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Inflammatory Arthritis


Rheumatoid arthritis causes stiffness and pain and may also cause fatigue. It can lead to difficulty with everyday tasks, such as turning a doorknob or holding a pen. Dealing with the pain and the unpredictability of rheumatoid arthritis can also cause symptoms of depression.

Rheumatoid arthritis may also increase your risk of developing osteoporosis, especially if you take corticosteroids. Some researchers believe that rheumatoid arthritis can increase your risk of heart disease. This may be because the inflammation that rheumatoid arthritis causes can also affect your arteries and heart muscle tissue.

In the past, people with rheumatoid arthritis may have ended up confined to a wheelchair because damage to joints made it difficult or impossible to walk. That's not as likely today because of better treatments and self-care methods.

In RA the synovial joints are attacked,the most movable and most flexiable joints in the body,which allows mobility in our wrists, fingers, shoulders, elbows,knees,and ankles. A tough joint capsule surrounds each joint and attaches to the edges of the bones like a loose-fitting sleeve. This assists the ligaments,which hold the bones together,along with the tendons,which attach muscles to bones. This capsule of parallel,interlacing bundles of dense, white, fibrous tissue is richly supplied with nerves,blood vessels,and lymphatic vessels.
A delicate membrane,the synovium,forms the thin,smooth,moist inner lining of the joint capsule. It also extends out into bursae (sac) near the joint that act as fluid-filled cushions between structures that would otherwise rub against each other,such as muscles and tendons. These bursae can sometimes become irritated and inflamed,resulting in the familiar pain of bursitis,a condition that may accompany RA but can occur independent of the disease. Where the lower layer of the thin joint membrane,the synovium,merges with the fibrous capsule,the area is filled with blood vessels,macrophages,fibroblasts and other cell types.
The normally,thin,synovial surface consists of one or two layers of cells embedded in a firm,moist layer. Some of those cells can act like macrophages and when necessary injest bacteria and debris within the joint. When inflammation sets in,it becomes a thick mass of inflammatory material.
Other synovial cells secrete special chemicals that,together with fluid from the blood filtered through the membrane vessels create a synovial fluid with the slick,gummy consistency of egg whites. The first joint tissue to be affected by sustained inflammation is the synovial membrane. The inflammation spreads to the fibrous joint capsule and surrounding ligaments and tendons,causing more pain and stiffness.
The precise progression of RA over time in different individuals may be similar,but it is not identical. The symptoms of RA vary among individuals. In a "typical" RA patient with severe RA,as early symptoms of joint pain and stiffness appear,new capillaries form in the synovium. The joint swells with fluid seeping in from the blood .
Hungry macrophages swarm actively and hold out antigens to T cells that have migrated into the joint there has been some kind of injury to the joint tissues, perhaps from a infection,and lots of different antigens,including self antigens,are present. Neutrophils,white blood cells that pick up and destroy debris,similar to the action of macrophages,accumulate in the joint fluid,now bolstered by added proteins and chemicals from synovial cells.
Simplifying what first goes on: The macrophage and the T cell talk to each other inside the synovial lining of the joint,first,they touch each other through T cell receptors and other types of cytokines meet. They start talking,and then cell messengers like TNF-alpha,and interleukin-1 are released from the macrophages and then these little substances are recognized on the surface of the T-cell and that sends messages into the T-cell,and the DNA (of the T-cell) allows other messages to occur. A biologic medicine could target or block this communication between the T cell and the macrophage. There are different  ways of doing this.
The T cells in rheumatoid joints are mainly of the T helper type (Th1) category. These Th1 cells (incontrast to TH2 cells,which slow down inflammation) promote inflammation by releasing stimulating cytokines.
Important chemical changes are underway in the small blood vessels in the area. Rather then move rapidly along in the blood stream,lymphocytes (white blood cells) begin to slow down and roll along the vessel walls. There,sticky proteins on the wall,formed in response to chemicals seeping in from the nearby inflammation,latch on to the attachment sites on the lymphocytes' outer membranes.
This slows the lymphocytes. Once slowed to a halt,the lymphocytes adorn their surface with another protein. This in turn grabs onto a compatible protein on the vessel lining,stopping the lymphocyte. Quickly attracted toward the tug of chemicls oozing out from the inflammation,the flexible lymphocytes worm their way between the cells of the blood vessels and move into the inflamed synovium.
These lymphocytes include many neutrophils,which make up seventy percent of our circulating white blood cells. In RA the neutrophils (billions each day) leave the blood vessels,move through the synovium,and enter the synovial fluid lubricating the joint.
