Recent progress in renal immunopathology

Progress in Pathology Recent Progress in Renal Immunopathology GIUSEPPEANDRES, MD, YUKIO YUZAWA,MD, AND FRANCO CAVALOT, MD One of the most remarkable contributions of the recent past was that of F.J. Dixon who, in the late 1960s, proposed classifications of renal diseases based on pathogenetic mechanisms and, when possible, on etiology. 1 The result of this approach was the distinction of glomerular diseases in two basic forms: one induced by circulating antibodies reactive with structural antigens of the glomerular basement membrane and characterized by immune deposits that, by immunofluorescence technique, appeared linear; and the other induced by circulating immune complexes passively trapped in glomerular structures and characterized by immune deposits that, by immunofluorescence and electron microscopy, appeared granular.1 For two decades, this concept provided a satisfactory picture of t h e g e n e s i s of glomerulonephritis, and .good criteria for the identification of immunologic injury in other parts of the kidney and also in other organs. New acquisitions have recently extended and, in part, modified these concepts, which nevertheless continue to exert a compelling force in the field of renal immunopathology, as shown by the need to evaluate the new data in light of the classical studies of experimental serum sickness, 2 and the discovery of autoimmune glomerulonephritis in humans. 3 W.ithconsiderabte.simplification, we~4ala~o describe progress in five arbitrarily selected areas of research: (1) structural renal antigens and antigens "planted" in glomeruli; (2) characteristics of antibodies and immune complexes present in the circulation, or deposited in diseased kidneys; (3) mechanisms of induction and regulation of the immune response; (4) mediators of inflammation; and (5) the role of T cellmediated hypersensitivity.

From the Departments of Microbiology,Pathology,and Medicine, State Universityof New York at Buffalo. Accepted for publication April 21, 1988. Presented in large part at the Third Annual Conrad L. Pirani Lecture, October 9, 1986, Columbia University, New York. Supported by grant no. DK-36807 from the National Institutes of Health, United States Public Health Service, and by a Fellowship from the International Rotary Club (F.C.). Key words: gtomerulonephritis, immune complexes, ~mmune deposits, mediators of inflammation, immunopathology. Address correspondence and reprint requests to Giuseppe Andres, MD, Department of Microbiology,Pathology and Medicine, State Universityof New York at Buffalo, Buffalo, NY 14214. 9 1988 by W.B. Saunders Company. 0046-8177/88/1910-000355.00/0

STRUCTURAL RENALANTIGENS AND ANTIGENS PLANTED IN GLOMERULI

During the last 5 years, several lines of investigation have shown that the basic morphologic and immunohistologic patterns described by Dixon depend on the localization of the antigen, the anatomic and physiologic properties of cells or tissues where the immune reaction occurs, and the biological characteristics of the antigen and the antibody. One of the most relevant factors is whether the antigen is firmly fixed or free for molecular rearrangement after antibody binding. For instance, a fixed renal antigen is that of Goodpasture's disease. The discovery of 7S collagen as the cross-linking domain of type IV collagen, 4 as well as the identification of the noncollagen 1 (NC1) globular domain and the application of the rotary shadowing technique to the study of collagen molecules, 5 allowed Timpl et al 6 to construct a model of type IV collagen where four molecules are joined by disulfide bonds in the 7S terminal region. Two collagen molecules are also connected to each other in the other terminal domain (NC1), giving rise to a fixed, wire-fence network forming the structural backbone on which at least three other protein components (laminin, proteoglycans, and entactin) are more loosely attached. It seems that the Goodpasture's antigen cannot be redistributed by antibody, at least when the disease is of short duration. Furthermore, the antibody response is of restricted specificity in Goodpasture's disease. TM The resulting immune deposits have a linear immunohistologic pattern reflecting binding of human IgG 8 and complement to the collagen scaffold of the glomerular basement membrane. Laminin 9 and proteoglycans 1~ are probably more movable than NC1, but studies in this area are just beginning. Granular immune deposits in glomeruli, originally ascribed to a passive trapping of circulating antigen-antibody complexes, 1 can certainly result from this mechanism, especially when the immune deposits are subendothelial or mesangial. However, they can also be formed "in situ." This latter event requires mobility of the antigen after antibody binding so that the immune complexes can aggregate. Three different mechanisms are now recognized.

In Viva Interaction of Circulating Antibodies With Cell Surface Antigens According to the hypothesis o f Singer and Nicholson, 12 most cell membranes have a fluid mosaic

1132

RENAL IMMUNOPATHOLOGY[Andres et al]

structure. Membrane proteins are free to diffuse in a lipid matrix and may assume a random distribution over the cell surface. However, this pattern is rapidly modified when surface proteins react in vitro with a ligand. An initial patching is followed by formation of coarse caps (capping), with subsequent disappearance of the antigen from the cell surface through endocytosis a n d / o r e x t e r n a l s h e d d i n g ( a n t i g e n i c modulation). 13 A similar immune complex redistribution occurs in vivo.14 The resulting lesions have variable morphologic and immunohistologic features. When the antigen is expressed on the surface of cells facing the blood stream in structures not specifically involved in filtration, the i m m u n e complexes are shed into the circulation and formation of granular immune deposits in the vasculature does not occur. This is the case of antibodies reactive with an antigen (angiotensin-converting enzyme) expressed on the surface of the pulmonary endothelium. In the renal glomerulus, however, the same angiotensinconverting enzyme complexes can be driven by hemodynamic forces of filtration within the context of the capillary wall, where they form small and transient granular immune deposits. In contrast, the results are different when the antigen is expressed on the surface of cells surrounded by (oocytes) or resting on (glomerular or tubular epithelial cells) a collagen matrix or basement membrane. The polysaccharide milieu of the basement membranes offers suitable conditions for attachment, 15 decreased solubility, ~6 precipitation, and aggregation 17 of immune complexes, with consequent formation of granular, large, and persistent immune deposits. Cationic Antigens or Antibodies Binding to Glomerular Structures

A second mechanism of in situ formation of granular immune deposits is that of relatively cationic antigens or antibodies binding to anionic structures within the glomerulus, 18,19 probably to heparan sulfate proteoglycans. 2~ Several cationic antigens have been used to induce glomerulonephritis, either by active immunization 21,22 or by direct renal perfusion, to plant the antigen before exposing the kidney to antibody. 23 The prevalent subepithelial localization of the immune deposits in the glomerular capillary wall probably reflects forces of filtration that move macromolecules toward the epithelial side, whereas their granularity reflects coalescence of anionic sites after interaction with cationic molecules 24 as well as rearrangement of complexes containing multivalent antigens and precipitating antibodies to condense into larger latticed structures? v Antibodies Reactive With Leaking or Secreted Antigens

T h e third condition for formation of granular immune deposits within the basement membranes or the mesangial matrix is that of circulating antibodies reactive with antigens leaking out or secreted by cells.

Rabbits receiving multiple renal allografts or immunized with homologous renal tissue develop tubular immune deposits resulting from circulating antibodies reactive with brush border and cytoplasmic antigens leaking out of the epithelial cells. 25 This mechanism has not been demonstrated in glomeruli. The second condition, implying that circulating antibodies react with basement membrane components synthetized by epithelial or mesangial cells, has been recently considered. Rabbits and rats injected with mercuric chloride develop an autoimmune glomerulonephritis c h a r a c t e r i z e d by g r a n u l a r subepithelial deposits, z6,27 Laminin antibodies eluted from glomeruli of nephritic rats react with laminin synthetized and secreted by cultured rat glomerular epithelial cells, consistent with the hypothesis that a prolonged interaction of circulating antibodies with laminin synthetized by the podocytes, and not firmly anchored to the type IV collagen scaffold of the basement membrane, may contribute to the generation of subepithelial immune aggregates. 9 The interest for interaction of antibodies with cell surface, leaking, or secreted antigens has been increased by the development of monoclonal antibody technology, 2s which has afforded new insight into the polyspecific reactivity o f several antisera. Schwartz and Stollar 29 have shown that monoclonal antibodies originally selected for reactivity with ssDNA recognize various purines and pyrimidine bases, and also react with cardiolipin and other phospholipids. Madaio et aP ~ have shown that monoclonal DNA antibodies, derived from MRL-lpr/lpr mice, react by immunoblotting with several 17,000- to 87,000dalton components present in mouse glomerular extracts. When injected into mice, these antibodies bind directly to glomerular non-DNA structures normally present in extracellular locations and form locally g r a n u l a r i m m u n e d e p o s i t s . 3~ M e n d r i c k a n d Rennke 31 injected rats with murine monoclonal antibodies, which recognize a single 81,000 molecular weight (tool wt) peptide present in the mesangial matrix, and induced immune deposits in the mesangiurn. The identification of the precise sites of these cross-reactive antigens could provide clues regarding the pathogenesis of glomerular lesions. I f the antibodies would primarily react with a cell surface antigen, the immune deposits might result from shedding of immune complexes from the cell surface into a polysaccharide medium, analogous to H e y m a n n g l o m e r u l o n e p h r i t i s o r to i m m u n e c o m p l e x oophoritis. 14 However, if the cross-reactive antigens are components of the basement membrane or the mesangial matrix, i m m u n e deposits might result from interaction of antibodies with the secretory products of cells involved in the synthesis and turnover of the extraceUular matrix. In this regard, it is noteworthy that DNA antibodies eluted from kidneys of mice or patients with systemic lupus erythematosus glomerulonephritis react with epitopes of heparan sulfate proteoglycans? 2 The introduction in renal immunopathology of

