with anti-DNA antibodies, C3
& C4 levels and with disease activity, but no clear association was found between
their levels and individual clinical manifestations of SLE separately. Both IL-6 and
CRP can be considered useful parameters for monitoring disease activity of SLE.

KEY WORDS:
         Systemic lupus erythematosus                       Interleukin-6
         C-reactive protein.


INTRODUCTION:                                  of SLE is complex2. B-cell hyper-
       Systemic lupus erythematosus            activity, T-cell abnormalities and
(SLE) is an autoimmune disease, most           abnormal cytokine production have
prevalent in women between the ages            been implicated to be of pathogenic
of twenty and sixty. Successful                importance in SLE3.
treatment remains challenging due to a
lack of understanding the underlying                  Tissue damage is caused by
mechanisms and multiple symptoms               pathogenic auto-antibodies that result
ranging from skin rashes to                    from B-cell hyper proliferation unique
glomerulonephritis1. The pathogenesis          to afflicted patients. These B-cells


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generate large quantities of IgG auto-              bodies, anti-nuclear antibodies (ANA),
antibodies that can lead to lupus                   C3, C4 and disease activity.
nephritis and renal failure1. The abnor-
mal immune response that permits                    SUBJECTS AND METHODS:
persistence of pathogenic B and T-cells              A. SUBJECTS:
has multiple components that include                        Sixty SLE female patients and
processing of both external and self-               thirty healthy controls were enrolled in
antigens by antigen-presenting cells                this study. Patients were examined for
with hyper activation of T and B-cells              detection of different manifestations of
and failure of multiple regulatory                  SLE; skin was examined, kidney
networks to interrupt this process. The             function tests and neurological assess-
immunologic abnormalities occur in a                ment were done and patients were
framework of interactions between                   examined for detection of articular
multiple susceptibility genes4,5 and                manifestations. Blood samples were
environmental stimuli. This results in              collected for assessment of anti-ds-
apoptosis in dermal cells and results in            DNA antibodies, anti-nuclear anti-
presentation of RNA-protein, DNA-                   bodies, C3, C4, IL-6 and C-reactive
protein, and phospholipid self-antigens             protein (CRP) levels and gene
to the immune system6.                              expression of IL-6 from whole blood.
                                                    Disease activity was simultaneously
        The significance of cytokines in            assessed using the Systemic Lupus
SLE has been debated, particularly                  Activity Measure (SLAM) index.
with respect to B-cell activity.
Interleukin IL-6 and other cytokines as              B. METHODS
IL-10 have been shown to be key                     PBMC isolation and RNA extraction
factors in regulating autoantibody-                         EDTA anti-coagulated venous
secreting B-cell activity in lupus and              blood samples were used for the
contributing to disease activity1.                  isolation of peripheral blood mono-
                                                    nuclear cells (PBMC) using the Ficoll-
        C-reactive protein (CRP) is a               hypaque density gradient technique.
trace constituent of normal human                   After gathering the cells in RLT buffer
serum and an acute phase reactant,                  total RNA was extracted using an
which increases in amount rapidly and               RNeasy minikit (Qiagen, Hilden
extensively during inflammation7. CRP               Germany) in accordance with the
was found not only to be elevated in                manufacturer’s protocol. The integrity
patients with rheumatoid arthritis, giant           of extracted RNA was assessed by
cell    arteritis    and      polymyalgia           spectrophotometer measurement at 260
rheumatica, but also it correlated fairly           nm.
well with clinical symptoms and is
valuable in diagnosis and monitoring                RT-PCR
effect of treatment in these rheuma-                        2 µg of total RNA were reverse
tological disorders. However, in SLE                transcribed into cDNA in the presence
and systemic sclerosis, the serum                   of 50 pmol of random hexamers, 40
levels of CRP are relatively low in                 units/µl of RNase inhibitor, 10 mM of
relation to disease activity8,9. This study         each dNTPs, first-strand buffer 5x, and
was undertaken to estimate serum                    60 units/µl of Moloney murine
levels of IL-6 and CRP in serum of                  leukemia virus in a final reaction
patients with systemic lupus erythe-                volume of 25 µl. The mixture was
matosus and their relation to anti-                 incubated at 37°C for 1 h, and the
double-stranded-DNA (ds-DNA) anti-                  cDNA synthesis was stopped by


