Goodpasture disease is an autoimmune kidney disease mediated by autoAbs against NC1 monomers of α3(IV) collagen that bind to the glomerular basement membrane (GBM), usually causing rapidly progressive glomerulonephritis. We identified a novel type of human IgG4-restricted anti-GBM autoAbs associated with mild non-progressive glomerulonephritis, which specifically targeted α345NC1 hexamers but not α3NC1 monomers. The mechanisms eliciting these anti-GBM autoAbs were investigated in mouse models recapitulating this phenotype. Wild type and FcγRIIB−/− mice immunized with autologous murine GBM NC1 hexamers produced mouse IgG1-restricted autoAbs specific for α345NC1 hexamers, which bound to the GBM in vivo but did not cause glomerulonephritis. In these mice, intact collagen IV from murine GBM was not immunogenic. However, in Col4a3−/− Alport mice, both intact collagen IV and NC1 hexamers from murine GBM elicited IgG antibodies specific for α3α4α5NC1 hexamers, which were not subclass restricted. As heterologous antigen in COL4A3-humanized mice, murine GBM NC1 hexamers elicited mouse IgG1, IgG2a and IgG2b autoAbs specific for α345NC1 hexamers and induced anti-GBM Ab glomerulonephritis. These findings indicate that tolerance toward autologous intact α3α4α5(IV) collagen is established in hosts expressing this antigen, even though autoreactive B cells specific for α345NC1 hexamers are not purged from their repertoire. Proteolysis selectively breaches this tolerance by generating autoimmunogenic α3α4α5NC1 hexamers. This provides a mechanism eliciting autoAbs specific for α345NC1 hexamers, which are restricted to non-inflammatory IgG subclasses and non-nephritogenic. In Alport syndrome, lack of tolerance toward α3α4α5(IV) collagen promotes production of alloantibodies to α345NC1 hexamers, including pro-inflammatory IgG subclasses which mediate post-transplant anti-GBM nephritis.
Hereditary and acquired bisalbuminemia, in which the serum contains an albumin variant differing from albumin A by single amino-acid substitutions, have been reported in different races or ethnic groups and in association with various pathologic states. The importance of this rare condition in the pathophysiology of established diseases is uncertain. We evaluated a 68-year-old woman with chronic kidney disease who presented with worsened serum creatinine concentration despite lack of dietary or medical changes. Serum protein electrophoresis was performed with an automated rapid electrophoresis system. Bisalbuminemia was noted as an incidental finding on serum protein electrophoresis. The serum creatinine level stabilized with dietary protein restriction and a beta-blocking agent/diuretic combination for blood pressure control. Although the possibility that some physiologic or pharmacologic substances may not bind to abnormal albumin variants as well as they bind to normal albumin should not be discounted, the finding of bisalbuminemia did not influence the diagnosis, management, course, or prognosis of chronic kidney disease. The role of persistent bisalbuminemia in renal disease is uncertain.
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