1133

HUMANPATHOLOGY Volume19, No. 10 [October fl988]

new technologies, such as plasma membrane biochemistry, monoclonal antibodies, immunoblotting, and high performance liquid chromatography, has led to the identification and characterization of several new structural antigens relevant to the development of immunologically mediated renal disease in laboratory animals. However, the attempts to extend the list of structural antigens responsible for renal diseases in humans have not been equally successful. Nevertheless, progress has also been achieved in this field. Glomerular Basement M e m b r a n e

As previously mentioned, the Goodpasture's antigen has been isolated and characterized. 7'33-36 The antigen is present in collagenase-resistant domains of bovine glomerular basement membranes, with mol wts of 25,000 to 50,000 daltons. The domains were isolated and shown to be non-collagenous proteins with a monomer-dimer relationship. 35 It was subsequendy demonstrated that these peptides reside in the globular domain of collagen IV and, by using Goodpasture's antibodies, the peptides were separated into active and inactive monomers and dimers. The relevant epitope is sequestered inside a hexameric structure. 36 Similar studies were repeated using h u m a n glomerular basement membranes, and the m o n o m e r proteins (M 1, M z, M3) were immunochemically c o m p a r e d with the c o r r e s p o n d i n g bovine monomers and found to be identical. The Goodpasture's epitope was localized in the monomer peptide M z. Only the serum of one patient with Goodpasture's disease contained additional antibodies that reacted with the 7S domain of type IV collagen, indic a t i n g t h a t t h e i m m u n e r e s p o n s e is h i g h l y restricted. 7,s,37 The demonstration that the relevant epitope is sequestered at the cross-linking site of type IV collagen molecule and that reactivity with antibody requires dissociation gives additional credibility to the role o f infections 3s or exposure to toxic agents ~9 which frequently preceed the autoimmune response. These exogenous factors could expose the otherwise sequestered antigen in a variety of tissues, thereby initiating antibody production in genetically predisposed individuals. 4~ Tubular Basement M e m b r a n e

Another nephritogenic antigen recently isolated and characterized is that responsible for a rare but well-defined form of h u m a n tubulointerstitial nephritis induced by antibodies reactive with the basement membranes of proximal convoluted tubules. The disease occurs in idiopathic form or after renal transplantation, suggesting that the i m m u n e response is autoimmune or alloimmune in nature. The antibodies present in the sera of two patients were independently studied in three laboratories. 41-43 The results, obtained with different techniques, were concordant. T h e antigen isolated f r o m collagenase-

solubilized human tubular basement membrane is a 48,000 to 58,000 tool wt protein selectively recognized by the patients' antibodies. T h e antigen is similar to the rabbit t u b u l a r b a s e m e n t m e m b r a n e antigen 44 that induces antibody-mediated tubulointerstitial nephritis in guinea pigs, 45 indicating that the tubular basement m e m b r a n e target epitopes and their paratypic recognition are highly conserved among mammals. Mesangium

A glomerular structure presently considered a possible target of circulating antibodies is the mesangium. Cederholm et a146 showed that patients with IgA glomerulonephritis generate IgA antibodies reactive with type IV collagen o~ chains, and also reactive with epitopes of type I and II collagen. Antibodies to heparan sulfate proteoglycans were detected in the sera of patients with post-streptococcal glomerulonephritis, 47 and antibody to laminin were found in the sera of patients with Chagas' disease. 4s The latter antibodies recognize the terminal galactosil (o~ 1-3)-galactose epitopes o f m o u s e laminin. 49 Whether these antibodies are indeed nephritogenic remains to be demonstrated. GIomerular Visceral Epithelial Cells

The challenge to the concept that the immune deposits of human membranous glomerulonephritis are induced by local accumulation of immune complexes formed in the circulation originated from the study of Heymann glomerulonephritis. This disease develops in the rat when circulating antibodies react with antigens expressed on the plasma membrane of glomerular visceral epithelial cells. 5~ The most important antigen is a glycoprotein of 330,000 daltons (gp330) which is localized in the coated pits by immunocytochemistry.52 Whether gp330 is a split p r o d u c t o f a l a r g e r " H e y m a n n c o m p l e x , " and whether other antigens besides gp330 participate in the development of a severe, progressive, proteinuric disease, are still controversial matters.14 Nevertheless, it is established that the subepithelial foreign deposits are formed by immune complexes shed from the surface of the podocytes by a mechanism comparable with that described in in vitro systems when ligands react with surface antigens or receptors. 13,15 This understanding has given credibility to the hypothesis that h u m a n idiopathic membranous glomerulonephritis may also result from interaction of antibodies with antigens e x p r e s s e d on the surface o f the podocytes. To test the hypothesis, antigens are now isolated f r o m t h e p l a s m a m e m b r a n e s o f the podocytes and used to raise polyclonal and monoclonal antibodies. Initial results indicate that some antibodies can indeed redistribute i m m u n e complexes on the surface of cultured glomerular epithelial cells. When these antibodies are injected into monkeys or perfused t h r o u g h n o r m a l h u m a n kidneys, small granular deposits are seen first on the endothelial

1134

RENALIMMUNOPATHOLOGY[Andreset al]

and then on the epithelial site of the glomerular basement membrane. Failure to induce more severe lesions may be due to lack of relevant antigens on the surface of human glomerular epithelial cells (comparable with mouse gp330), lack of critical concentration of relevant antibodies, insufficient time of kidney perfusion, or a combination of these factors. 53 Another approach involves the use of antibodies eluted from glomeruli of patients with membranous glomerulonephritis for isolation of specific glomerular antigens. Endothelium

We are becoming aware of the role of endothelial antigens or receptors related to inflammatory injury of the vessels with the extraordinary progress of endothelial physiopathology. Endothelial cells possess properties that make them ideal candidates for imm u n e vascular injury. They are able to present antigen to lymphocytes54 and to regulate lymphocyte migration through vessel walls. 55 They express A, B, O, class I and class II histocompatibility antigens, and endothelial specific antigens on their s u r f a c e , 56'57 Moreover, cytokines released from inflammatory cells modify the expression of endothelial surface antigens or receptors and promote active binding of antibodies or immune complexes to the cell surface. 5s-6~ Two examples will confirm the importance of these acquisitions for renal immunopathology. Cines et a161 have shown that sera of patients with active systemic lupus erythematosus contain antiendothelial antibodies of the IgG class. These antibodies stimulate endothelial cells to secrete prostacyclin and cause adherence of platelets. Moreover, injury 62 or infections 63 lead to expression of Fc and C3b receptors on endothelial cells, with consequent adhesion of macrophages and activation of complement. Leung et a164 observed that patients with acute Kawasaki vasculitis have cytotoxic IgM antibodies to endothelial antigens expressed under the infuence of gamma interferon, a mediator secreted by activated T lymphocytes. In addition, these patients have IgG and IgM antibodies to endothelial antigens induced by interleukin- 1 (IL- 1) and by tumor necrosis factor, mediators secreted by activated monocyte/macrophages.65 The demonstration that cytoxine-inducible endothelial cell surface antigens or receptors may be targets for cytotoxic antibodies or immune complexes offers new clues for the understanding of vascular pathology. With the discovery of fixed negative charges in the .glomerular capillary walls 18,2~ and the demonstranon of charge permselectivity,~9 it became evident that a number of endogenous or exogenous antigens can be planted in glomeruli, and that subsequent passive injection (or spontaneous development) of antibodies in animals treated in this fashion can lead to glomerulonephritis. 66-68 Some studies indicate that a similar process can s p o n t a n e o u s l y i n d u c e glom e r u l a r lesions in animals 69 a n d probably in humans.70, 7x

CHARACTERISTICS OF ANTIBODIES AND IMMUNE COMPLEXES PRESENT IN THE CIRCULATION OR DEPOSITED IN DISEASED KIDNEYS Antibodies

The role of antibody class, affinity, avidity, and ability to fix c o m p l e m e n t has b e e n extensively reviewed. 66-6s,72 Several recent studies have established that the charge of circulating antibodies may influence their ability to localize in glomerular capillary walls, and cationic antibodies were preferentially eluted f r o m g l o m e r u l i o f mice with lupus-like syndrome. 7s Another area of productive investigation is that of antigenic mimicry revealed by monoclonal antibodies, raising the issue of antibody polyspecificity.29 An example of this research trend is the work performed at the H6pital Necker (Paris), demonstrating that DNA antibodies of patients with systemic lupus erythematosus recognize a 14,000- to 34,000-dalton protein (lupus-associated membrane protein [LAMP]) expressed on the surface of several human cells, including renal cells. 74,75 By immunoelectron microscopy, LAMP monoclonal antibodies identify antigens expressed in the coated pits of glomerular visceral epithelial cells75~ an interesting analogy with rat gp33052, the antigen of Heymann glomerulonephritis. ~4 Whether these new observations are relevant to the pathogenesis of human lupus nephritis is still an open question because o f the incomplete knowledge concerning antibody polyspecificity revealed by monoclonal antibody technology. Nevertheless, the demonstration by Madaio et aP ~ that monoclonal DNA antibodies bind to mouse glomeruli and induce immune deposits is consistent with the hypothesis that LAMP antibodies participate in the development of renal lesions by direct interaction with cell surface antigens x4 or with antigens of the connective tissue matrix. 3~ Circulating Immune Complexes