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EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009                        El-Damarany et al


heating the reaction mixture at 90 °C             (anti-sense)]. cDNA was submitted to
for 15 min. according to the manu-                40 cycles of amplification (1 cycle: 94
facturer’s instructions. The expression           °C for 1 min, 60 °C for 2 min, and 72
of IL-6 gene was determined by                    °C for 2 min) in the thermocycler and
polymerase chain reaction (PCR) kit               using a PCR kit (Invitrogen). Then, the
(Maxim Biotech, San Francisco, CA,                samples were separated on a 2%
USA). Primers were used for the                   agarose gel and visualized by ethidium
amplification of human IL-6 [5´-                  bromide staining.The PCR product is
TATTATCCCTTTCAGAGATGAG-                           118 (bp). The product of the gene was
3´         (sense)        and       5´-           semi-quantitated    by     using    the
CTGCAGTTGCTCCCTTTAGG-3´                           densitometry (USA)




             M        1         2           3          4           5        6
             7




Fig.1: Agarose gel electrophoresis 2% stained with ethidium bromide showing the
PCR product at 118 bp. M: Molecular weight marker. Lanes 1-5 cases of SLE. Lanes
6-7 control cases.


Quantitation of IL-6 in serum:                    coated on the microtiter well. After
        Serum IL-6 was quantitated by             incubation, the occasional excess of
using IL-6 EASIA kit provided by                  antigen is removed by washing. Mab,
Biosource Europe S.A. The Biosource               the horseradish peroxidase (HRP)-
IL-6 EASIA is a solid phase Enzyme                labeled-antibody, is then added.
Amplified Sensitivity Immunoassay
(EASIA) performed on microtiter                           After an incubation period
plate. The assay is based on an oligo-            allowing the formation of a sandwich;
clonal system in which a blend of                 coated MAbs1-IL-6-Mab 2-HRP, the
monoclonal       antibodies      (MAbs)           microtiter plate is washed to remove
directed against distinct epitopes of IL-         unbound enzyme labeled antibodies.
6 are used. Antibody- producing cells             Bound enzymes labeled antibodies are
are immortalized using the myeloma                measured through a chromogenic
cell fusion method of Kohler and                  reaction. Chromogenic solution (TMB
Milstein. A hybridoma cell is produced            + H2SO4) is added and incubated. The
which secretes specific homogeneous               reaction is stopped with the addition of
antibodies. The use of a number of                stop solution (H2SO4) and the
distinct MAbs avoids hyper specificity            microtiter plate is then read at 450 nm.
and allows high sensitive assays with             A standard curve is plotted and IL-6
extended standard range and short                 concentrations      in    samples     are
incubation time. Standards or samples             determined by interpolation from the
containing IL-6 react with capture                curve.
monoclonal      antibodies      (MAbs1)


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  EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009                        El-Damarany et al


  Quantitation of C- reactive protein               RESULTS:
  (CRP):                                                    The number of SLE patients
          CRP was quantitated by                    included in this study was 60, with a
  CRPRF ASLO ELISA diagnostic kit                   mean age of (24.9 ± 7.2 Years). The
  provided by Dia Med Eurogen, Swit-                mean duration of illness was (3.1±2.5
  zerland (Europe). The microstrips                 years). SLAM class was (15.2 ± 6.5).
  coated with antibody (anti-CRP) were              Patients were grouped according to
  incubated with diluted standard sera              various clinical manifestations; all of
  and patient samples. During this                  them had different skin lesions, 26 had
  incubation step, CRP was bound                    ulcerations, 36 presented with alopecia,
  specifically to the wells. After removal          50 with a malar rash and 50 with
  of the unbound serum protein by a                 photosensitivity. Twenty patients had
  washing procedure, the antigen                    lupus nephritis, 24 had neurological
  antibody complex in each well was                 manifestations, 36 had arthralgia, 10
  detected with specific peroxidase-                had arthritis and 6 had serositis.
  conjugated antibodies. After removal
  of the unbound conjugate, the strips                       The serum levels of IL-6 in the
  were incubated with a substrate                   SLE patients and the ten healthy
  solution     containing     tetramethyl-          controls were (47.5± 39.2 and 5.3 ± 2.4
  benzidin and hydrogen peroxide: a                 pg/ml) respectively. Also the levels of
  blue color developed in proportion to             the mRNA-IL6 were (1458±1296 and
  the amount of immunocomplex bound                 135 ±98.5 ug/ml) in SLE and control
  to the wells of the strips. The                   respectively. The difference was
  enzymatic reaction was stopped by the             statistically highly significant in both
  addition of 2 N H2SO4 and the                     cases (Table I).
  absorbance values at 450 nm were
  determined. A standard curve was                         The mean serum level of CRP
  obtained by plotting the absorbance               in SLE patients was (29.3± 21.3
  values versus the corresponding                   ug/ml), while in the control group, it
  standard values. The concentration of             was (6.4 ± 4.1 ug/ml). The difference
  CRP in patient samples was                        was also statistically highly significant
  determined by interpolation from the              (Table 1).
  standard curves 10.

