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Fast Facts: Rheumatoid Arthritis
By John D Isaacs, Larry W Moreland
Health Press Limited Copyright © 2011 John D Isaacs, Larry W Moreland
All rights reserved.
The normal joint
The synovial membrane lines the non-weight-bearing aspects of the synovial cavity and is divided into the lining layer or intima and sublining layer or subintima. It is the target tissue of the dysregulated inflammation and immunity that characterizes rheumatoid arthritis (RA) (Figure 1.1). The synovial membrane intima is just one or two cell layers thick and contains two major cell types: type A synoviocytes, which bear macrophage markers, and type B synoviocytes, which have fibroblastic characteristics. The intima lacks the typical features of an epithelium and does not possess a basement membrane or tight intercellular contacts between synoviocytes. The matrix of the intima is rich in proteoglycans and glycosaminoglycans, in particular hyaluronic acid.
The subintima is a loose vascular connective tissue stroma containing blood vessels, lymphatics and nerve endings within a matrix comprising varying proportions of lipid, collagen fibrils and more organized fibrous tissue.
The synovial membrane secretes lubricating and nourishing synovial fluid, a viscous fluid containing a high concentration of hyaluronic acid. Other constituents include nutrients and solutes that diffuse from the blood vessels in the subintima. The precise physiology of synovial fluid production is unknown, but exchange of fluid between the circulation and the joint space is governed by a balance of hydrostatic, osmotic and convective forces. As well as providing an osmotic force within the synovial cavity, hyaluronic acid contributes to the lubricating properties of synovial fluid although other constituents are also important.
Articular cartilage comprises chondrocytes embedded in a hydrated matrix composed of collagen, proteoglycans and other matrix proteins. It is an avascular structure lacking lymphatics, and the synovial fluid is critical for providing nutrients to this tissue. Water makes up approximately 70% of normal cartilage by weight, whereas chondrocytes occupy only 5–10% by volume. Because of their low density, chondrocytes do not come into contact with one another directly but possess cellular processes which abut the matrix. These cells are critical to the integrity of articular cartilage because they synthesize collagen, proteoglycans and also other components such as fibronectin. Each cell is surrounded by a zone of secreted proteoglycans and a basket-like mantle of fibrillar collagen, but the highest collagen content occurs in the more distal intercellular matrix.
Collagens are fibrillar proteins that, together with proteoglycans, account for the biomechanical properties of articular cartilage. There are 14 different types of collagen, divided into three major groups. The predominant collagen in articular cartilage is type II, constituting approximately 90% in the adult, with types IX and XI contributing most of the remainder. All collagens are based on a triple helical structure (Figure 1.2), and the differences between collagens relate to the length of the triple helix, the presence of non-collagenous units within the molecule that impart extra flexibility, or the addition of non-collagenous side-chains such as carbohydrates. The triple helical structure of collagens accounts for their tensile strength. Collagen biosynthetic and degradative pathways are quite well characterized.
Proteoglycans are large negatively charged macromolecules comprising a polypeptide core with glycosaminoglycan side-chains. The largest family of proteoglycans in articular cartilage is the aggrecans, which contain abundant chondroitin sulfate and keratan sulfate side-chains. They are complexed with hyaluronic acid and so-called link protein. Their main function relates to their anionic and water-trapping properties, which provide deformability and compressibility. The ratio of collagen to aggrecan is high in the superficial layers of articular cartilage and drops progressively toward the subchondral bone. Thus, the surface layers have high tensile strength and resilience whereas the lower layers have higher deformability and compressibility. During load-bearing, water and solutes are squeezed out of aggrecan, which increases the relative proteoglycan concentration, providing an osmotic drive to rehydration once the load is removed.
Breakdown of collagen and the surrounding matrix is mediated by enzymes such as collagenase, gelatinase, stromelysin and aggrecanase, which are zinc-dependent metalloproteinases. In turn, these enzymes are controlled by tissue inhibitors of metalloproteinases (TIMPs). Thus, tissue homeostasis is maintained by carefully balanced synthetic and catabolic pathways. Cartilage thinning and breakdown (chondrolysis) can be precipitated by either excessive loading or disuse. In osteoarthritis, genetic factors also contribute to loss of cartilage integrity (see Fast Facts: Osteoarthritis). In disease states such as RA, pro-inflammatory cytokines such as interleukin-1 (IL-1), and tumor necrosis factor (TNF) reduce synthesis and increase catabolism of articular cartilage, leading to rapid breakdown. In contrast, growth factors such as transforming growth factor ??(TGF?) and insulin-like growth factor-1 (IGF-1) stimulate synthesis of cartilage components.
