ANNUAL REVIEWS
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Annu. Rev. Med. 1991. 42:25-33 Copyright © 1991 by Annual Reviews Inc. All r(qhts reserved
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
CELL-MEDIATED IMMUNITY IN GLOMERULAR DISEASE Brad H. Ravin, M.D., and George F. Schreiner, M.D., Ph.D.
Departments of Medicine and Pathology, Washington University School of Medicine, St. Louis, Missouri 63110 KEY WORDS:
lymphocytes, macrophages, glomerulonephritis cytokines ,
ABSTRACT Our understanding of the role of the immune system in modulating glo merular injury continues to evolve. The participation of antibody, comple ment, and neutrophils alone cannot completely explain many aspects of the pathways of experimental and human glomerulonephritis. The elements of the immune system that mediate cellular immunity, T lymphocytes and monocytes, also appear to be important effectors of glomerulonephritis. An understanding of the role of cell-mediated immunity in renal disease is essential in designing ther a pies to interrupt immunologically sustained glomerular damage. INTRODUCTION The idea that a large proportion of glomerular diseases could be attributed to an immune etiology arose from the pioneering work of Dixon, Germuth, and others, who established the contributory role of immune complexes in experimental models of glomerular inflammation. Central to their understanding of glomerulonephritis was the following hypothesis: the presence within the glomerulus of immune complexes, whether as a deposit of previously circulating antigen-antibody aggregates or as a result of antibody binding to a glomerular antigen, initiates a common pathway of activation of the serum complement system, recruitment of neutrophils, and activation of platelets with consequent injury to glomerular cells and 25 0066-4219/91/0401-0025$02.00
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
26
ROVIN
& SCHREINER
their supporting matrix structures (1). While opening a new era in the classification and diagnosis of glomerular pathology, pathophysiological mechanisms centering upon humoral immune damage to the kidney have proven inadequate in explaining the diversity of glomerulonephritis with respect to etiology, prognosis, response to therapy, and the tendency for glomerular lesions to progress to eventual sclerosis (2). Studies of human glomerulonephritis and recent work on diverse modcls of cxperimental glomerulonephritis implicate cellular immune reactions, in both the initiation and the maintenance of glomerular dysfunction secondary to a host immune response. The elements of the immune system comprising the cellular arm of the immune response, lymphocytes and monocytes, appear to be significant effectors of glomerulonephritis. Both the cellular and the humoral arms of the immune effector system, in varying pro portions depending upon the nature of the initiating glomerular trauma and the chronicity of its presence, are involved in the pathogenesis of inflammatory glomerular dysfunction. The principal components of cell-mediated immunity are an antigen presenting cell, such as the macrophage or the dendritic cell, and the T lymphocyte, with unique requirements for recognition, activation, and the subsequent release of a variety of regulatory molecules that serve to coordinate cellular interactions directed at eliminating the identified anti gen (3). The macrophage, in particular, functions as an antigen-processing cell, in that it can ingest antigen, degrade it, and re-express immunogenic fragments on its cell surface in association with membrane-bound products of the major histocompatibility complex (4). Specific T lymphocytes of the CD4 + phenotype then recognize this "processed" antigen and respond by secreting a variety of cytokines, such as interleukin-2 and y-interferon, each exerting specific effects on various aspects of the immune response. These lymphocytes also proliferate, effecting the clonal expansion of the subset of lymphocytes capable of responding to that given antigenic stimu lus. The mature phase of the cellular immune response further includes participation of the cytolytic subset of T lymphocytes (CDS+), which are capable of directly damaging target cells or structures expressing the antigen. Additionally, there is recruitment and activation of other leuko cytes, particularly the macrophage, which contribute to the elimination of the stimulatory antigen by activating cellular processes such as phago cytosis and by releasing a variety of inflammatory mediators, potentially toxic to both antigen and bystander cells. In this review, we examine the growing body of evidence implicating macrophages and T lymphocytes in human and experimental glomerulonephritis. We then present an overview of the mechanisms by which such cells could either initiate or maintain glomerular injury.