  Table (I): Levels of IL-6 and CRP in the studied groups:

Group      (IL-6) m-RNA       IL-6 (protein)       P-value         CRP               P-value
Patients     1458±1296         47.5 ± 39.2                      29.3 ± 21.3
                                                    0.001                              0.02
Controls      135 ±98.5          5.3 ± 2.4                        6.4 ± 4.1



          Levels of IL-6 and CRP were                       A positive correlation was
  correlated to the age of the patients,            found between IL-6 and CRP in SLE
  disease duration and to SLAM class.               patients where r= 0.7988 and P- value
  There was a statistical significant               was < 0.001.
  difference between IL-6, CRP and
  SLAM score where P -values were <                     Levels of IL-6 (Protein and
  0.05.                                             mRNA) and CRP were correlated to


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    EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009                         El-Damarany et al


    levels of ANA, anti-DNA, C3 & C4                  anti-DNA, C3 and C4, while they were
    levels. SLAM score was also                       non-significant in relation to ANA.
    correlated to levels of ANA, anti DNA,            SLAM score was not found to be
    C3 & C4 levels. Both IL-6 and CRP                 significant in relation to any of them
    levels were significant in relation to            (Table 2).


    Table (2): Levels of IL-6, CRP and SLSM score according to ANA, anti-DNA, C3 & C4

     Item                      mRNA            P-                                           P-
               Serum IL-6                                CRP        P-value     SLAM
                                IL-6          value                                        value
ANA
+ (56)         48.7 ± 39.9    1353±1192               29.2 ± 32.1             15.9 ± 6.7
                                               NS                    NS                     NS
- (4)          29.6 ± 26.9    1218±1087               30.4 ± 21.9             14.5 ± 0.7
Anti-DNA
               55.8 ± 46.5    1552±1292               34.9 ± 38.1             14.6 ± 6
+ (40)                                        0.003                 0.0005                  NS
- (20)         34.2 ± 18.4    1118±1009               20.4 ± 12.4             16.1 ± 7
C3
               57.8 ± 61.9    1322±1212               42.5 ± 44.5             14 ± 6.5
Normal 20                                     0.003                  0.03                   NS
Decreased 40   44.6 ± 26      1016±987                23.2 ± 26.7             16 ± 6.5
C4
                                             31.3 ± 34.2                      13.9 ± 5.8
Normal 37      51 ± 48.8      1319±1076 0.03                        0.001                   NS
Decreased 23 45 ± 25.5        1115±954       26.3 ± 30.7                      17.6 ± 6.9


            Levels of IL-6 and CRP were               relation was found in patients with
    correlated to skin manifestations; IL-6           photosensitivity.
    levels were non-significant in patients
    with ulcerations, alopecia, malar rash                     SLAM score was correlated to
    and photosensitivity.                             skin manifestations. No significant
                                                      relation was found in patients with
            CRP     levels    were    non-            ulcerations, alopecia and photosen-
    significant in relation to ulcerations,           sitivity, but a significant relation was
    alopecia, malar rash, but a significant           found in patients with malar rash
                                                      (Table 3).