There the neutrophils contribute significantly to the inflammation itself. In the chemical environment of the RA joint, they leak corrosive enzymes and other chemicals,which attack the outer surface of the cartilage. At the same time some of those enzymes begin to degrade the molecules within the cartilage, causing the cartilage to absorb water and swell,leaving the cartilage vulnerable to mechanical damage from compression during weight bearing.
As these changes continue for a few months,T cells and macrophages emit cytokines,which provoke the synovial cells to mutiply and increase the size and volume of the synovium twenty to one hundred times its normal size. The majority of the cells in the synovium are macrophages. These play a pivotal role in perpetuating inflammation in RA because the release (among others) the dytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1).
Meanwhile B cells become active and make antibodies including the rheumatoid factor (RF),that antibody found in the majority of people with RA One result of this is that these antibodies combine with antigens. These antigen-antibody complexes,clumps of sticky proteins that form in the RA joint.
These immune complexes attract and activate white blood cells,thereby propagating the inflammation even more. In later stages of RA,immune complexes may cause vasculitis,inflammatory damage to the lining of blood vessels.
Deposits of these immune complexes within the outer layer of the cartilage attract the attention of an invasive,erosive mass of tissue known as the pannus,a tumour-like tissue now forming in the synovium Within a few months of developing RA symptoms,the lining of the inflamed synovium increases in depth and in number of cells and become highly folded,extending into finger-like projections that form the pannus.
Elongated cells in the synovium transform under the influence of cytokines -in to aggressive dividing cells that release several kind of cartilage destroying enzymes. The pannus becomes a tumourlike tissue,slowly moving in from the edges of the joint towards the centre,gradually eroding cartilage and even the underlying bones if left unchecked.
In RA there is evidence that some defects occur in this process of programmed cell death,which leads to a kind of abnormal accumulation of cells in the joints. during this progression from the early excitation of the immune system to the abnormal destruction of otherwise healthy tissue,many chemical signals are transferred among the cells taking part in the damaging process.
TNF and IL-1 Is among the most well known but there are numerous chemical conversations going on at least 10 other IL-type messengers.
Prominant among those other chemicals are the prostaglandins. These are made by neutrophils,macrophages and other cells in the joint joint in response to TNF-alpha and IL-1. The prostaglandins cause pain and also help to increase the flood of cells and fluid into the aching joints.
Note cartilage: The natural chemicals within the cartilage are strengthening agents that help to regulate the slow movement of synovial fluid throughout the cartilage. Without these substances normal weight bearing would soon press all the fluid out of the knee cartilage. Certain of these molecules act as a kind of pump,allowing just enough fluid to be pressed out so that there is always a thin film creating a smooth,moist cartilage surface.
Motion and weight bearing are necessary to optimize this pumping action. Use it or lose it. Prolonged nonuse of a joint reduces the effectiveness of this pumping mechanism and interferes with the nutrition of the living cells embedded in the cartilage. There are no blood vessels in the cartilage,so its health depends largely on the nourishment seeping into it from the synovial fluid. The cartilage needs oxygen-exercise provides the fuel.

The synovium lines the noncartilaginous surfaces of the diarthrodial joints, and synovial tissue is also found in tendon sheaths and bursae . Several rheumatic diseases are characterized by synovial inflammation. In these conditions, descriptive studies of synovial biopsy specimens may contribute to an understanding of the events that take place in vivo, and they complement experimental animal studies as well as in-vitro studies.
Examination of synovial tissue is generally more relevant than synovial fluid analysis, except, for example, the analysis of neutrophils and platelets, and studies of soluble mediators. Recently, there has been an enormous upsurge in investigations of the pathological changes in the synovium because of the availability of new methods to obtain synovial biopsy samples and because of the development of immunohistological methods, in-situ hybridization, and the polymerase chain reaction. Moreover, the complementary DNA microarray technology may hold great promise for synovial tissue analysis in the future.
Synovial tissue may be obtained either at surgery, by blind needle biopsy, or at arthroscopy. It is likely that tissue obtained at joint replacement differs from that obtained by blind-needle biopsy or arthroscopy because of clear differences in patient selection. Obviously, surgery is inappropriate for studies on early rheumatoid arthritis (RA) or for serial investigations. The blind-needle biopsy technique is safe, well tolerated and is technically easy to perform. A limitation of this method is that its use in clinical practice is often restricted to the suprapatellar pouch of the knee joint.
In addition, it is more difficult to obtain sufficient tissue from clinically uninvolved joints, for example after successful treatment. Arthroscopic sampling of synovial tissue under direct vision is a similarly safe and well tolerated procedure, but is more complicated and expensive. Most measures of inflammation in needle biopsies are similar to those selected at arthroscopy.
