Editorial

The pathogenesis of glomerulonephritis☆

Immunoglobulin A nephropathy (IgAN) is linked inextricably to the name Jean Berger, the Parisian pathologist who published the first description of IgAN in 1968. We reflect on the significance of Berger's first report and consider 40 years of progress in our understanding of IgAN since it was published. We also look back to the days before Berger, when IgAN could not have been identified (because there were no techniques for detecting IgA deposits), classification of glomerulonephritis was even more contentious and confusing than it is today, and it is likely that the literature describing focal glomerulonephritis contained many of the cases we would now identify as IgAN.

Le capillaire glomérulaire, de par sa structure, a une fonction de filtre branché entre l’espace sanguin et l’espace urinaire exposé aux macromolécules circulantes qui peuvent s’y déposer. La biopsie rénale a comme rôle de faire le diagnostic des glomérulonéphrites et des maladies systémiques auto-immunes et s’appuie toujours sur deux prélèvements techniqués en microscopie optique et en immunofluorescence. La microscopie électronique a des indications spécifiques. L’immunofluorescence qui identifie les dépôts immuns est nécessaire. C’est la biopsie qui a permis l’identification et la caractérisation des lésions, par exemple des nouvelles maladies virales apparues ces dix dernières années comme la cryoglobulinémie et le virus de l’hépatite C ou les lésions secondaires au virus BK en transplantation. Elle permet aussi de définir de nouveaux mécanismes ou de nouvelles règles diagnostiques comme la positivité du marqueur C4d dans le rejet humoral, et les atteintes glomérulaires liées aux immunoglobulines monoclonales. Par ailleurs les techniques récentes de biologie moléculaire en transplantation rénale vont permettre de mieux apparier donneur et receveur, d’intervenir sur le rejet de greffe en fonction de l’expression des gènes dans le tissu rénal.

Due to its structure, the glomerular capillary has a filtration function since it is interposed between the blood stream and the urinary space exposed to circulating plasma proteins, which are likely to form a deposit. The role of renal biopsy is to diagnose glomerulonephritis and systemic autoimmune diseases, on the basis of two samples: one for light microscopy and the other for immunofluorescence (IF). Electron microscopy has specific indications. IF is necessary to identify immune deposits. Renal biopsy has made possible the identification and characterization of lesions such as those related to the new viral diseases that emerged over the last decade: cryoglobulinemia and hepatitis C virus (HCV), the BK virus, the positivity of the C4d marker in humoural rejection of transplants, glomerular lesions due to monoclonal immunoglobulin. Besides, the recent molecular biology techniques as applied in renal transplantation are likely to improve the matching donors/recipients, and to treat graft rejections as revealed by gene expression in the renal tissue.

Membranous nephropathy is characterised by the deposition of immunoglobulin, predominantly of the IgG4 subclass, along the epithelial surface of the glomerular-basement membrane. Current models of pathogenesis usually assume in-situ immune-complex formation involving an as yet uncharacterised fixed glomerular antigen. I argue that the properties of IgG4 (inability to fix complement and therefore impaired clearance of IgG4-containing complexes; low affinity and therefore ability for IgG4-containing complexes to dissociate and traverse the glomerular-basement membrane) are compatible with a pathogenic mechanism that involves the deposition of circulating IgG4 immune complexes containing diverse antigens.

Antibody independent crescentic glomerulonephritis in μ chain deficient mice. The hypothesis that crescent formation in glomerulonephritis (GN) is a delayed type hypersensitivity (DTH)-like lesion, not dependent on a humoral immune response, was addressed using mice with deletion of the μ immunoglobulin heavy chain gene (μ chain deficient mice). Homozygous μ chain deficient mice do not develop mature B cells or produce immunoglobulin, but have intact cell mediated immunity. GN was induced in sensitized mice by a subnephritogenic dose of sheep anti-mouse GBM globulin. Heterozygous mice (μ chain +/−) demonstrated normal antibody and DTH responses to sheep globulin and developed a proliferative GN with proteinuria (6.4 ±1.4 mg/24 hr), renal impairment (serum creatinine 32.6 ±3.3 µmol/liter) and crescents in 33 ± 2.4% of glomeruli, when this antigen was planted in their glomeruli. This lesion was demonstrated to be T cell dependent by in vivo T cell depletion. Homozygous μ chain deficient mice (+/−) also developed proliferative GN, histologically indistinguishable from +/− mice. Proteinuria (3.8 ± 1.0 mg/24 hr), renal impairment (serum creatinine 24.5 ± 3.4 µmo/liter) and crescent formation (29 ± 2% of glomeruli) were no different from =/− mice. Mouse immunoglobulin was absent in their serum and glomeruli, however, cutaneous DTH to sheep globulin was identical to heterozygous mice. These results demonstrate that glomerular crescent formation and injury can occur independent of a humoral immune response to planted glomerular antigen and without glomerular deposition of autologous antibody. This strongly supports the hypothesis that crescent formation is a manifestation of DTH.