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  EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009                        El-Damarany et al


  Table (3): Levels of IL-6, CRP and SLAM score according to skin manifestations:

                                             P                                          P-
     Skin           Serum        mRNA
                                                        CRP         P       SLAM       valu
    manifest.        IL-6         IL-6
                                                                                        e
  Ulcer
  + (36)          47.1 ± 50.5 1253±1182              30.9 ± 31.2          15.8 ± 7.1
                                            NS                     NS                  NS
  - (24)          47.9 ± 50.5 1218±1187              27 ± 32.5            14.5 ± 5.7
  Alopecia
  + (36)          46.4 ± 45.9 1222±1412              31.5 ± 34.8          16.6 ± 6.4
                                            NS                     NS                  NS
   - (24)         49.1 ± 27.1 1317±1147              25.8 ± 25.9          13.2 ± 6.2
  Malar rash
  + (49)          49.4 ± 41.9 1319±1076              32.2 ± 34.3          16.4 ± 6
                                            NS                     NS                  0.05
  - (11)          39.5 ± 26.7 1115±954               17.1 ± 4.9           10.8 ± 3.7
  Photosensiti
  vity
                  47.4 ± 42.1 1327±1166              31.4 ± 33.8          16 ± 6.6
  + (49)                                                           0.00
                                            NS                                         NS
                                                                     1
  - (11)          47.9 ± 21.5 1316±1155              18.2 ± 4.3           11 ± 3.8

          Regarding lupus nephritis, no significant relation was found between IL-6 and
  CRP levels and lupus nephritis. Also, the relation between SLAM score and lupus
  nephritis was non-significant (Table 4).

  Table (4): Levels of IL-6, CRP and SLAM score according to lupus nephritis:

   Item          Serum      mRNAIL-6         P-         CRP          P-        IL-6       P-
                  IL-6                      value                   value                value
Nephritis +
               43.9 ± 26.9     1219±1036              30.1 ± 32.7      15.9 ± 4
   (20)
                                                NS                  NS          NS
Nephritis –
               49.1 ± 44.4     1238±1157              28.9 ± 31.4      14.9 ± 1
   (40)
          Neither IL-6 and CRP serum levels nor SLAM score were found to be
  significant in relation to neurological manifestations (Table 5).

   Table (5): Levels of IL-6, CRP and SLAM score according to neurological
   manifestations:
                                 mRNA
       Item        Serum IL-6            P     CRP      P    SLAM       P
                                  IL-6
  Neurological     53.7 ± 45.6 1305±1170      33.6 ±         14.7 ± 6
  + (33)                                       33.9
                                         NS            NS              NS
  Neurological – 39.9 ± 29.5 1280±1128      24 ± 28.1        15.9 ± 7
  (27)




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          Concerning articular manifest-               between IL-6 and CRP levels and
    tations, there was a significant relation          presence of arthralgias. Also, no
    between presence of arthritis and                  significant relation was found between
    serum levels of IL-6 and CRP, while                SLAM score and both arthralgia and
    no significant relation was found                  arthritis (Table 6).


    Table (6): Levels of IL-6, CRP and SLAM score according to articular manifestations:

Articular      Serum       mRNA IL-6            P          CRP            P        SLAM              P
manifest.       IL-6
Arthralgia
+ (35)         47.1 ±
                            1255±1464                   32.3 ± 30.1              15.8 ± 7.2
                50.5
                                                NS                       NS                       NS
- (40)         47.9 ±
                            1266±1128                   27.9 ± 32.4              14.5 ± 4.7
                39.4
Arthritis
+ (11)         53.4 ±
                            1499±1027                   31.5 ± 34.8              12.1 ± 3.8
                52.3
                                            0.003                        NS                       NS
- (64)         40.6 ±
                            1085±996                    25.8 ± 25.9               16.4 ± 6
                26.9