CELLULAR IMMUNITY IN GLOMERULONEPHRITIS
27
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
HUMAN GLOMERULONEPHRITIS Hypercellularity characterizes many forms of human glomerulonephritis. Although originally thought to be secondary to intrinsic glomerular cell proliferation, numerous studies employing histochemical analysis or monoclonal antibodies specific for leukocyte antigens have shown that infiltrating leukocytes constitute a significant proportion of the hyper cellular glomerulus (Table 1). Analysis of leukocyte subsets in glo merulonephritis has documented the presence of monocytes and lympho cytes in rapidly progressive glomerulonephritis (RPGN) with crescent formation (5, 6, 10), cryoglobulinemia (8), lupus nephritis (7, 10), post infectious glomerulonephritis (7, 10), Schonlein-Henoch purpura (10), membranoproliferative glomerulonephritis (8, 10), and transplant glo merulopathy (9). Typically, monocytes are found in much greater number in the glomerulus proper than are lymphocytes (5, 6, 10), although both cell types are distributed around the glomerular tuft (5, 10). T lymphocytes are often found in disproportionate numbers in pcriglomcrular and inter stitial locations (5, 10, 11). Glomerular crescents, characterized by the presence of abnormal numbers of cells and insoluble protein within the urinary space, contain highly variable but typically large numbers of macrophages and somewhat fewer T lymphocytes (5, 6, 10). T lymphocytes of both the suppressor/cytotoxic and helper subsets are typically repre sented in glomerular lesions, whereas a lymphoid-like cell, the natural Table 1
Infiltrating cclls in human glomerulonephritis Cells present Disease process
Monocytes
T cells
Neutrophils
Reference
Rapidly progressive glomerulonephritis Anti-GBM
+" +
+ +
NDb
5, 6,10
Vasculitis
ND
5
Immune complex
+
+
ND
5, 6, 10
No immune complex
+ + +
+
ND
5, 6, 10
ND
ND
8
+
+
ND
ND
8, 10
+
7, 10
Cryoglobulinemia Lupus nephritis
7, 9, 10
Membranoproliferative glomerulonephritis Postinfectious glomerulonephritis Transplant glomerulopathy
+ + +
" + indicates presence of cell type. b ND indicates not determined or discussed in reference. , - indicates absence of cell type.
+
ND
9
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
28
ROVIN & SCHREINER
killer cell, is rarely observed in the glomerulus except in transplant glo merulopathy (5, 6, 9, 10). Glomerular leukocyte infiltrates typically do not correlate with the presence or absence of glomerular deposits of immune complexes (5, 6, 7, 10). Indeed, immune-complex-negative RPGN as well as transplant glomerulopathy can exhibit large numbers of glomerular mononuclear leukocytes (5, 9, 10). Atkins and others have emphasized that many glomerular lesions classified as primary glomerulonephritides are frequently accompanied by highly significant interstitial infiltrates con sisting principally of T lymphocytes and lesser numbers of macrophages (5, 6, 9, II). In fact, glomerular dysfunction often correlates best with the intensity of the T-cell interstitial infiltrate rather than the degree of glomerular hypercellularity (11). Thus, the renal interstitium must be considered an additional context in which cellular immunity may affect glomerular function or structure. FUNCTIONAL AND STRUCTURAL IMPLICATIONS OF GLOMERULAR LEUKOCYTE INFILTRATION The functional significance of the presence of effector elements of cell-mediated immunity in glomerulonephritis has been the subject of investigation in both human and animal models of the proliferative glomerulonephritides. An inverse correlation has been postulated (5) between the response of RPGN to methylprednisolone treatment and the intensity of the leukocyte cellularity of the glomerulus and extraglomerular crescent. A positive correlation between the extent of the interstitial mononuclear cell infiltrate, which accompanies primary glomerular lesions, and declining renal function as measured by creatinine clearance has been established (11). Experimental work in immune glomerular pathology emphasizes the macrophage because of its predominance compared to other leukocytes within the glomerulus. An early model of antiglomerular basement mem brane (anti-GBM) antibody-mediated disease found a correlation between the presence of glomerular macrophages and sustained proteinuria (12). Deposition of immune complexes in chronic serum sickness disease in rabbits results in marked infiltration of the glomerulus by macrophages and nephrotic range proteinuria (13). Macrophage depletion prior to the induction of glomerulonephritis via bone marrow irradiation (12), administration of nitrogen mustard (14), or injection of antimacrophage serum (15) abrogates the cellular infiltrate and associated proteinuria in these models. In a recently described model of nutritional manipulation of inflammatory glomerular disease, rats made deficient in essential fatty acids prior to induction of anti-GBM nephritis were completely protected
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
CELLULAR IMMUNITY IN GLOMERULONEPHRITIS
29
against glomerular macrophage accumulation, proteinuria, and decreased glomerular filtration rate, despite the presence of antibody and comple ment within the glomerulus (16). The mechanism of this protection afforded by lipid restriction appears to be the inhibited release of a mono cyte lipid chemoattractant produced by intrinsic glomerular cells (17). In both human and animal models, the long-term scquclac of chronic glomerulonephritis are often glomerular obsolescence and sclerosis. Recent studies have documented a relationship between susceptibility to glomcrular sclerosis and glomerular macrophage infiltrates. In a rat model of the nephrotic syndrome, the appearance of proteinuria is followed by the infiltration of the glomerulus by activated macrophages (18) whose presence correlates with markedly diminished renal blood flow and decreased GFR (19). Sustained proteinuria in this model results in sig nificant glomerular sclerosis within several months. The degree of sclerosis is remarkably ameliorated if the animals are placed on a diet deficient in essential fatty acids. This protection correlates with inhibition of glomerular macrophage accumulation (20). In a similar model of focal glomerulosclerosis, rats treated with oral steroids demonstrated