In the last decade, studies of in situ formation of i m m u n e complexes have attracted great interest. Nevertheless, the role of circulating immune complexes in the pathogenesis of glomerulonephritis cannot be neglected because circulating immune complexes have the potential to induce at least subendothelial and mesangial lesions. 72,76 Composition. The composition of circulating immune complexes in patients with a variety of bacterial, viral, or parasitic infections has been established and several exogenous antigens have been identified. 72 However, in patients with idiopathic forms of glomerulonephritis, which are frequently observed in the Western world, immunoglobulins isolated from the circulation or eluted from nephritic kidneys have usually shown antiimmunoglobulin reactivity, suggesting an a u t o i m m u n e origin. Both rheumatoid factor and idiotype-antiidiotype complexes have been identified. IgG-IgM were first

1135

HUMAN PATHOLOGY

Volume 19, No. 10 [October 1988]

found in patients with primary cryoglobulinemia and in poststreptococcal glomerulonephritis. 67,72 More recently, IgG-IgA rheumatoid factors were demonstrated in the circulation and glomeruli of patients with IgA glomerulonephritis. 77,7s Concomitantly, we have learned that the variable region of the IgG molecule may bear epitopes relevant to the autoimmune response. In Balb/c mice, 95% of antibodies to phosphorylcholine have the same T15 idiotype. Goldman et a179 exploited this phenomenon, and showed that polyclonal B cell activation stimulated the simultaneous synthesis of antiidiotypes and antiantiidiotypes, with consequent formation of circulating immune complexes that localized in glomeruli. The importance of these experiments was better understood when Reeves and Chiorazzi s~ demonstrated that the sera of patients with systemic lupus erythematosus contained IgG reactive with a 75,000 tool wt DNA-binding protein and antibodies to the variable region of the anti-75,000 mol wt protein IgG. These two molecules formed circulating immune complexes whose, presumptive relevance to the development of tissue injury was strengthened when it was found that IgG eluted from glomeruli of lupus patients had antiidiotypic reactivity. 81 Since immune complexes are in a state of dynamic equilibrium in the circulation, and can serve as planted material in tissues, both rheumatoid factors and antiidiotypic molecules can bind to free reacting sites and modulate the formation of immune complexes, both in the circulation and in glomeruli. Circulating immune complexes that may have an important and frequently neglected role in the pathogenesis of autoimmune glomerulonephritis are those formed by antibodies to plasma proteins. Using a J e r n e plaque assay and spleen cells, Cohen et al s2 have shown that in mice with lupus nephritis there is a marked cellular secretion of antibodies to common serum proteins. These immune complexes are probably incorporated into other i m m u n e aggregates shortly a f t e r a n t i b o d y secretion because large amounts of antigen are available. For this reason, these antibodies are not easily detectable. Aggregation and precipitation. The mechanisms of aggregation and precipitation of circulating immune. complexes, relevant to the development of lesions m tissues, have received considerable attention. First, it has been observed that immune complexes aggregate as a consequence of Fc-Fc interaction, not by infinite, alternating, antigen-antibody bonds, s3 Second, it was established that the precipitability of circulating immune complexes---especially the cryoprecipitability--may not be a property of the immune complexes themselves but of a large group of serum proteins, responding as acute phase reactants, whose concentrauon Increases during inflammation to the point at which intramolecular attractive forces become prominent. One of these proteins is fibronectin. W h e n fibronectin concentration is increased, fibronectin and i m m u n e complexes act to decrease their collective solubility and i m m u n e complexes

precipitate. 84 Third, studies by Gyotoku et al s5 have shown that in autoimmune forms of glomerulonephritis, lesions occur with the cooperation of immunoglobulins that can aggregate and precipitate independently from their immunologic specificity. IgG3 has these properties. Solubility and clearance. Pertinent to the nephritogenicity of circulating immune complexes is work which has established that complement, by binding to antigen-antibody complexes, can modify their structure and biological activity. 86 The identification of the role of complement in the solubilization of immune complexes, and the identification of the structure and properties of receptors for activated C3, have led to a reappraisal of the mechanisms of immune complex clearance by the macrophage-phagocytic system, s7 In physiologic condition, a complement-dependent system is able to process immune complexes inside and outside the vascular compartments so that immune complexes remain soluble and can be transported to the macrophage-phagocytic system and eliminated. Complement solubilizes immune complexes by covalent binding of C3b to the antigen and the antibody so that the forces that hold the lattice together are reduced. The next step in handling circulating immune complexes is the interaction of opsonized complexes with the specific receptor for C3b, CR1 on the surface of mammalian erythrocytes and other cells, including glomerular visceral epithelial cells, s8 The erythrocytes transport the immune complexes to the liver, where the complexes are stripped from the erythrocytes and destroyed, while the erythrocytes are released into the circulation. 80 This physiologic system can fail for a variety of reasons (defects in CR1, in delivery, in uptake, etc), and single or multiple disorders can contribute to the development of glomerular diseases.87,89, 9o Charges and selective linkage with tissue receptors. Another area of progress concerns the charge of circulating immune complexes as a factor in glomerular localization. Kanwar et a191 have shown that cationic immune complexes deposit linearly along the glomerular basement membrane, precisely in the inner and outer layers, in a distribution that corresponds to that of fixed anionic sites. In contrast, neutral immune complexes are nonspecifically trapped in the mesangium. Moreover, the intravenous injection of covalently cross-linked (non-dissociable) cationic immune complexes induces formation of subepithelial immune deposits, 92 providing support to the thesis that membranous glomerulonephritis may not exclusively result from in situ formation of immune complexes. Other studies have established that cationic antibodies in circulating i m m u n e complexes have more propensity to localize in the glomerular capillary walls than the same antibodies alone. This property must probably be ascribed to the higher number of amino groups, to the larger lattice reaching more anionic sites, and to the superior ability of immune complexes to redistribute fixed anionic sites. 93 Besides electrostatic forces, another acquisition has

1136

RENAL IMMUNOPATHOLOGY[Andres et al]

contributed to extend the old notion that circulating immune complexes preferentially localize in the basement membranes because the steric exclusion of polysaccharide media decreases the solubility of filtering proteins and favors their precipitation: t6 Bohnsack et a194 observed that opsonized immune complexes bind directly to laminin. This selective interaction, stronger than that with fibronectin, occurs via Clq. Electron micrographs of rotary-shadowed preparations indicate that a short arm of laminin binds to the collagen-like tail of Clq. Since laminin is found only in basement membranes, the selective linkage may contribute to explain the preferential retention of immune complexes in these structures. MECHANISMS OF INDUCTION AND REGULATION OF THE IMMUNE RESPONSE

Induction and regulation of the i m m u n e response constitutes the area of research in which the most remarkable progress was recently achieved. Investigations on graft-v-host and host-v-graft reactions, on drug-induced hypersensitivity and on autoimmunity, have yielded convergent results which decisively contribute to establish that several forms of autoimmune glomerulonephritis result from an abnormal T-T-B cell cooperation. When glomerulonephritis is the consequence of exogenous or sequestered autologous antigens, the immune response is clonally restricted. In contrast, there is a polyclonal activation of immunoglobulinproducing B cells in the majority of glomerulonephritides of autoimmune origin. Whether B cell stimulation is totally unrestricted 95 or more confined to h u m a n Leu-1 + positive lymphocytes,96 equivalent to murine Ly-1 + positive lymphocytes, is still debated. Nevertheless, revealing information concerning the disorder that involves autoreactive B cells originated from the study of graft-v-host reaction. It was found that when F 1 hybrid mice are inoculated with parental spleen cells in appropriate genetic combinations, almost all mice develop a lupus-like glomerulonephritis (chronic allogeneic glomerulonephritis), 97 originally ascribed to anti-H 2 alloantibodies produced by donor B cells. 9s Rolink et al, 99 however, later demonstrated that the stimulus driving B cells to synthetize antibodies to a variety of autoantigens (erythrocytes, thymocytes, nuclear components, basement membranes, and immunoglobulins) stems from interaction of parental T cells with class II-encoded Ia determinants on the surface of the recipient's B cells. A similar mechanism is probably responsible for the host-v-graft glomerulonephritis induced by Hard et al ~~176 in parent/F 1 mouse chimeras, since there is triggering of autoreactive Fx donor B cells in these mice, with production of autoantibodies. ~~ Gleichmann et al 1~ also suggested that Ia determinants modified by drugs may stimulate autologous T cells resulting in autoimmune disorders, similar to those observed in graft-v-host reaction. This was tested by Pelletier et

aP ~ in mercuric chloride-induced glomerulonephritis, a model characterized by prevalent autoimmune reactivity to basement membrane antigens. 26,27 It was found that helper T cells exposed to mercury stimulate proliferation of normal autologous T lymphocytes in the presence of syngeneic Ia-positive cells. The results were interpreted as evidence that T cells modified by the drug incite syngeneic T cells to proliferate and stimulate B cells. All these important studies are consistent with the interpretation that a primary event in the pathogenesis of autoimmune glomerulonephritis might be a virus-, drug-, or environmental-induced alteration of Ia determinants at the level of B cells, or an alteration of T cell receptors, leading to aberrant T cell-B cell cooperation. In the mercuric chloride model of glomerulonephritis, the synthesis of basement m e m b r a n e autoantibodies is transient, thereby providing an opport u n i t y to i n v e s t i g a t e r e g u l a t o r y m e c h a n i s m s . Chalopin and Lockwood found that the production of autoantibodies is limited by the emergence of a clone of T suppressor cells ~~ and by the appearance of auto-antiidiotypic antibodies. 205 T h e identification of the roles of Ia determinants, antiidiotypic antibodies, and T suppressor cells in autoimmune glomerulonephritis reveals new therapeutic possibilities, and some investigators have already been successful in modulating the autoimmune response in mice with lupus-like s y n d r o m e or e x p e r i m e n t a l allergic encephalomyelitis. 106,107 MEDIATORS OF INFLAMMATORY INJURY

