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Inbred Strains of Mice: NZB


Inbr: F121 (J). Black. Genet: a. Origin: Outbred mice from Imp. Cancer Research Fund, London, to Univ. of Otago Med. School 1930. Inbred by Bielschowsky 1948. A number of other strains, including NZO, NZC, NZX and NZY, were developed from the same stock. (Bielschowsky and Goodall, 1970). Strain NZW was derived from the same outbred stock, but was inbred independently by Hall (Hall and Simpson, 1975).

Life-span, spontaneous disease and immunology

Develops autoimmune haemolytic anaemia of the Coombs-positive, warm antibody type (Simpson, 1976; Howie and Simpson, 1974) as well as a nephropathy which is variable in expression and unpredictable in progress, but is probably an immune-complex-induced glomerulonephritis. Burnet (1972a, b) considered that at least two genes are involved, one of which is also present in NZC. Genetic linkage to chromosomes 1, 4, 7, 10, 13 and 19 imply that multiple genes in different combinations contribute to the severe renal disease (Drake et al, 1995).

A virus may also be involved, although Simpson (1976) considered that: `. . .the case for a viral aetiology is unproven, although the possibility exists that virus may be present in incomplete form'. According to Burnet, NZB mice have an abnormally high immunological vigour and resistance to induction of immunological tolerance or paralysis, which is manifested before the animals become Coombs-positive. The condition may be transferred to young isogenic mice by cells from the spleen, but not from other lymphoid organs. Thus, the condition appears to depend on stem cells of immunocyte lines. Autoimmune plaque-forming cells, active against mouse erythrocytes, are present in old mice. Onset and severity of the condition can be influenced by diet (Fernandes et al., 1972., 1972). Theofilopoulos et al (1980) have compared immune function in this and other autoimmune strains. Only NZB splenic lymphocytes from autoimmune donors inoculated into pre-autoimmune NZB or in BALB/c mice could evoke a positive Coombs test (Jenkinson and East (1980). Diethyldithiocarbamate (DTC), an immunomodulative agent which may enhance T cells, prolongs life in autoimmune MRL-lpr/lpr mice, but not in autoimmune NZBxNZWF1 hybrids (Halpern and Yocum 1991). Defect in the expression of the alloantigen, Ly6C, which is not detectable on spleen or lymph node cells (c.f. NOD and ST but contrast most other strains) and may be due to an interruption in the flanking region of the Ly6C gene at a point 475 bp upstream of the transcription initiation site, as found in NOD (Philbrick et al 1990). Ultrastructural pathology of the thymic reticulum revealed several features in common with BXSB and MRL-lpr in varying degrees according to sex and age of the mice. Main anomalies included vacuolized aspect of the thymic epithelium, an increased number of macrophages, interdigitating cells and cystic cavities, the presence of a great number of plasmocytes and mastocytes and extensive interstitial fibrosis and arteriosclerosis. The most intriguing finding was the presence of crystal-like inclusions in epithelial cells (Nabarra et al 1990). Natural autoantibodies are involved in the heamolytic anaemia (Hentati et al, 1994).

Pure-line mice have a high level of natural thymocytotoxic autoantibodies (Auer et al., 1974., 1974), a low immune response to Dextran (cf. 6/10) (Blomberg et al., 1972., 1972), a low lymphocyte phytohaemagglutinin response (30/43) (Heiniger et al., 1975., 1975), a high 25% incidence of serum antinuclear factor (4/17) (Barnes and Tuffrey, 1967) and a poor immune response to DNP-keyhole limpet haemo-cyanin (9/11) (Borel and Kilham, 1974), and are discriminators between `H' and `L' sheep erythrocytes (cf. 12/18) (McCarthy and Dutton, 1975). Mean life-span short (2/17 = 459 days in males, 441 days in females) in SPF fostered conditions (Festing and Blackmore, 1971). Median life-span short (4/4 = 280 days males, 4/4 = 270 days females) (Stutman, 1974). Males resistant but females more susceptible to immunosuppression of contact hypersensitivity by ultraviolet B light (Noonan and Hoffman, 1994)

Hypertrophy of the pituitary in 80% of survivors to 1 year and pituitary tumours in 25% of aged breeders (Russfield, 1966).