better renal function than untreated animals (21). The steroid treatment did not alter glomerular sclerosis or glomerular macrophage infiltration, but it significantly reduced interstitial T lymphocytes, which suggests that glomerular sclerosis is related to macrophage accumulation, but that the accompanying interstitial infiltrates are important determinants of renal function (21). Infiltrating macrophages can potentially injure the glomerulus through a variety of products synthesized and secreted by these cells after activation. Such factors include proteolytic enzymes (collagenase, elastase), cytokines (IL-l), reactive oxygen metabolites (superoxide anion, hydrogen peroxide), cyclooxygenase and lipoxygenase products, platelet activating factors, and several growth factors (22). These secretory pro ducts may directly damage cells, influence glomerular hemodynamics, and alter glomerular cell growth and matrix production, all contributing to eventual glomerulosclerosis. Evidence suggesting that intraglomerular macrophages are indeed activated in nephrotic or nephritic states includes enhanced MHC class II antigen expression (23) and oxygen-radical pro duction (23, 24). Fibrin accumulates in and around the glomerulus in a variety of nephritides. In both human and experimental glomerulo nephritis, macrophages may be a source of the procoagulant tissue factor that may induce fibrin deposition (25, 26). Interleukin-l (IL-I) exerts multiple biological effects on intrinsic glo merular cells. IL-l production has been detected in cell cultures from patients with crescentic glomerulonephritis (27) and in rats with anti-GBM neph-
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
30
ROVIN & SCHREINER
ritis (28). IL-I increases proliferation of rat mesangial cells in culture (29) and stimulates the synthesis of type IV collagen by human glomerular epithelial cells (30). IL-I has also been shown to induce proliferation of cultured endothelial cells (31). The release by macrophages of proliferative stimuli such as IL- I may thus contribute to the accumulation of cells and matrix observed in the early stages of glomerular sclerosis, ultimately resulting in the obliteration of the vascular bed. Macrophage-derived IL-l also modulates sodium transport in both proximal and distal renal tubular epithelial (32). It is thus conceivable that cellular immune processes within the glomerulus may affect function in the rest of the nephron via the release from the glomerulus of products of an activated leukocyte infiltrate. Other macrophage products implicated in glomerular pathology include metabolites of arachidonic acid, such as the leukotrienes and thromboxane A2. As reviewed by Ardaillon et al (33), the sulfidopeptide leukotrienes can induce mesangial cell contraction, can reduce the glomerular ultrafiltration coefficient, and can regulate glomerular plasma flow via alterations in glomerular arteriolar resistance. The functional implications of T-cell infiltration into and around the glomerulus are much less clear. Peripheral blood lymphocytes from patients with glomerulonephritis underwent a greater degree of blast transformation than lymphocytes from patients with nonglomerular renal disease upon exposure to enzyme-treated human GBM (34). T-Iympho cyte production of )I-interferon may influence the response to injury by induc ing expression of MHC class II antigen on mesangial cells (35). This may enhance the ability of mesangial cells to interact with infiltrating leukocytes and present antigen or to serve as an antigenic stimulus. In experimental anti-GBM disease, the T-cell lymphokine migration inhibitory factor is released from glomeruli (36). The presence of this factor may serve to restrict macrophages to an intraglomerular area of inflammation. The most important role of reactive T cells in glomerular disease may be the recruitment of additional leukocytes, particularly maerophages, to an area of immune cellular reactivity. In this regard T lymphocytes are known to produce a 12,500-dalton peptide chemotactic factor for mono cytes (37). Thus the classic proof of the existence of cell-mediated immunity in any organ disease is the ability to transfer the disease to animals via lymphocytes, which subsequently serve to direct the focus of inflammation to the structures for which they possess specific recognition. In two models of rat glomerulonephritis, involving immune complexes or anti-GBM anti bodies, lymphocytes transferred from sensitized donors were able to induce a modest mononuclear cell infiltrate into glomeruli (38, 39): In a model of mesangial proliferative glomerulonephritis in chickens, splenocytes from
CELLULAR IMMUNITY IN GLOMERULONEPHRITIS
31
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
the nephritic animals could transfer the diseasc, albeit at a lesser intensity, to recipient birds (40). Models in other organs have established two requirements for cell-mediated immunity: (a) lymphocytes that recognize organ-spccific antigens, and (b) a concurrent stimulus, often traumatic, to the expression of an organ-specific neoantigen, which the lymphocytes recognize. Failure to identify what serves as a neoantigen in experimental glomerular pathology may account for the current lack of an unequivocal demonstration of glomerular disease in mammals being transferred by sensitized lymphocytes. CONCLUSION The evidence that the essential components of cell-mediated immunity are present in glomerulonephritis is unequivocal in both human and animal expressions of this disease process. There is an accumulating, although still limited, body of functional data that cellular immunity is active in human glomerular disease, particularly of a chronic or sclerosing nature. Experimental renal pathology demonstrates a correlation between the presence of mononuclear cell infiltrates and glomerular dysfunction, par ticularly with respect to proteinuria, diminished glomerular blood flow, and ultimate effacement of glomerular structure. Further work in the area of cell-mediated immunity in renal disease is critical to the development of specific therapy designed to interrupt immunologically sustained glomerular damage. The therapeutic potential of recent insights into the modulatory role of macrophages and lymphocytes in glomerular dys function has yet to be realized.
