The age-associated increase in autoreactive immunoglobulins reflects a quantitative increase in specificities detectable at lower concentrations in young mice.

Serum immunoglobulins reactive with several autoantigens have been reported to increase with age. The authors have studied the reactivity of serum immunoglobulins from mice between 2 and 24 months of age with antigens present in lysates of syngeneic tissue extracts from young mice. The profile of immunoglobulin binding with the immunoblots of spleen and brain tissue increased progressively with age, showing only minor differences from mouse to mouse and, with one exception, revealing that the age-associated increase in binding of immunoglobulins occurred with antigens with the same migratory position in the immunoblots detectable, at lower concentration, in sera from young mice. Not all sera from older mice had increased immunoglobulin binding when tested with extracts of skin, muscle and liver but those that did expressed increased binding with antigens in all three lysates and with the same profile shown by sera from young mice. These results are consistent with the hypothesis that the age-associated increase in autoreactive immunoglobulins represents a selective increase in autoreactive specificities expressed by serum immunoglobulins from young animals at lower levels.

Dysregulation of the humoral immune response in old mice.

The increase in autoantibodies with age of both experimental animals and humans has been thought to reflect a shift in the antibody repertoire from foreign to self antigens. In mice, before immunization, the age-associated increase in antibodies reactive with a prototypic autoantigen, bromelain-treated autologous erythrocytes (BrMRBC), reflected a 3-fold increase in serum IgM and the number of IgM-secreting spleen cells in old compared with young mice. However, the percentage of the IgM-secreting spleen cell repertoire reactive with BrMRBC in old mice was actually approximately 50% that in young mice. In contrast, after immunization with sheep erythrocytes (SRBC), old mice showed a 5-fold increase in the percentage of IgM-secreting cells reactive with BrMRBC while young mice showed no significant increase. The converse is true for the percentage of IgM-secreting spleen cells in old mice specific for SBRC, which is 10% the number generated by young mice. The increased autoantibody response of old mice is not, however, linked to their poor response to the nominal antigen. Thus, immunization with phosphorylcholine (PC) conjugated keyhole limpet hemocyanin, an antigen that induces a comparable anti-PC response in old and young mice, also induced more autoantibody forming cells in old than young mice. The increased autoantibody response of old mice after immunization can be accounted for by both an increased number of Ig-secreting spleen cells as well as an increased percentage of the expressed repertoire of IgM-secreting spleen cells that react with autoantigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for selective pressure in the appearance of monoclonal immunoglobulins during aging: studies in M54 mu-transgenic mice.

Serum monoclonal immunoglobulins (M-Ig) appear during aging but little is known about the immunological factors which lead to their development. We have investigated whether such M-Ig occur as a clonally random process or result from V-region-directed selective pressures. We have analyzed a mu-transgenic mouse strain in which over 95% of all splenic B cells express the transgenic mu chain. All endogenous repertoire and mu-chain diversity are generated from the 5% of the B cells which express endogenous mu chains. Not one of the M-Ig detected in these mice were of transgene origin alone; 11 of the 14 M-Ig did not express a mu chain and none of the mu chain containing M-Ig expressed the transgene allotype alone. This observation suggests that the B cells giving rise to M-Ig are heavily selected from among the small number of B cells which express endogenous Ig. The selective factors that might act on the endogenous B cell pools are discussed.