Clinical Investigation

Kidney International (1985) 27, 938–950; doi:10.1038/ki.1985.102

Influence of antigen distribution on the mediation of immunological glomerular injury

David J Salant1, Stephen Adler1, Christine Darby1, Neva J Capparell1, Gerald C Groggel1, Irwin D Feintzeig1, Helmut G Rennke1 and John E Dittmer1

1The Evans Memorial Department of Clinical Research and the Departments of Medicine and Anatomy, Boston University Medical Center, and the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

Correspondence: Dr D J Salant, Renal Section, Department of Medicine, Boston University Medical Center, 80 E. Concord Street, Boston, Massachusetts 02118, USA

Received 6 June 1984; Revised 28 November 1984.

Top

Abstract

Influence of antigen distribution on the mediation of immunological glomerular injury. To determine if the site of immune reaction could influence the mediation and morphological expression of glomerular injury in experimental anti-glomerular basement membrane (anti-GBM) nephritis and membranous nephropathy, we studied the events that followed the in situ reaction of rat antibody with antigen planted in either the GBM (especially the lamina rara interna) or in the subepithelial space (SE). Non-nephritogenic amounts of noncomplement-fixing sheep anti-GBM or anti-tubular brushborder antibody were injected into separate groups of rats to plant sheep IgG in the GBM and SE, respectively. Kidneys containing sheep IgG were then transplanted into naive recipients that were passively immunized with rat anti-sheep IgG. There was marked proteinuria after 2 days (antigen in GBM: 226 plusminus 50.7; antigen in SE: 69 plusminus 50.7 mg/24 hr) that was abrogated by prior depletion of complement in both groups (antigen in GBM: 10.2 plusminus 1.7; antigen in SE: 14.3 plusminus 8.7 mg/24 hr). When antigen was planted in SE, inflammatory-cell depletion with either anti-neutrophil (PMN) serum or lethal irradiation had no effect on proteinuria. In contrast, anti-PMN abolished proteinuria (12.0 plusminus 5.6 mg/24 hr) and irradiation reduced it by 60% when antigen was in GBM. Glomeruli of kidneys with antigen in GBM were significantly larger and more hypercellular than those with antigen in SE after transplantation into immunized recipients. Endothelial cell injury and adherence of inflammatory cells to denuded GBM were prominent in the former (antigen in GBM), while glomeruli with antigen in SE showed only subepithelial deposits, adjacent slit-diaphragm displacement, and epithelial cell foot-process effacement. Thus, the reaction of antigen and antibody in glomeruli produced complement-mediated injury which was cell-independent when complex formation occurred on the outer aspect of the GBM but was cell-dependent when the same reagents reacted more proximally to the circulation. We therefore conclude that antigen distribution can critically influence the mediation and morphologic expression of immune glomerular injury and may, in part, account for variations in the clinical and histological manifestations of antibody-induced glomerular disease in humans.

Influence de la distribution antigénique sur la médiation des lésions glomérulaires immunologiques. Afin de déterminer si le site de la réaction immune pourrait influencer la médiation et l'expression morphologique des lésions glomérulaires lors d'une néphrite expérimentale anti-membrane basale glomérulaire (anti-GBM) et d'une néphropathie extra-membraneuse, nous avons étudié les événements qui suivaient la réaction in situ d'anticorps de rat avec un antigène fixé soit dans la GBM (surtout dans la lamina rara interna), soit dans l'espace sous-épithélial (SE). Des quantités non nephritogènes d'anticorps anti-GBM, ou anti-bordure en brosse tubulaire de mouton ne fixant pas le complément ont été injectées à différents groupes de rats pour fixer de l'IgG de mouton dans la GBM et le SE, respectivement. Les reins contenant l'IgG de mouton étaient alors transplantés à des receveurs vierges passivement immunisés avec de l'IgG de rat antimouton. Il existait une protéinurie marquée après deux jours (antigène dans la GBM: 226 plusminus 50,7; antigène dans SE: 69 plusminus 50,7 mg/24 hrs) qui à été abrogé par une déplétion du complement dans les deux groupes (antigène dans la GBM: 10,2 plusminus 1,7; antigène dans SE: 14,3 plusminus 8,7 mg/24 hr). Lorsque l'antigène était fixé dans SE, une déplétion en cellules inflammatoires par du sérum anti-neutrophile (PMN) ou une irradiation léthale n'avaient pas d'effet sur la protéinurie. A l'opposé, anti-PMN supprimait la protéinurie (12,0 plusminus 5,6 mg/24 hr) et l'irradiation la réduisait de 60% lorsque l'antigène était dans la GBM. Les glomérules de reins ayant l'antigène dans la GBM étaient significativement plus gros et plus hyper-cellulaires que ceux ayant l'antigène dans SE après transplantation chez des receveurs immunisés. Les lésions cellulaires endothéliales et l'adhérence des cellules inflammatoires à des GBM nues étaient prédominantes chez les premiers (antigène dans la GBM) alors que les glomérules ayant l'antigène dans SE présentaient uniquement des dépôts sous-épithéliaux, un déplacement du slit-diaphragme adjacent et un effacement des pédicelles des cellules épithéliales. Ainsi, la réaction d'un antigène et d'un anticorps dans des glomérules a produit des lésions à médiation complémentaire indépentantes des cellules lorsque la formation de complexes survenait dans la partie extérieure de la GBM, mais dépendantes des cellules lorsque les mêmes réactifs interagissaient de façon plus proximale dans la circulation. Nous concluons donc que la distribution antigénique peut influencer de manière critique la médiation et l'expression morphologique des lésions glomérulaires immunes et qu'elle peut, en partie, rendre compte de variations dans les manifestations cliniques et histologiques de glomérulopathies à médiation par anticorps chez l'homme.

