The Pathogenesis of Idiopathic Membranous Nephropathy: A 50-Year Odyssey
2010; Elsevier BV; Volume: 56; Issue: 1 Linguagem: Inglês
10.1053/j.ajkd.2010.01.008
ISSN1523-6838
Autores Tópico(s)Vasculitis and related conditions
ResumoEver since its first delineation as a distinct clinicopathologic entity in 1957, idiopathic membranous nephropathy (MN) has been the subject of intense laboratory and clinical investigation. The availability of laboratory models (particularly active and passive Heymann nephritis) of this disorder has been a boon to investigators. Concepts regarding the fundamental mechanisms of immune deposit formation, a sine qua non of idiopathic MN, have evolved and now are firmly established. Circulating autoantibodies (immunoglobulin G4 and immunoglobulin G1 subclasses) interacting with antigens native to or planted in the glomerular capillary wall at the podocyte cell membrane–basement membrane interface generally are regarded as the fundamental pathobiological mechanism. Thus, MN now is regarded as a podocytopathy. The immune deposits evoke an alteration in glomerular capillary permeability, probably through complement-mediated injury of the podocyte and its slit-pore membrane; however, cell-mediated immunity also may have a role, and the physical presence of immune deposits and basement membrane alterations also may participate. The exact nature of the autoantibody systems operative in human idiopathic MN is being uncovered rapidly. It is hoped that this 50-year odyssey will culminate in real progress in the diagnosis, prognosis, and therapy for the human disease. Ever since its first delineation as a distinct clinicopathologic entity in 1957, idiopathic membranous nephropathy (MN) has been the subject of intense laboratory and clinical investigation. The availability of laboratory models (particularly active and passive Heymann nephritis) of this disorder has been a boon to investigators. Concepts regarding the fundamental mechanisms of immune deposit formation, a sine qua non of idiopathic MN, have evolved and now are firmly established. Circulating autoantibodies (immunoglobulin G4 and immunoglobulin G1 subclasses) interacting with antigens native to or planted in the glomerular capillary wall at the podocyte cell membrane–basement membrane interface generally are regarded as the fundamental pathobiological mechanism. Thus, MN now is regarded as a podocytopathy. The immune deposits evoke an alteration in glomerular capillary permeability, probably through complement-mediated injury of the podocyte and its slit-pore membrane; however, cell-mediated immunity also may have a role, and the physical presence of immune deposits and basement membrane alterations also may participate. The exact nature of the autoantibody systems operative in human idiopathic MN is being uncovered rapidly. It is hoped that this 50-year odyssey will culminate in real progress in the diagnosis, prognosis, and therapy for the human disease. The exploration of fundamental mechanisms responsible for idiopathic membranous nephropathy (MN) has traced a long, enigmatic, and frustrating history for scientists, clinicians, and patients. The logical beginning of this saga can be traced to its recognition as a distinct clinicopathologic entity by David Jones1Jones D. Nephrotic glomerulonephritis.Am J Pathol. 1957; 33: 313-329PubMed Google Scholar in 1957 and the most recent chapter defined by the possible identification of an autoantibody-mediated pathogenetic mechanism responsible for the human disease by Beck et al2Beck L.H. Bonegio R.G. Lambeau G. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1564) Google Scholar in 2009. The approximately 50-year period encompassed by these bookends delineates a fascinating tale of “short feasts and long famines” of scientific progress.3Kerjaschki D. Pathomechanisms and molecular basis of membranous nephropathy.Lancet. 