Abstract
The initial description of murine strains deficient in complement component C5 has been followed by the recognition in a range of animal species of a variety of natural complement component deficiencies, many of which have been characterized at the molecular level. The use of such species in inflammatory and infectious experimental models has led to significant progress in understanding the role of specific complement factors (and pathways) in disease pathogenesis. Deficiencies of early complement factors are characterized by impairment of immune response, possibly due to defective processing of immune complexes. Complete (but not partial) deficiency of the central component C3 predisposes affected animals to significant risk of infection and renal disease. Studies in species deficient in the terminal pathway component C6 are particularly relevant for investigating the pathogenetic role of the terminal membrane attack complex (MAC), implicating it as a causative agent in diverse inflammatory insults such as reperfusion injury, glomerular damage, and xenograft hyperacute rejection. Further investigations in such naturally deficient strains, added to results derived from studies in knockout animals, are likely to expand our understanding of the role of the activated complement system in experimental inflammatory disease, with significant potential implications for the treatment of human disease.
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Arroyave, C. M., Levy, R. M., and Johnson, J. S. (1977) Genetic deficiency of the fourth component of complement (C4) in Wistar rats. Immunology 33, 453–459.
Bitter-Suermann, D., Hoffmamn, T., Burger, R., et al. (1981) Linkage of total deficiency of the second component (C2) of the complement system and of genetic C2-polymorphism to the major histocompatibility complex of the guinea pig. J. Immunol. 127, 608–612.
Ellman, L., Green, I., and Frank, M. (1970) Genetically controlled total deficiency of the fourth component of complement in the guinea pig. Science 170, 74,75.
Frank, M. M., May, J., Gaither, T., et al. (1971) In vitro studies of complement function in sera of C4-deficient guinea pigs. J. Exp. Med. 134, 176–187.
Colten, H. R. Biosynthesis of the MHC-linked complement proteins (C2, C4 and factor B) by mononuclear phagocytes. Mol. Immunol. 19, 1279–1285.
Bitter-Suermann, D. and Burger, R. (1986) Guinea pigs deficient in C2, C4, C3 or the C3a receptor. Progr. Allergy 39, 134–158.
Bottger, E. C., Hoffmann, T., Hadding, U., et al. (1985) Influence of genetically inherited complement deficiencies on humoral immune response in guinea pigs. J. Immunol. 135, 4100–4107.
Bottger, E. C., Hoffmann, T., Hadding, U., et al. (1986) Guinea pigs with inherited deficiencies of complement components C2 or C4 have characteristics of immune complex disease. J. Clin. Invest. 78, 689–695.
Wagner, E., Plat, J. L., Howell, D. N., et al. (1999) IgG and complement-mediated tissue damage in the absence of C2: evidence of a functionally active C2-bypass pathway in a guinea pig model. J. Immunol. 163, 3549–3558.
Wicher, K., Wicher, V., and Gruhn, R. F. (1985) Differences in susceptibility to infection with Treponema pallidum Nichols between five strains of guinea pigs. Genitourin. Med. 61, 21–26.
Wicher, V., Wicher, K., Abbruscato, F., et al. (1999) The time-dependent clearance of virulent Treponema pallidum in susceptible and resistant strains of guinea pigs is significantly different. Clin. Immunol. 91, 77–83.
Singer, L., Colten, H. R., and Wetsel, R. A. (1994) Complement C3 deficiency: Human, animal and experimental models. Pathobiology 62, 14–28.
Schurman, S. J., McAdams, A. J., Beischel, L., et al. (1995) C3-independent glomerulonephritis in guinea pigs: dependence upon primary humoral response. Clin. Immunol. Immunopath. 74, 51–58.
Braidley, P. C., Dunning, J. J., Wallwork, J., et al. (1994) Prolongation of survival of rat heart xenografts in C3 deficient guinea pigs. Trans. Proc. 26, 1259–1260.
