ANIMAL MODEL OF HUMAN DISEASE
Glomerulonephritis, Autoimmunity, Autoantibodv Animal Model: Anti-Glomerular Basement Membrane Antibody in Horses
Contributed by: Keith L. Banks, DVM, PhD, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164.
Bioogic Features
Glomerulonephritis may be caused by the deposition of antigen-antibody complexes w%ithin the glomerulus or by the attachment of autoantibody to the glomerular basement membrane (GMB). Although immune mechanisms have been shown to contribute to glomerular damage in several animal species,1'2 damage induced by anti-GBMi antibody has only been observed in the horse.3 When kidney specimens wvere taken from Shetland, Standardbred, and Thoroughbred horses of the northw estern area of the United States, 3 of 83 horses had immunoglobulin and complement (C3) attached to the GBM in a smooth, linear pattern (Figure 1). The linear pattern was distinct from granular localization of immunoglobulin and complement in glomeruli of other horses.3 The 3 horses did not have equine infectious anemia, a chronic virus disease associated with circulating immune complexes and a high incidence of glomerulitis.4 Kidney tissue from these 3 horses was further examined by light and electron microscopy and by the elution of immunoglobulins from the glomeruli. The glomerular eluate from one of the animals readily bound to normal horse GBM, demonstrating the presence of anti-GBM antibody. The horse with anti-GBMI antibody wvas a 6-year-old Thoroughbred mare, submitted to a veterinarian because of difficult breathing and epistaxis. Clinical laboratory data indicated a slight anemia, but blood urea nitrogen and leukocvte levels wvere within the normal range. Therapy was unsuccessful, and, following radiographic demonstration of a large mass in the nasal cavity, the animal was euthanized. At necropsv the horse had a localized hemangiosarcoma in the nasal cavity with no lesions of Publication sponsored by the Registrv of Comparative Pathology of the Armed Forces Institute of
Pathology and supported bv Public Health Sen-ice Grant RR 00301 from the Division of Research Resources. US Department of Health. Education and wN'elfare. under the auspices of Universities
Associated for Research and Education in Pathology. Inc. This sork wlas supported by Public Health Service Grant Al 07471 from the National Institute of Allergy and Infectious Diseases and bv the USDA Cooperative Agreement 12-14-100-9067. 0002-9440/79/0208-04431.00 443 0 1979 American Association of Pathologists
444
BANKS
American Journal of Pathology
Figure 1-Linear pattern of inmunoglobulin on equine glo-
merular basement membrane stained with fluorescein-labeled
anti-equine Immunoglobulin.
other organs. No glomerular abnormalities were observed by light microscopy; however, electron microscopic examination revealed extensive subendothelial deposition of granular material and fusion of cellular foot processes. The GBM of all glomeruli had an irregular increase in thickness. Several kidney samples from this horse yielded immunoglobulin on acid elution, and each of these eluates readily attached to GBM of normal horses (Figure 2). The eluates did not bind to glomeruli of mink, rabbits, guinea pigs, mice, pigs, or dogs. The anti-CBM antibody did not attach to basement membrane of equine renal tubules, testicles, lung, spleen, or' liver. Whole serum or the IgG serum fraction of serum from this animal did not contain detectable anti-GBM antibody when tested by indirect immunofluoresence. In the general population, glomerulonephritis was observed in 7 of 45 horses, and this disease occasionally was responsible for renal failure and death. Glomerular eluates were examined from 16 horses, including the 3 with linear deposits of immunoglobulin and complement. Anti-GBM antibody was only found in the horse described above. These data suggest that not all animals with a linear staining GBM have the autoantibody. Most glomerulitis cases in horses would appear to be caused by the deposition of immune complexes, although it is not known what antigen(s) is involved. The factors necessary for the induction of anti-GBM antibody in humans have not been established, although there is an association between occurrence of the autoantibody and A2 influenza virus infection,' exposure to hydrocarbon solvents,' and methicillin toxicity.' Experimen-
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8d Figure 2-Glomerular
eFuate was incubated with normal horse glomerulus and stained with fluorescein-labeled anti-equine immunoglobulin. The stained glomerulus demonstrates anti-GBM antibody in the glomerular eluate.