2004; 364: 1194-1196Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar The challenge of idiopathic MN during these 5 decades recalls the tribulations and cunning intelligence of Ulysses in Homer's epic poem The Odyssey, written approximately 28 centuries ago. In this essay, I attempt to capture the high points of this adventure, rather than be comprehensive. The focus is on the idiopathic disease (idiopathic MN). However, the reader should be fully aware that similar glomerular lesions can be produced in humans (and animals) by a wide variety of events, some secondary to recognized diseases, such as cancer, systemic lupus erythematosus, and other autoimmune processes; graft-versus-host reactions; many drugs; and chronic viral, bacterial, and parasitic infections.4Glassock R.J. Secondary membranous nephropathy.Nephrol Dial Transplant. 1992; 7: S64-S71PubMed Google Scholar The term membranous glomerulonephritis was used first by Bell5Bell E.T. Renal Diseases.in: Lea & Febiger, Philadelphia, PA1946: 141-253Google Scholar in 1946 to describe a category of glomerular renal disease classified within the spectrum of Ellis type II glomerulonephritis, characterized clinically by a more insidious onset and marked proteinuria and edema. This category also included lipoid nephrosis, lobular glomerulonephritis, and chronic glomerulonephritis (not otherwise specified). Thus, membranous glomerulonephritis (later to morph into MN) was “lumped” together with other histologic lesions subsumed by the Ellis classification of glomerulonephritis.6Ellis A. Natural history of Bright's disease Clinical, histological and experimental observations.Lancet. 1942; 1: 1-7Abstract Scopus (61) Google Scholar In 1957, David Jones,1Jones D. Nephrotic glomerulonephritis.Am J Pathol. 1957; 33: 313-329PubMed Google Scholar a renal pathologist from Syracuse University in New York, separated membranous glomerulonephritis as a distinct morphologic entity using the special stain periodic acid–silver methenamine (now known as Jones stain), applied to human renal biopsy specimens. In this seminal study, Jones1Jones D. Nephrotic glomerulonephritis.Am J Pathol. 1957; 33: 313-329PubMed Google Scholar fully illustrated the special features of this lesion not shared by other lesions, such as lobular glomerulonephritis (now known as membranoproliferative glomerulonephritis), lipoid nephrosis (now known as minimal change disease), and chronic glomerulonephritis (now known as focal and segmental glomerulosclerosis). The thickening of the capillary wall and alteration in basement membrane structure, so characteristic of the membranous lesion, were convincingly shown (Fig 1). The electron-dense subepithelial location of the deposits occupying the spaces between the altered glomerular basement membrane (GBM) also subsequently were identified by Movat and McGregor7Movat H.Z. McGregor D.D. The fine structure of the glomerulus in membranous glomerulonephritis (lipoid nephrosis) in adults.Am J Clin Pathol. 1959; 32: 100-127PubMed Google Scholar in 1959 using electron microscopic methods applied to renal biopsy specimens pioneered by Farquhar et al8Farquhar M. Vernier R. Good R. An electron microscope study of the glomerulus in nephrosis, glomerulonephritis and lupus erythematosus.J Exp Med. 1957; 106: 649-660Crossref PubMed Scopus (114) Google Scholar in 1957. Mellors et al9Mellors R.C. Ortega L.G. Holman H.R. Role of gammaglobulins in pathogenesis of renal lesions in systemic lupus erythematosus and chronic membranous glomerulonephritis, with an observation of the lupus erythematosus cell reaction.J Exp Med. 1957; 1065: 191-202Crossref Scopus (68) Google Scholar in 1957 had identified the third component of the unique lesion of membranous glomerulonephritis; namely, the presence of immunoglobulin in the deposits, using the immunofluorescence technique described by Coons and Kaplan10Coons A.H. Kaplan M.H. Localization of antigen in tissue cells; improvements in a method for the detection of antigen by means of fluorescent antibody.J Exp Med. 1950; 91: 1-13Crossref PubMed Scopus (812) Google Scholar in 1950. Thus, in a burst of morphologic investigations using newly developed technology, over the span of just 2 years, the triad of essential (diagnostic) features of the lesion of membranous glomerulonephritis were delineated; namely, alteration in basement membrane structure, subepithelial electron-dense deposits, the latter containing immunoglobulin G (IgG). These are still the fundamental features used today to identify membranous glomerulonephritis (called extramembranous glomerulonephritis or