An advantage of arthroscopy is that it is always possible to obtain tissue in adequate amounts, even in clinically quiescent joints. Moreover, arthroscopy allows access to most joints and to most regions within the joint, including the pannus-cartilage junction.
There is large variability of synovial inflammation between individuals, different joints, and even within joints. The degree of morphologic heterogeneity in synovial tissue samples obtained from a single joint could suggest that evaluation of synovial tissue is unreliable because of unavoidable sampling error. Several studies, however, have shown that, despite the degree of histologic variation, representative measures of several parameters of synovial inflammation may be obtained by examining a limited number of samples. For example, quantification of T-cell infiltration and activation in sections derived from at least six different biopsy specimens results in variance of less than 10%. It is generally not necessary to know the macroscopic appearance of the rheumatoid synovium in order to obtain representative samples.
There are essentially three methods to quantify the features of synovial inflammation in biopsy samples: semi-quantitative analysis, quantitative analysis and computer-assisted analysis. All three methods are reliable in experienced hands. It can be anticipated that digital image analysis will be increasingly important with the use of more advanced computer systems.
Histological features of the synovium have been documented in various clinical studies, describing associations with disease activity and prognosis. These studies underscore the important role of macrophages and macrophage-derived mediators of inflammation and destruction in RA. In addition, systematic comparison of synovial tissue from RA patients in different phases of the disease made it possible to define the cell infiltrate, as well as the expression of adhesion molecules, cytokines and degrading enzymes in early disease.
A major conclusion from this work is that so-called early RA is already a chronic disease. This may explain the observation that a notable percentage of RA patients have signs of joint destruction at the time of initial diagnosis.
Preliminary work has identified some immunohistological features that are characteristic for rheumatoid synovial tissue. More extensive future studies may provide helpful markers, which could be used for routine clinical practice.
Studies of synovial tissue may also play an important role in the development of rational therapies in which biotechnology products are used to influence defined pathogenetic mechanisms. The design of optimal treatment regimens for interventions with agents such as monoclonal antibodies, soluble receptors, cytokines and peptides can be facilitated by information regarding the actual achievement of the biological effect at the site of inflammation.
Such studies will also provide insight into the mode of action of such agents. Additionally, analysis of serial biopsy samples during treatment may provide useful alternative end points for both joint inflammation and joint destruction. This approach could lead to a rapid screening method that would require
relatively low numbers of patients to predict the effects of novel antirheumatic strategies. Studies of the relation between a defined modification of inflammation and the clinical course could also produce information about the pathogenesis of rheumatic diseases.
The synovium comprises the intimal lining layer and the synovial sublining. The intimal lining layer consists mainly of intimal macrophages and fibroblast-like synoviocytes. The synovium becomes hypertrophic and edematous in various arthritides. Angioneogenesis, recruitment of inflammatory cells under influence of chemokines, local retention and cell proliferation all contribute to the accumulation of cells in the inflamed synovium. The following discussion focuses on the major infiltrating cell populations.
Rheumatoid synovial tissue is characterized by marked intimal lining hyperplasia and by accumulation of T cells, plasma cells, macrophages, B cells, mast cells, natural killer cells and dendritic cells in the synovial sublining. Distinct patterns of lymphoid organization can occur in the synovium; diffuse, follicular and granulomatous variants have been distinguished. In contrast to general belief, proliferation of synovial tissue is mainly due to changes in the synovial sublining.
Important contributors are angioneogenesis, oedema, massive cell infiltration and fibrosis. The differences with other forms of arthritis are only gradual. There is, for example, on average stronger infiltration by macrophages, plasma cells and granzyme-positive cytotoxic cells in RA. So-called pannocytes have been observed at the pannus-cartilage junction. These cells exhibit phenotypic and functional features of both fibroblast-like synoviocytes and chondrocytes. Furthermore, cells with features of osteoclasts have been identified at the junction. they are probably derived from the monocyte/macrophage lineage.
Although the aetiology of RA remains elusive, immune-mediated mechanisms are probably of crucial importance. The evidence to support a role of CD4+ T cells in the immune response in RA patients  is substantial, but circumstantial. A subset of the CD4+ cells in the synovium shows phenotypic evidence of prior activation, but many of the T cells are small and few of them express activation molecules such as transferrin and the interleukin-2 receptor.
Of interest is that the percentage of interferon-? producing T cells and the detectable levels of T cell receptor-? protein are significantly lower in RA synovium than in a chronic T-cell-mediated immunological reaction, such as tonsillitis or tuberculous pleuritis. These data indicate that T cells in RA synovium are in a peculiar activation state.