J *
tallv, anti-GBM antibody has been induced in Brown Norwav rats bv injection of mercuric chloride.8 The reason for the appearance of antiGBM antibody in the horse was not determined, but the presence of new basement membrane in the vascular tumor raises the question whether neoplasm-derived basement membrane could have stimulated the formation of anti-GBM antibodv. However, attempts to induce anti-GBM antibody and glomerulonephritis in mice with a transmissible hemangiosarcoma were unsuccessful. Comparison With Htnan Disease
Anti-GBM antibody is present in approximately 5% of human cases of The disease most often has a progressive course with proliferative, necrotizing glomerulitis,>11 although rare individuals show spontaneous recovery.U 1.3 Approximately one half the affected individuals have concurrent pulmonary vascular damage resulting in lung hemorrhages (Goodpasture's syndrome).9"1 The diagnosis is based on clinical signs of kidney and/or pulmonary damage, linear staining of glomerular GBM by immunofluorescence, and the presence of anti-GBM antibody in the blood or glomeruli.9 The disease in the horse has been shown to have the tvpical glomerular immunohistochemical pattern, the presence of anti-GBM antibody in the glomerulus, and disruption of the normal glomerular architecture. Whether this condition would have resulted in progressive degeneration of the glomeruli could not be determined.
glomerulonephritis."90
446
BANKS
American Journal of Pathology
Availability
Of 83 kidney specimens examined by immunofluorescence, three stained in a pattern suggestive of anti-GBM-antibody-mediated glomerulonephritis. One of these three was proved to have anti-GBM antibody. This limited sample suggests that less than 1 % of horses have this disease. References
1. Cochrane CG, Koffler D: Immune complex disease in experimental animals and man. Adv Immunol 16:185-264, 1973 2. Tizard IR: An Introduction to Veterinary Immunology. Philadelphia, W. B. Saunders Co., 1977, pp 299-300 3. Banks KL, Henson JB: Immunologically mediated glomerulitis of horses. II. Antiglomerular basement membrane antibody and other mechanisms in spontaneous disease. Lab Invest 26:708-715, 1972 4. Banks KL, Henson JB, McGuire TC: Immunologically mediated glomerulitis of horses. I. Pathogenesis in persistent infection by equine infectious anemia virus. Lab Invest 26:701-707, 1972 5. Wilson CB, Smith RC: Goodpasture's syndrome associated with influenza A2 virus infection. Ann Intern Med 76:91-94, 1972 6. Zimmerman SW, Groehler K, Beirne GJ: Hydrocarbon exposure and chronic glomerulonephritis. Lancet 2:199-201, 1975 7. Wilson CG: Recent advances in the immunological aspects of renal disease. Fed Proc 36:2171-2175, 1977 8. Sapin C, Druet E, Druet P: Induction of anti-glomerular basement membrane antibodies in the Brown-Norway rat by mercuric chloride. Clin Exp Immunol 28:173-179, 1977 9. Wilson CB, Dixon FJ: Anti-glomerular basement membrane antibody-induced glomerulonephritis. Kidney Int 3:74-89, 1973 10. Wilson CB, Henderson LW, Dixon FJ: Glomerulonephritis. DM 22:1-66, 1976 11. Sisons JGP, Evans DJ, Peters DK, Eisinger AJ, Boulton-Jones JM, Simpson IJ, Macanouic M: Glomerulonephritis associated with antibody to glomerular basement membrane. Br Med J 4:11-14, 1974 12. Teichman S, Briggs WA, Knieser MR, Enquist RW: Goodpasture's syndrome: Two cases with contrasting early course and management. Kidney Int 6:105A, 1974 13. Agodoa LCY, Striker GE, George CRP, Glassock R, Quadracci LJ: The appearance of nonlinear deposits of immunoglobulins in Goodpasture's syndrome. Am J Med 61:407-413, 1976
Glomerulonephritis, Autoimmunity, Autoantibodv Animal Model: Anti-Glomerular Basement Membrane Antibody in Horses
Contributed by: Keith L. Banks, DVM, PhD, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164.