Literature Cited
I. McCluskey, R. T. 1983. Immunologic
mechanisms in glomerular disease. In Pathology of the Kidney, ed. R. Hep tinstall, pp. 301-86. Boston: Little, Brown 2. Hamburger, J. 1981. Immunology of glomerulonephritis. In Proc. 8th Int. Congr. Nephrol., ed. W. Zurukzoglu et ai, pp. 55-61. Basel: Karger 3. Kurnick, J. T., McCluskey, R. T. 1990. Perspectives on cell mediated immunity in vivo. In Lymphokines and the Immune Response, ed. S. Cohen, pp. 1-28. Boca Raton: CRC 4. Unanue, E. R., Allen, P. M. 1987. The basis for the immunoregulatory role of macrophages and of the accessory cells.
Science 236: 551-57
5. Bolton, W. K., Innes, D. J., Sturgill, B.
c., Kaiser, D. L. 1987. T cells and
macrophagcs in rapidly progressive glo merulonephritis: Clinicopathologic cor relations. Kidney Int. 32 : 869-76 6. Stachura, I., Lusheny, S., Whiteside, T. L. 1984. Mononuclear cell subsets in human idiopathic crescentic glomeru lonephritis (ICGN): Analysis in tissue section with monoclonal antibodies. J. Clin. Immunol. 4: 202 8 7. Hooke, D. H., Hancock, W. W., Gee, D. c., Kraft, N., Atkins, R. C. 1984. Mono clonal antibody analysis of glomerular hypercellularity in human glomeru lonephritis. Clin. Nephrol. 22: 163-68 8. Monga, G., Mazzucco, G., di Belgio joso, G. G., Busnach, G. 1979. The presence and possible role of monocyte infiltration in human chronic pro-
32
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& SCHREINER
liferative glomerulonephritides. Am. f. Pathol. 94: 271-84 9. Tuazon, T. V., Schreeberger, E. E., Bhan, A. K., McCluskey, R. T., Cosimi, A. B., et al. 1987. Mononuclear cells in acute allograft glomerulopathy. Am. f. Pathol. 129: 119-32 10. Nolasco, F. E. B., Cameron, J. S., Hartley, B., Coelho, A., Hildreth, G.,
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Reuben,
I I.
12.
\3.
14.
R.
1987. Intraglomerular T
cells and monocytes in nephritis: Study with monoclonal antibodies. Kidney Int. 3 1 : 1160-66 Hooke, D. H., Gee, D. c., Atkins, R. C. 1987. Leukocyte analysis using mono clonal antibodies in human glomerulo nephritis. Kidney Int. 31: 961-72 Schreiner, G. F., Cotran, R. S., Pardo, V., Unanue, E. R. 1978. A mononuclear cell component in experimental im munological glomerulonephritis. J. Exp. Med. 147: 369-84 Hunsicker, L. G., Shearer, T. P., Plattner, S. B., Weisenburger, D. 1979. The role of monocytes in serum sickness nephritis. J. Exp. Med. 150: 413-25 Holdsworth, S. R., Neale, T. J. 1984. Macrophage-induced glomerular injury:
Cell transfer studies in passive auto
logous anti-glomerular basement mem
brane antibody-initiated experimental glomerulonephritis. Lab. Invest. 51: 172-
80 15. Holdsworth, S. R., Neale, T. J., Wilson, C. B. 1981. Abrogation of macrophage dependent injury in experimental glo merulonephritis in the rabbit. J. C/in. Invest. 68: 686-98 16. Schreiner, G. F., Rovin B. H., Lefko with, J. B. 1989. The anti-inflammatory ,
effects of essential fatty acid deficiency in experimental glomerulonephritis. f. Immunol. 143: 3192-99
H., Lefkowith, J. B., Schreiner, G. F. 1990. Mechanisms underlying the anti-inflammatory effects of essential fatty acid deficiency in experimental glomerulonephritis: In hibited release of a monocyte chemo attractant by glomeruli. f. Immunol. 145:
17. Rovin,
B.
