CURRENT COMMENT Immune Deposit Diseases Or Of Mink and Mice Possible Analogies to the Connective Tissue Disorders B y RALPH C . WILLIAMS, JR. R a persuasive analogy has become apparent between certain aspects of several naturally occurring or experimental animal disease states and features shared by some of the connective tissue disorders-particularly disseminated lupus erythematosus. These similarities relate to the presence of antinuclear antibodies as well as circulating nuclear antigens in the sera of mink with Aleutian disease' as well as in NZB r n i ~ e in ~ -the ~ process of developing renal lesions. Most recently the animal model invoked by lymphocytic choriomeningitis has been compared or studied by Dixon and cow o r k e r ~as~another ~~ possible animal model for tissue lesions caused by deposition of immune complexes. A burgeoning array of new observations and evidence is now available implicating, at least in part, antinuclear antibodies and complexed nuclear antigens or other autologous immune complexes in the pathogenesis of immune deposit diseases*-ll and particularly glomerular lesions. In this setting the pathogenic significance of so-called autoantibodies must be carefully reappraised. Since disease such as Aleutian disease of mink or the ferret disease described by Buko and Kenyon12 appear to be directly related to very small filterable agents,13 antibodies with apparent antinuclear reactivity noted in these conditions may conceivably be directed primarily a t the infecting agents. Antinuclear antibodies in this setting may not be auto-reactors at all unless infecting virus or similar agents be generously classified as autologous materials. A review of the background of this resurgence of interest in the animal models of NZB disease of mice14J5 and Aleutian disease of mink seems in order. From the Department of Medicine, University Hospitals, Minneapolis, Minnesota. RALPH C. WILLIAMS, JR., M.D.: Associate Professor of Medicine. ECENTLY ALEUTIANDISEASE Aleutian disease of mink, first described by Hartsoughl6 and later studied by many independent groups of investigat~rs,l~-*~ afflicts many varieties of mink. It seems to be unusually severe in animals homozygous for the Aleutian gene; hence the origin of the name. Quite early in the series of clinical and pathologic studies of this disease the profound hypergammaglobulinemia present in some infected animals was noted.2l Further studies of the gamma globulin abnormalities in these mink indicated interesting complexes detectable by ultracentrifugation of some mink sera.22,23 Later this same group of workers described emergence of myeloma-like monoclonal yG immunoglobulin components in the sera of 10-15 per cent of diseased mink who sur- ARTHRITIS AND RHEUMATISM, VOL. 11, No. 4 (AUGUST1968) 593 594 RALPH C. W I L L l A M S , JR. vived and harbored the infection for peri- agent is present complexed to 7-globulins ods longer than 12 months.24 The serum circulating in plasma. protein abnormalities which also included NZB DISEASE OF MICE the presence of anti-y-globulin factors2j Considerable excitement was aroused by were matched by the striking histologic similarity of some of the lesions to those of the early reports2v3of serologic and pathoperiarteritis or disseminated lupus.26 These logic similarities between systemic lupus tissue and histopathologic parallels were erythematosus and an affliction of a paremphasized quite early by Leader and ticular strain of mice. It is not the purpose of this essay to trace the tremendous outof literature dealing with this interestput The situation in Aleutian disease then ing disease, but rather to point out how presented certain serum protein, serologic recent experimental work from several laband histologic similarities to human afflicoratories brings out the analogy to Aleutian tions like SLE or even the vasculitis of rheumatoid arthritis. Central to the enigma disease of mustelids and