Bioogic Features
Glomerulonephritis may be caused by the deposition of antigen-antibody complexes w%ithin the glomerulus or by the attachment of autoantibody to the glomerular basement membrane (GMB). Although immune mechanisms have been shown to contribute to glomerular damage in several animal species,1'2 damage induced by anti-GBMi antibody has only been observed in the horse.3 When kidney specimens wvere taken from Shetland, Standardbred, and Thoroughbred horses of the northw estern area of the United States, 3 of 83 horses had immunoglobulin and complement (C3) attached to the GBM in a smooth, linear pattern (Figure 1). The linear pattern was distinct from granular localization of immunoglobulin and complement in glomeruli of other horses.3 The 3 horses did not have equine infectious anemia, a chronic virus disease associated with circulating immune complexes and a high incidence of glomerulitis.4 Kidney tissue from these 3 horses was further examined by light and electron microscopy and by the elution of immunoglobulins from the glomeruli. The glomerular eluate from one of the animals readily bound to normal horse GBM, demonstrating the presence of anti-GBM antibody. The horse with anti-GBMI antibody wvas a 6-year-old Thoroughbred mare, submitted to a veterinarian because of difficult breathing and epistaxis. Clinical laboratory data indicated a slight anemia, but blood urea nitrogen and leukocvte levels wvere within the normal range. Therapy was unsuccessful, and, following radiographic demonstration of a large mass in the nasal cavity, the animal was euthanized. At necropsv the horse had a localized hemangiosarcoma in the nasal cavity with no lesions of Publication sponsored by the Registrv of Comparative Pathology of the Armed Forces Institute of
Pathology and supported bv Public Health Sen-ice Grant RR 00301 from the Division of Research Resources. US Department of Health. Education and wN'elfare. under the auspices of Universities
Associated for Research and Education in Pathology. Inc. This sork wlas supported by Public Health Service Grant Al 07471 from the National Institute of Allergy and Infectious Diseases and bv the USDA Cooperative Agreement 12-14-100-9067. 0002-9440/79/0208-04431.00 443 0 1979 American Association of Pathologists
444
BANKS
American Journal of Pathology
Figure 1-Linear pattern of inmunoglobulin on equine glo-
merular basement membrane stained with fluorescein-labeled
anti-equine Immunoglobulin.
other organs. No glomerular abnormalities were observed by light microscopy; however, electron microscopic examination revealed extensive subendothelial deposition of granular material and fusion of cellular foot processes. The GBM of all glomeruli had an irregular increase in thickness. Several kidney samples from this horse yielded immunoglobulin on acid elution, and each of these eluates readily attached to GBM of normal horses (Figure 2). The eluates did not bind to glomeruli of mink, rabbits, guinea pigs, mice, pigs, or dogs. The anti-CBM antibody did not attach to basement membrane of equine renal tubules, testicles, lung, spleen, or' liver. Whole serum or the IgG serum fraction of serum from this animal did not contain detectable anti-GBM antibody when tested by indirect immunofluoresence. In the general population, glomerulonephritis was observed in 7 of 45 horses, and this disease occasionally was responsible for renal failure and death. Glomerular eluates were examined from 16 horses, including the 3 with linear deposits of immunoglobulin and complement. Anti-GBM antibody was only found in the horse described above. These data suggest that not all animals with a linear staining GBM have the autoantibody. Most glomerulitis cases in horses would appear to be caused by the deposition of immune complexes, although it is not known what antigen(s) is involved. The factors necessary for the induction of anti-GBM antibody in humans have not been established, although there is an association between occurrence of the autoantibody and A2 influenza virus infection,' exposure to hydrocarbon solvents,' and methicillin toxicity.' Experimen-
ALlIrT tDS M&
ALICbf%r%V
AlNII-l-M ANI IDtUUT
Vo. 94, No. 2 February 1979
ILI
IN
LJ^rlCIC
HUMl;>t
AAC
445)
8d Figure 2-Glomerular
eFuate was incubated with normal horse glomerulus and stained with fluorescein-labeled anti-equine immunoglobulin. The stained glomerulus demonstrates anti-GBM antibody in the glomerular eluate.