1238-45
18 . Schreine r, G. F., Cotran, P. S., Unanue, E. R. 1984. The modulation of Ia and Lc antigen expression in rat glomeruli during the course of glomerulonephritis and aminonucieoside nephrosis. Lab. Invest. 51: 524-33 19. Harris, K., Lefkowith, J., Klahr, S., Schreiner, G. F. 1990. Essential fatty acid deficiency ameliorates acute renal dysfunction in the rat following the administration of the aminonucleoside of puromycin. J. Clin. Invest. In press
20. Diamond, J., Pesek, I., Ruggieri, S., Karnovsky, M. 1989. Essential fatty acid deficiency during acute puromycin nephrosis ameliorates late renal injury. Am. J. Physiol. 257: F798-807 21. Saito, T., Atkins, R. C. 1990. Con tribution of mononuclear leukocytes to the progression of experimental focal sclerosis. Kidney Int. 37: 1076-83 22. Nathan, C. F. 1987. Secretory products of macrophages. f. c/in. Invest. 79: 31926 23. Cook, H. T., Smith, J., Salmon, J. A., Cattell, V. 1989. Functional charac teristics of macrophages in glomeru lonephritis in the rat. Am. f. Pathol. 134: 4 3 1-3 7 24. Boyce, N. W., Tipping, P. G., Holds worth, S. R. 1989. Glomerular macro phages produce reactive oxygen species in experimental glomerulonephritis. Kidney Int. 35: 778-82 25. Neale, T. J., Carson, S. D., Tipping, P. G., Holdsworth, S. R. 1988. Participa tion of cell-mediated immunity in depo sition of fibrin in glomerulonephritis. Lancet I: 4 21-24 26. Tipping, P. G., Worthington, L. A., Holdsworth, S. R. 1987. Quantitation and characterization of glomerular pro coagulant activity in experimental glo merulonephritis. I�ab. Invest. 56: 155-59
27. Matsumoko, K., Dowling, T., Atkins, R. C. 1988. Production of interleukin I
in glomerular cell cultures from patients with rapidly progressive crescentic glo merulonephritis. Am. f. Nephrol. 8: 46370 28. Matsumoto, K., Hatano, M. 1989. Pro duction of interleukin I in glomerular cell cultures from rats with nephrotoxic serum nephritis. c/in. Exp. Immunol. 75:
123-28 29. Lovett, D. H., Ryan, J. L., Steizel, R. B. 1983. Stimulation of rat mesangial cell proliferation by macrophage interleukin I. f. Immunol. 131: 2830-36 30. Torbohm, 1., Berger, B., Sconermark, M., Von Kemp is, J., Rothen, K., Hansch, G. M. 1989. Modulation of collagen synthesis in human glomerular epithelial cells hy interleukin I. Clin. Exp. Immunol. 75: 427-31 31. Ooi, B. S., MacCarthy, E. F., Hsu, A.,
Ooi, Y. M. 1983. Human mononuclear cell modulation of endothelial cell proliferation. J. Lab. Clin. Med. 102:
428-33 32. Schreiner, G. F., Kohan, D. E. 1990. Regulation of renal transport processes
and hemodynamics by macrophages and lymp hocytes. Am. J. Physiol. 2 58: F761-
67
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
CELLULAR IMMUNITY IN GLOMERULONEPHRITIS
33. Ardaillon, R., Band, L., Sraer, J. 1989. Leukotrienes and reactive oxygen species as mediators of glomerular injury. Am. J. Nephrol. 9: 17-22 34. Fillit, N. M., Stanley, R. E., Sherman, R. L., Zubriskic, J. B., Van de Rijn, I. 1978. Cellular reactivity to altered glomerular basement membrane in glomerulonephritis. N. Engl. J. Med. 298: 861-68 35. Martin, M., Schwinzer, R., Schellekens, H., Resch, K. 1989. Glomerular mesan gial cells in local inflammation: Induc tion of the expression of MHC class II antigens by IFN-y. J. Immunol. 142: 1887-94 36. Boyce, N. W., Tipping, P. G., Holds worth, S. R. 1986. Lymphokine (MIF) production by glomerular T lympho cytes in experimental glomerulo nephritis. Kidney Int. 30: 673-77
33
37. Hayashi, H., Yoshimur, T., Jinyan, C. 1985. Chemotaxis of macrophage in inflammation. Camp. Immunol. Micro bial. Infect. Dis. 8: 73-87 38. Dhan, A. K., Collins, A. B., Schnee berger, E. E., McCluskey, R. T. 1979. A cell-mediated reaction against glo merular-bound immune complexes. J. Exp. Med. 150: 1410-20 39. Bhan, A. K., Schneeberger, E. E., Collins, A. B., McCluskey, R. T. 1978. Evidence for a pathogenic role of a cell mediated immune mechanism in experi mental glomerulonephritis. J. Exp. Med. 148: 246-60 40. BoIton, W. K., Chandra, M., Tyson, T. M., Kirkpatrick, P. R., Sadovnic, M. J., Sturgill, B. C. 1988. Transfer of experi mental glomerulonephritis in chickens by mononuclear cells. Kidney Int. 34: 598-610
Further
Quick links to online content
Annu. Rev. Med. 1991. 42:25-33 Copyright © 1991 by Annual Reviews Inc. All r(qhts reserved
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
CELL-MEDIATED IMMUNITY IN GLOMERULAR DISEASE Brad H. Ravin, M.D., and George F. Schreiner, M.D., Ph.D.