epimembranous nephropathy by some Europeans), henceforth called MN in this essay. The story of MN then moves from the human arena to the experimental laboratory. Walter Heymann and colleagues11Heymann W. Hackel D.B. Harwood S. Wilson S.G. Hunter J.L. Production of nephrotic syndrome in rats by Freund's adjuvant and rat kidney suspensions.Proc Soc Exp Biol Med. 1959; 100: 660-664Crossref PubMed Scopus (432) Google Scholar discovered in 1959 that active immunization of an outbred strain of rats by intraperitoneal administration of crude homologous rat renal homogenates along with complete Freund's adjuvant induced a disease identical, both clinically and morphologically, to human MN. This experimental model, subsequently known as Heymann nephritis, was believed to be caused by autoimmunity, although the autoantigen and the injurious autoimmune vector (or vectors) were unknown at that time. Heymann repeatedly stated that he regarded this kidney disease model as an example of “autoimmune nephrosis.”12Hunter J.L. Hackel D.B. Heymann W. Nephrotic syndrome in rats produced by sensitization to rat kidney proteins: immunologic studies.J Immunol. 1960; 85: 319-327PubMed Google Scholar A few years later, Dixon et al13Dixon F.J. Feldman J. Vasquez J.J. Experimental glomerulonephritis The pathogenesis of a laboratory model resembling human glomerulonephritis.J Exp Med. 1961; 113: 899-920Crossref PubMed Scopus (429) Google Scholar identified glomerular lesions very similar to MN in rabbits repeatedly immunized with intravenous heterologous serum proteins (such as bovine serum albumin or bovine γ-globulin) in sufficient quantities to maintain a slight excess of antigen over antibody. They postulated that immune complexes formed in the circulation in this situation acquired properties enabling them to localize in glomeruli and form the deposits located on the outer or subepithelial aspects of the GBM.13Dixon F.J. Feldman J. Vasquez J.J. Experimental glomerulonephritis The pathogenesis of a laboratory model resembling human glomerulonephritis.J Exp Med. 1961; 113: 899-920Crossref PubMed Scopus (429) Google Scholar, 14Dixon F.J. The role of antigen-antibody complexes in disease.Harvey Lectures. 1963; 58: 21-52PubMed Google Scholar The circulating immune complexes involving precipitating antibodies theoretically could disassociate, permeate, and re-form in the subepithelial space;15Agadoa L.M. Gauthier V.J. Mannik M. Precipitating antigen-antibody systems are required for the formation of subepithelial electron dense immune deposits.J Exp Med. 1983; 158: 1259-1271Crossref PubMed Scopus (22) Google Scholar however, evidence for their direct involvement in MN is scarce.16Mannik M. Mechanisms of tissue deposition of immune complexes.J Rheumatol Suppl. 1987; 13: 35-42Google Scholar In this chronic serum sickness model of MN, the perpetrators of disease (immune complexes) were derived from the circulation and glomeruli were passive victims. Not surprisingly, Heymann nephritis became the subject of intense laboratory investigation because it provided a reproducible and useful model to study the possible pathogenesis of human MN. Very quickly, it became clear that circulating autoantibodies developed in the actively immunized animals (active Heymann nephritis) and that a similar disease could be produced by passive administration of a heterologous antibody (made in sheep or rabbits) to the putative autoantigen contained in the crude renal homogenates used to induce the experimental disease (passive Heymann nephritis).17Feenstra H. van den Lee R. Greben H.A. Arends A. Hoedemaeker P.J. Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens I. The natural history: a histologic and immunohistologic study at the light microscopic and the ultrastructural level.Lab Invest. 1975; 32: 235-242PubMed Google Scholar, 18Fleuren G.J. Lee R. Greben H.A. Van Damme B.J. Hoedemaeker P.J. Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens IV. Investigations into the pathogenesis of the model.Lab Invest. 