the participation of this interesting animal model was the of apparent immune complexes in the NZB association of apparent high titers of the renal lesions. It was shown quite early in infectious agent in the serum or circulating the work on NZB mice that serum antiplasma of infected animals with concomi- nuclear factors paralleled the clinical protant marked hypergammaglobulinemia. The gression of disease in these animals.14 Requestion was raised quite properly if the cently elution experiments by Lambert and hypertrophy of y-globulin were truly anti- Dixon5 have indicated that the major porbody to the infecting agent or some type of tion of the yG globulin which can be eluted auto or anti-tissue antibody stimulated by from NZB kidneys is antinuclear antibody. cell breakdown and the chronic renal or Furthermore, the renal disease could be hepatic lesions. Attempts to characterize markedly accentuated by “boosting” these the exact segment of serum harboring the animals with DNA linked by methylation infectious principle were undertaken,2* but to BSA and thereby made antigenic? When it was not until the recent definitive experi- these recent findings are added to the prements of Porter and c o - w o r k e r ~that ~ ~ the liminary evidence cited by Mellors of viral the central core puzzle of co-existent infectious particles in lesions from NZB case for the possible interrelationship of agent and marked hypergammaglobulinechronic viral infections and this disease bemia was solved. comes even more intriguing. It is remarkIn this latter work it was shown that able how closely the observations concernspecific antiserum to mink y-globulin when ing elution of y-globulins from lesions in reacted with an infectious mink serum pool, human lupus glomeruli and NZB kidneys markedly reduced infectivity of such sera have paralleled each ~ t h e r . ~ . ~One J l finds as the y-globulins were precipitated out. it difficult to escape from the conclusion This fruitful approach, patterned after that the kidney lesions in both of these similar experiments previously done with conditions may be what has been called other chronic animal virus infections,30-32 immune deposit disease.s has greatly added to our understanding of Since the early observations on the posthis chronic infectious disease of mink. tulated contributions of antigen-antibody From the experiments of Porter and Lar- complexes to tissue lesions of hypersensisenz9 it thus appears that the infectious tivity, as in experimental serum ~ i c k n e s s ~ ~ ~ ~ IMMUNE DFPOSlT DISEASES 595 or experimental glomerulonephritis in rabbit~~ the~ ;concept of immune complexes being directly involved in tissue damage has been tremendously amplified and ex~ a n d e d . ~ Now, ’ - ~ ~ as has been pointed out above, in 2 animal models-Aleutian disease of mink and NZB disease of micethere is good experimental evidence for circulating nuclear antigens and antinuclear antibodies. The same situation has been carefully documented in a large series of human patients with systemic lupus,4O where in several instances serial observations have implicated disappearance of detectable nuclear antigens with a clinical exacerbation and concomitant depression of serum ~ o m p l e m e n t ~ oactivity. .~~ Coupling these interesting clinical observations with the recent report by Pincus and co-workers,4* one may speculate that the quality of antibody, particularly the non-precipitating antibody molecules, may have a distinct role in producing nephrotoxicity. The specific logistic requirements for production of immune complex lesions in the animal models of Aleutian disease or NZB disease can be more precisely approached when more is known of the causative agents. Precise knowledge of the intricate specificities and variability of various human antinuclear antibodies as defined by the work from many l a b o r a t o r i e ~may ~~-~ help ~ us to characterize or define the “nuclear” antigens detectable among Aleutian disease mink or NZB mice. The problem as to whether the nuclear antigens-seemingly so central to the main argument of immune deposit disease of mink, mice or man-are related to autologous nuclear breakdown products or to specific viral antigens, remains to be solved. REFERENCES 1. Barnett, E. V., Williams, R. C., Jr., Kenyon, A. J., and Henson, J. B.: Nuclear antigens and antinuclear antibodies in mink sera. Arthritis Rheum. 