Anti-dsDNA Antibodies Promote Initiation, and Acquired Loss of Renal Dnase1 Promotes Progression of Lupus Nephritis in Autoimmune (NZBxNZW)F1 Mice

BACKGROUND:Lupus nephritis is characterized by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes (GBM). The latter defines end-stage disease. METHODOLOGY/PRINCIPALS: In the present study we determined the impact of antibodies to dsDNA, renal Dnase1 and matrix metalloprotease (MMP) mRNA levels and enzyme activities on early and late events in murine lupus nephritis. The major focus was to analyse if these factors were interrelated, and if changes in their expression explain basic processes accounting for lupus nephritis. FINDINGS:Early phases of nephritis were associated with chromatin-IgG complex deposition in the mesangial matrix. A striking observation was that this event correlated with appearance of anti-dsDNA antibodies and mild or clinically silent nephritis. These events preceded down-regulation of renal Dnase1. Later, renal Dnase1 mRNA level and enzyme activity were reduced, while MMP2 mRNA level and enzyme activity increased. Reduced levels of renal Dnase1 were associated in time with deficient fragmentation of chromatin from dead cells. Large fragments were retained and accumulated in GBM. Also, since chromatin fragments are prone to stimulate Toll-like receptors in e.g. dendritic cells, this may in fact explain increased expression of MMPs. SIGNIFICANCE:These scenarios may explain the basis for deposition of chromatin-IgG complexes in glomeruli in early and late stages of nephritis, loss of glomerular integrity and finally renal failure

Human and murine anti-DNA antibodies induce the production of anti-idiotypic antibodies with autoantigen-binding properties (epibodies) through immune-network interactions.

To examine the potential role of immune-network interactions in the production of lupus autoantibodies, normal NZW rabbit antibody responses were analyzed after immunization with one of the following Ig preparations: human lupus serum anti-dsDNA antibodies, human lupus serum anti-ssDNA antibodies, a mixture of human lupus serum anti-dsDNA and anti-ssDNA antibodies, the MRL-lpr/lpr anti-dsDNA mAb H241, and the MRL-lpr/lpr anti-ssDNA mAb H130. Four of five rabbits produced Ig typical of lupus autoantibodies: individual rabbit Ig cross-reacted with multiple autoantigens including nucleic acids, cardiolipin, SmRNP, glomerular extract, laminin, and exogenous Ag. Rabbit anti-Id against human anti-dsDNA antibodies were highly specific for dsDNA. Notably, in each serum the autoantibody activity was confined to the anti-Id Ig fraction. A similar spontaneously occurring Id-anti-Id interaction was also found between anti-ssDNA and anti-dsDNA antibodies isolated from an individual lupus patient. These results indicate that lupus autoantibodies which share Ag binding properties with pathogenic Ig, including both cross-reactive and anti-dsDNA antibodies, can induce the production of Ig with similar autoantigen binding properties through immune-network interactions. This phenomenon, if unregulated, could lead to the amplification of pathogenic autoantibody production in individuals with systemic lupus

Variable region structure and Staphylococcal protein A binding specificity of a mouse monoclonal IgM anti-laminin-receptor antibody

Staphylococcal protein A is a cell wall-attached polypeptide that acts as a B-lymphocyte superantigen. This activation correlates with specific V-H gene segment usage in the B-cell receptor. B-cell receptor assembled from members of the V(H)3 family in humans, or S107 family in mice, has an intrinsic affinity for protein A. Human V(H)3-derived antibodies bind to domain D of protein A. We have characterized a mouse IgM monoclonal antibody that binds protein A. the sequencing of the variable region suggests an almost germline-encoded V-H derived from S107 family and a V kappa 8-derived V-L. the binding specificity of the monoclonal antibody was tested with various recombinant constructions derived from protein A. We show that, unlike human V(H)3-derived antibody, mouse S107-derived immunoglobulin binds to the B domain of the bacterial superantigen.UNIV BRASILIA,IB,DEPT CELL BIOL,BR-70910900 BRASILIA,DF,BRAZILUniversidade Federal de São Paulo,UNONEX,EXPT ONCOL UNIT,São Paulo,BRAZILUniversidade Federal de São Paulo,DEPT MICROBIOL IMMUNOL & PARASITOL,São Paulo,BRAZILUniversidade Federal de São Paulo,UNONEX,EXPT ONCOL UNIT,São Paulo,BRAZILUniversidade Federal de São Paulo,DEPT MICROBIOL IMMUNOL & PARASITOL,São Paulo,BRAZILWeb of Scienc