Hybrids with NZB

In hybrids with C57BL there is a late-appearing positive direct Coombs test. Hybrids with NZW develop an autoimmune disease resembling human systemic lupus erythematosus (Talal et al., 1972., 1972), with high titres of natural thymocyto-toxic autoantibody in many animals (Shirai and Mellors, 1972). NZBxNZWF1 hybrid B cells apparently differ from normal murine B cells in their capacity to produce IgG antibodies upon T cell-dependent antigenic stimulation. (Riley et al 1991). Genetic analysis of a backcross to NZW shows that one set of loci regulate serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones and chromatin, and these overlap with loci that control autoantibodies to the viral glycoprotein gp70. These latter loci are most strongly linked with renal disease. A locus on distil chromosome 4 was linked with nephritis but not with any of the autoantibodies measured (Vyse et al, 1996). Daily intraperitoneal injections of DNase from 4-7 months of age resulted in reduced proteinuria and serum creatinine and strikinly less severe renal pathology (Macanovic et al, 1996). Autoimmunity is associated with increased anxiety and less exploratory behaviour (Schrott and Crnic, 1996). Caloric restriction and supplementation with fish oil increases life span and diminishes histological evidence of glomerulonephritis. This is associated with decreased expression of platelet-derived growth factor-A (Troyer et al, 1997)..

Other characteristics

High balsa-wood gnawing activity (12/16) (Fawdington and Festing 1980). High coumarin hydroxylating ability (cf. 4/13) (Lush and Arnold, 1975). Pentobarbital i.p. induces hepatic epoxide hydrase (cf. 4/7) (Oesch et al., 1973., 1973). Sensitive to lethal effects of ozone (2/21) (Goldstein et al., 1973., 1973). Mineral oil injected i.p. induces plasmacytomas (Potter, 1972). High plasma triglyceride (9/11) and cholesterol (11/11) levels (Jiao et al 1990).

Susceptible to mouse hepatitis virus type 3 infection (cf. 5/14) (Le Prevost et al., 1975., 1975). No transmission of murine leukaemia virus (Scripps) to succeeding generations (Jenson et al., 1976., 1976). Carries no detectable endogenous ecotropic MuLV DNA sequences (Jenkins et al 1982). In contrast to ten other strains, it does not carry type I and II endogenous type-c viruses (cf. SWR) (Stephenson et al., 1975., 1975). Totally refractory to infection by Leishmania tropica parasite (Howard et al 1980i0 1980) and to Leishmania major mexicana (Lazama-Davila, 1997). Low immune response to ganglio-series gangliosides (c.f. 4/10) Kawashima et al (1992).

About 30-40% develop neocortical ectopias due to a recessive gene with incomplete penetrance (Sherman et al, 1994)

Poor reproductive performance (24/25). Litter size 3.8 at weaning, colony output 0.5 young/female/week (Festing, 1976a). First litter size high (1/6) but fourth litter low (6/6). Low proportion of females produce four or more litters (6/6) and low percentage of fertile matings (6/6) (Fernandes et al., 1973., 1973). Intermediate breeding performance (17/24) (Hansen et al., 1973., 1973). High bone density of femur (2/11) (Beamer et al, 1996).

Auer I. O., Tomasi T. B. Jr., and Milgrom F. (1974) Natural thymocytolytic autoantibodies in NZB and other strains of mice. Cell. Immunol. 10, 404-414.

Barnes R. D. and Tuffrey M. (1967) Serum antinuclear factor and the influence of environment in mice. Nature 214, 1136-1138.

Beamer W. G., Donahue L. R., Rosen C. J., and Baylink D. J. (1996) Genetic-variability in adult bone-density among inbred strains of mice. Bone 18, 397-403.

Bielschowsky M. and Goodall C. M. (1970) Origin of inbred NZ mouse strains. Cancer Res. 30, 834-836.

Blomberg B., Geckeler W. R., and Weigert M. (1972) Genetics of the antibody response to Dextran in mice. Science 177, 178-180.