1978; 38: 496-501PubMed Google Scholar In addition, cellular immunity was presumed to develop in the immunized animals and even was postulated to be pathogenically important, but the initial focus was on the role of autoantibodies in the disease. By 1968, the pathogenic antigen had been partially characterized.19Edgington T.S. Glassock R.J. Dixon F.J. Autologous immune complex nephritis induced with renal tubular antigen: I Identification and isolation of the pathogenetic antigen.J Exp Med. 1968; 127: 555-572Crossref PubMed Scopus (225) Google Scholar It was a component of the tubular cell–rich portion (called fraction IA [FxIA]) of the original whole-kidney crude homogenate, and further biochemical studies showed it to be a large glycolipoprotein (RTEα5) extensively expressed on the brush-border surface of proximal tubules.19Edgington T.S. Glassock R.J. Dixon F.J. Autologous immune complex nephritis induced with renal tubular antigen: I Identification and isolation of the pathogenetic antigen.J Exp Med. 1968; 127: 555-572Crossref PubMed Scopus (225) Google Scholar Immunization of susceptible strains of rats with as little as 3 μg of RTEα5 in a single injection in the foot pad was capable of inducing disease after a lag period of 4-8 weeks concomitant with the appearance of anti-RTEα5 autoantibody in the circulation.19Edgington T.S. Glassock R.J. Dixon F.J. Autologous immune complex nephritis induced with renal tubular antigen: I Identification and isolation of the pathogenetic antigen.J Exp Med. 1968; 127: 555-572Crossref PubMed Scopus (225) Google Scholar RTEα5 also was found in small amounts in the circulation of normal rats, but RTEα5 could not be identified in glomeruli of normal rat kidney using frozen sections and indirect immunofluorescence techniques, whereas large deposits of RTEα5 could be found in the subepithelial deposits present in active Heymann nephritis.19Edgington T.S. Glassock R.J. Dixon F.J. Autologous immune complex nephritis induced with renal tubular antigen: I Identification and isolation of the pathogenetic antigen.J Exp Med. 1968; 127: 555-572Crossref PubMed Scopus (225) Google Scholar Active Heymann nephritis could be transferred to naive rats by lymphoid cells (lymph node and spleen cells) and parabiosis; however, this probably was caused by a small amount of pathogenic antigen contaminating the lymphoid cell preparations because lethally irradiated (in vitro) lymphoid cells also could transfer the disease.20Glassock R.J. Watson J.I. Edgington T.S. Dixon F.J. Autologous immune complex glomerulonephritis III. Studies on cellular and parabiotic transfer.J Immunol. 1969; 102: 194-205PubMed Google Scholar, 21Hess E.V. Ashworth C.T. Ziff M. Transfer of an autoimmune nephrosis in the rat by means of lymph node cells.J Exp Med. 1962; 115: 421-438Crossref PubMed Scopus (21) Google Scholar A marked strain and species variation of susceptibility to the induction of active Heymann nephritis was established.22Stenglein B. Thoenes G.H. Gunther E. Genetically controlled autologous immune complex glomerulonephritis in rats.J Immunol. 1975; 115: 895-897PubMed Google Scholar The disease could not be induced in rabbits, and some strains of inbred rats were very resistant to induction of disease. Immunization of rats with human-derived FxIA induced the disease; however, the deposits contained only rat-derived RTEα5,23Edgington T.S. Glassock R.J. Dixon F.J. Autologous immune-complex pathogenesis of experimental allergic glomerulonephritis.Science. 1967; 155: 1432-1437Crossref PubMed Scopus (107) Google Scholar indicative of its autoimmune nature. All the mentioned information led to the construction of a hypothesis (called autologous immune complex nephritis) by Edgington et al23Edgington T.S. Glassock R.J. Dixon F.J. Autologous immune-complex pathogenesis of experimental allergic glomerulonephritis.Science. 