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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 42  |  Issue : 1  |  Page : 21-30

Ultrastructural characteristics of synovial fluid cells in rheumatoid arthritis and osteoarthritis


1 Department of Histology, Rheumatology & Rehabilitation, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of hysical Medicine, Rheumatology & Rehabilitation, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission20-Nov-2013
Date of Acceptance28-Dec-2013
Date of Web Publication7-Apr-2014

Correspondence Address:
Amal A Abd-El-Hafez
Tanta El-Geesh Street, Tanta
Egypt
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DOI: 10.4103/1110-1415.130114

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  Abstract 

Aim
The aim of the study was to evaluate the range of activation changes of polymorphonuclear leukocytes and the ratio of apoptosis and necrosis in synovial cells of patients with rheumatoid arthritis (RA) and osteoarthritis (OA), to study and compare the ultrastructural features of synovial fluid (SF) cells from RA and OA patients, to correlate it to activities of the diseases, and to produce microscopic translation to the events that occurred in the joint.
Patients and methods
Synovial effusions were aspirated from the knee joints of patients with RA (seven samples) and with primary OA (14 samples). Cytospin preparations were processed for transmission electron microscopy and assessed for the incidence of the neutrophil granulocytes, the dominating cell population in the arthritic SF, apoptosis, and cytophagocytic cells (CPCs) in the SF.
Results
In all samples under investigation, most of the synovial effusion cells had intact ultrastructure with a certain amount of apoptotic cells dominating over the cells with signs of necrosis and with few CPC. The highest rate of apoptosis was discovered in the synovial effusions of patients with RA and the lowest in those with OA; in addition, the incidence of CPC was lower in patients with OA. In RA, the current disease activity correlated with the incidence of the neutrophil granulocytes and of the apoptotic cells.
Conclusion
These data suggest that, in RA, despite exposure to the antiapoptotic signals, apoptosis of the synovial effusion polymorphonuclear leukocytes is maintained at a significantly higher level than in OA, providing elimination of the neutrophils accumulating in the joint cavity, and thus stimulating resolution of joint inflammation.

Keywords: Osteoarthritis, rheumatoid arthritis, synovial fluid


How to cite this article:
Abd-El-Hafez AA, El-Deeb A, Esmail M, Al Sernagawy R. Ultrastructural characteristics of synovial fluid cells in rheumatoid arthritis and osteoarthritis. Tanta Med J 2014;42:21-30

How to cite this URL:
Abd-El-Hafez AA, El-Deeb A, Esmail M, Al Sernagawy R. Ultrastructural characteristics of synovial fluid cells in rheumatoid arthritis and osteoarthritis. Tanta Med J [serial online] 2014 [cited 2017 Oct 18];42:21-30. Available from: http://www.tdj.eg.net/text.asp?2014/42/1/21/130114


  Introduction Top


Synovial fluid (SF) is a combined product of the synovial cells and ultrafilterate of capillaries. It is rich in hyaluronic acid, glycoproteins, and leukocytes [1]. The synovium is responsible for the secretion of SF and in normal conditions it produces very little fluid. In the knee, which is the largest joint of the body, the normal amount of SF is about 0.5 ml [2].

A characteristic aspect of joint inflammation is the abundance of inflammatory cells in the diseased joint, with the two main components of this permeate being the macrophages in the synovial tissue and the neutrophils in the SF [2],[3],[4],[5]. Under normal circumstances, SF contains very few cells, the majority being fibroblast-like synoviocytes (FLS) and few macrophage-like synoviocytes (MLS) sloughed off by the synovial lining and unusual leukocytes, mainly the mononuclear cells. In arthritis, the ratio of the synoviocytes and white blood cells in the synovial effusions becomes inverted, with high level of polymorphonuclear leukocytes (PMNs), which may comprise up to 80% of total cell count in the active phase of the disease [6],[7].

Neutrophils are short-lived leukocytes with a key role in host defense against pathogens; they enter apoptosis spontaneously within 24-48 h of leaving the bone marrow, although their lifespan can be extended during inflammatory responses by several proinflammatory cytokines [8]. The neutrophils contribute to different mechanisms of propagation of synovial inflammation and to the progress of joint destruction in arthritis.

