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Serologic Hallmarks of Patients with Systemic Autoimmune Disease

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Serologic Hallmarks of Patients with Systemic Autoimmune Disease rheumatic diseases rheumatic diseases are characterized by the presence of one or more autoantibodies that may be directed against components of the surface, cytoplasm, nuclear envelope, or nucleus of the cell. Immunofluorescence microscopy using human cellular extracts, such as HEp-2 cells, allows for the sensitive detection of serum antibodies that react very specifically with various cellular proteins and nucleic acids. Systemic Rheumatic Diseases and Related Disorders 1.Systemic lupus erythematosus (SLE) 2. Discoid lupus erythematosus (DLE) 3. Lupus-like syndromes 4. Drug-induced lupus erythematosus 5. Sjogren's syndrome 6. Scleroderma/CREST syndrome (calcinosis cutis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) 7. Rheumatoid arthritis (RA) 8. Dermatomyositis and polymyositis 9. Overlap syndromes a. Mixed Connective Tissue Disease (MCTD) b. RAand SLE(Rupus) c. SLEand scleroderma (Lupoderma) d. Scleroderma and dermatomyositis (Sclerodermatomyositis) e. Other 10. Systemic vasculitis a. Takayasu's arteritis b. Giant cell arteritis and polymyalgia rheumatica c. Wegener's granulomatosis d. Polyarteritis nodosa and Churg-Strauss syndrome e. Leukocytoclastic vasculitis f. Other 11. Poorly defined connective tissue disease syndromes SLE more than 110different types of autoantibodies have been identified in SLE Widely used tests for screening of intracellular autoantibodies are immunofluorescence microscopy and the immunoenzyme tests.The secondary definitive tests for specific identification of autoantibodies to nuclear antigens are immunodiffusion, immunoprecipitation, particle agglutination, enzyme-linked immunosorbent assay(ELISA), and immunoblolling methods. SLE SLE is characterized by a heterogeneous and polyclonal antibody response, and the usual case of SLE has an average of three different circulating antibodies present simultaneously, including antibody to native DNA (dsDNA), chromatin. Sm antigen, U I nRNP, SS-A/RO, SS-B/La, and several other nonhistone protein or nonhistone protein-RNA complexes . SLE specific for SLE: Anti-native-DNA (up to 90% of patients) anti-Sm anti-ribosomal-RNP and antibody to proliferating cell nuclear antigen (anti-PCNA) Polyclonality of antibodies is seen in SLE and scleroderma, and is rarely seen in the other systemic rheumatic diseases. Autoantibodies in SLE Antibodies to cell nucleus component ANA, anti-dsDNA, antibodies to extracellular nuclear antigen (ENA, anti-Sm, anti-RNP, anti-Jo1) Antibodies to cytoplasmic antigens anti-SSA, ANCA Cell-specific autoantibodies lymphocytotoxic antibodies, anti-neuron antibodies, anti-erythrocyte antibodies, anti-platelet antibodies Antibodies to serum components antiphospholipid antibody anticoagulants antiglobulin, rheumatoid factor Anti-nuclear antibodies(ANA) Antinuclear antibodies (ANAs, also known as antinuclear factor or ANF) are autoantibodies that bind to contents of the cell nucleus. There are many subtypes of ANAs such as: anti-Ro antibodies anti-La antibodies anti-Sm antibodies anti-nRNP antibodies anti-Scl-70 antibodies anti-dsDNA antibodies anti-histone antibodies Antibodies to nuclear pore complex anti-centromere antibodies anti-sp100 antibodies Each of these antibody subtypes binds to different proteins or protein complexes within the nucleus. They are found in many disorders including autoimmunity, cancer and infection, with different prevalences of antibodies depending on the condition. This allows the use of ANAs in the diagnosis of some autoimmune disorders, including systemic lupus erythematosus, Sjögren's syndrome, scleroderma mixed connective tissue disease polymyositis, dermatomyositis, autoimmune hepatitis and drug induced lupus. Serologic hallmarks of patients with systemic autoimmune disease: • SLE – sensitivity, 99 percent • Scleroderma – 97 percent • Mixed connective tissue disease – 93 percent • Polymyositis/dermatomyositis – 61 percent • Rheumatoid arthritis – 52 percent • Rheumatoid vasculitis – 33 percent • Sjögren's syndrome – 90 percent • Drug-induced lupus –100 percent • Discoid lupus – 15 percent • Pauciarticular juvenile chronic arthritis – 71 percent In Chronic infectious diseases (Mononucleosis, Subacute bacterial endocarditis Tuberculosis ) and Other disorders (Some lymphoproliferative diseases) and up to 50 percent of patients taking certain drugs and can also be found in otherwise normal individuals. Anti-nuclear antibodies(ANA) The common tests used for detecting and quantifying ANAs are indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA). In immunofluorescence, the level of autoantibodies is reported as a titer There are many