Lymphocyte aggregates are observed in 50-60% of RA patients, and can be surrounded by coronas of plasma cells. In these areas interdigitating dendritic cells are observed in proximity to CD4+ T-cells. Human leucocyte antigen class II molecules and the costimulatory molecule CD86 (B7-2), which has an important role in antigen presentation, are expressed on these cells, suggesting that interdigitating dendritic cells could present antigen to CD4+ T cells.
Whether this involves mainly endogenous autoantigens  or exogenous agents, such as bacteria and viruses, remains to be elucidated. Recent studies have shown that there is a much higher load of bacterial DNA and peptidoglycans in the synovium than previously expected. Conceivably, the T-cell response is directed at an array of different antigens, which might well be a secondary phenomenon.
When the perivascular lymphocyte aggregates are large, substantial numbers of B cells can be found in close association with CD4+ cells and follicular dendritic cells. Of importance is that fibroblast-like synoviocytes also have intrinsic properties of follicular dendritic cells . The aggregates that consist mainly of CD4+ T cells and B cells resemble germinal centers, although they are morphologically not identical to the germinal centers in lymphatic organs. The microenvironment suggests a close functional relationship between follicular dendritic cells and B cells in RA synovium, allowing activation and maturation of the humoral immune response.
It has become clear that cells other than lymphocytes, in particular activated macrophages and fibroblast-like synoviocytes, play a critical role as effector cells in chronic disease. Both cell types are highly activated and secrete a variety of cytokines, as well as matrix metalloproteinases. Fibroblast-like synoviocytes can also produce other factors, such as proteoglycans and arachidonic acid metabolites. The increase in the numbers of fibroblast-like synoviocytes can be explained in part by proliferation and by impaired apoptosis.
Although proliferation probably contributes to some extent, inhibition of apoptosis in particular provides an important explanation for the increased cellularity. Very few apoptotic cells are found in the synovium of RA patients, despite the presence of fragmented DNA in the intimal lining layer. Various mechanisms may be involved in causing inadequate apoptosis: the development of mutations of the p53 suppressor gene, deficient functional Fas ligand expression, overexpression of antiapoptotic molecules, such as sentrin and activation of nuclear factor-?B. The marked increase in the expression of granzymes A and B in RA patients could be a reactive attempt to induce apoptosis in synovial cells.
Interestingly, fibroblast-like synoviocytes from RA patients exhibit many features of transformed cells. The presence of these 'transformed' cells in the synovium may contribute to the autonomous progression of pannus and joint destruction in a subset of RA patients.
Two-thirds or more of the cells in the hyperplastic intimal lining layer in RA are macrophages, where they are particularly observed in the more superficial parts. It is generally believed that they originate from bone marrow-derived monocytes that have migrated in response to chemotactic factors. Relatively little is known about the factors that influence the specific retention of macrophages in the intimal lining layer. It has recently been suggested that the ligand pair CD55-CD97 could be involved.
Fibroblast-like synoviocytes can be distinguished from other fibroblasts by the marked expression of CD55 or complement decay accelerating factor. CD55 can act as a cellular ligand for the sevenspan-transmembrane molecule CD97, which is expressed by nearly all intimal macrophages. The microarchitecture of the intimal lining layer strongly suggests that intimal macrophages and fibroblast-like synoviocytes may specifically interact via this ligand pair. Of note is that intimal macrophages exhibit stronger expression of CD97 than macrophages in the synovial sublining, illustrating the highly activated phenotype of the intimal macrophages in rheumatoid synovial tissue. The exact role of the CD55-CD97 interaction in the pathogenesis of RA remains to be elucidated.
The macrophages often also constitute the majority of the inflammatory cells in the synovial sublining. Macrophage infiltration occurs preferentially in areas adjacent to the articular cartilage. Of interest is that most cells in areas where synovial cells display tumour-like morphology are macrophages. The preferential accumulation of macrophages at the pannus-cartilage junction is probably related to the expression of a range of adhesion molecules by macrophages and to the effects of selective chemotactic factors.
The importance of these cells and their soluble mediators is supported by clinical observations. Local disease activity is particularly associated with the number of macrophages and the expression of cytokines, such as tumour necrosis factor (TNF)-a and interleukin-6, in synovial tissue. There is also a significant positive correlation between intimal lining layer depth and cell counts for macrophages in the synovial sublining on the one hand, and radiographic signs of joint destruction after follow up on the other.
The pivotal role of TNF-a, at least in the majority of RA patients, has been confirmed by the impressive effects of specific therapeutic strategies targeting the TNF-a molecule. The importance of cytokines, which are mainly derived from macrophages, is also illustrated by the effects of treatment aimed at blocking the effects of interleukin-1 and interleukin-6.