Departments of Medicine and Pathology, Washington University School of Medicine, St. Louis, Missouri 63110 KEY WORDS:
lymphocytes, macrophages, glomerulonephritis cytokines ,
ABSTRACT Our understanding of the role of the immune system in modulating glo merular injury continues to evolve. The participation of antibody, comple ment, and neutrophils alone cannot completely explain many aspects of the pathways of experimental and human glomerulonephritis. The elements of the immune system that mediate cellular immunity, T lymphocytes and monocytes, also appear to be important effectors of glomerulonephritis. An understanding of the role of cell-mediated immunity in renal disease is essential in designing ther a pies to interrupt immunologically sustained glomerular damage. INTRODUCTION The idea that a large proportion of glomerular diseases could be attributed to an immune etiology arose from the pioneering work of Dixon, Germuth, and others, who established the contributory role of immune complexes in experimental models of glomerular inflammation. Central to their understanding of glomerulonephritis was the following hypothesis: the presence within the glomerulus of immune complexes, whether as a deposit of previously circulating antigen-antibody aggregates or as a result of antibody binding to a glomerular antigen, initiates a common pathway of activation of the serum complement system, recruitment of neutrophils, and activation of platelets with consequent injury to glomerular cells and 25 0066-4219/91/0401-0025$02.00
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
26
ROVIN
& SCHREINER
their supporting matrix structures (1). While opening a new era in the classification and diagnosis of glomerular pathology, pathophysiological mechanisms centering upon humoral immune damage to the kidney have proven inadequate in explaining the diversity of glomerulonephritis with respect to etiology, prognosis, response to therapy, and the tendency for glomerular lesions to progress to eventual sclerosis (2). Studies of human glomerulonephritis and recent work on diverse modcls of cxperimental glomerulonephritis implicate cellular immune reactions, in both the initiation and the maintenance of glomerular dysfunction secondary to a host immune response. The elements of the immune system comprising the cellular arm of the immune response, lymphocytes and monocytes, appear to be significant effectors of glomerulonephritis. Both the cellular and the humoral arms of the immune effector system, in varying pro portions depending upon the nature of the initiating glomerular trauma and the chronicity of its presence, are involved in the pathogenesis of inflammatory glomerular dysfunction. The principal components of cell-mediated immunity are an antigen presenting cell, such as the macrophage or the dendritic cell, and the T lymphocyte, with unique requirements for recognition, activation, and the subsequent release of a variety of regulatory molecules that serve to coordinate cellular interactions directed at eliminating the identified anti gen (3). The macrophage, in particular, functions as an antigen-processing cell, in that it can ingest antigen, degrade it, and re-express immunogenic fragments on its cell surface in association with membrane-bound products of the major histocompatibility complex (4). Specific T lymphocytes of the CD4 + phenotype then recognize this "processed" antigen and respond by secreting a variety of cytokines, such as interleukin-2 and y-interferon, each exerting specific effects on various aspects of the immune response. These lymphocytes also proliferate, effecting the clonal expansion of the subset of lymphocytes capable of responding to that given antigenic stimu lus. The mature phase of the cellular immune response further includes participation of the cytolytic subset of T lymphocytes (CDS+), which are capable of directly damaging target cells or structures expressing the antigen. Additionally, there is recruitment and activation of other leuko cytes, particularly the macrophage, which contribute to the elimination of the stimulatory antigen by activating cellular processes such as phago cytosis and by releasing a variety of inflammatory mediators, potentially toxic to both antigen and bystander cells. In this review, we examine the growing body of evidence implicating macrophages and T lymphocytes in human and experimental glomerulonephritis. We then present an overview of the mechanisms by which such cells could either initiate or maintain glomerular injury.
CELLULAR IMMUNITY IN GLOMERULONEPHRITIS
27
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
HUMAN GLOMERULONEPHRITIS Hypercellularity characterizes many forms of human glomerulonephritis. Although originally thought to be secondary to intrinsic glomerular cell proliferation, numerous studies employing histochemical analysis or monoclonal antibodies specific for leukocyte antigens have shown that infiltrating leukocytes constitute a significant proportion of the hyper cellular glomerulus (Table 1). Analysis of leukocyte subsets in glo merulonephritis has documented the presence of monocytes and lympho cytes in rapidly progressive glomerulonephritis (RPGN) with crescent formation (5, 6, 10), cryoglobulinemia (8), lupus nephritis (7, 10), post infectious glomerulonephritis (7, 10), Schonlein-Henoch purpura (10), membranoproliferative glomerulonephritis (8, 10), and transplant glo merulopathy (9). Typically, monocytes are found in much greater number in the glomerulus proper than are lymphocytes (5, 6, 10), although both cell types are distributed around the glomerular tuft (5, 10). T lymphocytes are often found in disproportionate numbers in pcriglomcrular and inter stitial locations (5, 10, 11). Glomerular crescents, characterized by the presence of abnormal numbers of cells and insoluble protein within the urinary space, contain highly variable but typically large numbers of macrophages and somewhat fewer T lymphocytes (5, 6, 10). T lymphocytes of both the suppressor/cytotoxic and helper subsets are typically repre sented in glomerular lesions, whereas a lymphoid-like cell, the natural Table 1
Infiltrating cclls in human glomerulonephritis Cells present Disease process
Monocytes
T cells
Neutrophils
Reference
Rapidly progressive glomerulonephritis Anti-GBM
+" +
+ +
NDb
5, 6,10
Vasculitis
ND
5
Immune complex
+
+
ND
5, 6, 10
No immune complex
+ + +
+
ND
5, 6, 10
ND
ND
8
+
+
ND
ND
8, 10
+
7, 10
Cryoglobulinemia Lupus nephritis
7, 9, 10
Membranoproliferative glomerulonephritis Postinfectious glomerulonephritis Transplant glomerulopathy
+ + +
" + indicates presence of cell type. b ND indicates not determined or discussed in reference. , - indicates absence of cell type.