Whatever the mechanism initiating glomerulonephritis, injury occurs by activation of humoral or cellular mediator systems, including complement, coagulation proteins, neutrophils, macrophages, platelets, and resident glomerular cells. Several factors determine which mediator predominates, and consequently what type of glomerular lesion is produced. These factors include the site, the mechanism, and the rate of formation of immune deposits, and the biological p r o p e r t i e s o f t h e a n t i g e n a n d the antibody. 6s The field of mediator is expanding so rapidly that only a few topics will be reviewed.

Neutrophils Using the model of nephrotoxic glomerulonephritis, Hawkins and Cochrane demonstrated approximately 20 years ago that lysosomal enzymes released from neutrophil cause disruption of the glomerular basement membrane, s~ Recent investigations have amplifed this concept, with the description of a new type of glomerular injury induced by oxygen radicals. Neutrophils respond to stimuli with a burst of oxygen consumption, and reactive oxygen species can exert a toxic effect on glomerular cells? ~ Bacteriologic studies by Klebanoff is~ have shown that the toxicity of H202 is greatly increased by reaction with the peroxidase of neutrophils and a halide, with the

1137

HUMANPATHOLOGY Volume19, No. 10 [October 1988]

halide undergoing oxidation to a toxic species, such as the hypohalous acid, or halogen. This notion was applied to experiments in which rat kidneys were first perfused with myeloperoxidase followed by H202 in a chloride-containing solution. It was found that myeloperoxidase localized in glomeruli, presumably on a charge basis, and that subsequent exposure to nontoxic concentration of H 2 0 2 resulted in severe glomerular damage associated with halogenation of the glomerular basement membrane.Ill In other experiments, performed with isolated human glomerular basement membranes and neutrophils activated by phorbol myristate acetate, activation of a metalloproteinase by reactive oxygen metabolites induced a significant degradation of the basement membrane, as measured by release of hydroxyproline. 112 The role of the myeloperoxidase-HzO-halide system was then tested in a model of glomerulonephritis characterized by in situ formation of immune deposits on the endothelial side of the glomerular basement membrane, and the system was found operative. 113 Monocyte/Macrophages

An increased number of blood-borne monocyte/ macrophages, some of them resident in the mesangium, have been identified in the glomeruli of laboratory animals114 or patients 115 with proliferative forms of glomerulonephritis. In experimental glomerulonephritis, specific depletion of macrophages prevents glomerular hypercellularity.116.117 The mechanisms by which macrophages damage glomerular structures are not precisely defined, but seem partly similar to those used by neutrophils. Macrophages are a source of oxygen-radical species,1 is elaborate proteases,a 19 and secreted chemotactic and vasoactive mediators, such as platelet-activating factor, 12~ thromboxane A2119 and leukotrienes. ~19.120 These cells are also involved in fibrin deposition since they produce a tissue f a c t o r t h a t activates the extrinsic c o a g u l a t i o n cascade 121 and, u n d e r appropriate stimuli (endotoxin, i m m u n e complexes, and complement) and with T cell cooperation] 22 express procoagulant activity. 123 Complement

Two decades of work in the laboratory of Cochrane et al have shown that complement-mediated chemotaxis and immune adherence of neutrophils have a central role in the pathogenesis of various forms of exudative glomerulonephritis. 124 Inflammatory cell influx and immune adherence are favored when the immune reaction in the glomerular capillary walls occurs in proximity to the circulation, as in the subendothelial space. 125 Couser et al extended the pathogenetic role of complement with the demonstration that Heymann glomerulonephritis is complement dependent.126 Cybulsky et a1127 have shown that injury, manifested by proteinuria, occurs when the membrane attack complex of the complement system (the sequence C5b-C9) is inserted into the lipid

bilayer of glomerular visceral epithelial cells. Binding of the membrane attack complex to the epithelial plasma m e m b r a n e and t r a n s m e m b r a n e channels were visualized by immunohistologic, immunocytochemical, and morphologic techniques. 128-1~2 A similar complement-mediated injury is induced in rat mesangial cells by anti-Thy 1-1 antibodies.13~.134 C5bC9 is not consistently found in the glomeruli of patients with idiopathic membranous glomerulonephritis, and its pathogenic role in this h u m a n disease therefore remains speculative. 135 Platelet-Activating Factor

New functions are now ascribed to the plateletactivating factor as the mediator of glomerular lesions. Platelet-activating factor is a mediator of cellto-cell communication involved in a broad range of biological activities relevant to acute inflammation. 120 Inhibitors of receptors for platelet-activating factor prevent the development of morphologic and functional changes in nephrotoxic glomerulonephritis.136 Other studies have demonstrated that competitive inhibition of platelet-activating factor suppresses inflammation in glomeruli and in the skin in conditions c h a r a c t e r i z e d by in situ f o r m a t i o n o f i m m u n e complexes. 137 Intrinsic Glomerular Cells and Polypeptide Mediator Network

The systemic use of glomerular cell cultures, introduced by Striker and colleagues,13a,l~9 has allowed establishment of the fact that glomerular cells contribute to the inflammatory process by generation of numerous mediators and exercise the role of effector cells. Mesangial cells can be activated by several stimuli including IL-1, c o m p l e m e n t , endotoxin, and platelet-activating factor. 14~ These cells respond to stimuli synthetizing and releasing prostaglandins, 144 oxygen radicals, 141 an I L- l-like factor, 145,146 neutral proteinases, 147 a growth factor similar to platelet-derived g r o w t h factor, 14s a n d plateletactivating factor. 149 Some mediators may have direct damaging effect on tissues. Others, such as IL-1, may reach the proximal tubules and increase Na+-linked glucose transport. 15~ Moreover, some mediators are part of the complex polypeptide network that amplifies the inflammatory injury? 5a One of the most original contributions to the understanding of the pathogenesis of immunologically mediated vascular diseases is the demonstration that endothelial cells, including glomerular endothelial cells, can be the target of immune mediator polypeptides. In cultured endothelial cells, IL-1 and tumor n e c r o s i s f a c t o r r e l e a s e d by a c t i v a t e d m a c r o phages 152,153 can induce expression of tissue factorlike procoagulant activity] 54,a55 leukocyte-adhesion p r o p e r t i e s , 59,156,157 a n d a u n i q u e a c t i v a t i o n antigen. 6~ Similar effects are promoted by endotoxin which, like IL-1, stimulate release o f plateletactivating factor. 12~ Expression of tissue factor

1138

RENAL IMMUNOPATHOLOGY(Andres et al]

and activation antigens was demonstrated in the endothelia of human glomeruli exposed in vitro to IL- 1 or endotoxin. ~59 Interferon gamma 58 and tumor necrosis factor ~53 induce expression of class II antigens, and tumor necrosis factor promotes morphologic r e a r r a n g e m e n t facilitating transendothelial trafficking.~53 One o f the most instructive examples of the pathogenic role of cytokine-inducible endothelial cell surface molecules is the previously mentioned observation that the sera of patients with Kawasaki vasculitis contain antibodies to antigens expressed by human cultured endothelial cells exposed to bacterial lipopolysaccharides (LPS), IL-1, or tumor necrosis factor. 64,65 Thus, mechanisms exist by which immune and non-immune stimuli directly or indirectly affecting glomerular mesangial and renal endothelial cells can ultimately lead to amplification of the immune response, hypercellularity, activation of coagulation, basement membrane injury, and alteration of glomerular and tubular functions. The discovery of this polypeptide network of interactive signals that orchestrate immunologic and inflammatory events raises the hope that new therapeutic strategies may soon be implemented. 106,107 ROLE OF T CELL-MEDIATED HYPERSENSITIVITY

