Glomerular sclerosis in kidneys with congenital nephrotic syndrome (NPHS1)

Congenital nephrotic syndrome of the Finnish type (NPHS1) is a rare genetic disease caused by mutations in the NPHS1 gene encoding a major podocyte slit-diaphragm protein, nephrin. Patients with NPHS1 have severe nephrotic syndrome from birth and develop renal fibrosis in early childhood. In this work, we studied the development of glomerular sclerosis in kidneys removed from 4- to 44-month-old NPHS1 patients. The pathological lesions and expression of glomerular cell markers were studied in nephrectomized NPHS1 and control kidneys using light and electron microscopy and immunohistochemistry. An analysis of 1528 glomeruli from 20 patients revealed progressive mesangial sclerosis and capillary obliteration. Although few inflammatory cells were detected in the mesangial area, paraglomerular inflammation and fibrosis was common. The podocytes showed severe ultrastructural changes and hypertrophy with the upregulation of cyclins A and D1. Podocyte proliferation, however, was rare. Apoptosis was hardly detected and the expression of antiapoptotic B-cell lymphoma-2 and proapoptotic p53 were comparable to controls. Moderate amounts of podocytes were secreted into the urine of NPHS1 patients. Shrinkage of the glomerular tuft was common, whereas occlusion of tubular opening or protrusion of the glomerular tuft into subepithelial space or through the Bowman's capsule were not detected. The results indicate that, in NPHS1 kidneys, the damaged podocytes induce progressive mesangial expansion and capillary obliteration. Podocyte depletion, glomerular tuft adhesion, and misdirected filtration, however, seem to play a minor role in the nephron destruction

Salivary antibodies induced by the seven-valent PncOMPC conjugate vaccine in the Finnish Otitis Media Vaccine Trial

BACKGROUND: Mucosal antibodies have been suggested to have a role in defence against pneumococcal infections. We investigated here the ability of a seven-valent pneumococcal conjugate vaccine, PncOMPC, to induce mucosal immune response. METHODS: Healthy Finnish children (n = 111), a subcohort of the Finnish Otitis Media Vaccine Trial, were recruited and 56 of them were immunised with the PncOMPC at the age of 2, 4, and 6 months. At 12 months of age, 49 of them received the PncOMPC and 7 were vaccinated with the pneumococcal polysaccharide vaccine (PncPS) as a booster. The control group of 55 children received a hepatitis B vaccine at the same ages. Salivary anti-Pnc IgG, IgA, IgA1, and IgA2 antibodies to serotypes 6B, 14, 19F, and 23F were measured in both groups at the age of 7 and 13 months. RESULTS: Salivary anti-Pnc IgG and IgA were detected more often in the PncOMPC than in the control group. However, the difference between groups was significant only for 19F and 23F IgA concentrations at the age of 7 months. At the age of 13 months, antibody concentrations did not differ between PncOMPC and control groups. The rises in IgA concentrations between 7 and 13 months of age were mainly of subclass IgA1. Further, there is a clear trend that PncPS booster induces higher salivary anti-Pnc PS antibody concentrations than the PncOMPC. CONCLUSION: We found that PncOMPC can induce a mucosal IgA response. However, the actual impact of mucosal antibodies in protection against pneumococcal infections is not clear

Metalloprotease Meprinβ in Rat Kidney: Glomerular Localization and Differential Expression in Glomerulonephritis

Meprin (EC 3.4.24.18) is an oligomeric metalloendopeptidase found in microvillar membranes of kidney proximal tubular epithelial cells. Here, we present the first report on the expression of meprinβ in rat glomerular epithelial cells and suggest a potential involvement in experimental glomerular disease. We detected meprinβ in glomeruli of immunostained rat kidney sections on the protein level and by quantitative RT-PCR of laser-capture microdissected glomeruli on the mRNA level. Using immuno-gold staining we identified the membrane of podocyte foot processes as the main site of meprinβ expression. The glomerular meprinβ expression pattern was altered in anti-Thy 1.1 and passive Heymann nephritis (PHN). In addition, the meprinβ staining pattern in the latter was reminiscent of immunostaining with the sheep anti-Fx1A antiserum, commonly used in PHN induction. Using Western blot and immunoprecipitation assays we demonstrated that meprinβ is recognized by Fx1A antiserum and may therefore represent an auto-antigen in PHN. In anti-Thy 1.1 glomerulonephritis we observed a striking redistribution of meprinβ in tubular epithelial cells from the apical to the basolateral side and the cytosol. This might point to an involvement of meprinβ in this form of glomerulonephritis