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MGI - Inbred Strains: MRL

Inbred Strains of Mice: MRL

Inbr (J) 65. Albino:

a,c.

Origin: Murphy from crosses started in about 1960 involving a number of standard inbred strains. Now estimated to have a composite genome of LG (75%), AKR/J (12.6%), C3H (12.1%) and C57BL/6 (0.3%). A mutation

lpr

(lymphoproliferation) was found in the 12th. generation of b x s. Homozygotes develop massive generalised enlargement of the lymph nodes and autoimmunity, and usually die at 14-16 weeks of age.

Characteristics

Origin and characteristics reviewed by Murphy (

1981

). Theofilopoulos et al (

1980

) have compared immune function in this and other autoimmune strains. Behavioural differences between MRL and MRL-

lpr

mice can be detected before the onset of immunological symptoms in the latter congenic strain (

Sakic et al 1992

). The

lpr

mutation is caused by the insertion of of the early transposable element ETn in the

Fas

gene. This causes a striking reduction in

Fas

mRNA expression and is associated clinically with marked acceleration of the lupus-like disease (

Drappa et al, 1993

). 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

). Mice with systemic lupus erythematosus (SLE) have unusual patterns of lymphocyte traffic characterised by diminished uptake of intravenously injected autoimmune cells into lymph nodes. This appears to result from defects intrinsic to the lymphocyte population and not the micro-environment. (

Manolios et al 1990

). Levels of circulating immune complexes rise enormously from about three months of age in MRL

-lpr/lpr

but not in MRL mice. These results corresponded to histopathological glomerular findings. (

Hewicker et al 1990

). Ultrastructural pathology of the thymic reticulum revealed several features in common with NZB and

BXSB

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

). Renal thrombrexane is increased in

lpr/lpr

mice, and this is temporally associated with a decrease in glomerular thrombexane binding sites without a change in receptor affinity (

Spurney et al, 1993

). Homozygous

lpr

mice spontaneously develop lacrimal gland inflamatory lesions and are a model of human Sjogren's syndrome. These lesions were not decreased by monoclonal anti-CD4 antibodies, though the morphology was different (

Jabs et al, 1996

). Serum has high concentrations of nitrite/nitrate and peritoneal cells produce markedly higher levels of interleukin 12 (IL-12) than in MRL-+/+ controls. The high capacity to produce an enhanced responsiveness to IL-12 leads to the production of high levels of NO. These are important contributory factors in the development of autoimmunity (

Huang et al, 1996

High susceptibility of MRL-lpr to Mycobacterium leprae (contrast NOD) (Yogi et al 1989). Molecular heterogeneity of auto-anti-idiotypic antibodies has been studied by Koisumi et al (1991).

Develop a mild spontaneous arthritis which can be enhanced by intradermal injection of complete Freund's adjuvant. This appears to be due largely to background genes rather than lpr (Ratkay et al, 1994).

Embryonic stem cell lines have been established (Kawase et al, 1994).

MRL/Mp-+/+ mice develop pancreatitis and sialoadenitis from seven months of age and also drastic thymic involution. Transplantation of allogeneic foetal thymus (from C57BL/6 mice) plus either foetal bone marrow or hematopoetic cells resulted in normal T and B cell function, and the pancreatitis and sialoadenitis was also fully corrected (Hosaka et al, 1996).

Maint. by J, Ola.

Drappa J., Brot N., and Elkon K. B. (1993) The Fas protein is expressed at high levels on CD4+CD8+ thymocytes and activated mature lymphocytes in normal mice but not in the lupus-prone strain, MRL lpr/lpr. Proceedings of the National Academy of Sciences of the United States of America 90, 10340-10344.

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.

Hewicker M., Kromschroder E., and Trautwein G. (1990) Detection of circulating immune complexes in MRL mice with different forms of glomerulonephritis. Z. Versuchstierk. 33, 149-156.

Hosaka N., Nose M., Kyogoku M., Nagata N., Miyashima S., Good R. A., and Ikehara S. (1996) Thymus transplantation, a critical factor for correction of autoimmune disease in aging MRL/+ mice. Proceedings of the National Academy of Sciences of the United States of America 93, 8558-8562.

Huang F. P., Feng G. J., Lindop G., Stott D. I., and Liew F. Y. (1996) The role of interleukin 12 and nitric oxide in the development of spontaneous autoimmune disease in MRL/MP-lpr/lpr mice. Journal Of Experimental Medicine 183, 1447-1459.

Jabs D. A., Burns W. H., and Prendergast R. A. (1996) Paradoxic effect of anti-CD4 therapy on lacrimal gland disease in MRL/Mp-lpr/lpr mice. Investigative Ophthalmology & Visual Science 37, 246-250.

Kawase E., Suemori H., Takahashi N., Okazaki K., Hashimoto K., and Nakatsuji N. (1994) Strain difference in establishment of mouse embryonic stem (ES) cell lines. International Journal of Developmental Biology 38, 385-390.

Manolios N., Geczy C. L., and Schrieber L. (1990) Aberrant lymphocyte migration patterns in systemic lupus erythematosus (MRL/l, MRL/n) mice are independent of the micro-environment. Autoimmunity 7, 139-148.

Murphy E. D. (1981) Lymphoproliferation (lpr) and other sinbgle-locus models for murine lupus, in Immunologic defects in laboratory animals Vol. I (Gershwin M. E. and Merchant B., eds), pp. 143-173. Plenum Press, New York,London.

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.

Ratkay L. G., Tait B., Tonzetich J., and Waterfield J. D. (1994) Lpr and MRL background gene involvement in the control of adjuvant enhanced arthritis in MRL-lpr mice. Journal of Autoimmunity 7, 561-573.