Immune response, tolerance circumvention and autoantibodies in aging MRL/Mp-lpr and MRL/Mp-+ mice.

Isotype distribution was analyzed, as a function of age in MRL/Mp-lpr and MRL/Mp-+ mice. The mice were tested for: (1) "spontaneous" response to nucleic acid (2) induced response to alum-precipitated phosphorylcholine-rabbit gamma globulin (PC-RGG) (immunized animals) and (3) induced response to alum-precipitated PC-RGG after pretreatment with aggregate-free RGG (tolerized-immunized animals). "spontaneous" nucleic acid antibodies of isotypes, other than IgM, increased as animals became older. The quantity of RGG antibody declined as a function of the age at which animals were immunized. Young tolerized-immunized animals made less antibody of all isotypes than did immunized animals. In later life, resistance against tolerance induction developed. Aggregate-free RGG sensitized older animals and, thus, augmented the response to alum-precipitated PC-RGG. Up to the age of 20 weeks, spontaneous antibody and antibody of tolerized-immunized animals showed striking similarities in age- and strain-dependent changes of IgG2b and IgA isotypes. Results were discussed in terms of: (1) a defect in down regulation of immune responsiveness, which contributes to the initiation of autoimmunity and age-dependent resistance to tolerance induction; (2) regulatory mechanisms for isotype switching, which contribute to resistance to tolerance induction, whether naturally occurring or experimentally induced; and (3) age-related immunological changes which are inherent in the MRL/Mp genome, the mutant gene, lpr/lpr, accelerating the changes.