nephrin and Lupus-Erythematosus--Systemic

We have found that calcium calmodulin kinase IV is increased in T cells, podocytes, and mesangial cells from patients with systemic lupus erythematosus, as well as in lupus-prone mice, podocytes of patients with focal segmental glomerulosclerosis, and in mice injected with doxorubicin. We showed that this accounts for aberrant T cell function and glomerular damage. Using nanoparticles (nlg) loaded with a small drug inhibitor of calcium calmodulin kinase IV and tagged with antibodies directed to CD4 we have been able to show inhibition of autoimmunity and lupus nephritis. Also, using nlg tagged with antibodies to nephrin, we showed suppression of nephritis in lupus-prone mice and of glomerular damage in mice exposed to doxorubicin. We propose the development of approaches to deliver drugs to cells in a targeted and precise manner.

Topics: Animals; Antibiotics, Antineoplastic; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 4; CD4 Antigens; Disease Models, Animal; DNA Methylation; Doxorubicin; Drug Delivery Systems; Glomerulosclerosis, Focal Segmental; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Membrane Proteins; Mice; Mice, Inbred MRL lpr; Molecular Targeted Therapy; Nanoparticles; Protein Kinase Inhibitors; Sulfonamides; T-Lymphocytes; T-Lymphocytes, Regulatory; Th17 Cells

Childhood-onset systemic lupus erythematosus (SLE) is frequently complicated with lupus nephritis (LN), which is characterized by the deposition of DNA-containing immune complex to the glomerulus. Toll-like receptor 9 (TLR9), capable of recognizing the microbially derived CpG oligonucleotide, plays a crucial role in the innate immunity. TLR9 is also assumed to be related to the aetiology of SLE in the recognition of anti-DNA antibody-containing immune complex, but this remains controversial. We conducted a study to elucidate the association between TLR9 and LN in childhood-onset SLE.. We compared the expression and localization of TLR9 and the slit membrane-related protein in the biopsied kidney sample by immunostaining in four children with active or inactive LN. We also evaluated their laboratory findings, such as anti-DNA antibody, complement and proteinuria at biopsy, to assess the correlation to the findings of the immunostaining.. TLR9 is not expressed in a normal control kidney. However, TLR9 develops in podocytes only in active LN but disappears in remission. Meanwhile, the slit membrane-related proteins such as nephrin, podocin and synaptopodin in podocytes express clearly and uniformly in remission, but their expression is markedly diminished in active LN, which results in podocyte injury. When TLR9 is expressed in podocytes, all the patients simultaneously showed hypocomplementaemia, high titre of anti-double-stranded DNA (dsDNA) antibody and proteinuria.. Injured podocytes in active LN express TLR9. This expression could be associated with proteinuria and increased anti-dsDNA antibody. This is the first report indicating that TLR9 is involved in the aetiology of LN and that it may play some role in podocyte injury.

Topics: Adolescent; Antibodies, Anti-Idiotypic; Biopsy; Child; DNA; Female; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Membrane Proteins; Microfilament Proteins; Podocytes; Toll-Like Receptor 9