Winkelstein, J. A., Cork, L. C., Griffin, D. E., et al. (1981) Genetically determined deficiency of the third component of complement in the dog. Science 212, 1169–1170.
Ameratunga, R., Winkelstein, J. A., Brody, L., et al. (1998) Molecular analysis of the third component of canine complement (C3) and identification of the mutation responsible for hereditary canine C3 deficiency. J. Immunol. 160, 2824–2830.
Cork, L. C., Morris, R. M., Olson, J. L., et al. (1991) Membranoproliferative glomerulonephritis in dogs with a genetically determined deficiency of the third component of complement. Clin. Immunol. Immunopath. 60, 455–470.
Quezado, Z. M. N., Hoffmann, W. D., Winkelstein, J. A., et al. (1994) The third component of complement protects against Eschericia Coli endotoxin-induced shock and multiple organ failure. J. Exp. Med. 179, 569–578.
Gillinov, A. M., Redmond, J. M., Winkelstein, J. A., et al. (1994) Complement and neutrophil activation during cardioplumonary bypass: A study in the complement-deficient dog. Ann. Thorac. Surg. 57, 345–352.
Komatsu, M., Yamamoto, K., Nakano, Y., et al. (1988) Hereditary C3 hypocomplementemia in the rabbit. Immunology 64, 363–368.
Cinader, B., Dubiski, S., and Wardlaw, A. C. (1964) Distribution, inheritance and properties of an antigen, MuB1, and its relation to haemolytic complement. J. Exp. Med. 120, 897–924.
Nilsson, U. R. and Müller-Eberhard, H. J. (1967) Deficiency of the fifth component of complement in mice with an inherited complement defect. J. Exp. Med. 125, 1–16.
Rosenberg, L. T. and Tachibana, D. K. (1986) Mice deficient in C5. Progr. Allergy 39, 169–191.
Wheat, W. H., Wetsel, R., Falus, A., et al. (1987) The fifth component of complement (C5) in the mouse. J. Exp. Med. 165, 1442–1447.
Wetsel, R. A., Fleischer, D. T., and Haviland, D. L. (1990) Deficiency of the murine fifth complement component (C5). J. Biol. Chem. 265, 2435–2440.
Toyka, K. V., Drachman, D. B., Griffin, D. E., et al. (1977) Myasthenia gravis: Study of humoral immune mechanisms by passive transfer to mice. N. E. J. M. 296, 125–131.
Christadoss, P. (1988) C5 gene influences the development of murine myasthenia gravis. J. Immunol. 140, 2589–2592.
Liu, L., Lioudyno, M., Tao, R., et al. (1999) Hereditary absence of complement C5 in adult mice influences Wallerian degeneration, but not retrograde responses, following injury to peripheral nerve. J. Peripher. Nerv. Syst. 4, 123–133.
Kyriakides, C., Austen, W. Jr., Wang Y., et al. (1999) Membrane attack complex of complement and neutrophils mediate the injury of acid aspiration. J. Appl. Physiol. 87, 2357–2361.
Sakakibara, N., Wolf, P., Kriett, J., et al. (1996) Cardiac xenotransplantation into complement-5-deficient mice. Trans. Proc. 28, 689,690.
Liu, Z., Giudice, G. J., Zhou, X., et al. (1997) A major role for neutrophils in experimental bullous pemphigoid. J. Clin. Invest. 100, 1256–1263.
Nieuwenhuizen, G. A. P., Meyer, M. P. D., Hendriks, T., et al. (1995) Deficiency of complement factor C5 reduces early mortality but does not prevent organ damage in an animal model of multiple organ dysfunction syndrome. Crit. Care Med. 23, 1686–1693.
Miller, C. G., Cook, D. N., and Kotwal, G. J. (1997) Two chemotactic factors, C5a and MIP-1α, dramatically alter the mortality from zymosan-induced multiple organ dysfunction syndrome (MODS): C5a contributes to MODS while MIP-1α has a protective role. Mol. Immunol. 33, 1135–1137.
