Phenotypic Abnormalities in hr-locus Mutants

JAX® NOTES Issue 436, January 1989

Defects in the Immune System

Our understanding of immunological diseases has advanced through study of spontaneous mutations that cause defects in the development or regulation of the immune system. Although the congenitally athymic nude (nu/nu) mouse is the most widely studied of the immunological mutants, there are many euthymic mutants of the mouse with marked immunological deficits (1). Since the skin appears to function, in part, as an immunological organ, it is not surprising that several spontaneous mutations cause defects in both the skin and the immune system, (2). Unlike congenitally athymic nude mice, which are essentially devoid of hair throughout life, mice homozygous for the "hairless" (hr) mutation on Chromosome 14 develop and maintain a normal coat up at 10 days of age, at which time they lose their hair (3,4). Although hr/hr mice are euthymic, they undergo a thymic cortical atrophy by 6 months of age (5).

Lymphomagenesis in HRS/J-hr/hr

Studies of HRS/J-hr/hr mice were stimulated by the report of Meier et al. that these animals have a 45% incidence of thymic lymphomas by 10 months of age, the incidence of lymphoma in +/hr controls being only 1% (6). However, Mucerski et al. (7) have recently reported that in both HRS/J-hr/hr and hr/+ mice, the lymphoma incidence is currently nearly 100% by 18 months of age, with a mean average age of onset of approximately 10 months. Lymphomagenesis in HRS/J-hr/hr mice is associated with the expression of polytropic retroviruses during the leukemic and preleukemic periods (8). An association between impaired immune function and lymphomagenesis was suggested by decreased immune responsiveness to syngeneic lymphoma cells and purified murine leukemia viruses (9). Altered immune function in hr/hr mice may be associated with abnormalities at the level of T cells. Although splenic T cells from this mutant generate a strong cytotoxic T cell response, such cells have depressed proliferative responses to I-region alloantigens (10). Since mixed lymphocyte reactions are mediated by helper T cells, it has been suggested that the impairment in allogeneic responses reflects a selective defect in this T cell subset. Splenocytes from hr/hr mice show decreased proliferative responses to B cell mitogens and impaired plaque-forming cell responses to T-independent antigens (11). Homozygosity for the rhino (hrrh) mutation, a second recessive allele at the hr locus, also results in premature thymic involution and impaired helper T cell function (12). Homozygotes (hrrh/hrrh) are similar in appearance to hr/hr mice except that their skin becomes thickened and enormously wrinkled. It has been suggested that the T cell abnormalities in rhino mice may be associated with autoimmunity. High levels of circulating autoantibodies and other autoimmune changes are evident by 3-5 months of age (13).

Investigation of Skin

Histomorphologic investigation of the skin of hairless and rhino mice revealed hyperkeratosis of the stratified epithelium and upper part of the hair canals by 2 weeks of age. Hair loss in these mice may be related to malpositioning of the internal root sheath. The most striking feature of the skin following hair loss is the formation of cutaneous cysts from hair follicles and isolated sebaceous glands (4). Occasional skin abscesses are observed in aging mice. Langerhans cells in the epidermis of hr/hr mice express Ia antigen and are evenly distributed in the interfollicular epidermis and the outer root sheath of degenerate hair follicles (14). Although the functional capacity of Langerhans cells in hr/hr mice is unknown, an abnormality in these cells is suggested by defective contact sensitivity responses in this mutant (15).

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  11. Vogel, S.S., Weinblatt, A.C. Rosenstreich, D.L. 1981. Inherent macrophage defects in mice. In: Immunologic Defects in Laboratory Animals, Vol 1, ed. M.E. Gershwin, B. Merchant, pp. 215-65. New York, Plenum.
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  13. Kawaji, H., Tsukuda, R., Nakaguchi, T. 1980. Immunopathology of rhino mouse, an autosomal recessive mutant with murine lupus-like disease. Acta. Pathol. Jpn. 30:515.
  14. Baker, K.W., McKee-Protopapas, S., Habowsky, J.E.J. 1983. The Langerhans cell in hairless mouse epidermis. In: Scanning Electron Microscopy, ed. Johiri, Sharma, pp. 457-465. Chicago, SEM.
  15. Shultz, L.D., Heiniger, H. Potathil, R. 1976. Impaired cellular immunity and leukemogenesis. Jackson Laboratory Ann. Rep. 47:25.