    DISCUSSION:                                                Mellor Pita, et al, 200813,
            Systemic lupus erythematosus               concluded that monocytes and T-
    (SLE) is an autoimmune disease with a              lymphocytes (CD4+ and CD8+)
    complex       pathogenesis2.      B-cell           contribute to an overproduction of IL-6
    hyperactivity, T-cell abnormalities and            and IL-10 in SLE; this correlates with
    abnormal cytokine production have                  the disease activity but is independent
    been implicated to be important in                 of the treatment the patients are
    SLE3.The significance of cytokines in              receiving.
    SLE has been debated, particularly
    with respect to B-cell activity.                           Brink et al.14, Davas et al.15, Hu
    Cytokine production reflects disease                    16
                                                       et al. , and Viallard et al.17 measured
    activity and development of different              serum     levels     of    several      pro
    organ manifestations3.                             inflammatory cytokines by ELISA; one
                                                       of these is IL-6. They found that its
            Interleukin 6 is of particular             serum level was higher in patients with
    importance in regulating autoantibody-             SLE. They all concluded that pro
    secreting B-cell activity in lupus and             inflammatory cytokines are involved in
    contributing to disease activity1.                 the pathogenesis of SLE. Grondal et
                                                       al.3 found that SLE patients had
            In our work, serum levels of               significantly increased numbers of
    IL-6 in SLE patients were significantly            cells spontaneously producing IL-6 as
    higher than those of controls. This                compared to healthy controls. Su et
    result correlated well with those of               al.18 detected increased levels of IL-6
    Lacki et al.11 and Robak et al.12 who              and IL-8 in pregnant women with SLE
    reported elevated levels of IL-6 in SLE            than those in normal pregnants. They
    patients.                                          suggested that IL-6 and IL-8 might be


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EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009                        El-Damarany et al


helpful to monitor the progress of SLE            there was a significant correlation
during pregnancy. Takeda et al.19                 between levels of IL-6, CRP and those
reported a case of markedly increased             of C3 and C4. This may be attributed
levels of IL-6 in pleural fluid in an             to the fact that CRP and many of
elderly person with overlap syndrome              complement proteins are considered
of systemic sclerosis and SLE.                    acute phase reactants, the synthesis of
                                                  which, can be modulated by a variety
        Robak and Robak 200820 stated             of immune mediators including IL-1,
that Pro inflammatory cytokines such              IL-6, TNF-α and interferon gamma
as tumor necrosis factor-alpha (TNF-α)            (IFN-gamma)23.
and (IL-6) play an important role in
propagating the inflammatory process                     C3 and C4 levels are reduced
responsible for tissue         damage.            during the disease activity, due to
Blocking of these cytokines by mAbs               increased utilization in immune
can be also a successful therapy for              complex formation and because of
patients with SLE. Finally, mAb                   reduced synthesis 24.
eculizumab that specifically inhibits
terminal complement activation has                        In our work, there was no
been recently developed and investi-              significant relation between SLAM
gated in the phase I single dose study            score and levels of C3 and C4. Our
in SLE.                                           findings coincide with those of Davas
                                                  et al.15 who found no significant
        In this work, a positive                  differences observed for C3 and C4
correlation was found between IL-6                levels before and after treatment,
and CRP levels. This coincides with               which suggests that these are not
Lacki et al.11, who also found a                  sensitive markers of disease activity.
significant correlation between them,
but differs from Liu et al.21, who did                    Robak et al.12,25 detected a
not find this correlation.                        positive correlation between serum
                                                  concentrations of IL-6 and SLE
        In the present work, IL-6 levels          activity and Davas et al. in 199915,
were non-significant in relation to               found that serum levels of cytokines
ANA, but there was a significant                  and their soluble receptors of patients
elevation of IL-6 levels in relation to           with active disease were significantly
anti-DNA. This correlates well with               higher than those with inactive disease.
the study done by Liu et al.21. Sun et            In our study, we proved this relation.
al.22 demonstrated that the monoclonal            However, when levels of IL-6 were
anti-double-stranded DNA autoant-                 correlated to skin manifestations
ibody stimulates the expression and               separately, no significant relation was
release of IL-6 and other cytokines               found between them. Also no
from mononuclear cells involved in the            significant relation was found between
lupus pathogenesis. However, in the               CRP and skin manifestations except
study of Hu et al.16 and Grondal et al.3,         for photosensitivity.
no significant correlation was found
between      IL-6     and     anti-DNA                    Concerning other individual
antibodies.                                       clinical manifestations, only arthritis
                                                  was found to correlate with levels of
        Meanwhile, CRP also showed a              IL-6 and CRP, while no significant
positive correlation with anti-DNA and            relation was found between their serum
no correlation with ANA. In this study,           levels and presence of, lupus nephritis,


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EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN., 2009                     El-Damarany et al


neurological manifestations, arthralgia            9. Heyreh SS, Podhajsky PA. and
or serositis. Also, no significant              Raman R. (1997): Giant cell arteritis:
relation was found between SLAM                 Validity and reliability of various
score and individual clinical manifest-         diagnostic criteria. Am J Ophthal-
tations except for malar rash.                  mology, 123: 285-296.
                                                   10. Gewurz H, Mold C, Siegel J,
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‫9002 ,.‪EL-MINIA MED., BULL., VOL. 20, NO. 1, JAN‬‬                                 ‫‪El-Damarany et al‬‬