Contrary to a rooted belief of the past, we have learned that T cells and effector mononuclear cells act as co-equal partners of antibodies and immune complexes in the pathogenesis of proliferative, especially crescentic, glomerulonephritis, and in tubulointerstitial nephritis. 16~ This evidence was initially based on morphology. Mononuclear cells were seen in hypercellular glomeruli. 114,163,164 Macrophages, however, bear receptors for C3b and Fc, and can be recruited at the sites of inflammation by the chemotactic properties of C3b and C5a and by adhesion to the Fc portion of immunoglobulins. With the development of monoclonal antibodies to mononuclear cell markers, it became feasible to analyze the phenotype of renal cells and of cells infiltrated in the kidney. It was recognized that intrinsic glomerular, vascular, and tubulointerstitial cells express class II antigens, in normal conditions or after exposure to cytokines. 165A66 Ia or Ia-like molecules are required for the development of T cell-mediated hypersensitivity. 167 Schreiner et a1168,169 identified Ia-positive macrophages resident in the mesangium of the rat, and showed that these cells responded to antigenic challenge in a genetically restricted fashion. Other glomerular cells expressing class II molecules, and therefore qualified to present the antigen to sensitized T cells, are monokine-activated endothelial cells. 54"167 Still not firmly established is whether T cells infiltrate glomeruli, and whether from there they can direct the influx of mononuclear phagocytes. A small number of T lymphocytes were found in the glomeruli of rats with nephrotoxic glomerulonephritis, a7~ and discordant results were obtained

in studies designed to quantitate T lymphocytes in the glomeruli of patients with proliferative glomerulonephritis, a73,174 To investigate the role of T cells, Bhan et a1175,176 planted subnephritogenic amounts of rabbit anti-rat glomerular basement membrane IgG, or immune complexes containing rabbit IgG, in the glomeruli of rats. Proliferation of glomerular ceils and macrophage infiltration were observed only when rats received T cells passively transferred from donors specifically sensitized to rabbit IgG. The lesions were mild. The best available evidence of an antibody-independent role for T cells derives from the study of B cell-deficient chickens immunized with glomerular basement membrane. Bolton and colleagues iv;A;8 showed that bursectomized chickens developed proliferative, crescentic, glomerulonephritis without marked immune deposits. Furthermore, the disease was inducible by passive transfer of sensitized lymphocytes derived from syngeneic chickens immunized with glomerular basement membranes. In human tubulointerstitial nephritis, T cells and Ia-positive monocytes/macrophages consistently infiltrate the interstitium. Moreover, cells with these phenotypic markers are frequently found in the interstitium of patients with various forms of glomerulonephritis. 179,~8~ Therefore, as shown by studies on renal allograft rejection, the interstitium is the structure most vulnerable to T cell-mediated hypersensitivity. This topic was the focus of studies performed by Neilson and collaborators.162 The model used was the tubulointerstitial nephritis induced in guinea pigs, rats, and mice immunized with an antigen of the basement m e m b r a n e of proximal tubules. 44 T h e findings indicated that full expression of the disease required cytotoxic T cells. The severity of the symptoms was decreased by the development or administration of antiidiotypic antibodies, or by immunization designed to foster the emergence of clones of T suppressor cells. An analysis of the induction and regulation of the immune response in animals with severe and progressive tubulointerstitial nephritis showed that this ominous course was associated with an excessive and indiscriminate effect of T suppressor cells that blocked the beneficial antiidiotypic response. 181 The large body of information generated by the effort to understand the relevance of T cell-mediated hypersensitivity in renal pathology should lead to more specific ways to prevent activation of macrophages and, perhaps, provide tools necessary to neutralize the effect of mediators released by activated mononuclear cells. The field of renal immunopathology is undergoing a process of growth which parallels that of basic immunology. Recent achievements have reinvigorated the hope that a better understanding of inflammatory mechanisms responsible for nephritis and allograft rejection may--in a not too distant f u t u r e - r e n d e r the need for chronic dialysis and renal transplantation a little less imperative.

1139

HUMAN PATHOLOGY

Volume 19, No. 10 [October 1988]

Acknowledgment. Dedicated, with admiration and affection, to Professor Conrad L. Pirani, whose academic life has been of guidance to a generation of renal pathologists. T h e authors thank Marilyn Fitzsimmons for excellent typographic assistance. REFERENCES 1. Dixon FJ: The pathogenesis of glomerulonephritis. Am J Med 44:493, 1968 2. Dixon FJ: The role of antigen-antibody complexes in disease. The Harvey Lectures. New York, Academic 58:21, 1962-1963 3. Lerner RA, Glassock RJ, Dixon FJ: The role of antiglomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med 126:989, 1967 4. K/ihn K, Wiedemann H, Timpl R, et ah Macromolecular structure of basement membrane collagen. Identification of 7S collagen as a crosslinking domain of type IV collagen. FEBS Lett 125:123, 1981 5. Furthmayer H, Madri J: Rotary shadowing of connective tissue molecules. Coll Relat Res 2:349, 1982 6. Timpl R, Wiedmann H, Van Delden V, et al: A network model for the organization of type IV collagen molecules in basement membranes. Eur J Biochem 120:203, 1981 7. Wieslander J, Bygren P, Heinegard D: Anti-glomerular basement membrane antibody: Antibody specificity in different forms of glomerulonephritis. Kidney Int 23:855, 1983 8. Bowman C, Ambrus K, Lockwood CM: Restriction of human IgG class expression in the population of auto-antibodies to glomerular basement membrane. Clin Exp Immunol 69:341, 1987 9. Fukatsu A, Brentjens JR, Killen PD, et al: Studies on the formation of glornerular immune deposits in Brown Norway rats injected with mercuric chloride. Clin Immunol Immunopathol 45:35, 1987 10. Miettinen A, Stow JL, Meritone S, et al: Antibodies to basement membrane heparan sulfate proteoglycans bind to the laminae rarae of the glomerular basement membrane (GBM) and induce subepithelial GBM thickening. J Exp Med 163:1064, 1986 11. Makino H, Gibbons JT, Reddy K, et al: Nephritogenicity of antibodies to proteoglycans of the glomerular basement membrane. I. J Clin Invest 77:142, 1986 12. Singer SJ, Nicholson GL: The fluid mosaic model of the structure of cell membrane. Science 175:720, 1972 13. Schreiner GF, Unanue ER: Membrane and cytoplasmic changes in B lymphocytes induced by ligand-surface immunoglobulin interaction. Adv Immunol 24:37, 1976 14. Andres G, Brentjens JR, Caldwell PRB, et ah Biology of disease. Formation of immune deposits and disease. Lab Invest 55:510, 1986 15. Kerjaschki D, Miettinen A, Farquhar MG: Initial events in the formation of immune deposits in passive Heymann nephritis. J Exp Med 166:109, 1987 16. Hellsing K: Immune reactions in polysaccharide media: Investigation on complex formation between some polysaccharides, albumin and immunoglobulin G. Biochem J 112:483, 1969 17. Mannik M, Agodoa LYC, David KA: Rearrangement of immune complexes in glomeruli leads to persistence and development of electron dense deposits. J Exp Med 157:1516, 1983 18. Rennke HG, Cotran RS, Venkatachalam MA: Role of molecular charge in glomerular permeability: Tracer studies with cationized ferritin. J Cell Biol 67:638, 1975 19. Chang RL, Deen WM, Robertson CR, et al: Permselectivity of the glomerular capillary wall. III. Restricted transport of polyanions. Kidney Int 8:212, 1975 20. Kanwar YS, Farquhar MG: Presence of heparan sulfate in the glomerular basement membrane. Proc Natl Acad Sci USA 76:1303, 1979 21. Border WA, Ward HJ, Kamil ES, et ah Induction of membranous nephropathy in rabbits by administration of an exogenous cationic antigen: Demonstration of the pathogenic role for electric charge. J Clin Invest 69:451, 1982 22. Oite T, Batsford SR, Mihatsch MJ, et ah Quantitative studies of "in situ" immune complex glomerulonephritis in the rat induced by planted cationized antigen. J Exp Med 155:460, 1982