1967; 155: 1432-1437Crossref PubMed Scopus (107) Google Scholar and Glassock et al24Glassock R.J. Edgington T.S. Watson J.I. Dixon F.J. Autologous immune complex nephritis induced with renal tubular antigen II. The pathogenetic mechanism.J Exp Med. 1968; 127: 573-588Crossref PubMed Scopus (108) Google Scholar that active Heymann nephritis was caused by the formation of circulating immune complexes by the interaction of anti-RTEα5 autoantibodies with the small amount of RTEα5 constantly supplied to the circulation by the proximal renal tubules. We proposed that the small soluble circulating autoantigen-autoantibody immune complexes escaped rapid removal by the reticuloendothelial system and preferentially deposited in glomeruli (in a subepithelial location, similar to the chronic serum sickness model mentioned previously), provoking MN. Sensitized lymphoid cells (cellular immunity) were not regarded as important to the pathogenesis of the model, although such sensitization was likely to have occurred as the result of the immunization process. Although fully consistent with the available observations at the time, this hypothesis was to have only a short-lived period of validity. The crucial bit of missing data was whether the normal (naive) susceptible rat did or did not have pathogenetic antigen present in glomerular structures. These missing data were resolved by the publications of Van Damme et al25Van Damme B.J. Fleuren G.J. Bakker W.W. Vernier R.L. Hoedemaeker P.J. Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens V. Fixed glomerular antigens in the pathogenesis of heterologous immune complex glomerulonephritis.Lab Invest. 1978; 38: 502-510PubMed Google Scholar in April 1978 and Couser et al26Couser W.G. Steinmuller D.R. Stilmant M.M. Salant D.J. Lowenstein L.M. Experimental glomerulonephritis in the isolated perfused rat kidney.J Clin Invest. 1978; 62: 1275-1287Crossref PubMed Scopus (267) Google Scholar in December 1978 showing that deposition of antibody to FxIA in glomeruli was independent of circulating antigen (using cell- and blood-free ex vivo organ perfusion). The pathogenic antigen (FxIA containing RTEα5) was a normal constituent of the clathrin-coated pits found on podocytes. These pivotal observations, which were anticipated by Okuda et al27Okuda R. Kaplan M.H. Cuppage F.E. Heymann W. Deposition of autologous gamma globulin in kidneys of rats with nephrotic renal disease of various etiologies.J Lab Clin Med. 1965; 66: 204-215PubMed Google Scholar working in Heymann's laboratory in 1965, meant that immune complexes were formed in situ and were not necessarily deposited as preformed immune complexes from the circulation. Subsequent studies using autoantibodies, reactive solely with the in situ autoantigen, eluted from the kidneys of animals with active Heymann nephritis confirmed this hypothesis.28Makker S.P. Moorthy B. In situ immune complex formation in isolated perfused kidney using homologous antibody.Lab Invest. 1981; 44: 1-5PubMed Google Scholar Thus, the autologous (circulating) immune complex nephritis hypothesis had to be discarded and replaced with an in situ immune complex formation explanation. In retrospect, the difficulty detecting RTEα5 in the normal kidney and the ease of showing RTEα5 in the diseased kidney may have been caused by the enhanced synthesis of RTEα5 by podocytes in the presence of disease.29Makker S.P. Widstrom R. Huang J. Transcription and translation of gp600 and receptor-associated protein (RAP) in active Heymann nephritis.Am J Pathol. 1995; 146: 1481-1487PubMed Google Scholar The biochemical and molecular characteristics of pathogenic antigen present in or on these clathrin-coated pits of podocytes (and also expressed in microvilli of the brush border of the proximal tubule) became a subject of intense investigation. Makker30Makker S.P. Evidence that the antigen of autologous immune complex glomerulonephritis of rats is a mannose or glucose-containing glycoprotein.Proc Soc Exp Biol Med. 1980; 163: 95-99Crossref PubMed Scopus (13) Google Scholar showed it to be a mannose-containing glycoprotein in 1978. Purification of the antigen using lectin affinity chromatography was accomplished by Kerjaschki and Farquhar31Kerjaschki D. Farquhar M.G. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border.Proc Natl Acad Sci U S A. 1982; 79: 5557-5561Crossref PubMed Scopus (409) Google Scholar and Makker and Singh32Makker S.P. Singh A.K. Characterization of the antigen (gp600) of Heymann nephritis.Lab Invest. 1984; 50: 287-293PubMed Google Scholar in 1982. The antigen isolated by Kerjaschki and Farquhar31Kerjaschki D. Farquhar M.G. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border.Proc Natl Acad Sci U S A. 1982; 79: 5557-5561Crossref PubMed Scopus (409) Google Scholar was a 330-kDa glycoprotein, whereas the antigen isolated by Makker and Singh32Makker S.P. Singh A.K. Characterization of the antigen (gp600) of Heymann nephritis.Lab Invest. 