J *
tallv, anti-GBM antibody has been induced in Brown Norwav rats bv injection of mercuric chloride.8 The reason for the appearance of antiGBM antibody in the horse was not determined, but the presence of new basement membrane in the vascular tumor raises the question whether neoplasm-derived basement membrane could have stimulated the formation of anti-GBM antibodv. However, attempts to induce anti-GBM antibody and glomerulonephritis in mice with a transmissible hemangiosarcoma were unsuccessful. Comparison With Htnan Disease
Anti-GBM antibody is present in approximately 5% of human cases of The disease most often has a progressive course with proliferative, necrotizing glomerulitis,>11 although rare individuals show spontaneous recovery.U 1.3 Approximately one half the affected individuals have concurrent pulmonary vascular damage resulting in lung hemorrhages (Goodpasture's syndrome).9"1 The diagnosis is based on clinical signs of kidney and/or pulmonary damage, linear staining of glomerular GBM by immunofluorescence, and the presence of anti-GBM antibody in the blood or glomeruli.9 The disease in the horse has been shown to have the tvpical glomerular immunohistochemical pattern, the presence of anti-GBM antibody in the glomerulus, and disruption of the normal glomerular architecture. Whether this condition would have resulted in progressive degeneration of the glomeruli could not be determined.
glomerulonephritis."90
446
BANKS
American Journal of Pathology
Availability
Of 83 kidney specimens examined by immunofluorescence, three stained in a pattern suggestive of anti-GBM-antibody-mediated glomerulonephritis. One of these three was proved to have anti-GBM antibody. This limited sample suggests that less than 1 % of horses have this disease. References
1. Cochrane CG, Koffler D: Immune complex disease in experimental animals and man. Adv Immunol 16:185-264, 1973 2. Tizard IR: An Introduction to Veterinary Immunology. Philadelphia, W. B. Saunders Co., 1977, pp 299-300 3. Banks KL, Henson JB: Immunologically mediated glomerulitis of horses. II. Antiglomerular basement membrane antibody and other mechanisms in spontaneous disease. Lab Invest 26:708-715, 1972 4. Banks KL, Henson JB, McGuire TC: Immunologically mediated glomerulitis of horses. I. Pathogenesis in persistent infection by equine infectious anemia virus. Lab Invest 26:701-707, 1972 5. Wilson CB, Smith RC: Goodpasture's syndrome associated with influenza A2 virus infection. Ann Intern Med 76:91-94, 1972 6. Zimmerman SW, Groehler K, Beirne GJ: Hydrocarbon exposure and chronic glomerulonephritis. Lancet 2:199-201, 1975 7. Wilson CG: Recent advances in the immunological aspects of renal disease. Fed Proc 36:2171-2175, 1977 8. Sapin C, Druet E, Druet P: Induction of anti-glomerular basement membrane antibodies in the Brown-Norway rat by mercuric chloride. Clin Exp Immunol 28:173-179, 1977 9. Wilson CB, Dixon FJ: Anti-glomerular basement membrane antibody-induced glomerulonephritis. Kidney Int 3:74-89, 1973 10. Wilson CB, Henderson LW, Dixon FJ: Glomerulonephritis. DM 22:1-66, 1976 11. Sisons JGP, Evans DJ, Peters DK, Eisinger AJ, Boulton-Jones JM, Simpson IJ, Macanouic M: Glomerulonephritis associated with antibody to glomerular basement membrane. Br Med J 4:11-14, 1974 12. Teichman S, Briggs WA, Knieser MR, Enquist RW: Goodpasture's syndrome: Two cases with contrasting early course and management. Kidney Int 6:105A, 1974 13. Agodoa LCY, Striker GE, George CRP, Glassock R, Quadracci LJ: The appearance of nonlinear deposits of immunoglobulins in Goodpasture's syndrome. Am J Med 61:407-413, 1976