These observations have stimulated studies of the factors that drive the production of proinflammatory cytokines, such as TNF-a. It has been suggested that cytokinestimulated T cells may contribute to the excessive production of TNF-a in synovial tissue. Among the cytokines that can promote a Th1-like proinflammatory response in the synovium are interleukin-12 and probably also IL-18. Interleukin-15 is another cytokine that has drawn a lot of attention as a potential factor implicated in the interaction between T cells and TNF-a-producing macrophages. In addition to cytokines, cell-surface molecules may also play a role in driving the production of proinflammatory cytokines and matrix metalloproteinases by macrophages and fibroblast-like synoviocytes.
There has been increased interest in the pathological changes at the site of inflammation in patients with various forms of arthritis. Several studies have focused on methodological matters concerning synovial biopsy procedures, sampling error and the methods used to quantify synovial inflammation. This has led to the first steps in the development of quality control systems and the standardization of methodology.
Preliminary studies have identified features of synovial tissue that are associated with specific arthritides. More extensive studies could yield important information for differential diagnosis and estimating prognosis. Moreover, studies on serial biopsy samples after experimental therapy may help to understand the mechanism of action of specific interventions. Such studies may also provide insight into the role of specific cells and molecules in the pathogenesis. Based on these and other investigations, macrophages and fibroblast-like synoviocytes have been recognized as key players in the effector phase of rheumatoid arthritis.
There is an increasing recognition that patients with synovitis of recent onset have divergent pathogenic mechanisms underlying what appear to be relatively similar clinical phenotypes. There is also a recognition that there are major differences in the outcome of early synovitis. The challenge facing investigators in this area is clarifying how these mechanisms determine outcome and, in turn, which mechanisms are the most appropriate therapeutic targets.
Current experimental results strongly suggest that by direct cell-cell contact, membranes of stimulated T lymphocytes attracted by specific chemokines potentiate the inflammatory response. They do so by favouring the extravasation of cells from the immune system into the target tissue through the endothelium, and by activating the production of proinflammatory cytokines and MMPs at inflammatory sites (ie by stimulating monocytes and synoviocytes).
This mechanism (cell-cell contact with stimulated T lymphocytes) induces an unbalanced production of MMPs and TIMP-1 in vitro and may lead to tissue destruction in vivo. We thus hypothesize that cell-cell contact between stimulated T lymphocytes and surrounding cells represents an important mechanism that contributes to the pathogenesis of inflammation and tissue destruction in chronic inflammatory diseases such as rheumatoid arthritis.
Despite the impressive clinical results obtained with anti-TNF therapy, approximately 25% of the patients seem to be resistant. This hints at the possibility that, during the course of the disease, other important mechanisms trigger synovitis and tissue destruction.
 In addition to newly described interleukins (IL-15, IL-17, IL-18), some of the mechanisms could involve direct contact between stimulated T cells and macrophages or synoviocytes. If partly induced by TNF-a, the production of IL-1 can also be triggered by mechanisms independent of TNF, and the production of MMPs is not solely induced by TNF. It is therefore likely that therapeutic intervention will have to aim at additional cytokines and direct cellular contact to block fully the pathogenesis of rheumatoid arthritis.

In chronic inflammation, which leads to tissue destruction and fibrosis, immunocompetent cells migrate through the vascular endothelium to the target tissue. A prototype of these events is synovitis, which occurs in diseases such as rheumatoid arthritis. The hypothesis that cells from the bone marrow could also migrate directly to the synovium through channels interconnecting the two compartments is still under debate. Also, there is no definitive answer regarding the number of cells that result from infiltration of the synovium after migration, or from proliferation at the local site.
Furthermore, the survival of the cells in synovitis is being subjected to some scrutiny, because there is some evidence for a lack of apoptosis in pathological conditions. The interaction between lymphocytes of different subsets and monocyte/macrophages (type A synovial cells) results in the production of proinflammatory cytokines. These include interleukin (IL)-1 and tumour necrosis factor (TNF)-a, which induce connective tissue cells (type B synovial cells or synoviocytes) to produce large amounts of matrix metallo-proteinases (MMPs), which in turn degrade extracellular matrix components (eg collagens and proteoglycans).
Simultaneously, counter-regulatory mechanisms (cytokine inhibitors, anti-inflammatory cytokines and protease inhibitors) are triggered in an attempt to block inflammation and tissue destruction. During, and shortly after the onset of synovitis chondrocytes and bone-derived cells (osteoblasts and osteoclasts) are activated by the same cytokines, together with prostanoids [mainly prostaglandin E2 (PGE2)], to degrade the extracellular matrix via MMPs and to remove the mineral phase of the bone.
