Anticancer Activity and Mechanisms of Action of MAPK pathway inhibitors


3e). matrix may be crucial to initiate glomerular swelling. This may accelerate and exacerbate glomerular immune complex formation in human being and murine lupus nephritis. Intro The contribution of anti-DNA antibody to glomerulonephritis in mouse (1) and human being (2) systemic lupus erythematosus (SLE) is definitely well established. Although anti-double-stranded DNA (dsDNA) antibody is the best serological correlate for lupus nephritis (3, 4), the frequent lack of correlation between serum anti-dsDNA and glomerulonephritis is definitely a long acknowledged conundrum in the medical evaluation of individual SLE individuals (3, 5, 6). The lack of correlation between anti-dsDNA and lupus nephritis within individual patients may be a consequence of how anti-dsDNA antibodies bind in the glomerulus and initiate glomerulonephritis (6), a process not yet fully resolved (7). Mechanisms proposed to explain glomerular deposition of anti-DNA antibody include glomerular binding of soluble immune complexes of nucleosomes and IgG anti-DNA (2, 8C10), formation of immune complexes when anti-DNA antibody binds to chromatin that has bound to glomerular basement membrane (GBM) or mesangial matrix (MM) (11C17), and direct binding of anti-DNA antibody that cross-reacts with GBM or cell surface antigens (18C25). Recent morphologic studies (12C14, 16) have recognized chromatin and IgG within the glomerular subendothelial and subepithelial electron dense deposits (EDS) in nephritic kidneys from lupus individuals (26) and lupus-prone mice (27). The recent results were interpreted to indicate that anti-DNA antibody could form glomerular deposits only when bound to chromatin or nucleosomes (28C30). Mouse monoclonal to MSX1 The present experiments were designed to test the hypothesis that initial glomerular binding of anti-DNA antibody in lupus nephritis R 80123 is definitely a function of direct, cross-reactive binding to glomerular antigens, particularly in GBM or MM, and self-employed of DNA, nucleosomes, or chromatin. R 80123 The experiments took advantage of a panel of anti-DNA monoclonal antibodies (mAbs) with related relative affinities for DNA and chromatin but different relative affinities for basement membrane (BM) antigens in GBM and MM. Only anti-DNA mAbs that also bound BM antigens bound glomeruli and induced proteinuria. Glomerular binding of the anti-DNA mAbs was self-employed of DNA, nucleosomes, or chromatin. The results may clarify why some anti-DNA mAbs are very effective at inducing lupus nephritis, but others are not. Similarly, the results may help to explain why SLE individuals with related serum anti-dsDNA antibody may have different susceptibility for lupus nephritis. Results In vitro binding of anti-DNA mAb to BM Tradition supernatants from 69 autoimmune anti-DNA mAbs from eight different (NZB NZW)F1 mice (BWF1) were randomly selected for analysis (Table 1). Total IgG and relative affinity for binding to ssDNA, dsDNA, chromatin, and BM were quantified for each supernatant. The mAbs were stratified by relative affinity for BM into four different specificity organizations (Table 1). There is a significant difference R 80123 among the four specificity organizations for competitive binding to ssDNA and dsDNA and direct binding to BM but not for direct binding to chromatin. There is a strong and highly significant correlation between binding to BM and binding to dsDNA and a moderate, R 80123 highly significant inverse correlation between binding to BM and binding to ssDNA. Anti-DNA mAbs that bound best to dsDNA are generally the mAbs that also bound best to BM. The correlation between BM and chromatin binding, although significant, was low compared to that for BM and dsDNA. The results indicate that mAbs with high relative affinity for dsDNA are more likely to bind BM than mAbs with high relative affinity for ssDNA. The results also indicate that anti-DNA mAb binding to BM is definitely unrelated to relative affinity for chromatin. Table 1 Specificity of Monoclonal Antibodies = n.s.; chromatin, when injected either only or co-injected having a mAb of different IgG subclass (Table 2 and Fig. 2). Glomerular binding was unrelated to relative affinity of the mAbs for DNA, chromatin, or mononucleosomes or to IgG subclass. Open in a separate window Number 2 Detection of glomerular (a) IgG2b, 163p.77 but not (b) IgG2a, 452s.160 in kidney serial cryosections 24 hours after co-injecting 1 mg of each purified mAb into a BALB/c mouse. Serial cryosections experienced granular IgG2b but no IgG2a within MM. Mice injected with 163p.64, IgG2a and 452s.46,.