The basal layer of articular cartilage is calcified and is attached directly to subchondral bone, which has a similar structure. Collagen I comprises most of the collagen present in bone, however, and is calcified with hydroxyapatite. This provides bone with both tensile and compressive strength. The remaining bone matrix is made up of proteoglycans, glycoproteins, glycosaminoglycans such as hyaluronic acid, and proteins such as osteocalcin; as in articular cartilage, these are incorporated into macromolecular complexes. Glycoproteins such as osteopontin, osteonectin and bone sialoproteins function as anchoring molecules, bridging matrix constituents such as collagen to bone cells. Bone also contains important growth factors such as IGF-1 and 2, and the bone morphogenetic proteins (BMPs) which are members of the TGFβ superfamily.
Formation and destruction. Bone contains two major cell types: osteoblasts and osteoclasts. Mesenchymal osteoblasts are critical for the synthesis of collagen and bone matrix (osteoid). Conversely, osteoclasts – multinucleate cells of macrophage lineage – break down bone via a combination of lysosomal enzymes and low pH. Bone is constantly remodeled to fulfill two major functions.
To optimize load-bearing capacity, bone is remodeled according to compressive forces acting upon it.
Bone remodeling also plays an important role in metabolic homeostasis, particularly of calcium and magnesium.
Therefore, in addition to mechanical forces, stimuli to bone formation and breakdown include circulating hormones and vitamins, such as parathyroid hormone, thyroid hormone, vitamin D, calcitonin and sex hormones (Figure 1.3).
In young adults, bone formation and destruction are carefully balanced to maintain overall bone mass. In the elderly, however, and particularly in postmenopausal women, breakdown may exceed synthesis, leading to osteoporosis (see Fast Facts: Osteoporosis). Resorption is also accelerated by drugs such as corticosteroids, and by inflammation. Bone density measurements using dual emission X-ray absorptiometry (DEXA), ultrasound or quantitative CT (qCT) provide surrogate measures of bone strength and fracture risk.CHAPTER 2
As with many common diseases, rheumatoid arthritis (RA) represents a balance between nature and nurture, in which environmental factors act upon a genetically predisposed host. In the past few years great advances have been made in dissecting the gene–environment interactions that predispose to RA.
Family studies and twin studies indicate that there is a genetic susceptibility to RA, which is higher in families with more severe disease. Genetic predisposition is estimated to contribute between a half and two-thirds to RA susceptibility. Unlike classic Mendelian diseases such as cystic fibrosis or sickle cell disease, RA is a polygenic and genetically heterogeneous disease. Thus, a number of different genes predispose to RA, and these may differ from patient to patient (Figure 2.1). Essentially, various combinations of polymorphisms in a selection of different genes (genotype) predispose to the clinical picture (phenotype) that is recognized as RA. Additionally, some genes may influence severity rather than occurrence of RA.
Until recently, the major histocompatibility complex (MHC) was the only genetic region that had been consistently linked to RA. This is a large genetic region on the short arm of chromosome 6 that encompasses a variety of genes and contributes approximately one-third of the genetic susceptibility to RA. A large part of the MHC comprises the human leukocyte antigen (HLA) genes. These encode an individual's tissue type and include class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DR, HLA-DQ, HLA-DP) genes. The encoded proteins are critical in determining the manner by which an individual's immune system recognizes and responds to provocative stimuli, and the MHC also contains many other genes related to immune function. The strongest genetic link to RA is the class II HLA region and, in particular, HLA-DRB1. HLA-DR molecules comprise an invariant alpha chain (encoded by HLA-DRA) and a highly polymorphic beta chain (encoded by HLA-DRB1), and constitute a platform upon which antigenic peptides are presented to and seen by the immune system. Particular HLA-DRB1 molecules are more common in individuals with RA, and these share a sequence in a part of the molecule that influences the peptides that are bound and therefore viewed by the immune system (Figure 2.2). This core amino acid sequence is termed the 'shared epitope'. The shared epitope influences both the incidence and the severity of RA, and individuals who inherit two shared epitope-encoding HLA-DRB1 alleles suffer particularly aggressive disease.
It has been hypothesized that the shared epitope specifically binds an autoantigen-derived peptide with high affinity, thereby predisposing to an autoimmune arthritis. Although the autoantigen in RA has not been definitively identified, a number have been proposed (see Chapter 3) and, in most cases, specific peptides derived from these proteins can bind to HLA-DR molecules containing the shared epitope.