The inflammatory and destructive process is often followed by attempts at repair which, unfortunately, result mostly in fibrosis and nonfunctional tissue. The role of cytokines (eg TNF-a and IL-1), growth factors and tissue destruction has been extensively reviewed, and, owing in particular to the concept of inhibition of TNF-a, crucial advances in therapeutic intervention have been made.
The research of the past few years has mostly focused on soluble factors [mainly proinflammatory and anti-inflammatory cytokines derived from T helper (Th)1, Th2 or Th3] as well as on growth factors and angiogenic factors, and more recently cytokines such as IL-15, IL-16, IL-17 and IL-18 were analyzed in depth in the context of synovitis. IL-15 plays a proinflammatory role in rheumatoid arthritis by inducing cell migration and the production of TNF-a. IL-16 released by tissue-infiltrating CD8+ T cells in rheumatoid synovitis influences the anti-inflammatory activity by inhibiting the production of interferon-?, IL-1 and TNF-a in synovium. 
IL-17 secreted by CD4+-activated memory T cells induces nuclear factor-? B, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and PGE2 production by human fibroblasts and acts synergistically with TNF-a and IL-1. IL-18, together with IL-12 or IL-15, induces significant interferon-? production by synovial tissue in vitro, TNF-a synthesis by CD14+ macrophages in synovial culture, and promotes GM-CSF and nitric oxide production.
IL-18 is upregulated by TNF-a and IL-1 and promotes Th1 cell development in synovial membrane. In collagen-induced arthritis in a murine model, IL-18 facilitates the development of erosive, inflammatory arthritis. The role of IL-18 is complex, however, and it can also act as an inhibitor of osteoclast formation; this process is contact dependent. IL-18 produced by osteoblastic stromal cells inhibits osteo-clast formation in murine haematopoietic and primary osteoblast stromal cells.
This action is mediated via GM-CSF production, and not interferon-?, because neutralizing antibodies to GM-CSF were able to rescue IL-18-induced inhibition of osteoclastogenesis. The elevated levels of IL-18 production in osteoblastic cells appear to correlate with cells at a more differentiated stage. Thus, IL-18 production by mature osteoblasts may be one of the mechanisms that limit osteoclast formation by these cells. By counteracting IL-1, IL-18 may regulate bone homeostasis.
It was not until recently that the role of direct contact between cells was studied more systematically. Even in severe diseases, in which the activation and interaction of circulating blood cells such as monocytes and lymphocytes might be expected, it is very difficult to demonstrate that cell-cell contact is direct and that it leads to the production of cytokines or MMPs in the blood stream. This is illustrated by the difficulty in measuring circulating pro-inflammatory cytokines such as IL-1 and TNF-a, even if their abundance is clearly established at the local inflammatory site.
However, as soon as the inflammatory cells have migrated to the tissue, it is likely that, in addition to the role of soluble products, direct cell contact prompts the release of inflammatory mediators and proteolytic enzymes. This suggests that many molecules, mostly large macromolecules, present in the plasma prevent cell-cell contact. These molecules may occur in much lesser concentrations, or be absent in the interstitial tissue, thus permitting cell-cell contact.
Many investigators have advanced sound arguments for T lymphocytes playing a pivotal role in the pathogenesis of synovitis, at least at some stage of the disease. In rheumatoid arthritis, T lymphocytes that display a mature helper phenotype are the main infiltrating cells in the synovium, accounting for 16% of total cells in 'transitional areas' and for 75% in lymphocyte-rich areas.
Extravasation of T lymphocytes occurs at the level of high endothelial venules.
In the perivascular space, activated T lymphocytes bind to matrix proteins. They are in close contact with monocytes, and also with synoviocytes at a more advanced stage of the disease. The T-cell population in inflamed synovial tissue belongs predominantly to the Th1 subset. Interestingly, these T cells show a marked staining for the chemokine receptors CCR5 and CXCR3, and are only occasionally positive for CCR3. It appears that CCR5 is highly expressed on Th1 cells and is rarely present in Th2 cells, whereas CCR3 is found in Th2 cells but not in Th1 cells and CXCR3 is highly expressed in both T-cell subsets. MIP-1 appears to be a selective ligand for CCR5, eotaxin is a ligand for CCR3, and IP-10 is a ligand for CXCR3.
The importance of cell contact, and not only soluble factors, has been emphasized in transgenic mice expressing T cell-targeted membrane-associated human mutant TNF-a, which displayed proliferative synovitis and chronic inflammatory arthritis. This suggests that at least part of the pathogenic activity of T cells in vivo may be due to the expression of the membrane-associated form of TNF-a by T lymphocytes. In addition to T cells, macrophage-derived cells play a crucial part, and indeed a positive correlation was established between CD14 cell counts of both lining and sublining CD68 cells and articular destruction.