The PMNs recruited in the joint cavity in rheumatoid arthritis (RA) possess potent degradative enzymes and proinflammatory mediators: elastase, metalloproteinases, and collagenase (MMP-8) are responsible for articular cartilage destruction; prostaglandins and leukotrienes serve as chemoattractants of the mononuclear cells; defensins interact with the host immune system, mediating acute inflammatory response correlated with the destructive course of the disease; and proteases are involved in the regulation of cytokine activity and pannus formation. The PMNs release reactive oxygen intermediates such as superoxide anion (O2 - ), which is a potent mediator of inflammation. The adherence of PMNs to the articular cartilage, eventually mediated by immunocomplexes, activates these cells with subsequent secretion of destructive enzymes and reactive oxygen products, resulting in cartilage degradation. For this reason, their removal is vital to normal inflammatory resolution [9],[10],[11],[12],[13],[14],[15],[16].

Recently, some new mechanisms of PMNs involvement in the pathogenesis of RA were investigated: the physical interaction between SF neutrophils and FLS that promotes and maintains joint inflammation and the synthesis of large amounts of class II major histocompatibility complex by the neutrophils of rheumatoid synovial effusions, displaying a novel interaction of the neutrophils with T cells, which is important in terms of immune arthritis pathology [17,18].

Despite that, the role of neutrophils in joint destruction remains underestimated [16]. Synovial effusions are shown to have PMN predominance in all forms of chronic inflammatory arthritis, irrespective of the possible underlying cause [7], whereas in arthritides other than RA, in which joint destruction is milder than in RA with different underlying mechanisms and the considerably lower level of cytosis, the role of neutrophils is less understood [19,20]. The ability to modulate inflammatory PMN infiltration, including apoptosis induction, represents a potentially important mechanism of joint inflammation pathogenesis. Apoptosis as a major route for disposal of extravasated PMN is followed by rapid recognition and intact phagocytosis of PMN by mature tissue macrophages [7]. Decreased rates of apoptosis of SF neutrophil amplify inflammatory response in arthritis [8],[21].

There are very few studies on the apoptosis of synovial exudate cells in joint diseases [9],[21],[22],[23],[24],[25]; most of them are concerned with synovial effusions of the patients with RA and osteoarthritis (OA) and few are conducted on the ultrastructural level [26],[27]. The reported data regarding incidence of apoptosis in synovial effusions and its promotion and inhibition are controversial. Some investigators present evidence that SF from a variety of arthritic patients generally promotes neutrophil apoptosis, and the rate of spontaneous apoptosis of the synovial PMN considerably exceeds its rate in the peripheral blood [22],[24],[28].

Other investigators found a high antiapoptotic activity of SF and a decreased amount of apoptotic PMN in the synovial effusions as a result of the altered sensitivity of SF neutrophils to apoptosis-inducing stimuli in RA [8, 24, 29, 30]. Altered signaling by the Fas receptor and phosphatidylinositol 3-kinase-dependent antiapoptotic influence of interferon-β may explain the observed prolongation of neutrophil lifespan and the associated tissue injury at the inflammatory sites [8,23].

Thus, the fate of neutrophils at the sites of inflammation, where these cells are likely exposed to both antiapoptotic and proapoptotic influences, needs to be clarified [23]. Detailed analysis of spontaneous PMN apoptosis rate in inflammatory (rheumatoid and nonrheumatoid) and degenerative joint diseases may help to elucidate the persistence of neutrophils in the joint cavity in different arthropathies and its relevance to clinical manifestations of the joint diseases.


  Patients and methods Top


Study design

This study was conducted on two groups of patients who were selected from the outpatients clinic of Department of Physical Medicine, Rheumatology and Rehabilitation, Tanta University Hospitals. It was first designed to achieve a control group also, but there were no volunteers from healthy individuals and the SF from post-traumatic arthroscopy was not suitable to be considered as control. Hence, the results of the cell counts were compared with the standard values for normal, degenerative, and inflammatory arthritis, present in the text books [28],[29],[30].

Group I consisted of seven patients with RA who were diagnosed according to the ACR [31] criteria. Five samples were aspirated from five patients with unilateral knee effusion and two samples from one patient with bilateral knee effusion. Their age range was 20-65 years.