23. Oite T, Shimitzn F, Kihara I, et ah An active model of immune complex glomerulonephritis in the rat employing cationized antigen. Am J Pathol 112:185, 1983 24. Tanaka T: Gels. Scientific Amer 224:124, 1981 25. Klassen J, Milgrom F, McCluskey RT: Studies of the antigens involved in an immunolgic renal tubular lesion in rabbits. Am J Pathol 88:135, 1977 26. Roman-Franco AA, Turiello M, Albini B, et ah Antibasement membrane antibody (A-BM- Ab) and antigen-antibody complexes in rabbits injected with mercuric chloride (HgC12). Kidney Int 10:549, 1976 27. Druet E, Sapin G, Giinther E, et al: Mercuric-chloride induced anti-glomerular basement antibodies in the rat. Eur J Immunol 7:348, 1977 28. Kohler G, Milstein C: Derivation of specific antibodyproducing tissue culture and tumor lines by cell fusion. Eur J Immunol 6:511, 1976 29. Schwartz RS, Stollar BD: Origin of anti-DNA antibodies.J Clin Invest 75:321, 1985 30. Madaio MP, Carlson J, Cataldo J, et al: Murine monoclonal anti-DNA antibodies bind directly to glomerular antigens and form immune deposits. J Immunol 138:2883, 1987 31. Mendrick DL, Rennke HG: Immune deposits formed "in situ" by a monoclonal antibody recognizing a new intrinsic rat mesangial matrix antigen. J Immunol 137:1517, 1986 32. Faaber P, Rijke TPM, Levinus BA, et al: Cross-reactivity of human and murine anti-DNA antibodies with heparan sulfate. J Clin Invest 77:1824, 1986 33. Holdworth SR, Globus SM, Wilson CB: Characterization of collagenase solubilized human glomerular basement membrane antigens reacting with human antibodies. Kidney Int 16:797, 1979 34. Fish AJ, Lockwood MC, Wong M, et al: Detection of Goodpasture antigen in fractions prepared from collagenase digests of human glomerular basement membrane. Clin Exp Immunol 55:58, 1984 35. Wieslander J, Barr JF, Butkowski RJ, et ah Goodpasture antigen of the glomerular basement membrane: Localization to the noncollagenous regions of type IV collagen. Proc Natl Acad Sci USA 81:3838, 1984 36. Wieslander J, Langeveld J, Butkowski R, et al: Physical and immunochemical studies of the glomerular domain of type IV collagen. J Biol Chem 260:8564, 1985 37. Wieslander J, Kataja M, Hudson BG: Characterization of the human Goodpasture antigen. Clin Exp Immunol 69:332, 1987 38. Rees AJ, Lockwood CM, Peters DK: Enhanced allergic tissue injury in Goodpasture's syndrome by intercurrent bacterial infections. Br Med J 2:723, 1977 39. Beirne GJ, Brennan JT: Glomerulonephritis associated with hydrocarbon solvent: Mediated by antiglomerular basement membrane antibody. Arch Environ Health 25:365, 1972 40. Rees AJ, Peters DK, Compston DAS, et al: Strong association between HLA-DRW2 and antibody-mediated Goodpasture's syndrome. Lancet 1:966, 1978 41. Glayman MD, Michaud L, Brentjens J, et ah Isolation of the target antigen of human anti-tubular basement membrane antibody-associated nephritis. J Clin Invest 77:1143, 1986 42. Yoshioka K, Morimoto Y, Iseki T, et al: Characterization of tubular basement membrane antigens in human kidney. J Immunol 136:1654, 1986 43. Fliger DF, Wieslander J, Brentjens JR, et al: Identification of a target antigen in human anti-tubular basement membrane nephritis. Kidney Int 31:800, 1987 44. Clayman M, Martinez-Hernandez A, Michaud L, et ah Isolation and characterization of the nephritogenic antigen producing anti-tubular basement basement membrane disease. J Exp Med 161:290, 1985 45. Steblay RW, Rudofsky U: Renal tubular disease and autoantibodies against tubular basement membrane induced in guinea pigs. J hnmunol 107:589, 1971 46. Cederholm B, Wieslander J, Bygren P, et al: Patients with IgA nephropathy have circulating anti-basement membrane antibodies reacting with structures common to collagen I, II and IV. Proc Natl Acad Sci USA 83:6151, 1986 47. Fillit H, Damle S, Gregory JD, et al: Sera from patients with poststreptococcal glomerulonephritis contain antibodies to

1140

RENAL IMMUNOPATHOLOGY[Andres et al] glomerular heparan sulfate proteoglycans. J Exp Med 161:277, 1985 48. Szarfman A, Terranova VP, Rennard SL, et al: Antibodies to laminin in Chagas' disease. J Exp Med 155:1161, 1982 49. Towbin H, Rosenfelder G, WieslanderJ, et al: Circulating antibodies to mouse laminin in Chagas' disease, american cutaneous leishmaniosis, and normal individuals recognize terminal galactosyl (al-3)-galactose epitopes. J Exp Med 166:419, 1987 50. Van Damme BJC, Pleuren GJ, Bakker WW, et al: Experimental glomerulonephritis in the rat induced by antibodies against tubular antigens. V. Fixed glomerular antigens in the pathogenesis of heterologous immune complex glomerulonephritis. Lab Invest 38:502, 1978 51. Couser WG, Steinmuller DR, Stilmant MM, et al: Experimental glomerulonephritis in the isolated perfused kidney. J Clin Invest 62:1275, 1978 52. Kerjaschki D, Farquhar MG: Immunocytochemical localization of the Heymann antigen (gp330) in glomerular epithelial cells of normal Lewis rats. J Exp Med 157:667, 1983 53. Fukatsu A, Milgrom M, Miller J, et al: Interaction of antibodies with surface antigens of human and monkey glomerular epithelial cells (GEC). Kidney Int 33:314, 1988 54. Hirschberg H, Bergh OJ, Thorsby E: Antigen-presenting properties of human vascular endothelial cells. J Exp Med 152:249s-255s, 1980 55. Stevens SK, Weissman IL, Butcher EC: Differences in the migration of B and T lymphocytes: Organ selective localization "in vivo" and the role of lymphocyte-endothelial cell recognition. J Immunol 128:844, 1982 56. Natali PG, DeMartino C, Marcellini M, et al: Expression of Ia-like antigens on the vasculature of human kidney. Clin Immunol Immunopathol 20:11, 1981 57. Paul LC, van Es LA, Baldwin WM: Antigens in human renal allografts. Clin Immunol Immunopathol 19:206, 1981 58. Pober JS, Giambrone MA, Cotran RS, et al: Ia expression by vascular endothelium is inducible by activated T cells and by human gamma-interferon. J Exp Med 157:1339, 1983 59. Bevilaoqua MP, PoberJS, Wheeler ME, et ah Interleukin1 acts on cultured human vascular endothelium to increase adhesion of polymorphonuclear leukocytes, monocytes and related leukocyte cell lines. J Clin Invest 76:2003, 1985 60. PoberJS, Bavilacqua MP, Mendrick DL, et al: Two distinct monokines, interleukin-1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol 136:1680, 1986 61. Cines DB, Lyss AP, Reeber M, et al: Presence of complement-fixing anti-endothelial cell antibodies in systemic lupus erythematosus. J Clin Invest 73:611, 1984 62. Ryan VS, Schultz DR, Ryan JW: Fc and C3b receptors on pulmonary endothelial cells; induction by injury. Science 214:557, 1981 63. Cines DB, Lyss AP, Bina M, et al: Fc and C3 receptors induced by herpes simplex virus on cultured human endothelial cells. J Clin Invest 69:123, 1982 64. Leung DYM, Collins T, Lapierre A, et al: IgM antibodies present in the acute phase of Kawasaki syndrome lyse cultured vascular endothelial cells stimulated by gamma interferon. J Clin Invest 77:1428, 1986 65. Leung DYM, Geha RS, Newberger JW, et al: Two monokines interleukin-1 and tumor necrosis factor, render cultured vascular endothelial cells susceptible to lysis by antibodies circulating during Kawasaki syndrome. J Exp Med 164:1958, 1986 66. Couser WG, Salant DJ: "In situ" immune complex formation and glomerular injury. Kidney Int 17:1, 1980 67. Cameron SJ: Glomerulonephritis: Current problems and understanding. J Lab Clin Med 99:755, 1982 68. Couser WG: "In situ" formation of immune complexes and the role of complement activation in glomerulonephritis. Clin Immunol Allergy 6:267, 1986 69. Aikawa M, Abramowsky C, Powers KG, et al: Dirofilariasis. IV. Glomerulonephritis induced by dirofilaria immitis infection. Am J Trop Med Hyg 30:84, 1981 70. Lange K, Seligson G, Cronin W: Evidence for the "in situ" origin of post-streptococcal glomerulonephritis: Glomerular local-