Top

References

  1. Couser WG, Salant DJ: Immunopathogenesis of glomerular capillary wall injury in nephrotic states, in Contemporary Issues in Nephrology. Nephrotic Syndrome, edited by Myers BD, Brenner BM, Stein JH. New York, Churchill Livingstone, 1982, vol 9, p 47
  2. Adler S, Salant DJ, Dittmer JE, Rennke HG, Madaio MP, Couser WG: Mediation of proteinuria in membranous nephropathy due to a planted glomerular antigen. Kidney Int 23:807–815, 1983
  3. Naish PF, Thomson NM, Simpson IJ, Peters DK: The role of polymorphonuclear leukocytes in the autologous phase of nephrotoxic nephritis. Clin Exp Immunol 22:102–111, 1975 | PubMed | ISI | ChemPort |
  4. Schreiner GF, Cotran RS, Pardo V, Unanue ER: A mononuclear cell component in experimental immunological glomerulonephritis. J Exp Med 147:369–384, 1978 | Article | PubMed | ISI | ChemPort |
  5. Holdsworth SR, Neale TJ, Wilson CB: Abrogation of macrophage-dependent injury in experimental glomerulonephritis in the rabbit. J Clin Invest 68:686–698, 1981 | PubMed | ISI | ChemPort |
  6. Unanue ER, Dixon FJ: Experimental glomerulonephritis. V. Studies on the interaction of nephrotoxic antibodies with tissues of the rat. Exp Med 121:697–714, 1965
  7. Madaio MP, Salant DJ, Adler S, Darby C, Couser WG: Effect of antibody charge and concentration on deposition of antibody to glomerular basement membrane. Kidney Int 26:397–103, 1984
  8. Salant DJ, Darby C, Couser WG: Experimental membranous glomerulonephritis in rats. Quantitative studies of glomerular immune deposit formation in isolated glomeruli and whole animals. J Clin Invest 66:71–81, 1980 | PubMed | ISI | ChemPort |
  9. Salant DJ, Belok S, Madaio MP, Couser WG: A new role for complement in experimental membranous nephropathy in rats. J Clin Invest 66:1339–1350, 1980 | PubMed | ISI | ChemPort |
  10. Mancini O, Carbonara AO, Heremans JR: Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry 2:235–254, 1965 | Article | PubMed |
  11. Ouchterlony O: Handbook of Immunodiffusion and Immunoelectrophesis. Ann Arbor, Ann Arbor Science Publishers, Inc., 1970, p 21
  12. Ouchterlony O: Handbook of Immunodiffusion and Immunoelectrophesis. Ann Arbor, Ann Arbor Science Publishers, Inc., 1970, p 47
  13. McConahey PJ, Dixon FJ: A method of trace iodination of proteins for immunologic studies. Int Arch Allergy Appl Immunol 29:185–189, 1966 | PubMed | ISI | ChemPort |
  14. Lee S: An improved technique of renal transplantation in the rat. Surgery 61:771–773, 1967 | PubMed | ISI | ChemPort |
  15. Weibel ER: Sterological Methods, in Practical Methods for Biological Morphometry. New York, Academic Press, 1979, vol 1, p 101
  16. Hirose K, Osterby R, Nozawa M, Gunderson HJG: Development of glomerular lesions in experimental long-term diabetes in the rat. Kidney Int 21:689–695, 1982 | PubMed | ISI | ChemPort |
  17. Yam LT, Li CY, Crosby WH: Cytochemical identification of monocytes and granulocytes. Am J Clin Pathol 55:283–290, 1971 | PubMed | ISI | ChemPort |
  18. Sterzel RB, Ehrich JHH, Lucia H, Thomson D, Kashgarian M: Mesangial deposition of glomerular immune deposits in acute malarial glomerulonephritis of rats. Lab Invest 46:209–214, 1982
  19. Siegel S: Nonparametric Statistics for the Behavioral Sciences (International student edition). Tokyo, McGraw-Hill Kogakusha, Ltd., 1965, pp 116, 184
  20. Snedecor GW, Cochrane WG: Statistical Methods (6th ed). Ames, The Iowa State University Press, 1967, pp 120, 135
  21. Schreiner GF, Kiely J-M, Cotran RS, Unanue ER: Characterization of resident glomerular cells in the rat expressing la determinants and manifesting genetically restricted interactions with lymphocytes. J Clin Invest 68:920–931, 1981 | PubMed | ChemPort |
  22. Bhan AK, Schneeberger EE, Collins AB, McCluskey RT: Evidence for a pathogenic role of a cell-mediated mechanism in experimental glomerulonephritis. J Exp Med 148:246–260, 1978 | Article | PubMed | ISI | ChemPort |
  23. Thompson NM, Naish PF, Simpson IJ, Peters DK: The role of C3 in the autologous phase of nephrotoxic nephritis. Clin Exp Immunol 24:464–473, 1976