Group II consisted of 13 patients with primary OA who were diagnosed according to Altman et al. [32]. Twelve samples were obtained from 12 patients with unilateral knee effusion and two samples from one patient with bilateral knee effusion. Their age range was 46-63 years.

Inclusion criteria

The study only included patients with primary OA diagnosed according to Altman and colleagues and RA patients diagnosed according to the ACR criteria. Both groups had to have moderate to severe effusion.

Exclusion criteria

We excluded patients with secondary OA, patients with mild effusion, and also patients who had received previous intra-articular corticosteroids.

Examinations used

(1) All patients were subjected to complete history taking, general examination to exclude secondary causes of OA, locomotor system condition assessment, radiologic investigations, and laboratory investigations including complete blood examination, rheumatoid factor, erythrocyte sedimentation rate (ESR), and C-reactive protein.

(2) The aspiration of SF samples was carried out under complete aseptic condition. Samples were submitted for SF analysis and electron microscopic examination.

(3) Assessment of the disease activity was carried out for both groups and then correlated with the microscopic findings.

(a) Assessment of disease activity in rheumatoid arthritis patients: The disease activity of the RA patients was assessed using the modified Disease Activity Score (DAS) [33] in which each patient was assessed by the following parameters:

(i) Number of tender joints (28 joints count: both shoulders, both elbows, both wrists, both knees, all MetaCarpi Phalangial joints (MCPS), and all Proximal Inter Phalangial joints (PlPs),

(ii) Number of swollen joints (28 joints count),

(iii) ESR (mm after 1 h),

(iv) Patient's global assessment of disease activity (on visual analog).

Using the visual analog scale (VAS) in which a 10-cm horizontal line is marked 'not active at all' at one end and 'extremely active' at the other end, the patient is asked to mark X on the horizontal line where he thinks he stands. The distance from the start to the mark X is measured in centimeters and recorded.

Calculation of the DAS-28 score was carried out using DAS calculator.

Patients were divided into three groups: mild, moderate, and severe disease activity [32], which are listed as follows: mild activity, <2.3-3.8; moderate activity, 3.8-4.9; severe activity, >4.9.

(b) Assessment of disease activity in osteoarthritis patients:

(i) Pain: Analysis of pain was performed, such as the site, type, character, radiation, what aggravates and what relieves pain, whether there is rest pain, pain on motion, or pain at night, and whether it occurs occasionally, frequently, or every night.

The patient's sense of stiffness was graded on a scale of 0-3 [34]: 0, nil; l, slight; 2, moderate; 3, severe.

(ii) Tenderness and its site: Tenderness was then graded on a four-point rating scale [35]:0, the patient has no tenderness; l, the patient has tenderness; 2, the patient has tenderness and winces; 3, the patient winces and withdraws the joint.

A point was also scored for each tender area. If more than two separate areas were present, it was considered a generalized tenderness scoring 3 points. Hence, the maximum score for tenderness was 6 for severe generalized tenderness.

(iii) Joint swelling: Joint swelling was graded according to a four-point scale as follows: 0, absent; 1, just palpable swelling; 2, palpable visible swelling; 3, palpable visible swelling changing the contour of the joint (by measuring the knee circumference at the upper pole of the patella) [34].

Additional point was scored for palpable synovial hypertrophy and for joints effusion (1 point was scored for effusions just detected by the bulge test, whereas 2 points were scored for effusions detected by the cross-fluctuation test).

(4) Synovial fluid analysis: The cells of the specimens were counted using a hemocytometer as usual.

(5) Sample preparation for transmission electron microscopy [36]: Cytospin preparations of the synovial effusions were processed for transmission electron microscopy as follows. Under complete aseptic technique, 5 ml of SF was aspirated from the knee joint, transferred to centrifuge tube, and then centrifuged for 10 min at 1000 rpm. A pellet was formed and the supernatant was pipetted off carefully; 1% glutaraldehyde fixative was added to the pellet and kept for at least 2 h. The specimens were processed as usual and embedded in Araldite resin. Ultrathin sections were stained with uranyl acetate-lead citrate and viewed under JEM 100S (JEOL Solutions for Innovation, Peabody, MA, USA) transmission electron microscope in the EM Department, Faculty of Medicine, Tanta University. The neutrophils percentage of total cells, the apoptotic index (calculated by counting the number of apoptotic cells/50 effusion cells), and the proportion of cytophagocytic cells (CPCs) in the synovial effusions were then recorded.