ization of endostreptosin and the clinical significance of the subsequent antibody response. Clin Nephrol 19:3, 1983 71. Vogt A, Batsford S, Rodriguez-Iturbe B, et al: Cationic antigens in poststreptococcal glomerulonephritis. Clin Nephrol 20:271, 1983 72. Wilson CB, Dixon FJ: The renal response to immunological injury, in Brenner BM, Rector RC Jr (eds): The Kidney. Philadelphia, Saunders, 1985, p 800 73. Ebling F, Hahn BH; Restricted subpopulations of DNA antibodies in kidneys of mice with systemic lupus. Comparison of antibodies in serum and renal eluates. Arthritis Rheum 23:392, 1980 74. Jacob L, Lety MA, Louvard D, et al: Binding of a monoclonal anti-DNA antibody to identical protein(s) present at the surface of several human cell types involved in lupus pathogenesis. J Clin Invest 75:315, 1985 75. Jacob L, Lety MA, Monteiro RC, et al: Altered cell-surface protein(s) crossreactive with DNA, on spleen cells of autoimmune lupic mice. Proc Natl Acad Sci USA 84:1361, 1987 75a. Jacob L, Lety MA, Kerjaschki D, et al: Potential pathogenic role of lupus associated membrane protein (LAMP) in systemic lupus erythematosus. Kidney Int 33:317, 1988 76. Mannik M: Pathophysiology of circulating immune complexes. Arthritis Rheum 25:783, 1982 77. Czerkinsky C, Koopman WJ, Jackson S, et al: Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies. J Clin Invest 77:1931, 1986 78. Sinico RA, Fornasieri A, Oreni N, et al: Polymeric IgA rheumatoid factor in idiopathic IgA mesangial nephropathy (Berger's disease). J Immunol 137:536, 1986 79. Goldman M, RenversezJC, Lambert PH: Pathological expression of idiotypic interactions: Immune complexes and cryoglobulins. Springer Semin Immunopathol 6:33, 1983 80. Reeves WH, Chiorazzi N: Interaction between anti-DNA and anti-DNA-binding protein autoantibodies in cyroglobulins from sera of patients with systemic lupus erythematosus. J Exp Med 164:1029, 1986 81. Isenberg DA, Collins C: Detection of cross-reactive antiDNA idiotypes on renal tissue-bound immunoglobulinsfrom lupus patients. J Clin Invest 76:287, 1985 82. Cohen P, Rapaport RG, Eisenberg RA: Hidden autoantibodies against common serum proteins in murine systemic lupus erythematosus. J Exp Med 161:1587, 1985 83. Moller NPH. Fc-mediated immune precipitation. I. A new role of the Fc portion of IgG. Immunology 38:631, 1979 84. Baatrup G, Svehag SE: Serum and plasma fibronectin binds to complement reacted immune complexes primarily via Clq. Scand J Immunol 24:583, 1986 85. Gyotoku Y, Abdelmoula M, Spertini F, et al: Cryoglobulinemia induced by monoclonal immunoglobulin G rheumatoid factors derived from autoimmune MRL/MpJ-lpr mice. J Immunol 138:3785, 1987 86. Miller GW, Nussenzweig V: A new complement function: Solubilization of antigen-antibody aggregates. Proc Natl Acad Sci USA 72:418, 1975 87. SchifferliJA, Ng YC, Peters KD: The role of complement and its receptors in the elimination of immune complexes. N Engl J Med 315:488, 1986 88. Gelfand MC, Frank MM, Green I: A receptor for the third component of complement in the human renal glomerulus. J Exp Med 142:1029, 1975 89. Cornacoff JB, Hebert LA, Smead WL, et al: Primate erythrocyte-immune complex-clearing mechanism. J Clin Invest 71:236, 1983 90. Peters DK, Lachmann PJ: Immunity deficiency in pathogenesis of glomerulonephritis. Lancet 1:58, 1974 91. Kanwar YS, Caulin-Glaser T, Gallo G, et ah Interaction of i m m u n e complexes with g l o m e r u l a r h e p a r a n sulfateproteoglycans. Kidney Int 30:842, 1986 92. Caulin-GlaserT, Gallo G, Lamm ME: Nondissociating cationic immune complexes can deposit in glomerular basement membrane. J Exp Med 158:1561, 1983 93. Mannik M, Gauthier VJ, Stapleton SA, et al: Immune

1141

HUMAN PATHOLOGY

Volume 19, No. 10 [October 1988]

complexes with cationic antibodies deposit in glomeruli more effectively than cationic antibodies alone. J Immunol 38:4209, 1987 94. BohnsackJF, Tenner AJ, Laurie GW, et al: The Clq subunit of the first component of complement binds to laminin: A mechanism for the deposition and retention of immune complexes in basement membrane. Proc Natl Acad Sci USA 82:3824, 1985 95. Klinman DM, Steinberg AD: Systemic autoimmune disease arises from polyclonal B cell activation. J Exp Med 165:1755, 1987 96. Casali P, Burastero SE, Nakamura M, et al: Human lymphocytes making rheumatoid factor and antibodies to ss-DNA belong to Leu-1 + B cell subset. Science 236:77, 1987 97. Lewis RM, Armstrong MYK, Audre'-Schwartz J, et al: Chronic allogeneic disease. I. Development of glomerulonephritis. J Exp Med 128:653, 1968 98. Kano K, Beldotti L, Milgrom F, et al: Glomerulonephritis in the graft-vs-host reaction: Serologic demonstration of anti-host antibodies. J Immunol 112:410, 1974 99. Rolink AG, Gleichmann H, Gleichmann E: Diseases caused by reactions of T lymphocytes to incompatible structures of the major histocompatibility complex. VII. Immune Complex glomerulonephritis. J Immunol 130:209, 1983 100. Hard RC, Moncure CW, Still WJS: Renal lesions with organized deposits and lipids as part of the host verus graft syndrome in parent/F1 mouse chimeras. Lab Invest 28:468, 1973 101. Luzuy S, Merino J, Engers H, et al: Autoimmunity after induction of neonatal tolerance to alloantigens: Role of B cell chimerism and F 1 donor B cell activation. J Immunol 136:4420, 1986 102. Gleichmann E, Rolink AG, Pals ST: Graft-versus-host reactions (GVHRs): Clues to the pathogenesis of a broad spectrum of immunologic diseases. Transplant Proc 15:1436, 1983 103. Pelletier L, Pasquier R, Hirsch F, et al: Autoreactive T cells in mercury-induced autoimmune disease: "In vitro" demonstration. J Immunol 137:2548, 1986 104. Chalopin JM, Lockwood CM: Autoregulation of autoantibody synthesis in mercuric chloride nephritis in the Brown Norway rat. I. A role for T suppressor cells. Eur J Immunol 14:464, 1984 105. Chalopin JM, Lockwood CM: Autoregulation of autoantibody synthesis in mercuric chloride nephritis in the Brown Norway rat. II. Presence of antigen-augmentable plaque forming cells in the spleen is associated with homoral factors behaving as auto-anti-idiotypic antibodies. E u r J Immunol 14:470, 1984 106. Bach JF, Strom TB (eds): The Mode of Action of Immunosuppressive Agents, ed 2. Amsterdam, Elsevier, 1986 107. Strom TB: Toward more selective therapies to block graft rejection. AKF Nephrol Lett 4:13, 1987 108. Hawkins D, Cochrane CG: Glomerular basement membrane damage in immunological glomerulonephritis. Immunology 14:665, 1968 109. Rehan A, Johnson KJ, Wiggins RC, et al: Evidence for the role of oxygen radicals in acute nephrotoxic nephritis. Lab Invest 51:396, 1984 110. Klebanoff SJ: Myeloperoxidase-halide-hydrogen peroxide antibacterial system. J Bacteriol 95:2131, 1968 111. Johnson RJ, Couser WG, Chi EY, et al: New mechanisms for glomerular injury. Myeloperoxidase-hydrogen-halide system. J Clin Invest 79:1379, 1987 112. Shah SV, Baricos WH, Basci A: Degradation of human glomerular basement membrane by stimulated neutrophils. J Clin Invest 79:25, 1987 113. Johnson RJ, KlebonoffSJ, Ochi RF, et al: Participation of the myeloperoxidase-H202-halide system in immune complex nephritis. Kidney Int 32:342, 1987 114. Shingematsu H: Glomerular events during the initial phase of rat Masugi nephritis. Virchows Arch [B] 5:187, 1970 115. Atkins RC, Holdworth SR, Glasgow EF, et al: The macrophages in rapidly progressive glomerulonephritis. Lancet 1:830, 1976 116. Hunsicker LG, Shearer TP, Plattner SB, et al: The role of monocytes in serum sickness nephritis. J Exp Med 150:413, 1979 117. Holdsworth SR, Neale TJ, Wilson CB: Abrogation of macrophage-dependent injury in experimental glomerulonephritis in the rabbit. J Clin Invest 68:686, 1981