11:92,1968. 2. Helyer, B. J., and Howie, J. B.: Renal disease associated with positive lupus erythematosus tests in a cross-bred strain of mice. Nature 197:197, 1963. 3. Holmes, M. C., and Burnet, F. M.: The natural history of autoimmune disease in NZB mice. Ann. Intern. Med. 59:265, 1963. 4. Norins, L. C., and Holmes, M. C.: Antinuclear factor in mice. J. Immun. 93:148, 1964. 5. Lambert, P. H., and Dixon, F. J.: Pathogenesis of the glomerulonephritis of NZB/W mice. J. Exp. Med. 127507, 1968. 6. Oldstone, M., and Dixon, F. J.: Production of anti-LCM antibody by “tolerant” LCM infected mice. Science 158:1193, 1967. 7. Dixon, F. J.: Personal communication, 1968. 8. Michael, A. F., Jr., Drummond, K. N., Good, R. A., and Vernier, R. L.: Acute poststreptococcal glomerulonephritis: immune deposit disease. J. Clin. Invest. 45237, 1966. 9. Krishnan, C., and Kaplan, M. H.: Immunopathologic studies of systemic lupus erythematosus. 11. Anti-nuclear reaction of y-globulin eluted from homogenates and isolated glomeruli of kidneys from patients with lupus nephritis. J. Clin. Invest. 46:569, 1967. 10. Edgington, T. S., Glassock, R. J., and Dixon, F. J.: Autologous immune complex pathogenesis of experimental allergic glomerulonephritis. Science 155:1432,1967. 11. Koffler, D., Schur, P. H., and Kunkel, H. G.: Immunologic studies concerning the nephritis of systemic lupus erythematosus. J. Exp. Med. 126: 607, 1967. 12. Kenyon, A. J., Magnano, T., Helmboldt, C. F., and Buko, L.: Aleutian disease in the ferret. J. Amer. Vet. Med. Assoc. 149:920, 1966. 13. Buko, L., and Kenyon, A. J.: Aleutian disease gammopathy of mink induced with an ultrafiltrable agent. Nature 216:69, 1967. 14. McGiven, A. R., and Lynraven, G. S.: Glomerular lesions in NZB/NZW mice. Electron microscopic study of the development. Arch. Path. (Chicago) 852.50, 1968. 15. Mellors, R. C.: Autoimmune disease in NZB/BL mice. I. Pathology and pathogenesis of a model. System of spontaneous glomerulonephritis. J. Exp. Med. 122325, 1965. 16. Hartsough, G. R., and Gorham, J. R.: Aleu- 596 tian disease in mink. Natl. Fur News 28:11, 1956. 17. Helmboldt, C. F., Jungherr, E. L.: The pathology of Aleutian disease in mink. Am. J. Vet. Res. 19:212 ,1958. 18. Henson., J. B., Gorham, J. R., Leader, R. W., and Wagner, B. M.: Experimental hypergammaglobulinemia in mink. J. Exp. Med. 116:357, 1962. 19. Kenyon, A. J., Trautwein, G., and Helmboldt, C. F.: Characterization of blood serum proteins from mink with Aleutian disease. Amer. J. Vet. Res. 24:168, 1963. 20. Karstad, L., and Pridham, T. J.: Aleutian disease of mink. I. Evidence of its viral etiology. Canad. J. Comp. Med. 26:97, 1962. 21. Henson, J. B., Leader, R. W., and Gorham, J. R.: Hypergammaglobulinemia in mink. Proc. Soc. Exp. Biol. Med.107:919,1961. 22. Larsen, A. E., and Porter, D. D.: Host response to Aleutian disease virus of mink. Fed. Proc. 26:482, 1967. 23. Porter, D. D., Dixon, F. J., and Larsen, A. F.: Metabolism and function of gamma globulin in Aleutian disease of mink. J. Exp. Med. 121: 889,1965. 24. Porter, D. D., Dixon, F. J., and Larsen, A. E.: The development of a myeloma-like condition in mink with Aleutian disease. Blood 25:736, 1965. 25. Williams, R. C., Jr., Russell, J. D., and Kenyon, A. J.: Antigammaglobulin factors and immunofluorescent studies in normal mink and mink with Aleutian disease. Amer. J. Vet. Res. 27:1447, 1966. 26. Thompson, G. R., and Aliferis, P.: A clinical-pathological study of Aleutian mink disease; an experimental model for study of the connective tissue diseases. Arthritis Rheum. 