UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Cellular abnormalities seen in the autoimmune MRL-lpr mouse strain Kaminski, Debra Ann


The MRL-+ and MRL-/pr mouse strains spontaneously develop autoimmune disease similar to human SLE. The autosomal recessive Ipr gene causes extensive lymphoproliferation of a unique DN T cell. The transfer of the Ipr gene to non-autoimmune mice [B6- lpr] has revealed other functions of the Ipr gene, among them autoAb production. The study of disease in MRL and Ipr mouse models affords an opportunity to determine the cellular basis of immune dysregulation seen in ensuing disease. The observation that Ipr mice elicit a decreased ability to respond to mitogen or alloantigen activation was initially investigated. Coincident with the age-dependent hyporesponsiveness, an increase in the number of cells bearing the tumour-specific marker recognized by the YE19.1.3 McAb was demonstrated. These YE19.1.3+ cells were separated from cells not bearing the marker, and those bearing the marker were unable to respond to conA activation. The YE19.1.3- cells could respond to conA, but demonstrated an age related decrease in responsiveness. These results were demonstrated in both MRL- lpr and B6- lpr mice. Lastly, the involvement of thymus education in the development of lymphadenopathy was investigated by making B6- lpr ->B6- lpr and ->B6 chimeras. The percent of YE19.1.3+ cells and mitogen reactivity of these cells and the YE19.1.3- cells were comparable to B6- lpr controls in ->B6- lpr mice; the percent of YE19.1.3+ cells for ->B6 mice was greatly reduced, but mitogen responsiveness had not changed for these cells, hence the cells could not respond, demonstrating an intrinsic defect in YE19.1.3+ cells that cannot be overcome by education in a normal thymus. No age related hyporesponsiveness to conA was seen for the YE19.1.3- cells from ->B6 mice. Several aspects of certain APCs in Ipr mice were examined. The assays used demonstrated both qualitative and quantitative abnormalities seen in MRL-+, MRL- lpr and B6- lpr mice. First of all, quantification by esterase staining implied that with age, MRL-lpr PECs contained very high numbers of 1710s which resulted in less than optimal conditions for responder T cells to proliferate to conA or alloAg presentation. B6- lpr PECs had normal numbers of esterase positive PECs. When B6- lpr mice were old, their PECs augmented T cell responses, suggesting a qualitative rather than a quantitative defect in these mice when compared to MRL-lpr mice. Unfortunately, quantification using the McAb F4/80 could not support or refute the above results. ‖1 production from either Ipr animal strain did not appear to be much different from H-2 compatible controls. The studies performed on DC-enriched populations suggested that peculiar differences between MRL-lpr and B6- lpr DCs exist. MRL-lpr mice were tested for in vitro TsC function. It had previously been shown that preculture allowed for responsiveness by MRL-lpr NWT, thus experimentation was done and confirmed earlier results. Mixing experiments suggested that there may be some in vitro TsC function, but culture with a McAb specific for TsCs and TsFs [B16G] could not support those results. The above observations were not seen with B6- lpr NWT. Lastly, in vivo TsC function with respect to auto a-DNA production was assessed. MRL-+, MRL- lpr and B6- lpr mice were treated once, at the age of two months, with the immunotoxin B16G-HP to remove TsCs. Control CBA and B6 mice were also treated. This treatment led to elevated auto a-DNA production in all experimental mice; due to the variability in autoAb production for individual mice, significant differences between the treated and untreated groups could only be shown for B6- lpr mice, one week after treatment. The same treatment in control mice failed to induce auto α-DNA IgG.

Item Media

Item Citations and Data


For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.