+
ND
9
Annu. Rev. Med. 1991.42:25-33. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.
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killer cell, is rarely observed in the glomerulus except in transplant glo merulopathy (5, 6, 9, 10). Glomerular leukocyte infiltrates typically do not correlate with the presence or absence of glomerular deposits of immune complexes (5, 6, 7, 10). Indeed, immune-complex-negative RPGN as well as transplant glomerulopathy can exhibit large numbers of glomerular mononuclear leukocytes (5, 9, 10). Atkins and others have emphasized that many glomerular lesions classified as primary glomerulonephritides are frequently accompanied by highly significant interstitial infiltrates con sisting principally of T lymphocytes and lesser numbers of macrophages (5, 6, 9, II). In fact, glomerular dysfunction often correlates best with the intensity of the T-cell interstitial infiltrate rather than the degree of glomerular hypercellularity (11). Thus, the renal interstitium must be considered an additional context in which cellular immunity may affect glomerular function or structure. FUNCTIONAL AND STRUCTURAL IMPLICATIONS OF GLOMERULAR LEUKOCYTE INFILTRATION The functional significance of the presence of effector elements of cell-mediated immunity in glomerulonephritis has been the subject of investigation in both human and animal models of the proliferative glomerulonephritides. An inverse correlation has been postulated (5) between the response of RPGN to methylprednisolone treatment and the intensity of the leukocyte cellularity of the glomerulus and extraglomerular crescent. A positive correlation between the extent of the interstitial mononuclear cell infiltrate, which accompanies primary glomerular lesions, and declining renal function as measured by creatinine clearance has been established (11). Experimental work in immune glomerular pathology emphasizes the macrophage because of its predominance compared to other leukocytes within the glomerulus. An early model of antiglomerular basement mem brane (anti-GBM) antibody-mediated disease found a correlation between the presence of glomerular macrophages and sustained proteinuria (12). Deposition of immune complexes in chronic serum sickness disease in rabbits results in marked infiltration of the glomerulus by macrophages and nephrotic range proteinuria (13). Macrophage depletion prior to the induction of glomerulonephritis via bone marrow irradiation (12), administration of nitrogen mustard (14), or injection of antimacrophage serum (15) abrogates the cellular infiltrate and associated proteinuria in these models. In a recently described model of nutritional manipulation of inflammatory glomerular disease, rats made deficient in essential fatty acids prior to induction of anti-GBM nephritis were completely protected
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against glomerular macrophage accumulation, proteinuria, and decreased glomerular filtration rate, despite the presence of antibody and comple ment within the glomerulus (16). The mechanism of this protection afforded by lipid restriction appears to be the inhibited release of a mono cyte lipid chemoattractant produced by intrinsic glomerular cells (17). In both human and animal models, the long-term scquclac of chronic glomerulonephritis are often glomerular obsolescence and sclerosis. Recent studies have documented a relationship between susceptibility to glomcrular sclerosis and glomerular macrophage infiltrates. In a rat model of the nephrotic syndrome, the appearance of proteinuria is followed by the infiltration of the glomerulus by activated macrophages (18) whose presence correlates with markedly diminished renal blood flow and decreased GFR (19). Sustained proteinuria in this model results in sig nificant glomerular sclerosis within several months. The degree of sclerosis is remarkably ameliorated if the animals are placed on a diet deficient in essential fatty acids. This protection correlates with inhibition of glomerular macrophage accumulation (20). In a similar model of focal glomerulosclerosis, rats treated with oral steroids demonstrated better renal function than untreated animals (21). The steroid treatment did not alter glomerular sclerosis or glomerular macrophage infiltration, but it significantly reduced interstitial T lymphocytes, which suggests that glomerular sclerosis is related to macrophage accumulation, but that the accompanying interstitial infiltrates are important determinants of renal function (21). Infiltrating macrophages can potentially injure the glomerulus through a variety of products synthesized and secreted by these cells after activation. Such factors include proteolytic enzymes (collagenase, elastase), cytokines (IL-l), reactive oxygen metabolites (superoxide anion, hydrogen peroxide), cyclooxygenase and lipoxygenase products, platelet activating factors, and several growth factors (22). These secretory pro ducts may directly damage cells, influence glomerular hemodynamics, and alter glomerular cell growth and matrix production, all contributing to eventual glomerulosclerosis. Evidence suggesting that intraglomerular macrophages are indeed activated in nephrotic or nephritic states includes enhanced MHC class II antigen expression (23) and oxygen-radical pro duction (23, 24). Fibrin accumulates in and around the glomerulus in a variety of nephritides. In both human and experimental glomerulo nephritis, macrophages may be a source of the procoagulant tissue factor that may induce fibrin deposition (25, 26). Interleukin-l (IL-I) exerts multiple biological effects on intrinsic glo merular cells. IL-l production has been detected in cell cultures from patients with crescentic glomerulonephritis (27) and in rats with anti-GBM neph-