  Results Top


This study was conducted on 21 patients divided into two groups: group I comprised RA patients and group II comprised OA patients.

Group correlations

There was a significant difference in the neutrophil count between the two groups [Table 1]; [Figure 1]). The apoptotic index of both studied groups showed significant difference between the two groups ([Table 2]; [Figure 2]). There was a positive correlation between tender joints, swollen joints, morning stiffness/min, ESR (first hour), VAS, DAS, and neutrophil count in RA patients [Table 3]. The correlation between tender joints, swollen joints, morning stiffness/min, ESR (first hour), VAS, DAS, and apoptotic index in RA group was significantly positive [Table 4]. The correlation between tender joints, swollen joints, morning stiffness/min, VAS, ESR, and neutrophil count in the OA group was nonsignificant [Table 5]. The relationship between tender joints, swollen joints, morning stiffness/min, VAS, ESR, and apoptotic index in the OA group showed no correlation [Table 6].
Table 1: Neutrophil count in both groups

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Table 2: Apoptotic index of both studied groups

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Table 3: Correlation between tender joints, swollen joints, morning stiffness/min, erythrocyte sedimentation rate (first hour), visual analog scale, disease activity score, and neutrophil count in rheumatoid arthritis patients

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Table 4: Correlation between tender joints, swollen joints, morning stiffness/min, erythrocyte sedimentation rate (first hour), visual analog scale, disease activity score, and apoptotic index in the rheumatoid arthritis group

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Table 5: Correlation between tender joints, swollen joints, morning stiffness/min, visual analog scale, erythrocyte sedimentation rate, and neutrophil count in the osteoarthritis group

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Table 6: Correlation between tender joints, swollen joints, morning stiffness/min, visual analog scale, erythrocyte sedimentation rate, and apoptotic index in the osteoarthritis group

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Figure 1:

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Figure 2:

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Electron microscopic assessment of the samples collected from knee synovial effusions demonstrated that, in all patients with RA or OA, neutrophils were the predominant cells [Figure 3], whereas other white blood cells such as lymphocytes and monocytes were less frequent [Figure 4]a and b). Connective tissue cells such as macrophages were abundant, whereas mast cells were rarely observed. FLS, which is normally the prominent cell in SF, became infrequent [Figure 5], whereas MLS were seen only twice during the examinations [Figure 6]. Some of these cells had intact ultrastructure, whereas others contained changes consistent with cellular anomalies, necrosis, or apoptosis.
Figure 3:

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Figure 4:

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Figure 5:

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Figure 6:

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In the samples of both groups, neutrophils were the predominant cells. In OA samples, the neutrophils were relatively inactive (with smooth external contour and intact evenly distributed granules) [Figure 3].

In RA samples, the neutrophils displayed signs of moderate activation without manifestations of cellular lesion (pseudopodia, bleb-like protrusions, redistributed granules, moderate amounts of phagosomes) [Figure 7].
Figure 7:

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Furthermore, some cells exhibited signs of functional overstrain (more irregular surface, large and numerous vacuoles and phagosomes, expanded perinuclear cisterna, and signs of cellular lesions in the cytoplasm such as rarefactions and rat-eaten destruction) [Figure 8].
Figure 8:

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Most of the cells containing features characteristic of apoptosis were identified as neutrophils. These cells exhibited typical cap-shaped or crescent-shaped chromatin margination and condensation, increased density of the cytoplasm, closely packed organelles with subsequent bleb formation, and formation of apoptotic bodies often ingested by macrophages. In addition, most of the neutrophils were found apoptotic at the early, advanced, and late stages of cell death [Figure 9]. FLS and MLS were present in both groups but they were predominant in RA samples, with the ultrastructure appearing mostly unchanged [Figure 10].
Figure 9:

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Figure 10:

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CPC, which are blood-borne macrophages having phagosomes (engulfing bodies such as apoptotic cells or nuclei), were identified among the cells of effusions [Figure 11]. The incidence of CPC is used as a complementary index of apoptosis intensity in the synovial effusions. As neutrophils embrace the largest cell population in the synovial effusions of inflamed joints determining the local disease activity, and their fate is essential for the resolution of inflammation, we assumed an assessment of the apoptotic index in synovial effusions from both groups. The incidence of apoptotic index was 5-12% in RA samples and 2-8% in OA samples.
Figure 11:

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The mean incidence of CPC in the synovial effusions was lower in OA samples (5.5% of effusion cells) than in RA samples (6.8%); the difference between RA and OA samples was nonsignificant.


