Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-11-20
2004-03-16
Le, Long V. (Department: 1641)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S004000, C435S005000, C435S006120, C435S007100, C435S007210, C435S007200, C435S007220, C435S007230, C435S007310, C435S007320, C435S007360, C435S007400, C436S057000, C436S172000, C436S501000, C436S504000, C436S528000, C436S542000, C436S544000, C436S545000, C436S546000, C436S800000, C436S804000, C436S807000, C422S051000, C422S067000
Reexamination Certificate
active
06706490
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the diagnosis of rheumatoid arthritis, a chronic disease of the joints and other tissue that is a serious health problem worldwide. In particular, the present invention is directed to providing a predictive test for rheumatoid arthritis in its early stages which shows high specificity and sensitivity, enabling prompt and accurate diagnosis and hence effective treatment with appropriate drugs. Such early treatment can limit irreversible joint damage which is known to occur within the first few years or even months after the onset of rheumatoid arthritis.
BACKGROUND OF THE INVENTION
Rheumatoid arthritis is the most serious of the rheumatic disorders in terms of population prevalence, potential for crippling and morbidity, and life-shortening effects. The disease is characterised by the symmetrical inflammation of multiple joints (polyarthritis). It most frequently affects the small joints of the hands and feet, but inflammation can occur in virtually any joint including spinal joints. Pain, stiffness and swelling of the joints are the main symptomatic features, resulting in loss of function. Damage to the joints leads to serious deformities and functional impairment. Apart from the effects on the joints, rheumatoid arthritis may be associated with a wide range of extra-articular features affecting various organs, such as the heart, blood vessels, lungs and kidneys. Although these extra-articular features are most common in the case of serious forms of rheumatoid arthritis, they may also provide the first symptom of the disease. There is at present no reliable cure for rheumatoid arthritis. Treatment is essentially directed towards alleviating the discomfort caused by the symptoms and arresting the progression of the disease. Sometimes, however, the disease appears to resolve spontaneously, or in response to one or other of the drug regimens currently employed.
Rheumatoid arthritis generally appears after puberty. The prevalence rises with age, and it is 2-3 times more frequent among women than men. The prevalence of definite rheumatoid arthritis is between 1-2% in the majority of white populations (Hochberg, MC, 1981), and the treatment of patients with rheumatoid arthritis consumes a significant component of the health care budget.
Rheumatoid arthritis is included among the autoimmune diseases. Many authors assume that exposure to an infectious agent, bacterium or virus, can initiate rheumatoid arthritis in individuals with a genetic predisposition to the disease. The actual disease is generated by an abnormal reaction of the immune system, which then plays a central role in the progression of articular damage and extra-articular lesions. Since no infectious agent has in fact been convincingly implicated in the disease, rheumatoid arthritis may be a spontaneously occurring autoimmune process, in which the primary response is to an autoantigenic component of the joint itself, rather than to an extrinsic infectious agent.
The idea that rheumatoid arthritis is an autoimmune response to a component of cartilage is traced back to Steffen and Timpl (1963) who first showed antibodies to collagen in rheumatoid arthritis and proposed that rheumatoid arthritis results from an autoimmune response to the collagen molecule present in cartilage now know to be type II collagen. This idea is strongly supported by the observation that immunization with type II collagen induces an arthritis with similarities to human rheumatoid arthritis in appropriate strains of rats, mice or primates (Courtney et al 1980, Trentham et al, 1977).
In human rheumatoid arthritis, autoantibodies to native and denatured type II collagen are detectable in the serum and synovial fluid of up to 30% of patients according to data derived from cross-sectional studies on patients with generally long-standing disease (Morgan et al, 1987; Terato et al, 1990; Rowley et al, 1992). However, the importance of such antibodies to type II collagen has long remained controversial in view of their low frequency in most reported studies, the lack of correlation between antibody levels and disease status (Clague et al, 1980b Stuart et al, 1983; Collier et al, 1984; Morgan et al, 1989; Stockman et al, 1989) and the reported presence of these antibodies in a range of disease other than rheumatoid arthritis (Clague et al, 1980; Trentham et al, 1981; Gioud et al, 1982; Rosenberg et al, 1984; Charriere et al, 1988; Choi et al, 1988; Rowley et al, 1988, 1992). As mentioned, most of the positive associations of about 30% between antibodies and disease have been based on patients with rheumatoid arthritis of long duration. More recently, several studies have shown that the frequency of autoantibodies to type II collagen may be as high as 60-75% in patients tested very early in the course of rheumatoid arthritis, and levels of autoantibody tend to fall as the disease progresses to levels ascertained in the earlier cross-sectional studies (Pereira et al, 1985; Fujii et al, 1992, Cook et al, 1994, 1996). Accordingly, it has been proposed that antibodies to collagen will provide a useful predictive marker of early rheumatoid arthritis and particularly so for those patients in whom rapid progression to joint destruction will occur.
The main structural proteins of the connective tissue in the body are collagens, of which at least 19 genetically different types have so far been described (Brodsky and Shah, 1995). The types of collagen found in a specific tissue are related to the function of the tissue, and they have specific distributions within individual tissues. Articular cartilage in mature joints contains a number of different collagen types, of which type II collagen is the most abundant. It is the major fibrous collagen in all hyaline cartilage and represents 80-90% of the collagen content. Its role is to build up a fibrous network which, together with proteoglycans and hyaluronan, creates an extremely strong structure with the capacity to withstand high pressures (Heinegard and Paulsson, 1987). Type II collagen is a highly conserved molecule between species. It consists of 3 identical a chains, and is moderately glycosylated (Miller, 1985). It is restricted to cartilage and few other tissues, these being the vitreous humour of the eye, and intervertebral discs, in contrast to the more universal distribution of type I and III collagens (Gay et al, 1980).
In general, the basic structure of all native collagen consists of three polypeptide &agr;-chains in the form of a triple helical domain(s) with repeating glycine-X-Y triplets, in which X is often proline and Y is often hydroxyproline (Piez, 1982). Hydroxyproline is essential for the formation of hydrogen bonds that stabilize the helix. Each &agr;-chain is coiled into a tight left-handed helix which averages about 3 amino acid residues per twist. Three &agr;-chains coil about one another in a right-handed manner to create a 300 nm long, 1.5 nm thick, superhelix which is stabilized by hydrogen bonds formed between the &agr;-chains. About 25 to 30 amino acid residues are required on each chain to complete one turn of the superhelix. Heat denaturation of collagen molecules at 45° C. leads to unfolding of the triple helix to display the linear sequence of amino acids along the length of the individual &agr;-chains.
Collagen is stabilized by the formation of covalent cross-links. Two kinds of cross-links are formed in the collagen fibre, intra- and inter- molecular. Cross-link formation involves enzymatic conversion of lysine and hydroxylysine residues, to allysine and hydroxyallysine respectively, by peptidyl lysine oxidase. Allysine and hydroxallysine react with each other, or with lysine, spontaneously, to form aldol and aldimine condensation products. No enzyme catalysis is required for this process, only the physical proximity of the appropriate side chain (Miller, 1985). Cross-links are formed between a modified lysyl or hydroxlysyl residue in the telopeptide region and a hydroxylysyl residue in the conserved triple helical region, and the amo
Cook Andrew
Mackay Ian
Rowley Merrill
Cook Lisa V.
Foley & Lardner
Le Long V.
Montech Medical Developments Pty. Ltd.
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