Kyriakides, C., Austen, W. G. Jr., Wang, Y., et al. (2000) Neutrophil mediated remote organ injury after lower torso ischaemia and reperfusion is selectin and complement dependent. J. Trauma 48, 32–38.
Hsueh, W., Sun, X., Rioja, L. N., et al. (1990) The role of the complement system in shock and tissue injury induced by tumour necrosis factor and endotoxin. Immunology 70, 309–314.
Barton, P. A. and Warren, J. S. (1993) Complement component C5 modulates the systemic tumor necrosis factor response in murine endotoxic shock. Infect. Immun. 61, 1474–1481.
Mori, L. and de Libero, G. (1998) Genetic control of susceptibility to collagen-induced arthritis in T-cell receptor β-chain transgenic mice. Arthritis Rheum. 41, 256–262.
Wang, Y., Kristan, J., Hao, L., et al. (2000) A role for complement in antibody-mediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis. J. Immunol. 164, 4340–4347.
Cerquetti, M. C., Sordelli, D. O., Bellanti, J. A., et al. (1986) Lung defenses against Pseudomonas aeruginosa in C5-deficient mice with different genetic backgrounds. Infect. Immun. 52, 853–857.
Jagannath, C., Hoffmann, H., Sepulveda, E., et al. (2000) Hypersusceptibility of A/J mice to tuberculosis is in part due to deficiency of the fifth complement component. Scand. J. Immunol. 52, 369–379.
Miller, C. G., Justus, D. E., Jayaraman, S., et al. (1995) Severe and prolonged inflammatory response to localized cowpox virus infection in footpads of C5-deficient mice: Investigation of the role of host complement in poxvirus pathogenesis. Cell. Immunol. 162, 326–332.
Byron, J. K., Clemons, K. V., McCusker, J. H., et al. (1995) Pathogenicity of Saccharomyces cerevisiae in complement factor five-deficient mice. Infect. Immun. 63, 478–485.
Rother, K., Rother, U., Muller-Eberhared, H. J., et al. (1966) Deficiency of the sixth component of complement in rabbits with an inherited complement defect. J. Exp. Med. 124, 773.
Leenaerts, P. L., Stad, R. K., Hall, B. M., et al. (1994) Hereditary C6 deficiency in a strain of PVG/c rats. Clin. Exp. Immunol. 97, 478–482.
Goldman, M. B., Cohen, C., Stronski, K., et al. (1982) Genetic control of C6 polymorphism and C6 deficiency in rabbits. J. Immunol. 128, 43–48.
Parra, G., Takekoshi, Y., Striegel, J., et al. (1992) Acute serum sickness in normal and C6 deficient rabbits: role of membrane attack complex. Int. J. Exp. Path. 73, 299–312.
Ito, W., Schafer, H. J., Bhadki, S., et al. (1996) Influence of the terminal complement-complex on reperfusion injury, no-reflow and arrythmias: a comparison between C6-competent and C6-deficient rabbits. Cardiovasc. Res. 32, 294–305.
Kilgore, K. S., Park, J. L., Tanhehco, E. J., et al. (1998) Attenuation of interleukin-8 expression in C6-deficient rabbits after myocardial ischaemia/reperfusion. J. Mol. Cell. Cardiol. 30, 75–85.
Schmiedt, W., Kinscherf, R., Deigner, H. P., et al. (1998) Complement C6-deficiency protects against diet-induced atherosclerosis in rabbits. Arterioscler. Thromb. Vasc. Biol. 18, 1790–1795.
Inoue, K., Niesen, N., Biesecker, G., et al. (1993) Role of late complement components in experimental auto-immune thyroiditis. Clin. Immunol. Immunopath. 66, 1–10.