  Discussion Top


RA is a chronic inflammatory rheumatic disorder of unknown etiology characterized by symmetrical polyarticular inflammation, including small, medium, and large joints of the upper and lower extremities. It is characterized by marked intimal hyperplasia and by accumulation of T cells, plasma cells, macrophages, B cells, mast cells, natural killer cells, and dendritic cells in the synovial sublining layer. Only few neutrophils are found in rheumatoid synovial tissue. However, large numbers of neutrophils diffuse through the intimal layer into the SF [37].

Primary OA is a multifactorial disease process that involves joint constituents - chondrocytes, collagen, proteoglycans, subchondral bone, and synovial membrane - in various ways [38].

The major clinical manifestations of RA and OA show abnormal degradation of cartilage and synovial and bony tissues, resulting in severe mobility impairment. The severity of the disease is generally scored according to the pain and mobility indices [39].

The aim of this study was to assess and compare the ultrastructural features of SF cells from RA and OA patients and to correlate it to activities of the diseases. This study also aimed to investigate whether or not the ultrastructural features of SF cells can help in the diagnosis and prognosis of arthritis.

Twenty-one patients were evaluated; 14 of them were suffering from primary OA and seven of them were suffering from RA.

In this study, RA patients had significantly high ESR (P < 0.001). These results agreed with that of Thompson et al. [40] who proved that ESR is increased in the active stage of RA. However, Harvey et al. [41] found that not all patients with RA have an elevated ESR because of a variety of reasons such as alternation of the shape and size of the red cells, influencing the ability of cells to form rouleaux.

In this study, synovial effusion from patients with RA or OA was collected and examined using an electron microscope to evaluate the count of PMNs, the rate of apoptosis, and its relationship with the activity of the disease.

Synovial effusion characterized by increased level of neutrophils in both RA and OA secretes strong chemotaxic factors, powerful oxidative and proteolytic lysosomal enzymes, proinflammatory cytokines, and reactive oxygen intermediates that may amplify inflammation in the joints and, directly or by implication, affect articular cartilage resulting in joint destruction [42].

The high level of neutrophils may be because they hardly re-enter once having left the microcirculatory bed and they instead get accumulated at the inflammatory site and lead to continuous destruction [42].

In this study, the neutrophils were predominant in RA samples (75-83%) with the mean value of 79.167 ± 3.0610, and it was significantly increased with the activity of the disease. However, in OA, the neutrophils were less frequent (63-82%) with the mean value of 70.5 ± 5.431.

This is in agreement with the study by Koizumi et al. [42] who found that the incidence of neutrophils infiltration was 60% in RA. In addition, Francis et al. [43] reported the same incidence of neutrophils in SF of RA patients.

In contrast to our results, in another analysis by Jones et al. [34], they suggested a negative correlation between the disease activity and the level of neutrophils in the synovial samples because they assumed that one would expect an accelerated neutrophil apoptosis in the active fluid to decrease the level of inflammatory cells and decrease the disease activity.

Apoptosis is the process of programmed cell death. It is a form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing harmful substances in the surrounding area. Apoptosis plays a crucial role in developing and maintaining health by eliminating old cells, unnecessary cells, and unhealthy cells. The changes that occur in the cell during apoptosis include blebbing, loss of cell membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation [43].

The regulation of elimination of inflammatory cells from the joint cavity is important for the management of the course of inflammation; evaluation of PMN apoptosis in SF gains special importance [43].