7:521, 1964. 27. Leader, R. W.: Lower animals, spontaneous disease and man. Arch. Path. (Chicago) 78: 390, 1964. 28. Henson, J. B., Williams, R. C., Jr., and Gorham, J. R.: Isolation of serum fractions capable of producing Aleutian disease in mink. J. Immun. 97:344, 1966. 29. Porter, D. D., and Larsen, A. E.: Aleutian disease of mink: infectious virus-antibody complexes in the serum. Proc. SOC.Exp. Biol. Med. 126:680, 1967. 30. Notkins, A. L., Mahar, S., Scheele, C., and Goffman, J.: Infectious virus-antibody complex in the blood of chronically infected mice. J. Exp. Med. 124:81, 1966. 31. Notkins, A. L.: Lactic dehydrogenase virus. RALPH C. WILLIAMS, JR. Bact. Rev. 29:143, 1965. 32. Volkert, M., and Lundstedt, C.: The provocation of latent lymphocytic choriomeningitis virus infections in mice by treatment with antilymphocytic serum. J. Exp. Med. 127:327, 1968. 33. Mellors, R. C., and Huang, C. Y.: Immunopathology of NZB/BL mice. V. Virus-like (filterable) agent separable from lymphoma cells and identifiable by electron microscopy. J. Exp. Med. 124:1031, 1966. 34. Germuth, F. G., Jr., Flanagan, C., and Montenegro, M. R.: The relationships between the chemical nature of the antigen, antigen dosage, rate of antibody synthesis and the occurrence of arteritis and glomerulonephritis in experimental hypersensitivity. Bull. Hopkins Hosp. 101:149, 1957. 35. Dixon, F. J.: Experimental serum sickness. In Samter, M. (Ed.): Immunological Diseases. Boston, Little, Brewn, p. 161. 36. Dixon, F. J., Feldman, J. D., and Vasquez, J. J.: Experimental glomerulonephritis. The pathogenesis of a laboratory model resembling the spectrum of human glomerulonephritis. J. Exp. Med. 113:899, 1961. 37. Ishizaka, K., Ishizaka, T., and Campbell, D. H.: The biological activity of soluble antigenantibody complexes. 11. Physical properties of soluble complexes having skin imtating activity. J. Exp. Med. 109:127, 1959. 38. Cochrane, C. C.: Studies on the localization of circulating antigen-antibody complexes and other macromolecules in vessels. I. Structural studies. J. Exp. Med. 118:489, 1963. 39. Kniker, W. T., and Cochrane, C. C.: The localization of circulating immune complexes in experimental serum sickness. The role of vasoactive amines and hydrodynamic forces. J. Exp. Med. 127:119, 1968. 40. Schur, P. H., and Sandson, J.: Immunologic factors and clinical activity in lupus erythematosus. New Eng. J. Med. 278:533, 1968. 41. Tan, E. M., Schur, P. H., Carr, R. I., and Kunkel, H. G.: Deoxyribonucleic acid (DNA) and antibodies to DNA in serum of patients with systemic lupus erythematosus. J. Clin. Invest. 45: 1732,1966. 42. Pincus, T., Haberkern, R., and Christian, C. L.: Experimental chronic glomerulitis. J. Exp. Med. 127:819, 1968. 43. Tan E. M., and Kunkel, H. G. Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus. J. Immun. 96:464, 1966. 44. Tan, E. M.: An immunologic precipitin sys- IMMUNE DEPOSIT DISEASES tem between soluble nucleoprotein and serum antibody in systemic lupus erythematosus. J. Clin. Invest. 46:735, 1967. 45. Tan, E. M.: Relationship of nuclear staining patterns with precipitating antibodies in systemic lupus erythematosus. J. Lab. Clin. Med. 70:800, 1967. 46. Barnett, E. V., Condemi, J. J., Leddy, J. P., and Vaughen, J. H.: y z , yla, and yl, antinuclear factors in human sera. J. Clin. Invest. 43: 1104,1964. 47. Arana, R., and Seligmann, M.: Antibodies to 597 native and denatured deoxyribonucleic acid in systemic lupus erythematosus. J. Clin. Invest. 46: 1867,1967. 48. Stollar, D., Levine, L., Lehrer, H. I., and Van Vunakis, H.: The antigenic determinants of denatured DNA reactive with lupus erythematosus serum. Proc. Nat. Acad. Sci. U. S. A. 48:874, 1962. 49. Gonzales, E. N., and RoMeld, N. F.: Immunoglobulin class and pattern of nuclear fluorescence in systemic lupus erythematosus. New Eng. J. Med. 274:1333, 1966.