                    ‫دور االنترلوكين السادس والبروتين المتفاعل سي‬
                        ‫بالدم في حدوث مرض الذئبة الحمراء‬

                     ‫إيمان المصري الدمراني* – احمد محمد محمود*-‬
                          ‫مصطفي مراد محمد *- مي محمد فوزي**‬
                       ‫أقسام *الكيمياء الحيوية الطبية - كلية طب المنيا‬
                           ‫و**األمراض الباطنية - كلية طب القاهرة‬

‫يعد مرض الذئبة الحمراء من ممنراض المعة نة الذا ذنة ااس اب نبةع المعاندت دالم عندثت دي نر‬
‫الخنننعل أنننة ملمذنننة المنننواث الخأوينننة دالم نننة عس الحنننةثت تنن ننندد لنننذا المنننرض ديع بنننر‬
   ‫االن رلوكذ السةثس ةمل رئذس ت عظذم نشةط دإترازاس خعينة يذ نة ال ن نبدر ينددرلة تن‬
‫نشةط المرض, كذلك تاد دجد من نسبة البرد ذ الم ة نل ن مر عنة تن ندت ممنراض معة ذنة‬
                                                    ‫دانه يأعب ثدرا لةمة ت نشةط لذه ابمراض.‬
‫يةلدم ت مرضة‬               ‫مجريت لذه الدرا ة يهدل قذةس االن رلوكذ السةثس دالبرد ذ الم ة ل‬
‫الذئبة الحمراء دمعرتة عق همة يمانةيذ المنرض المخ أ نة ابخنرأل كةبجسنةم المانةثت الذا ذنة‬
                                                                     ‫دنسبة الم مل دنشةط المرض.‬
  ‫مجرينننت الدرا نننة أن ن نن ذ مريان نة يةلذئبنننة الحمنننراء د دعدنننذ من ن ابشنننخة الطبذعذنننذ‬
  ‫كمجمو ننه ضننةيطه د م قذننةس نسننبة الجننذ د يننرد ذ االن رلننوكذ السننةثس د كننذلك يننرد ذ‬
  ‫ت ثمهم كمة م مل ثرا ةس إ صةئذة لأع نةئ دثرا نة مندأل ار بنةط لنذه الع نةئ‬                    ‫الم ة ل‬
    ‫يماةثاس الحةمض العودي الريبوزأل الغذر مبكسد المندثد دمانةثاس العنوات دالم منل ال ةلن‬
                                                                   ‫دالرايع دكذلك مع نشةط المرض.‬
‫ينةالن رلوكذ السنةثس‬           ‫دقد مظهرس الع ةئ ار ةع نسبة ال غذر الجذع د كذلك البرد ذ الخنة‬
‫تن مرضنة الذئبنة الحمنراء عنه تن المجمو نة الانةيطة دار ب كنع‬                        ‫دالبرد ذ الم ة ل‬
‫معهمة ينةخخر كمنة كنةن لعنةت ار بةرنة ررثينة ينذ مسن والم يةلندم دمسن وأل مانةثاس الحنةمض‬
  ‫العننودي الريبننوزأل الغذننر مبكسنند المنندثد دالم مننل ال ةلنن دالرايننع دار ب معنند البننرد ذ‬
    ‫الم ة ننل ن يةلحسة ننذة الجأديننة الاننوئذة المصننة بة لأمرض كمننة مر ننب كننع معهمننة يحنندد‬
‫االل هةع الم صنأ يذعمنة لنم وجند عقنة يذعهمنة دينذ ال هنةع ال أنة صالم الم ة نل اإل نةيةس‬
                    ‫العصبذة مد ال هةيةس ابغشذة المبطعة لأاأب دالرئة دالبط المصة بة لأمرض.‬
   ‫ديعةء أة النك يم ن ا بنةر االن رلنوكذ السنةثس دالبنرد ذ الم ة نل ن مانةيذ لةمنة تن‬
                                                                  ‫قذةس نشةط مرض الذئبة الحمراء.‬




                                                 ‫672‬

				
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