There are other potential explanations for this genetic association, however. For example, HLA type also biases the repertoire of T cells generated in the thymus, and the shared epitope could, by chance, select T cells with a particular affinity for joint antigens. In this context, non-inherited maternal HLA molecules may also influence RA susceptibility. The shared epitope itself could also become an autoantigen. Certain viruses and bacteria contain an identical peptide sequence within one or other of their proteins. An immune response against the microbe could then trigger an autoimmune response against HLA-DR-expressing cells, a process termed 'molecular mimicry'.
Non-MHC genes. Genome-wide association studies (GWAS) have revolutionized our understanding of complex diseases such as RA. The human genome sequencing project highlighted the abundance of single nucleotide polymorphisms (SNPs) in human DNA. These are single base-pair differences in DNA sequence between different individuals, which do not usually change the function of the gene. The development of high-throughput genotyping technologies has enabled large-scale GWAS in which hundreds of thousands of SNPs that span the entire genome are rapidly compared in patients with a particular disease and matched controls. SNPs that appear more commonly in individuals with the disease in question should lie within or close to genes that are associated with the disease. The Wellcome Trust Case Control Consortium published the first GWAS of RA and, with subsequent studies, has identified and confirmed a number of genes associated with the disease. These include genes encoding proteins such as protein tyrosine phosphatase-22 (PTPN22), an important regulator of lymphocyte activation, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a downregulator of T cell activation, and STAT4, a signaling molecule downstream of the interleukin (IL)-12/IL-23 receptor. Table 2.1 lists genetic loci that have been reproducibly linked to RA in populations of European descent. It has been estimated that approximately 35% of the genetic risk for RA has now been established, most of which is attributable to the MHC. Consequently, many minor genetic influences await identification, including more recent concepts such as gene copy number variants.
A seminal study has irrefutably linked smoking to the etiology of RA in patients carrying a predisposing genotype. A healthy individual carrying two copies of the shared epitope (one on each chromosome 6, see pages 14–15) has an odds ratio (OR) of developing anti-citrullinated peptide antibody (ACPA)-positive RA that is about five times that of someone who is shared-epitope negative. If the individual smokes, the OR increases to approximately 23 times. PTPN22 also contributes to RA risk in this model, which clearly demonstrates the influence of smoking on RA development (Figure 2.3). Smoking appears to interact with the shared epitope, leading to the production of ACPA, perhaps via the citrullination of proteins in the lung, thereby increasing their immunogenicity. (Citrullination is the post-translational modification of an arginine to form citrulline [see page 61].) Other airborne exposures, for example to silica dust and coal dust, have also been associated with the development of RA. The shared epitope and PTPN22 appear to be associated only with ACPA-positive RA, and seronegative disease appears to have a distinct, and much less well defined, etiology.
A number of studies over the past 10 years have indicated that the process that culminates in RA may start up to 15 years before signs and symptoms appear. For example, autoantibodies (rheumatoid factor [RF] and ACPA) first appear in blood 10–15 years before clinical onset, suggesting that immune tolerance breaks down around that time. Similarly, inflammatory markers, cytokines and chemokines start to rise or appear in blood around 5 years before symptoms are evident. Whether all individuals who develop autoantibodies will ultimately develop RA is currently uncertain, but there may be important additional environmental triggers for disease onset.
Infectious agents can be associated with arthritic illness in both humans and in animals. For example, parvovirus B19 causes a transient illness with features of RA in man, and Lyme disease, a chronic infection by a tick-transmitted spirochete, has chronic joint manifestations. Lentiviruses can cause arthritis in mammals, and HIV may precipitate an arthritic illness in man. Reactive arthritis provides an obvious example of self-limiting arthritis triggered by a variety of bacterial infections. In animals, adjuvant arthritis is triggered by immunization with extracts of mycobacteria. Despite these examples, no consistent association has been found between RA and any infectious agent, and the disease does not occur in clusters or demonstrate seasonal variation. Thus, any infectious trigger may be ubiquitous in different populations, and have a high infectivity. Epstein–Barr virus (EBV) has been implicated in some studies, and certain EBV proteins provide shared-epitope-binding peptides as well as a sequence that mimics the shared epitope. The absence of an infectious agent in arthritic tissue does not exclude a potential etiologic role, because a transient infection could trigger a chronic inflammatory process. It is also possible that RA is the consequence of a chronic infection with an as yet unidentified organism.
Excerpted from Fast Facts: Rheumatoid Arthritis by John D Isaacs, Larry W Moreland. Copyright © 2011 John D Isaacs, Larry W Moreland. Excerpted by permission of Health Press Limited.
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