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ritis (28). IL-I increases proliferation of rat mesangial cells in culture (29) and stimulates the synthesis of type IV collagen by human glomerular epithelial cells (30). IL-I has also been shown to induce proliferation of cultured endothelial cells (31). The release by macrophages of proliferative stimuli such as IL- I may thus contribute to the accumulation of cells and matrix observed in the early stages of glomerular sclerosis, ultimately resulting in the obliteration of the vascular bed. Macrophage-derived IL-l also modulates sodium transport in both proximal and distal renal tubular epithelial (32). It is thus conceivable that cellular immune processes within the glomerulus may affect function in the rest of the nephron via the release from the glomerulus of products of an activated leukocyte infiltrate. Other macrophage products implicated in glomerular pathology include metabolites of arachidonic acid, such as the leukotrienes and thromboxane A2. As reviewed by Ardaillon et al (33), the sulfidopeptide leukotrienes can induce mesangial cell contraction, can reduce the glomerular ultrafiltration coefficient, and can regulate glomerular plasma flow via alterations in glomerular arteriolar resistance. The functional implications of T-cell infiltration into and around the glomerulus are much less clear. Peripheral blood lymphocytes from patients with glomerulonephritis underwent a greater degree of blast transformation than lymphocytes from patients with nonglomerular renal disease upon exposure to enzyme-treated human GBM (34). T-Iympho cyte production of )I-interferon may influence the response to injury by induc ing expression of MHC class II antigen on mesangial cells (35). This may enhance the ability of mesangial cells to interact with infiltrating leukocytes and present antigen or to serve as an antigenic stimulus. In experimental anti-GBM disease, the T-cell lymphokine migration inhibitory factor is released from glomeruli (36). The presence of this factor may serve to restrict macrophages to an intraglomerular area of inflammation. The most important role of reactive T cells in glomerular disease may be the recruitment of additional leukocytes, particularly maerophages, to an area of immune cellular reactivity. In this regard T lymphocytes are known to produce a 12,500-dalton peptide chemotactic factor for mono cytes (37). Thus the classic proof of the existence of cell-mediated immunity in any organ disease is the ability to transfer the disease to animals via lymphocytes, which subsequently serve to direct the focus of inflammation to the structures for which they possess specific recognition. In two models of rat glomerulonephritis, involving immune complexes or anti-GBM anti bodies, lymphocytes transferred from sensitized donors were able to induce a modest mononuclear cell infiltrate into glomeruli (38, 39): In a model of mesangial proliferative glomerulonephritis in chickens, splenocytes from
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the nephritic animals could transfer the diseasc, albeit at a lesser intensity, to recipient birds (40). Models in other organs have established two requirements for cell-mediated immunity: (a) lymphocytes that recognize organ-spccific antigens, and (b) a concurrent stimulus, often traumatic, to the expression of an organ-specific neoantigen, which the lymphocytes recognize. Failure to identify what serves as a neoantigen in experimental glomerular pathology may account for the current lack of an unequivocal demonstration of glomerular disease in mammals being transferred by sensitized lymphocytes. CONCLUSION The evidence that the essential components of cell-mediated immunity are present in glomerulonephritis is unequivocal in both human and animal expressions of this disease process. There is an accumulating, although still limited, body of functional data that cellular immunity is active in human glomerular disease, particularly of a chronic or sclerosing nature. Experimental renal pathology demonstrates a correlation between the presence of mononuclear cell infiltrates and glomerular dysfunction, par ticularly with respect to proteinuria, diminished glomerular blood flow, and ultimate effacement of glomerular structure. Further work in the area of cell-mediated immunity in renal disease is critical to the development of specific therapy designed to interrupt immunologically sustained glomerular damage. The therapeutic potential of recent insights into the modulatory role of macrophages and lymphocytes in glomerular dys function has yet to be realized.
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