1984; 50: 287-293PubMed Google Scholar was a 600-kDa glycoprotein. Both these purified proteins subsequently were called megalin,33Farquhar M.G. Saito A. Kerjaschi D. Orlando R.A. The Heymann nephritis antigen complex: megalin (gp330) and RAP.J Am Soc Nephrol. 1995; 6: 35-47PubMed Google Scholar and the molecular mass of megalin is now believed to be 600 kDa. Megalin copurifies with its chaperone, called receptor-associated protein; however, megalin alone is capable of inducing active Heymann nephritis.34Huang J. Makker S. Role of receptor-associated 39/45 kD protein in active Heymann nephritis.Kidney Int. 1995; 47: 432-441Crossref PubMed Scopus (19) Google Scholar Megalin is a multipurpose cell-membrane receptor capable of binding lipoproteins (such as low-density lipoprotein) and other proteinaceous substances33Farquhar M.G. Saito A. Kerjaschi D. Orlando R.A. The Heymann nephritis antigen complex: megalin (gp330) and RAP.J Am Soc Nephrol. 1995; 6: 35-47PubMed Google Scholar and is present on the brush border of proximal tubules and on the glomerular podocyte (the latter only in murine species, eg, rats). Megalin in the proximal tubule participates (along with another protein called cubulin) in the endocytic reabsorption of filtered proteins, including albumin.33Farquhar M.G. Saito A. Kerjaschi D. Orlando R.A. The Heymann nephritis antigen complex: megalin (gp330) and RAP.J Am Soc Nephrol. 1995; 6: 35-47PubMed Google Scholar Its exact physiologic function in the podocyte is uncertain. The actual epitopes in megalin responsible for the production of active Heymann nephritis are limited to only a small portion of the molecule.35Olienikov A.V. Feliz B.J. Makker S.P. A small N-terminal 60-kD fragment of gp600 (megalin), the major auto-antigen of active Heymann nephritis, can induce a full-blown disease.J Am Soc Nephrol. 2000; 11: 57-64PubMed Google Scholar, 36Ronco P. Debiec H. Molecular dissection of target antigens and nephritogenic antibodies in membranous nephropathy: towards epitope-driven therapies.J Am Soc Nephrol. 2006; 17: 1772-1774Crossref PubMed Scopus (17) Google Scholar, 37Tramontano A. Knight T. Vizzuso D. Makker S.P. Nested N-terminal megalin fragments induce high-titer autoantibody and attenuated nephritis.J Am Soc Nephrol. 2006; 17: 1979-1985Crossref PubMed Scopus (19) Google Scholar Megalin is now known to contain many such epitopes,33Farquhar M.G. Saito A. Kerjaschi D. Orlando R.A. The Heymann nephritis antigen complex: megalin (gp330) and RAP.J Am Soc Nephrol. 1995; 6: 35-47PubMed Google Scholar, 36Ronco P. Debiec H. Molecular dissection of target antigens and nephritogenic antibodies in membranous nephropathy: towards epitope-driven therapies.J Am Soc Nephrol. 2006; 17: 1772-1774Crossref PubMed Scopus (17) Google Scholar, 37Tramontano A. Knight T. Vizzuso D. Makker S.P. Nested N-terminal megalin fragments induce high-titer autoantibody and attenuated nephritis.J Am Soc Nephrol. 2006; 17: 1979-1985Crossref PubMed Scopus (19) Google Scholar and glycosylation of the epitopes is critically involved in its pathogenicity.38Tramontano A. Makker S.P. Conformation and glycosylation of a megalin fragment correlates with nephritogenicity in Heymann nephritis.J Immunol. 2004; 172: 2367-2373PubMed Google Scholar In the active Heymann nephritis model, intramolecular epitope spreading is observed as the disease progresses.39Shah P. Tramontano A. Makker S.P. Intramolecular epitope spreading in Heymann nephritis.J Am Soc Nephrol. 2007; 18: 3060-3066Crossref PubMed Scopus (39) Google Scholar An additional new twist appeared in 1980 and 1981 by the novel findings of Batsford et al40Batsford S. Oite T. Takamiya H. Vogt A. Anionic binding sites in the glomerular basement membrane: possible role in the pathogenesis of immune complex glomerulonephritis.Ren Physiol. 1980; 3: 336-340PubMed Google Scholar and Border et al,41Border W.A. Kamil E.S. Ward H.J. Cohen A.H. Antigenic changes as a determinant of immune complex localization in the rat glomerulus.Lab Invest. 