  24. Sindrey M, Naish P: The mediation of the localization of polymorphonuclear leukocytes in glomeruli during the autologous phase of nephrotoxic nephritis. Clin Exp Immunol 35:350–355, 1979 | PubMed |
  25. Holdsworth SR: Fc dependence of macrophage accumulation and subsequent injury in experimental glomerulonephritis. J Immunol 130:735–739, 1983 | PubMed |
  26. Unanue ER, Schreiner GF, Cotran RS: A role of mononuclear phagocytes in immunologically induced glomerulonephritis, in Immune Mechanisms in Renal Disease, edited by Cummings NB, Michael AF, Wilson CB, New York, Plenum Medical Book Company, 1983, p 443
  27. van Zyl-Smit R, Rees AJ, Peters DK: Factors affecting severity of injury during experimental nephrotoxic nephritis in rabbits. Clin Exp Immunol 54:366–372, 1983
  28. Cochrane CG, Unanue E, Dixon FJ: A role of polymorphonuclear leukocytes and complement in nephrotoxic nephritis. J Exp Med 122:99–119, 1965 | Article | PubMed | ISI | ChemPort |
  29. Henson PM, Cochrane CG: The effect of complement depletion on experimental tissue injury. Ann NY Acad Sci 258:426–440, 1975
  30. Andres GA, Morgan C, Hsu KC, Rifkind RA, Seegal BC: Electron microscopic studies of experimental nephritis with ferritin-conjugated antibody. The basement membranes and cisternae of visceral epithelial cells in nephritic rat glomeruli. J Exp Med 115:929–936, 1962
  31. Arthelger RB, Gronvall JA, Carr OB, Brunson JG: Electron microscopic localization of nephrotoxic serum in rabbit glomeruli with ferritin-conjugated antibody. Lab Invest 12:33–37, 1963
  32. Vogt A, Bockhorn H, Kozima K, Sasaki M: Electron microscopic localization of the nephrotoxic antibody in the glomeruli of the rat after intravenous application of purified nephritogenic antibody-ferritin conjugates. J Exp Med 127:867–878, 1968
  33. Hoedemaker PJ, Feenstra K, Nijkeuter A, Arends A: Ultrastructural localization of heterologous nephrotoxic antibody in the glomerular basement membrane of the rat. Lab Invest 26:610–613, 1972
  34. Druet P, Bariety J, Bellon B, Laliberte F: Nephrotoxic serum nephritis in the rat. Ultrastructural localization of nephrotoxic rabbit antibodies using peroxidase-labelled conjugates. Lab Invest 27:157–164, 1972
  35. Fresen KO, Vogt A: Ultrastructural localization of peroxidase-labelled nephrotoxic antibodies after intravenous application. Exp Pathol 8:276–282, 1973
  36. Fish AJ, Carmody KM, Michael AF: Spatial orientation and distribution of antigens within human glomerular basement membrane. J Lab Clin Med 94:447–457, 1979
  37. Courtoy PJ, Picton DH, Farquhar MG: Resolution and limitations of the immunoperoxidase procedure in the localization of extracellular matrix antigens. J Histochem Cytochem 31:945–951, 1983 | PubMed | ChemPort |
  38. Feldman JD, Hammer D, Dixon FJ: Experimental glomerulonephritis. III. Pathogenesis of glomerular structural lesions in nephrotoxic serum nephritis. Lab Invest 12:748–763, 1963
  39. Jeraj K, Ferrara B, Vernier RL, Michael AF: A new glomerular antigen in passive Heymann nephritis (abstract). Kidney Int 19:183, 1981
  40. Kerjaschki D, Farquhar MG: Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J Exp Med 157:667–686, 1983 | Article | PubMed | ISI | ChemPort |
  41. Davies M, Barrett AJ, Travis J, Sanders E, Coles GA: The degradation of human basement membrane with purified lysosomal proteinases: Evidence for the pathogenic role of the polymorphonuclear leucocyte in glomerulonephritis. Clin Sci Mol Med 54:233–240, 1978 | PubMed |
  42. Fantone JC, Ward PA: Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions. Am J Pathol 107:397–418, 1982 | ISI | ChemPort |
  43. Blantz RC, Tucker BJ, Wilson CB: The acute effects of antiglomerular basement membrane antibody upon glomerular filtration in the rat. The influence of dose and complement depletion. J Clin Invest 61:910–921, 1978
  44. Groggel GC, Adler S, Rennke HG, Couser WG, Salant DJ: Role of the terminal complement pathway in experimental membranous nephropathy in the rabbit. Clin Invest 72:1948–1957, 1983

Extra navigation

.
ADVERTISEMENT