Complement activation contributes to both glomerular and tubulointerstitial damage in adriamycin nephropathy in mice.

Adriamycin nephropathy is a model of focal segmental glomerulosclerosis, characterized by proteinuria and progressive glomerulosclerosis and tubulointerstitial damage. In this study, we examined the role of complement in the etiology of adriamycin nephropathy in mice. We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls. C3 deposition occurred in the glomeruli of wild-type mice as early as 48 h following a single i.v. injection of adriamycin. C3-deficient mice developed significantly less proteinuria and less podocyte injury at day 3 postadriamycin than controls, suggesting that complement is important in mediating the early podocyte injury. At later time points, C3-deficient mice were protected from glomerulosclerosis, tubulointerstitial injury, and renal dysfunction. Factor D-deficient mice were also protected from renal disease, confirming the importance of alternative pathway activation in this model. In contrast, C1q-deficient mice developed similar disease to controls, indicating that the complement cascade was not activated via the classical pathway. CD59-deficient mice, which lack adequate control of C5b-9 formation, developed significantly worse histological and functional markers of renal disease than controls. Interestingly, although more C9 deposited in glomeruli of CD59-deficient mice than controls, in neither group was tubulointerstitial C9 staining apparent. We have demonstrated for the first time that alternative pathway activation of complement plays an important role in mediating the initial glomerular damage in this in vivo model of focal segmental glomerulosclerosis. Lack of CD59, which regulates the membrane attack complex, led to greater glomerular and tubulointerstitial injury.

Sepsis recurrente por Streptococcus pneumoniae en niña con asplenia y déficit de C3 / Recurrent sepsis due to Streptococcus pneumoniae in a girl with asplenia and C3 deficit

Streptococcus pneumoniae puede originar infecciones invasoras: graves en niños, como la meningitis, con una alta morbi-mortalidad. La sepsis con shock séptico y fracaso multiorgánico, de etiología neumocócica, es un cuadro clínico muy poco frecuente. En ocasiones, los factores que predisponen a padecer enfermedad neumocócica invasora no han sido diagnosticados previamente y pueden dar lugar a cuadros clínicos de repetición. Presentamos un caso de sepsis neumocócica recurrente en una niña con asplenia y déficit de 0. Es necesario realizar estudios detallados en los niños que padecen enfermedad invasora grave por neumococo, para detectar esos factores de riesgo. La vacuna conjugada heptavalente es el método más eficaz de prevención de esta grave enfermedad (AU)

Lipodistrofia parcial adquirida / Partial acquired lipodystrophy

La lipodistrofia es un trastorno infrecuente en que el tejido adiposo está disminuido o ausente. Puede ser congénita o adquirida, y generalizada o localizada. Presentamos el caso de un varón de 7 años con adelgazamiento de las mejillas sin otra sintomatología asociada. De entre las pruebas realizadas destaca una hipercolesterolemia y un descenso del factor C3 del complemento. La lipodistrofia parcial adquirida es la forma de presentación más frecuente. En estos pacientes hay que descartar una resistencia insulínica y dislipemias, así como los niveles de factor C3 del complemento y la función renal por la posibilidad de asociación con glomerulonefritis. Desde el punto de vista estético no hay ninguna terapia eficaz (AU)

Complement-mediated antiinflammatory effect of bisbenzylisoquinoline alkaloid fangchinoline.

Complement-mediated mode of action of bisbenzylisoquinoline alkaloid fangchinoline was investigated in vivo and in vitro. The application of fangchinoline intraperitoneally (i.p.) to complement normal mice, strain ICR, inhibited the complement activity in serum and peritoneal exudate. The substance activated serum complement of C5-deficient DBA/2 mice. Fangchinoline was able to provoke local inflammatory reaction in both strains after subcutaneous (s.c.) injection. The alkaloid suppressed paw swelling induced by live Candida albicans in ICR and DBA/2 mice. Its effect depended on the dose and time of injection prior to inflammatory reaction. The in vitro experiments proved the interference of fangchinoline action with post-C5 reactions. The substance augmented C5-convertase formation and functional activity. These results are in correspondence with our previous investigations, proving the complement-mediated action of fangchinoline. The antiinflammatory effect could be a consequence of the caused complement exhaustion.

Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired defect of bone marrow stem cells in which the affected clones produce erythrocytes (also granulocytes and platelets) with membranes that are abnormally sensitive to complement-mediated lysis. Abnormal erythrocytes (E) from patients with PNH (PNH-E) are 3-5 times more sensitive (type II PNH-E) or 15-25 times more sensitive (type III PNH-E) to lysis in vitro by human complement than normal E from unaffected individuals and the functionally normal E that arise from unaffected clones and the functionally normal E that arise from unaffected clones in PNH patients (type I PNH-E). After complement activation by either the classical or alternative pathway, abnormal amounts of C3b are deposited on the membranes of PNH-E compared with normal E, suggesting that the PNH-E membrane cannot regulate the events responsible for C3b deposition. Two proteins that decrease the stability of the classical and alternative pathway C3 convertases on target cells have been isolated from normal human E stroma: the 70,000 Mr decay accelerating factor of stroma (DAF) and the 250,000 Mr C3b receptor (C3bR). Specific immune precipitates of solubilized membranes from 125I-surface-labeled normal E demonstrate both proteins. In contrast, specific immune precipitates of PNH-E from three patients show C3bR but are deficient in DAF; type II PNH-E are relatively deficient and type III PNH-E are totally deficient in DAF. Antibody that neutralizes the activity of isolated DAF is adsorbed by intact normal E under conditions in which it is weakly adsorbed by type II PNH-E and not adsorbed by type III PNH-E. The deficiency of DAF antigen in PNH-E, as assessed by lack of immunoprecipitation and antibody adsorption, could explain the abnormal sensitivity of PNH-E to complement-mediated lysis and suggests that DAF may protect the membranes of normal E from damage resulting from autologous complement activation.