Thus, many observations suggest that both T cells and macrophages are important and that contact between T cells and macrophages, or even synoviocytes of the fibrob-last lineage, in the pannus may be involved in the pathogenesis of inflammatory destructive arthritis. Other cells may play an important role in the onset of the inflammatory process, such as mast cells, which are often associated with the production of TNF-a and IL-1 by adjacent cells, especially at sites of cartilage erosion.
The activation of effector cells mediated by T lymphocytes has been well documented by the induction of B-cell production and antibody secretion, both requiring direct cell-cell contact and soluble factors. The claim that autoan-tibodies induce arthritis has recently been challenged.
Therefore, similar to the direct contact between T and B cells, the T cell-monocyte interaction occurs as shown in experimental systems. Surface molecules involved in the T-cell signalling of monocyte/macrophages by direct contact is being investigated and has resulted in the observation that this contact leads to the production of IL-1 and TNF-a by monocytes, and more markedly after differentiation into macrophages by 1,25-dihydroxyvitamin D3. This has been further illustrated in terms of specificity, because IL-10 is not produced in a similar system.
Membrane-associated cytokines such as TNF and IL-1, and other surface molecules, could activate monocyte/macrophages upon contact with stimulated T cells. The cooperation between activated monocyte/macrophages and interferon-? -secreting CD4 helper (Th1) cells is controlled by two categories of molecules: cell-surface molecules including major histocompatibility complex antigen, B7.1/2, lymphocyte-function-associated antigen (LFA3), LFA1, CD40 on macrophage, and T cell receptor, CD28, cytotoxic T-lymphocyte-associated antigen-4, CD2, intercellular adhesion molecule-1, CD40L on Th1 cells.
During the course of this interaction, Th1 cells produce IL-2 and IL-17, which act on T cells in an autocrine or paracrine fashion, and interferon-?, which acts on the interferon-? receptor on macrophages. In turn, macrophages produce IL-1 and TNF, which also act in an autocrine fashion but, more important, on other target cells in the synovium. A great deal of attention is being paid to CD40/CD40L, which is involved in the contact activation of both human and murine monocyte/macrophages by T lymphocytes stimulated for a short period.
Furthermore, peripheral blood T lymphocytes isolated from CD40L-knockout mice and stimulated for a short period failed to induce monocyte activation. In contrast, when stimulated for a longer period, T lymphocytes isolated from both CD40L-knockout and wild-type mice triggered monocyte activation, but to a lower extent.
An argument against the predominant role of CD40/CD40L is the fact that the most effective human T-cell line for inducing signalling of monocytes by direct contact (human lymphocytic cell line HUT-78) does not express CD40L messenger RNA, whether in resting or activated conditions. This suggests that CD40/CD40L might be involved in contact-activation of monocyte/ macrophages  by T lymphocytes stimulated for short periods of time, but not for long periods, the latter cells by then no longer expressing CD40L.
One study has shown that functional CD40L was expressed by T lymphocytes from the synovial fluid of rheumatoid arthritis patients. Although immunohisto-chemical analysis of synovial tissue demonstrated CD40L expression in infiltrating cells of the vascular/perivascular area, no staining was observed in infiltrating cells that migrated farther. These results suggest that CD40L may be predominantly involved in the extravasation of T lymphocytes into the pannus through the vascular endothelium, but have less involvement in IL-1/TNF and MMP production.
The study also implies that cell-surface factors other than CD40L were involved in T lymphocyte contact-signalling of monocytes. The general conclusion to be drawn is that, depending on the timing and consequently the stage of the immunoinflammatory condition, different molecules could be used for similar functions, and these points have to be taken into consideration for therapeutic intervention. Other studies have shown that cytokine production was induced in monocytes by soluble CD23.
Clinical tudies have shown that LFA-1 (CD11a/CD18) and CD69 play a role in the activation of human monocytic cells by stimulated T cells. Antibodies to CD11a, CD11b, CD11c and CD69 partially inhibited the activity of contact-activation factors. The latter data were recently confirmed by a study [24] that showed that IL-15 induced synovial T cells from rheumatoid arthritis patients to activate the production of TNF-a by macrophages.
This effect was inhibited by antibodies to CD69, LFA-1 and intercellular adhesion molecule-1. Antibodies to known cell-surface antigens (CD2, CD11a,CD11b, CD11c, CD14, CD18, CD23, CD29, CD40, CD40L, CD54, CD69, cytotoxic T-lymphocyte associated antigen-4, CD95, CD95L) or membrane-associated cytokines (interferon-?, IL-2, GM-CSF, IL-1, TNF-a, leukotrienes), and cytokine inhibitors (IL-1 receptor antagonist, TNF soluble receptors) failed to abolish the activity of contact-activation factors in monocytes.