Groggel, G. C. and Terreros, D. A. (1990) Role of complement pathway in accelerated autologous antiglomerular basement membrane nephritis. Am. J. Path. 136, 533–540.
van Dixhoorn, M. G. A., Timmerman, J. J., van Gijlswijk-Janssen, D. J., et al. (1997) Characterisation of complement C6 deficiency in a PVG/c rat strain. Clin. Exp. Immunol. 109, 387–396.
Brauer, R. B., Gegenfurtner, C., Neumann, B., et al. (2000) Endotoxin-induced lung inflammation is independent of the complement membrane-attack complex. Infect. Immun. 68, 1626–1632.
Brandt, J., Pippin, J., Schulze, M., et al. (1996) Role of the complement membrane attack complex (C5b-9) in mediating experimental mesangioproliferative glomerulonephritis. Kidney Int. 49, 335–343.
Timmerman, J. J., Mieneke, G. A., van Dixhoorn, G. A., et al. (1997) Extrahepatic C6 is as effective as hepatic C6 in the generation of renal C5b-9 complexes. Kidney Int. 51, 1788–1796.
Brauer, R. B., Baldwin, III, W. M., Ibrahim S., et al. (1995) The contribution of terminal complement components to acute and hyperacute allograft rejection in the rat. Transplantation 59, 288–293.
Qian, Z., Jakobs, F.M., Pfaff-Amesse, T., et al. (1998) Complement contributes to the rejection of complete and class I major histocompatibility complex- incompatible cardiac allografts. J. Heart Lung Transplant. 17, 470–478.
Merten, S., Chen, J. C., Ha, H., et al. (1998) The cellular basis of cardiac allograft rejection: VIII. Mechanisms underlying delayed allograft rejection in PVG C6-deficient rats. Transplantation 65, 1152–1158.
Brauer, R. B., Baldwin, III, W. M., Wang, D., et al. (1994) Hepatic and extrahepatic biosynthesis of complement factor C6 in the rat. J. Immunol. 153, 3168–3176.
Brauer, R. B., Baldwin, III, W. M., Daha, M. R., et al. (1993) Use of C6-deficient rats to evaluate the mechanism of hyperacute rejection of discordant cardiac xenografts. J. Immunol. 151, 7240–7248.
Lin, Y., Sobis, H., Vandeputte, M., et al. (1995) Natural killer cells, antibody-dependent cellular cytotoxicity and complement synthesis by the xenograft itself play a role in xenograft rejection. Trans. Proc. 27, 286–287.
Jakobs, F. M., Davis, E. A., Qian, Z. P., et al. (1997) The role of CD11b/CD18 mediated neutrophil adhesion in complement deficient xenograft recipients. Clin. Transplantation 11, 516–521.
Kronson, J. W., Hering, B. J., Sutherland, D. E., et al. (1998) Posttransplant nonfunction of canine islets in PVG rats deficient in complement component C6. Transplantation 65, 1549–1554.
Jakobs, F. M., Davis, E. A., White, T., et al. (1998) Prolonged discordant xenograft survival by inhibition of the intrinsic coagulation pathway in complement C6-deficient recipients. J. Heart and Lung Trans. 17, 306–311.
Alwayn, I. P., van Bockel, H. J., Daha, M. R., et al. (1999) Hyperacute rejection in the guinea pig-to-rat model without formation of the membrane attack complex. Transpl. Immunol. 7, 177–182.
Kerr, S. R., Dalmasso, A. P., Apasova, E. V., et al. (1999) Mouse-to-rabbit xenotransplantation: a new small animal model of hyperacute rejection mediated by the classical complement pathway. Transplantation 67, 360–365.
Wu, G. S., Korsgren, O., Wennberg, L., et al. (1999) Deoxyspergualin delays xenograft rejection in the guinea pig-to-C6-deficient rat heart transplantation model. Transpl. Int. 12, 415–422.
