Serum antiguanosine antibodies as a marker for SLE disease activity and pathogen potential.

BACKGROUND: This article reviews research conducted on the immunogenicity of the nucleosides of DNA, especially guanosine, the most immunologically active nucleoside. Discussed is the relationship between circulating antibodies to guanosine, their potential role in SLE disease activity, the binding properties of monoclonal antiguanosine antibody (4H2) compared to polyclonal antiguanosine antibodies in humans with SLE, cell membrane penetration by these antibodies and their interference with signal transduction possibly related to their binding to mitochondria and their apparent GTPase activity. METHODS: Enzyme-linked immunosorbent assay methodology was used to show clinical relationships between antiguanosine antibody levels and disease activity in SLE. These results are discussed along with methods of detecting cell penetration by this antibody using special staining techniques, laser-scanning microscope detection of mitochondrial localization, and interference of cAMP and pKA production/activation. Additionally, there is some discussion regarding the assay used to detect enzymatic activity of antiguanosine antibodies. RESULTS: Enhanced circulating levels of antiguanosine antibodies in patients with SLE correlate closely with SLE disease activity. Other factors are discussed that support the pathogenic potential of these antibodies, including their ability to penetrate lymphocytes, bind to mitochondria, inactivate mitochondrial function, interfere with signal transduction, and their potential enzymatically activity. CONCLUSIONS: Antiguanosine antibodies correlate with SLE disease activity and may be pathogenically important in SLE by interfering with signal transduction, inactivating mitochondrial and cell function in patients with SLE.

Development and evaluation of a patient self-report case-finding method for rheumatoid arthritis.

OBJECTIVE: To describe the development and evaluation of a patient self-report case-finding method for rheumatoid arthritis (RA) not dependent on direct contact with the treating physicians. METHODS: The American College of Rheumatology criteria for RA diagnosis were adapted for patient self-report using a questionnaire, and alternative scoring algorithms were evaluated to balance case-finding sensitivity and specificity. Positive rheumatoid factor tests were used to identify 1053 individuals in 2 large healthcare organizations; 440 agreed to receive study materials. Case-finding results were validated by medical record review (MRR) for a random sample of 90 patients. Three scoring algorithms were compared with MRR for likelihood of RA diagnosis. Cases not classifiable by algorithm were flagged and reviewed by 2 expert physicians for likelihood of RA diagnosis. RESULTS: Pilot testing demonstrated that patients comprehended the questionnaire and were willing to answer the questions. Completed questionnaires were returned by 265 (60%) of the 440 patients contacted. Following expert physician review of 16 flagged cases in the 90-patient MRR subsample, the most accurate scoring algorithm demonstrated 80% sensitivity, 67% specificity, 74% accuracy, and 77% positive predictive value for detecting early RA. CONCLUSION: The case-finding method represents a promising tool for identifying RA patients, with potential application in research and quality-assurance activities. RELEVANCE: This case-finding method should be useful in research and quality-assurance efforts requiring identification of RA patients treated by all types of providers in healthcare organizations in which centralized laboratory data are available.

Antiguanosine antibodies in murine and human lupus have the internal image of G-binding proteins.

OBJECTIVE: To examine the binding specificities of serum IgG antibodies of mouse and human origin directed against guanosine. The immunodominance of guanosine compared with the other nucleosides was established in the MRL/lpr murine model of systemic lupus erythematosus (SLE). Serum antiguanosine autoantibodies in human lupus correlate with nephritis and polyserositis in acute disease as well as in exacerbations of disease symptoms. METHODS: Antiguanosine autoantibodies obtained from humans with SLE were compared to a murine monoclonal antiguanosine antibody, 4H2. The fine specificity of the antiguanosine-binding site was determined by methylation of specific positions on the guanosine molecule and using defined analogs in competitive ELISA. RESULTS: Competitive inhibition assays revealed that serum antiguanosine antibodies bind across the 1 and 7 positions of the guanosine molecule (p < 0.01) and that an oxygen is necessary at position 6 in the molecule. 4H2 exhibited the same binding specificity for guanosine as human polyclonal antiguanosine antibodies, showing a conserved epitope across species. When the fine specificity was compared with known epitopes, the antiguanosine antibodies were found to have the internal image of a G-binding protein, identical to that of the Ha-ras oncogene product p21. CONCLUSION: The finding that antiguanosine autoantibodies vary directly with specific features of SLE, especially nephritis and polyserositis, suggests that they may contribute to the pathology of SLE. Our findings that antiguanosine antibodies have G-binding protein active site homology support the possibility that this species of antibody might interfere with cell signal transduction.

Abnormalities of serum antielastin antibodies in connective tissue diseases.

BACKGROUND: Antibodies (Abs) to alpha-elastin (elastin breakdown product) and tropoelastin (elastin precursor) are found in the serum of all human subjects and correlate with their respective serum peptide levels; however, peptide levels vary with age and some disease states. This study was undertaken to determine if serum elastin Abs, peptides, and elastin metabolism were altered in autoimmune diseases by detecting a changing ratio of serum anti-alpha:tropoelastin Ab levels. METHODS: Serum from patients with a variety of connective tissue diseases, including 28 with systemic lupus erythematosus (SLE), 24 with scleroderma, 18 with rheumatoid arthritis (RA), 10 with polymyositis, and 39 with vasculitis, was compared with serum from 19 age-matched healthy subjects for levels of antitropoelastin and anti-alpha-elastin Abs. RESULTS: We found an increase in IgG anti-alpha-elastin and a decrease in antitropoelastin Abs in the sera of patients with scleroderma (p < .02 and .00005) and SLE (p < .006 and .011). There was also a marked increase in anti-alpha-elastin Abs in patients with polyarteritis nodosa (p < .0005) and decreases in antitropoelastin Abs in patients with RA (p < .05), polymyositis (p < .01), and a variety of other vasculidities (p < .0003). CONCLUSIONS: Abnormal variations in elastin metabolism may be detected in several connective tissue diseases by measuring ratios of alpha- and tropoelastin IgG Abs as markers of elastin degradation and synthesis.