118. Fantone JC, Ward PA: Role of oxygen-derived free radicals and metabolities in leukocyte-dependent inflammatory reactions. Am J Pathol 107:397, 1982 119. Adams DO, Hamilton TA: The cell biology of macrophage activation. Annu Rev Immunol 2:283, 1984 120. Camussi G: Potential role of platelet-activating factor in renal pathophysiology. Kidney Int 29:469, 1986 121. Rothberger H, Zimmerman TS, Spiegelberg HL, et al: Leukocyte procoagulant activity. J Clin Invest 59:549, 1977 122. Helin JH, Fox RI, Edgington TS: The instructor cell for the human procoagulant monocyte response to bacterial lipopolysaccharide is a Leu-3a + T cell by fluorescence-activated cell sorting. J Immunol 131:749, 1983 123. Schwartz BS, Levy GA, Fair DS, et al: Murine lymphoid procoagulant activity induced by bacterial lipopolysaccharide and immune complexes is a monocyte prothrombinase. J Exp Med 155:1464, 1982 124. Cochrane CG, Unanue ER, Dixon FJ: A role of polymorphonuclear leukocytes and complement in nephrotoxic nephritis. J Exp Med 122:99, 1965 125. Salant DJ, Adler S, Darby C, et al: Influence of antigen distribution on the mediation of immunological glomerular injury. Kidney Int 27:938, 1985 126. Couser WG, Baker PJ, Adler S: Complement and the direct mediation of immune glomerular injury: A new prospective. Kidney Int 28:879, 1985 127. Cybulsky A, Rennke HG, Feintzeig ID, et al: Complement-induced glomerular epithelial cell injury. J Clin Invest 77:1096, 1986 128. Koffler D, Biesecker G, Noble B, et al: Localization of the membrane attack complex (MAC) in experimental immune complex glomerulonephritis. J Exp Med 157:1885, 1983 129. Adler S, Baker PJ, Pritzl P, et al: Detection of terminal complement components in experimental immune glomerular injury. Kidney Int 26:830, 1984 130. Biesecker G, Noble B, Andres GA, et al: Immunopathogenesis of Heymann's nephritis. Clin Immunol Immunopathol 33:333, 1984 131. de Heer E, Daha MR, Bhakdi S, et al: Possible involvement of terminal complement complex in active Heymann nephritis. Kidney Int 22:388, 1985 132. Camussi G, Salvidio G, Biesecker G, et al: Heymann antibodies induce complement-dependent injury of rat glomerular visceral epithelial cells. J Immunol 139:2906, 1987 133. Bagghus WM, Hoedemaeker PhJ, Razing J, et al: Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies. Lab Invest 55:680, 1986 134. Yamamoto T, Wilson CB: Complement dependence of antibody-induced mesangial cell injury in the rat. J Immunol 138:3758, 1987 135. Hinglais N, Kazatchkine MD, Bhakdi S, et al: Immunohistochemical study of the C5b-9 complex of complement in human kidneys. Kidney Int 30:399, 1986 136. Bertani T, Livio M, Macconi D, et al: Platelet activating factor (PAF) as a mediator of injury in nephrotoxic nephritis. Kidney Int 31:1248, 1987 137. Camussi G, Pawlowski I, Saunders R, et al: Receptor antagonist of platelet activating factor inhibits inflammatory injury induced by "in situ" formation of immune complexes in renal glomeruli and in the skin. J Lab Clin Med 110:196, 1987 138. Quadracci LJ, Striker GE: Growth and maintenance of glomerular cells "in vitro." Proc Soc Exp Biol Med 135:947, 1970 139. Striker GE, Striker LJ: Biology of disease: Glomerular cells in culture. Lab Invest 53:122, 1985 140. Lovett DH, Ryan JL, Sterzel RB: Stimulation of rat mesangial cell proliferation by macrophage interleukin 1. J Immunol 131:2830, 1983 141. Adler S, Baker PJ,Johnson RJ, et al: Complement membrane attack complex stimulates production of reactive oxygen metabolites by cultured rat mesangial cells. J Clin Invest 77:762, 1986 142. Gemsa D, Resch K, Bursten S, et al: Glomerular mesangial cells secrete interleuken 1 and PGE in response to bacterial endotoxin. Kidney Int 31:320, 1987 (abstr) 143. Schlondorff D, Satriano JA, Hagege J, et al: Effect of platelet activating factor and serum-treated zymosan on prosta-

1142

RENAL IMMUNOPATHOLOGY[Andres et al] glandin E2 synthesis, arachidonic acid release and contraction of cultured rat mesangial cells. J Clin Invest 73:1227, 1984 144. Sraer J, Foidart J, Chansel D, et al: Prostaglandin synthesis by rat isolated glomeruli and glomerular cultured cells. Int J Biochem 12:203, 1980 145. Lovett DH, Ryan LR, Sterzel RB: A thymocyte-activating factor derived from glomerular mesangial cells. J Immunol 130:1796, 1983 146. MacCarthy EP, Hsu A, Ooi YM, et al: Evidence for a mouse mesangial cell-derived factor that stimulates lymphocyte proliferation. J Clin Invest 76:426, 1985 147. Lovett DH, Sterzel RB, Kashgarian M, et al: Neutral proteinase activity produced "in vitro" by cells of the glomerular mesangium. Kidney Int 23:342, 1983 148. Abboud HE, Poptic E, DiCorleto P: Rat mesangial cells secrete a platelet derived growth factor-like molecule. Kidney Int 29:263, 1986 (abstr) 149. Schlondorff D, Goldwasser P, Neuwirth R, et al: Production of platelet-activating factor in glomeruli and cultured glomerular mesangial cells. Am J Physiol 250:F1123, 1986 150. Kohan D, Schreiner GF: Mechanism of interleukin I (ILI) stimulation of proximal tubular (PT) glucose transport. Kidney Int 33:319, 1988 151. Old LJ: Polypeptide mediator network. Nature 326:330, 1987 152. Dinarello CA: Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med 411:1413, 1984 153. Beutler B, Cerami A: Cachectin: More than a tumor necrosis factor. N Engl J Med 316:379, 1987 154. Bevilacqua MP, Pober JS, Wheeler ME, et al: Interleukin-1 activation of vascular endothelium. Effects on procoagulant activity and leukocyte adhesion. Am J Pathol 121:393, 1985 155. Bevilacqua MP, PoberJS, Majeau GR, et ah Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: Characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 83:4533, 1986 156. Gamble JR, Harlau JM, Klebanoff SJ, et al: Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci USA 82:8667, 1985 157. Schleimer RP, Rutledge BK: Cultured human vascular endothelial cells acquire adhesiveness for neutrophils after stimulation with interleukin 1, endotoxin, and tumor-promoting phorbol diesters. J Immunol 136:649, 1986 158. Prescott SM, Zimmerman GA, McIntyre TM: Human endothelial cells in culture produce platelet activating factor (1alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) when stimulated with thrombin. Proc Natl Acad Sci USA 81:3534, 1984 159. Hancock WW, Cotran RS: Induction of activation antigens on human glomerular endothelium by interleukin 1 (IL-1), interferon gamma (IFN-g), and endotoxin (LPS). Kidney Int 31:322, 1987 160. Cotran RS: Monocytes, proliferation and glomerulonephritis. J Lab Clin Med 92:837, 1978 161. Fillit HM, Zabriskie JB: Cellular immunity in glomerulonephritis. Am J Pathol 109:227, 1982 162. Neilson EG, Zakheim B: T cell regulation, anti-idiotypic immunity, and the nephritogenic immune response. Kidney Int 24:289, 1983

163. Atkins RC, Holdsworth SR, Glasgow EF, et al: The macrophage in human rapidly progressive glomerulonephritis. Lancet 1:830, 1976 164. Holdworth SR, Thomson NM, Glasgow EF, et al: Tissue culture of isolated glomeruli in experimental crescentic glomerulonephritis. J Exp Med 147:98, 1978 165. Unanue ER, Schreiner GF, Cotran RS: A role of mononuclear phagocytes in immunologicallyinduced glomerulonephritis, in Cummings NB, Michael AF, Wilson CB (eds): Immune Mechanisms in Renal Disease. New York, Plenum, 1983, p 443 166. Mayrhofer G, Schon-Hegrad MA: Ia antigens in rat kidney, with special reference to their expression in tubular epithelium. J Exp Med 157:2097, 1983 167. Unanue ER, Allen PM: Comment on the finding of Ia expression in nonlymphoid cells. Lab Invest 55:123, 1986 (editorial) 168. Schreiner GF, Cotran RS, Pardo V, et al: A mononuclear cell component in experimental immunological glomerulonephritis. J Exp Med 147:369, 1978 169. Schreiner GF, Kiely J-M, Cotran RS, et al: Characterization of resident glomerular cells in the rat expressing Ia determinants and manifesting genetically restricted interactions with lymphocytes. J Clin Invest 68:920, 1981 170. Tipping PG, Neale TJ, Holdsworth SR: T lymphocyte participation in antibody-induced experimental glomerulonephritis. Kidney Int 27:530, 1985 171. Boyce NW, Tipping PG, Holdsworth SR: Lymphokine (MIF) production by glomerular T lymphocytes in experimental glomerulonephritis. Kidney Int 30:673, 1986 172. Eldredge C, Wiggins RC: T cells in the glomerulus, periglomerular region and around venules early in crescentic nephritis in the rabbit. Evidence for glomerulo-interstitial signals. Kidney Int 31:318, 1987 173. Nolasco FEB, Cameron JS, Hartley B, et al: Intraglomerular T cells and monocytes in nephritis: Study with monoclonal antibodies. Kidney Int 31:1160, 1987 174. Hooke DH, Gee DC, Atkins RC: Leukocyte analysis using monoclonal antibodies in human glomerulonephritis. Kidney Int 31:964, 1987 175. Bhan AK, Schneeberger EE, Collins AB, et al: Evidence for a pathogenic role of cell-mediated immune mechanism in experimental glomerulonephritis. J Exp Med 148:246, 1978 176. Bhan AK, Collins AB, Schneeberger EE, et al: A cell mediated reaction against glomerular-bound immune complexes. J Exp Med 150:1410, 1979 177. Bohon WK, Tucker FL, Sturgill C: New avian model of experimental glomerulonephritis consistent with mediation by cellular immunity. J Clin Invest 73:1263, 1984 178. Chandra M, Tyson T, Sturgill B, et al: Transfer of experimental autoimmune glomerulonephritis in chickens by sensitized cells. Kidney Int 27:208, 1985 179. Boucher A, Droz D, Adafer E, et al: Characterization of mononuclear cell subsets in renal cellular interstitial infiltrates. Kidney Int 29:1043, 1986 180. Brunati C, Brando B, Confalonieri R, et al: Immunophenotyping of mononuclear cell infiltrates associated with renal diseases. Clin Nephrol 26:15, 1986 181. Kelly CJ, Neilson EG: Contrasuppression in autoimmunity. J Exp Med 165:107, 1987

1143