Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 25 or more amino acid residues in defined sequence
Reexamination Certificate
1992-09-09
2003-08-26
Sisson, Bradley L. (Department: 1634)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
25 or more amino acid residues in defined sequence
C530S387900
Reexamination Certificate
active
06610823
ABSTRACT:
BACKGROUND OF THE INVENTION
This relates to human antigens that can be used for the diagnosis of myositis and myositis-overlap syndromes that have an autoimmune pathogenesis and more particularly relates to the Mi-2 and PM-Scl antigens.
Autoimmune disorders arise when the immune system reacts against its own tissues. Autoimmune diseases are often classified on the basis of whether a single organ or tissue is involved or whether multiple organs or tissues are involved. Generalized or systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), characterized by the involvement of multiple organs and tissues, are often associated with the presence of autoantibodies to fundamental cellular components. Other autoimmune diseases are characterized by autoantibodies to antigens associated with a single organ or tissue.
Systemic autoimmune diseases are typically characterized by the presence of autoantibodies. Some of the autoantibodies associated with the particular disease may be disease specific and others may be common to many autoimmune diseases. For example, SLE, which is a prototypical immune disorder, is characterized by the presence of autoantibodies that are detectable in other autoimmune disease, such as anti-single-strand DNA antibodies, anti-histones antibodies, and anti-ribonuclear particle (RNP) antibodies, and also by the presence of autoantibodies that are SLE-specific, such as the anti-double-stranded DNA antibodies. Other systemic autoimmune disorders, such as rheumatoid arthritis and idiopathic inflammatory myopathies, are also characterized by the presence of autoantibodies in the sera of patients that react with fundamental nuclear and cytoplasmic intracellular components. As with SLE, some of these autoantibodies are associated with other autoimmune disorders and some are specifically associated with autoimmune myositis.
The idiopathic inflammatory myopathies polymyositis, dermatomyositis and the related overlap syndromes disorder, such as polymyositis-scleroderma overlap, are inflammatory myopathies that are characterized by chronic muscle inflammation and proximal muscle weakness. The muscle inflammation causes muscle tenderness, muscle weakness, and ultimately muscle atrophy and fibrosis as described by Plotz et al.,
Annals of Internal Med
. 111:143-157 (1989). Also associated with the muscle inflammation are elevated serum levels of aldolase, creatine kinase, transaminases (such as alanine aminotransferase and aspartate aminotransferase) and lactic dehydrogenase. Other systems besides muscle can be affected by these conditions, resulting in arthritis, Raynaud's phenomenon, and interstitial lung disease. Clinically, polymyositis and dermatomyositis are distinguished by the presence of a characteristic rash in patients with dermatomyositis. Differences in the myositis of these conditions can be distinguished in some studies of muscle pathology.
Autoantibodies can be detected in about 90% of patients with polymyositis and dermatomyositis according to Reichlin and Arnett,
Arthritis and Rheum
. 27:1150-1156 (1984). Sera from about 60% of these patients form precipitates with bovine thymus or human spleen extracts on Ouchterlony immunodiffusion (ID), while sera from about 80% of these patients stain tissue culture substrates, such as HEp-2 cells, by indirect immunofluorescence (IIF) (Targoff and Reichlin,
Arthritis and Rheum
. 28:796-803 (1985); Nishikai and Reichlin
Arthritis and Rheum
. 23:881-888 (1980); Reichlin et al.,
J. Clin. Immunol
. 4:40-44 [1984]). There are numerous precipitating autoantibody specificities in myositis patients, but each individual antibody specificity occurs in only a fraction of the patients.
