Antiguanosine Antibodies in Murine and Human Lupus Have the Internal Image of G-Binding Proteins

KEITH K. COLBURN, ANDREW L. WONG, RICHARD H. WEISBART, and LORA M. GREEN

ABSTRACT.

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. (J Rheumatol 2003;30:993-7)

Key Indexing Terms:

ANTIGUANOSINE
AUTOANTIBODIES
SYSTEMIC LUPUS ERYTHEMATOSUS
G-PROTEINS

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From the J.L. Pettis Memorial Veterans Medical Center; the Department of Rheumatology, Loma Linda University Medical School, the Radiobiology Program, Loma Linda University, and the Department of Microbiology and Molecular Genetics and Department of Physiology, Loma Linda University Graduate School, Loma Linda; Department of Medicine, Veterans Medical Center-Sepulveda; and Department of Medicine, Division of Rheumatology, UCLA, Sepulveda, California, USA.

Supported in part by the California Chapter of the Arthritis Foundation and Basic Research Science Grants, Loma Linda University, to Drs. Colburn and Green.

K.K. Colburn, MD, Chief of Rheumatology; J.L. Pettis Memorial Veterans Medical Center and Department of Rheumatology, Loma Linda University Medical School; L.M. Green, PhD, Molecular Immunologist, Radiobiology Program, Loma Linda University, and Departments of Microbiology and Molecular Genetics, and Physiology, Loma Linda University Graduate School; R.H. Weisbart, MD; A.L. Wong, MD, Veterans Medical Center-Sepulveda, Department of Medicine, Division of Rheumatology, UCLA.

Address reprint requests to Dr. K.K. Colburn, 11201 Benton Street, Loma Linda, CA 92357. E-mail: Keith.Colburn@med.va.gov

Submitted May 30, 2002; revision accepted October 21, 2002.

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