Borel Y. and Kilham L. (1974) Carrier-determined tolerance in various strains of mice: the role of isogenic IgG in the induction of hapten specific tolerance. Proc. Soc. Exp. Biol. Med. 145, 470-474.

Drake C. G., Rozzo S. J., Hirschfeld H. F., Smarnworawong N. P., Palmer E., and Kotzin B. L. (1995) Analysis of the New Zealand black contribution to lupus-like renal disease: Multiple genes that operate in a threshold manner. J. Immunol. 154, 2441-2447.

Fernandes G., Yunis J., Smith J., and Good R. A. (1972) Dietary influence on breeding behaviour, hemolytic anemia and longevity in NZB mice. Proc. Soc. Exp. Biol. Med. 139, 1189-1196.

Fernandes G., Yunis E. J., and Good R. A. (1973) Reproductive deficiency of NZB male mice. Possibility of a viral basis. Lab. Invest. 29, 278-281.

Festing M. F. W. and Blackmore D. K. (1971) Life span of specified-pathogen-free (MRC category 4) mice and rats. Lab. Anim. 5, 179-192.

Goldstein B. D., Lai L. Y., Ross S. R., and Cuzzi-Spada R. (1973) Susceptibility of inbred mouse strains to ozone. Arch. Environ. Health 27, 412-413.

Hall W. H. and Simpson L. 0 (1975) The origins of some hitherto undescribed inbred mouse strains. Lab. Anim. 9, 139-142.

Halpern M. D. and Yocum D. E. (1991) The paradoxical effects of diethyldithiocarbamate: comparisons between New Zealand black/white F1 hybrid and Balb/c mice. Clin. Immunol. Immunopathol. 58, 69-79.

Hansen C. T., Judge F. J., and Whitney R. A. (1973) Catalog of NIH rodents. National Institutes of Health. DHEW publication (NIH) 74-606, Bethesda.

Heiniger H. J., Taylor B. A., Hards E. J., and Meier H. (1975) Heritability of the phytohaemagglutinin responsiveness of lymphocytes and its relationship to leukemogenesis. Cancer Res. 35, 825-831.

Hentati B., PayelleBrogard B., Jouanne C., Avrameas S., and Ternynck T. (1994) Natural autoantibodies are involved in the haemolytic anaemia of NZB mice. Journal of Autoimmunity 7, 425-439.

Howard J. G., Hale C., and Chan-Liew W. L. (1980) Immunological regulation of experimental cutaneous leishmaniasis 1. Immunogenetic aspects of susceptibility to Leishmania tropica in mice. Parasite Immunol. 2, 303-314.

Jenkins N. A., Copeland N. G., Taylor B. A., and Lee B. K. (1982) Organization, distribution, and stability of endogenous ecotropic murine leukemia virus DNA sequences in chromosomes of Mus musculus. J. Virol. 43, 26-36.

Jenkinson A. M. and East J. (1980) The cellular basis of autoimmunity: precocious immunological maturity in NZB mice. J. Clin. Lab. Immunol. 3, 145-152.

Jenson A. B., Groff D. E., McConahey P. J., and Dixon F. J. (1976) Transmission of murine leukemia virus (Scripps) from parent to progeny mice as determined by P30 antigenemia. Cancer Res. 36, 1228-1232.

Jiao S., Cole T. G., Kitchens R., Pfleger B., and Schonfeld G. (1990) Genetic heterogeneity of lipoproteins in inbred strains of mice: analysis by gel-permeation chromatography. Metabolism 39, 155-160.

Kawashima I., Nakamura O., and Tai T. (1992) Antibody responses to ganglio-series gangliosides in different strains of inbred mice. Molecular Immunology 29, 625-632.

Le Prevost C., Virelizier J. L., and Dupuy J. M. (1975) Immunopathology of mouse hepatitis virus type 3 infection. III. Clinical and virologic observation of a persistent viral infection. J. Immunol. 115, 640-643.

Lush I. E. and Arnold C. J. (1975) High coumarin 7-hydroxylase activity does not protect mice against Warfarin. Heredity 35, 279-281.