1981; 45: 442-449PubMed Google Scholar who described the production of typical MN in animals by intravenous infusion of cationized foreign serum proteins (such as cationic human IgG, ferritin, or bovine serum albumin). These investigators convincingly showed that the lesion was produced by the electrochemically mediated deposition of the cationized antigen in the subepithelial aspect of the GBM through interaction with electrically negative charged (anionic) components of GBM (possibly heparan sulfate proteoglycans). This led to a “planted” foreign antigen in glomeruli to which circulating antibody could react and form immune complexes in situ, eventually producing the typical MN lesion. In addition, experimental models of MN have been developed by exposure to toxic agents (eg, mercuric chloride). In these models, marked genetically based susceptibility is noted and autoantibodies to nonhistone nucleoproteins are found.42Bariety J. Druet P. Laliberte F. Sapin C. Glomerulonephritis with γ and β1c deposits induced in rats by mercuric chloride.Am J Pathol. 1971; 85: 293-302Google Scholar Thus, by 1982, a quarter century after its initial description, the pathogenetic mechanisms responsible for the formation of subepithelial electron-dense deposits containing immunoglobulin in both active and passive Heymann nephritis were reasonably well understood. Antibodies (IgG) appearing in the circulation (actively induced or passively administered) permeated the GBM and bound to a native antigen (megalin) present on the podocyte surface, forming immune complexes in situ in close approximation to the clathrin-coated pits of podocytes. These immune complexes grew in size and subsequently were shed into the subepithelial space, where they interacted with matrix components of the GBM (perhaps covalently) and accumulated as electron-dense aggregates that persisted long after the antibody has disappeared from the circulation.43Lewis E.J. Bolton W.K. Spargo B. Stuart F.J. Persistent proteinuria in the rat with Heymann nephritis [abstract].Clin Res. 1971; 20: 763Google Scholar It was clear even in 1982 that the finding of electron-dense deposits containing immunoglobulin could be a manifestation of more than one pathogenetic mechanism, including the Heymann-type mechanism of in situ formation of immune complexes when circulating antibodies (heterologous or autologous) interact with a native podocyte membrane-derived antigen, the chronic serum sickness–type mechanism in which immune complexes deposit from the circulation, and the planted antigen mechanism in which antibodies in the circulation deposit by interacting with non-native antigens artificially planted in the subepithelial space because of a biophysical or immunologic affinity for GBM structural elements (Fig 2). The next series of questions, which would prove to be even more controversial, involved a search for better understanding of the linkage between the formation and persistence of the in situ immune complexes to the mediation of proteinuria and whether the Heymann models of disease were relevant to the pathobiological process of human disease. Marked proteinuria and nephrotic syndrome are the hallmarks of MN in humans and animal models (including Heymann nephritis). Even at an early stage of development in our understanding of MN, it was clear that proteinuria could not always be taken per se as a sign of the active formation and in situ deposition of immune complexes42Bariety J. Druet P. Laliberte F. Sapin C. Glomerulonephritis with γ and β1c deposits induced in rats by mercuric chloride.Am J Pathol. 1971; 85: 293-302Google Scholar, 43Lewis E.J. Bolton W.K. Spargo B. Stuart F.J. Persistent proteinuria in the rat with Heymann nephritis [abstract].Clin Res. 1971; 20: 763Google Scholar because irreversible damage to the glomerular capillary wall could induce changes in the permselectivity barrier that could persist even in the absence of autoantibody to megalin.43Lewis E.J. Bolton W.K. Spargo B. Stuart F.J. Persistent proteinuria in the rat with Heymann nephritis [abstract].Clin Res. 1971; 20: 763Google Scholar Nevertheless, proteinuria is a regular feature associated with active formation of in situ immune complexes and local complement activation in the developing experimental disease.44Makker S.P. Kanalas J.J. Course of transplanted Heymann nephritis kid
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