Many autoantibodies associated with myositis or myositis-overlap syndrome have been defined and in some cases the antibodies have been identified. These include antibodies that are present in other disorders and also disease-specific antibodies as described by Targoff and Reichlin,
Mt. Sinai J. of Med
. 55:487-493 (1988). Characteristic antibodies and their respective specificities are listed in Table 1. For example, a group of myositis-associated autoantibodies have been identified which are directed at cytoplasmic proteins that are related to tRNA and protein synthesis, particularly aminoacyl-tRNA synthetases. These include anti-Jo-1, which is directed against histidyl-tRNA synthetase and is the most common autoantibody associated with myositis autoimmune disorders (about 20% of such patients according to Nishikai and Reichlin,
Arthritis Rheum
. 23:881-888 [1980]); anti-PL-7, which is directed against threonyl-tRNA synthetase; and anti-PL-12, which is directed against alanyl-tRNA synthetase. A characteristic group of features is associated with anti-synthetases (Love et al.,
Medicine
70:360-374 [1991]). Anti-U1 RNP, which is frequently found in patients with SLE, may also be found in mixed connective tissue disease, overlap syndromes involving myositis, or in some cases of myositis alone. This antibody reacts with proteins that are uniquely present on the U1 small nuclear ribonucleoprotein, one of the nuclear RNPs that are involved in splicing mRNA. Autoantibodies that are associated with other conditions are sometimes found in patients with overlap syndrome such as anti-Sm, anti-Ro/SSA and anti-La/SSB. Anti-Ku has been found in myositis-scleroderma overlap syndrome and in SLE. The Ku antigen is a DNA binding protein complex with two polypeptide components, both of which have been cloned. Anti-Jo-1 and other anti-synthetases are disease-specific. Other myositis-associated antibodies are anti-PM-Scl, which is present in about 5-10% of myositis patients, many of whom have polymyositis-scleroderma overlap, and anti-Mi-2, which is present in about 8% of myositis patients, almost exclusively in dermatomyositis. Anti-Mi-2 is found in high titer in about 20% of all dermatomyositis patients and in low titer, by ELISA only, in less than 5% of polymyositis patients (Targoff and Reichlin,
Mt. Sinai J. of Med
. 55:487-493 [1988]).
Anti-Mi was first described by Reichlin and Mattioli,
Clin. Immunol. and Immunopathol
. 5:12-20 (1976). A complement-fixation reaction was used to detect it and, in that study, patients with dermatomyositis, polymyositis and polymyositis overlap syndrome had positive reactions. The prototype or reference serum, from patient Mi, forms two precipitin lines on immunodiffusion (ID) with calf thymus antigens, Mi-1 and Mi-2. Mi-1, which has been purified from bovine thymus nuclear extracts (Nishikai et al.,
Mol. Immunol
. 17:1129-141 [1980]) is rarely found in other sera and is not myositis specific (Targoff et al.,
Clin. Exp. Immunol
. 53:76-82 [1983]).
Anti-Mi-2 was found to be a myositis-specific autoantibody by Targoff et al.,
Arthritis and Rheum
. 28:796-803 (1985). Furthermore, all patients with the precipitating antibody have the dermatomyositis rash. It is therefore potentially important as a diagnostic tool and, perhaps, ultimately as a tool for understanding the disease etiology. Anti-Mi-2 is also the only antibody response that appears to be selective for dermatomyositis and not for other subgroups of inflammatory myopathy without skin involvement.
Bovine thymus Mi-2 antigen was originally found to be a nuclear protein that separates in SDS polyacrylamide (SDS-PAGE) gels into two bands with apparent molecular weights of 53 kilodaltons (hereinafter kDa) and 61 KDa, respectively. Recently, additional higher molecular weight bands have been found. The bovine thymus antigenic activity is destroyed by SDS-PAGE and is trypsin sensitive, but not RNAse sensitive (Targoff et al.,
Arthritis and Rheum
. 28:796-803 [1985]). Its nature and function have not as yet been identified.
Anti-PM-1 was first identified as an antibody found in 61% of dermatomyositis/polymyositis patients, including patients with polymyositis-scleroderma overlap (Wolfe et al.,
J. Clin. Invest
. 59:176-178 [1977]). Anti-PM-1 was subsequently shown to be
Ge Qun
Targoff Ira N.
Board of Regents of the University of Oklahoma
Holland & Knight LLP
Sisson Bradley L.
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