Macanovic M., Sinicropi D., Shak S., Baughman S., Thiru S., and Lachmann P. J. (1996) The treatment of systemic lupus erythematosus (SLE) in NZB/W F1 hybrid mice; studies with recombinant murine DNase and with dexamethasone. Clin. Exp. Immunol. 106, 243-252.

McCarthy M. M. and Dutton R. W. (1975) The humoral response of mouse spleen cells to two types of sheep erythrocytes. J. Immunol. 115, 1316-1321.

Nabarra B., Dardenne M., and Bach J. F. (1990) Thymic reticulum of autoimmune mice. II: Ultrastructural studies of mice with lupus-like syndrome (NZB, BXSB, MRL/l). Journal of Autoimmunity 3, 25-36.

Noonan F. P. and Hoffman H. A. (1994) Susceptibility to immunosuppression by ultraviolet B radiation in the mouse. Immunogenet. 39, 29-39.

Oesch F., Morris N., and Daly J. W. (1973) Genetic expression of the induction of epoxide hydrase and aryl hydrocarbon hydroxylase activities in the mouse by phenobarbital or 3-methylcholanthrene. Molec. Pharmacol. 9, 692-696.

Philbrick W. M., Maher S. E., Bridgett M. M., and Bothwell A. L. (1990) A recombination event in the 5' flanking region of the Ly-6C gene correlates with impaired expression in the NOD, NZB and ST strains of mice. EMBO Journal 9, 2485-2492.

Potter M. (1972) Immunoglobulin-producing tumors and myeloma proteins of mice. Physiol. Rev. 52, 631-719.

Riley R. L., Kruger M. G., Landa B., Elia J., and Ringel A. (1991) B cells in autoimmune (NZB x NZW)F1 mice show altered IgG isotype switching upon T cell-dependent antigenic stimulation in vitro. Clin. Immunol. Immunopathol. 58, 33-45.

Russfield A. B. (1966) Tumors of endocrine glands and secondary sex organs. US Dept. of Health, Education & Welfare, Pub. Health Service Publ. 1332, Washington, DC.

Schrott L. M. and Crnic L. S. (1996) Anxiety behavior, exploratory behavior, and activity in NZB x NZW F1 hybrid mice: Role of genotype and autoimmune disease progression. Brain Behav. & Immunity 10, 260-274.

Sherman G. F., Stone L. V., Denenerg V. H., and Beier D. R. (1994) A genetic analysis of neocortical ectopias in New Zealand black autoimmune mice. Neuroreport 5, 721-724.

Shirai T. and Mellors R. C. (1972) Natural cytotoxic autoantibody against thymocytes in NZB mice. Clin. Exp. Immunol. 12, 133-152.

Simpson L. O. (1976) An NZB virus or NZB mice with viral infections? Lab. Anim. 10, 249-260.

Stephenson J. R., Reynolds R. K., Tronick S. R., and Aaronson S. A. (1975) Distribution of three classes of endogenous type-C RNA viruses among inbred strains of mice. Virology 67, 404-414.

Stutman O. (1974) Cell-mediated immunity and aging. Fed. Proc. 33, 2028-2032.

Talal N., Sternberg A. D., and Staples P. L. (1972) Immunological hyperactivity in New Zealand mice, in Tolerance, Autoimmunity and Aging (Sigel M. M. and Good R. A., eds), pp. 127-131. Thomas, Springfiled, Ill.

Theofilopoulos A. N., McConahey P. J., Izui S., Eisenberg R. A., Pereira A. B., and Creighton W. D. (1980) A comparitive immunologic analysis of several murine stains with autoimmune manifestations. Clin. Immunol. Immunopathol. 15, 258-278.

Troyer D. A., Chandrasekar B., Barnes J. L., and Fernandes G. (1997) Calorie restriction decreases platelet-derived growth factor (PDGF)-A and thrombin receptor mRNA expression in autoimmune murine lupus nephritis. Clin. Exp. Immunol. 108, 58-62.

Vyse T. J., Drake C. G., Rozzo S. J., Roper E., Izui S., and Kotzin B. L. (1996) Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice. J. Clin. Invest. 98, 1762-1772.

Updated 9 Apr. 1998
Michael FW Festing
MRC Toxicology Unit, Hodgkin Building,
University of Leicester, UK

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