The inbred diabetic mutant mouse, C57BL/KsJ db +/db + (db +/db +), spontaneously develops diabetes mellitus when allowed food ad libitum. However, restriction of food intake prevents the expression of this genetic predisposition for diabetes. This experimental design has been used previously to demonstrate a deficient neutralizing antibody response to coxsackievirus B4 (CB4) in mutants with the genetic predisposition only. These observations demonstrate that in the genetically predisposed diabetic mutant, deficient humoral immunity extends further to a general impairment in both total IgM and IgG production after CB4 infection. Furthermore, these mice are unable to produce a virus-specific IgG response but do show a high level of nonspecific antibody suggesting a polyclonal activation following CB4 challenge. In addition, we observed an increase in the number of spleen IgM antibody-forming cells to sheep erythrocytes (SRBC) in the overtly diabetic animal following CB4 infection with little change apparent in the genetically predisposed animal after infection. These results were identical to the changes seen in total spleen cell numbers. Our animal model provides an opportunity to distinguish between the genetic predisposition to diabetes and the overt disease and suggests that some of the immune impairment found prior to diabetes onset may be partially diminished afterwards.
Using the criteria of virus susceptibility as defined by the 50 percent lethal dose response and the percent cumulative mortality response it was shown that the diabetic mutation db, located on chromosome 4, exerted a particular influence on the host response to CB4 challenge. Neither the yellow obese mutation Ay on chromosome 2 nor the misty coat color mutation located one centimorgan from the db mutation had the same effect on CB4 response. The obese diabetic mutation ob located on chromosome 6 appeared to enhance susceptibility to CB4. However, the high susceptibility of the inbred C57BL/6J line on which the ob mutation is found was apparently a significant contributing factor to the ob mutant high virus susceptibility. The response to CB4 was also a useful criteria to discern differences in the genetic background of closely related inbred lines. Based on the CB4 LD50 values the C57BL/6J inbred line was the most susceptible while the C57BL/Ks inbred line was the most resistant. However, using the percent cumulative mortality response as an index of host resistance, the C57BL/KsJ was the most susceptible and the C57BL/Ks the least. These findings further support the thesis that genetic predisposition to diabetes mellitus, as characterized by the mutation db on chromosome 4 is associated with a particular susceptibility and host response to coxsackie-virus B4. It also illustrates that under specific conditions, comparison of the response to virus challenge can be used as an indicator of genetic differences between closely related inbred lines.
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