Wu, G. S., Korsgren, O., van Rooijen, N., et al. (1999) The effect of macrophage depletion on delayed xenograft rejection studies in the guinea pig-to-C6-deficient rat heart transplantation model. Xenotransplantation 6, 262–270.
Wu, G. S., Korsgren, O., Tibell, A. (2000) Cyclosporine induces long-term xenograft survival in the mouse-to-C6-deficient rat heart transplantation model. Transplant. Proc. 32, 1015.
Suhr, B. D., Guzman-Paz, M., Apasova, E. P., et al. (2000) Induction of accommodation in the hamster-to-rat model requires inhibition of the membrane attack complex of complement. Transplant. Proc. 32, 976.
Ji, P., Xia, G. L., and Waer, M. (2000) Complement-and xenoantibody-independent discordant xenograft rejection in a guinea pig to rat model. Transplant. Proc. 32, 935.
Meyer zu Vilsendorf, A., Nagel, E., Link, C., et al. (2000) Prolonged survival of guinea pig-to-rat heart xenografts following complement depletion and B-cell-directed immunosuppression by malononitrilamide. Transplant. Proc. 32, 864,865.
Nangaku, M., Alpers, C. E., Pippin, J., et al. (1997) Renal microvascular injury induced by antibody to glomerular endothelial cells is mediated by C5b-9. Kidney Int. 52, 1570–1578.
Hughes, J., Nangaku, M., Alpers, C. F., et al. (2000) C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis. Am. J. Physiol. Renal Physiol. 278, F747-F757.
Nangaku, M., Pippin, J., and Couser, W. G. (1999) Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome. J. Am. Soc. Nephrol. 10, 2323–2331.
Orren, A., Wallace, M. E., Hobart, M.J., et al. (1996) C6 polymorphism and C6 deficiency in site strains of the mutation-prone Peru-Coppock mice. Complement Inflamm. 6, 295–296 (Abstr.).
Zhou, W., Farrar, C. A., Abe, K., et al. (2000) Predominant role for C5b-9 in renal ischaemia/reperfusion injury. J. Clin. Invest. 105, 1363–1371.
Komatsu, M., Yamamoto, K.-I., Kawashima, T., et al. (1985) Genetic deficiency of the α-γ subunit of the eighth complement component in the rabbit. J. Immunol. 134, 2607–2609.
Komatsu, M., Yamamoto, K.-I., Mikami, H., et al. (1991) Genetic deficiency of complement component C8 in the rabbit: Evidence of a translational defect in expression of the α-γ subunit. Biochem. Genet. 29, 271–274.
Tanaka, S., Suzuki, T., Sakaizumi, M., et al. (1991) Gene responsible for deficient activity of the β subunit of C8, the eighth component of complement, is located on mouse chromosome 4. Immunogenetics 33, 18–23.
Hogasen, K., Jansen, J. H., Mollnes, T. E., et al. (1995) Hereditary porcine membranoproliferative glomerulonephritis type II is caused by Factor H deficiency. J. Clin. Invest. 95, 1054–1061.
Gerardy-Schahn, R., Ambrosius, D., Saunders, D., et al. (1989) Characterisation of C3a receptor-proteins on guinea pig platelets and human polymorphonuclear leukocytes. Eur. J. Immunol. 19, 1095–1102.
Regal, J. F. and Klos, A. (2000) Minor role of the C3a receptor in systemic anaphylaxis in the guinea pig. Immunopharm. 46, 15–28.
Pruitt, S. K., Baldwin, III, W. M., and Sanfilippo, F. (1996) The role of C3a and C5a in hyperacute rejection of guinea pig-to-rat cardiac xenografts. Trans. Proc. 28, 596.
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Linton, S. Animal models of inherited complement deficiency. Mol Biotechnol 18, 135–148 (2001). https://doi.org/10.1385/MB:18:2:135
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DOI: https://doi.org/10.1385/MB:18:2:135