nuclear staining patterns seen on HEp-2 cells(Human epidermoid cancer cells ): Homogeneous speckled Nucleolar nuclear membranous Centromeric nuclear dot pleomorphic. ANA Screen 8 ELISA (IBL) dsDNA ………………………………plasmid……………………………………………SLE RNP (proteins A, C, 68kDa) ……..human, recombinant ……….MCTD, SLE, RA, PSS Sm (proteins B, B', D) ……………..bovine thymus …………………………………..SLE SS-A/Ro (60kDa-proteAin)………..bovine thymus ……………………………..SS, SLE SS-B/La human,…………………….recombinant ……………………………….SS, SLE Scl-70 (DNA-topoisomerase I)……human, recombinant …………………………..PSS CENP-B human,…………………….recombinant …………………………PSS (CREST) Jo-1 (Histidyl-tRNA-synthetase) ….human, recombinant…………………………… PM disadvantages of the ELISA compared to IFA include a lack of sensitivity to unknown nuclear and cytoplasmic antigens the lack of an ANA pattern that has historically been reported with the IFA the diagnostic utility of an ANA of unknown specificity is not clear at this time since many healthy people are ANA positive but negative for diagnostically important autoantibodies once a specific reactivity is identified in the serum, the ANA pattern is no longer as important for diagnosis. Thus, the ANA ELISA clearly has a useful place in a clinical laboratory. Nucleolar Nucleolar proteins Ro La dsDNA Smith Rim RNP Jo-1 Speckled Scl-70 Ro Homogenous Nucleosomes homogeneous pattern is seen when the condensed chromosomes and interphase chromatin stain. This pattern is associated with anti-dsDNA antibodies, antibodies to nucleosomal components, and anti-histone antibodies. There are two speckled patterns: fine and coarse. The fine speckled pattern has fine nuclear staining with unstained metaphase chromatin, which is associated with anti-Ro and anti-La antibodies. The coarse staining pattern has coarse granular nuclear staining, caused by anti-U1-RNP and anti-Sm antibodies. The nucleolar staining pattern is associated with many antibodies including anti-Scl- 70, anti-PM-Scl, anti-fibrillarin and anti-Th/To. Nuclear membrane staining appears as a fluorescent ring around the cell nucleus and are produced by anti-gp210 and anti-p62 antibodies. The centromere pattern shows multiple nuclear dots in interphase and mitotic cells, corresponding to the number of chromosomes in the cell. Nuclear dot patterns show between 13–25 nuclear dots in interphase cells and are produced by anti-sp100 antibodies. Pleomorphic pattern is caused by antibodies to the proliferating cell nuclear antigen. Indirect immunofluorescence has been shown to be slightly superior compared to ELISA in detection of ANA from HEp-2 cells Antigen Molecular Structure Autoantibody Frequency (%) Native DNA Double-strand DNA 40-90 Denatured DNA Single-strand DNA 70 Histones Hl,H2A.H2B,H3,H4 50-70 Chromatin(nucleosome) DNA·histones complex 50-90 Sm Proteins 29 (B'), 28 (B). 16 (D).and 13(E) 15-30 kDa, complexed with UI ,U2. and U4·U6 snRNAs; spliceosome component Nuclear RNP (Ul nRNP) Proteins 70, 33(A), and 22 (C) kDa. 30-40 complexed with Ul snRNA; spliceosome component SS-A/Ro Proteins 60 and 52 kDa, 24-60 Complexed with Yl-Y5 RNAs SS-B/La Phosphoproteins 48 kDa, 9-35 complexed with YI nascenl RNA Pol transcripts Antigen Molecular Structure Autoantibody Frequency (%) Ku Proteins 86 and 66 kDa. 1-19 DNA-binding proteins hnRNP protein Al Nuclear protein 34 kDa 31-37 PCNA Protein 36 kDa; auxiliary protein 3 of DNA polymerase Ribosomal RNP Phosphoproteins 38. 16, and 10-20 IS kDa associated with ribosomes Hsp·90 Heat-shock protein 90 kDa 5-50 Golgi complex Golgins, giantin Unknown HMG-17 DNA-associated proteins, 9 to 34-70 17 kDa B2-glycoprotein I Anionic phospholipids. cardiolipin 25 Antibodies to Native DNA or Double-Stranded DNA specific for SLE 40-90% in SLE in 75-90% of active untreated SLE patients Transient increases in anti-DNA antibodies were recently described in RA patients treated with anti- TNF therapy reactive antibodies to DNA in the other diseases are anti-single-stranded-DNA antibodies. antibody to DNA is followed by the appearance of circulating DNA antigen, Such DNA-anti-DNA immune complexes, mostly containing complement- activating IgG3, have a special tropism for basement membranes and are readily deposited in the kidney glomeruli. Hypothetical mechanism for the initiation of lupus nephritis by basement membrane (BM)–binding anti- double-stranded DNA (dsDNA) antibody. The stage I to II transition is likely to be reversible.62 The stage II to III transition associated with the progressive accumulation of antibody and chromatin into immune complexes will eventually reach a threshold for which the immune complex deposition is no longer reversible. This stage would yield chronic inflammation and lupus nephritis Confocal micrographs of kidney cryosections Co-localization of IgG with heparan sulfate proteoglycan
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