Thus, it is possible that some already identified surface molecules are involved in T-cell-signalling of monocyte/macrophages. Inhibitors (eg antibodies) to these molecules fail to abolish monocyte activation altogether, however, suggesting that the required factor(s) for T-cell-signalling of human monocytes by direct contact remain(s) to be identified.
Subcellular fractionation showed that the activation factors are located in the plasma membranes of stimulated T cells. T-cell clones expanded from a single healthy blood donor express surface factors that activate monocyte/ macrophages, but to varying extents. Interestingly, the products that are induced in the target cell differ depending on the nature of the stimulating agent and the time of stimulation of T lymphocytes.
This could imply that several contact-activation factors, probably acting synergistically, are expressed on the surface of stimulated T lymphocytes in a hierarchy that varies depending on the type and time of activation. The T-cell subsets are important because Th1 clones that preferentially express CCR5 are, because of cell-cell contact, potent inducers of IL-1 and TNF-a on macrophages while inducing virtually no IL-1 receptor antagonist, whereas Th2 clones induce large amounts of IL-1 receptor antagonist and almost no IL-1.
Plasma cell membranes from antigen-activated Th1 and Th2 clones also proved to be potent inducers of MMP-1 production by a human monocytic cell line, whereas tissue inhibitor of metalloproteinase (TIMP)-1 levels were not affected. Using neutralizing reagents, cell membrane-associated TNF was found to be partially involved in this MMP-1 induction by both Th1 and Th2 cells.
During advanced chronic inflammation, stimulated T lymphocytes can also potentially contact cells other than mononuclear phagocytes that are involved in pathogenesis. Such target cells include synoviocytes. Indeed, upon contact with membranes of stimulated T lymphocytes, synoviocytes produce large amounts of MMP-1 and PGE2, but no TIMP-1. The surface factors involved in contact activation of synoviocytes have been identified as membrane-associated cytokines, mainly TNF-a and IL-1a.
These cytokines are not involved in the activation of monocyte/macrophages by T-cell membranes. It is therefore intriguing that T lymphocytes should have developed different cell-signalling systems adapted to the different target cells.
Current experimental results strongly suggest that by direct cell-cell contact, membranes of stimulated T lymphocytes attracted by specific chemokines potentiate the inflammatory response. They do so by favouring the extra vasation of cells from the immune system into the target tissue through the endothelium, and by activating the production of proinflammatory cytokines and MMPs at inflammatory sites (ie by stimulating monocytes and synoviocytes).
This mechanism (cell-cell contact with stimulated T lymphocytes) induces an unbalanced production of MMPs and TIMP-1 in vitro and may lead to tissue destruction in vivo. We thus hypothesize that cell-cell contact between stimulated T lymphocytes and surrounding cells represents an important mechanism that contributes to the pathogenesis of inflammation and tissue destruction in chronic inflammatory diseases such as rheumatoid arthritis.
Despite the impressive clinical results obtained with anti-TNF therapy, approximately 25% of the patients seem to be resistant. This hints at the possibility that, during the course of the disease, other important mechanisms trigger synovitis and tissue destruction. In addition to newly described interleukins (IL-15, IL-17, IL-18), some of the mechanisms could involve direct contact between stimulated T cells and macrophages or synoviocytes. If partly induced by TNF-a, the production of IL-1 can also be triggered by mechanisms independent of TNF, and the production of MMPs is not solely induced by TNF. It is therefore likely that therapeutic intervention will have to aim at additional cytokines and direct cellular contact to block fully the pathogenesis of rheumatoid arthritis.

Simplified Disease Process:
The Disease process leading to RA begins in the synovium membrane that surrounds a joint,and create a protective sac. This sac is filled with lubricating liquid,the synovial fluid. In addition to cushioning joints,this fluid supplies nutrients and oxygen to cartilage,a tissue that coats the ends of bone.
Cartilage is composed primarily of collagen,the structural protein in the body,which forms a mesh to give support and flexibility to joints. In RA,an abnormal immune system produces a number of destructive molecules (cytokines)  that cause continuing inflammation of the synovium. Collagen is gradually destroyed,narrowing the joint space and eventually damaging bone.
If the disease develops into a form of progressive RA,destruction to the cartilage accelerates. Fluid and immune system cells accumulate in the normally thin synovium to produce a pannus,a cancer-like growth composed of thickened synovial tissue.
The pannus produces more enzymes that destroy nearby cartridge,aggravating the area and attracting more inflammatory white blood cells,thereby escalating the process. This inflammatory process not only affects cartridge and bones but can also harm organs in other parts of the body.