In this study, apoptosis was found in both RA and OA samples but the level of apoptosis in RA samples was significantly higher. The apoptotic index was 5-12% in RA patients and 2-8% in OA patients. This is in agreement with the findings reported by Renshaw et al. [44] who evaluated 28 patients with RA with an average age of 42.3 ± 5 years and nine patients with OA with an average age of 51 years. They found that the level of apoptosis was 3.36% in RA patients, whereas in OA patients it was 9.5%.

In addition, these results are in agreement with those reported by Kapitonova and Othman [45] who found that synovial effusion contains factors capable of directly or indirectly promoting neutrophil apoptosis that are normally powerful enough to overcome the apoptosis-inhibiting effects of cytokines.

This is not in agreement with the results found by Ottonello et al. [25] in which spontaneous and immune complex-triggered neutrophil apoptosis was reduced in the SF of patients with RA, its microenvironment being a proinflammatory milieu responsible for the persistence of activated and long-surviving neutrophils, with adenosine playing a crucial role in the inhibition of apoptosis.

Normal synovial tissue consists of two anatomically distinct layers: a surface layer (intima or synovial lining) and an underlying layer (subintima). In the normal intima and subintima, two cell types predominate: MLS (type A) and FLS (type B) [46].

FLS are inflammatory cells that play crucial roles in both joint damage and propagation of inflammation. FLS express a variety of promitotic and antiapoptotic mutations; whether these are primarily a cause or a consequence of the disease remain a matter of conjecture. FLS mediate inflammation by responding to and also by production of interleukin 1 (IL1), IL4, IL6, IL8, IL15, tumor necrosis factor-α, and transforming growth factor-β [46].

In this study, FLS were overexpressed in RA samples; they consisted about 10% of the inflammatory cells in RA samples, especially in long-term disease, but they were less frequent in OA samples. One possibility is that FLS in RA are hyperproliferative and divide more rapidly than the cells from OA samples [47].

These results were also in agreement with the study by Jungel et al. [47] and Kojima et al. [48], who found that, although the SF became infiltrated with a variety of inflammatory cells, the FLS were markedly overexpressed and secreted metalloproteinases (MMPs) that diffused in the joint space leading to the loss of cartilage over the articular surface.

However, in contrast, Giannelli et al. [49] found that, although the level of FLS was extremely high in the SF, they play critical roles in joint homeostasis and secrete high levels of long chain, polymeric hyaluronan into the joint cavity, which has both lubricating and immunomodulatory properties. It also produces glycoprotein lubricin as well as plasminogen activator. Lubricin contributes to joint space viscosity. Plasminogen activator may prevent fibrous adhesions in the joint, promoting normal movement.

As neutrophil has few organelles for protein synthesis, it has a limited capacity to regenerate secreted proteins and specific enzymes that are depleted by the phagocytic activity. The neutrophil is thus incapable of continuous function and degenerates after a single burst of activity. This may explain the excess apoptosis.

Neutrophils also secrete granule contents into the extracellular environment by degranulation. This may clarify the homogenized degranulated cytoplasm in some neutrophils.

The incidence of CPCs in synovial effusion samples from RA patients was found to be related to the current disease activity. This discrepancy might be explained by the different methodological approaches, among which ultrastructural examination provides stronger evidence of apoptotic cell death and their engulfment by the macrophages. Besides relevance to disease activity, the incidence of CPC was also associated with the course of the disease, being significantly higher in the active RA.

In addition, in this study the mean incidence of CPC in the synovial effusion samples from RA patients was lower (5.5%) compared with that in RA samples (6.8%); the difference between RA and OA samples was nonsignificant.

Thus, there is a distinct connection between the apoptosis rate among the trigger cells in the SF and the clinical characteristics of RA [50].

Both apoptotic neutrophils and CPC could be found in the SF of OA patients, with much smaller amounts in synovial effusion.


  Conclusion Top


Participation of neutrophils in joint inflammation is an important factor of homeostasis that is concerned with host defense and is responsible for clinically significant complications of the joint inflammatory process. It may be utilized as a prophylactic and therapeutic target.


  Acknowledgements Top


First and foremost, the authors thank Allah, the most merciful, gracious, and compassionate. The authors thank Professor Ezzat A Aldryni, professor and former head of Histology Department, for his continuous help, endless support, and encouragement.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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Abstract
Introduction
Patients and methods
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