The response to a foreign antigen in an autoimmune animal

Abstract

The immune response to influenza A virus hemagglutinin (HA) was studied in NZB/W F{dollar}\sb1{dollar} lupus-prone mice in order to analyze whether an immune system in which much of the B cell compartment is allocated toward the production of autospecificities could respond normally to a foreign antigen, and to address whether the response to a foreign antigen could stimulate the production of autospecificities. The HA antigenic system was selected because a heavy chain variable region gene commonly used in the non-autoimmune mouse response to HA, V{dollar}\sb{lcub}\rm H{rcub}{dollar}11, is also commonly found in NZB/W F{dollar}\sb1{dollar} anti-dsDNA antibodies. Hence, it allowed simultaneous observation of a particular idiotype in the context of both foreign- and auto-immune responses.;The serological expression of V{dollar}\sb{lcub}\rm H{rcub}{dollar}11-encoded anti-HA and anti-DNA antibodies was studied in influenza A virus-primed NZB/W F{dollar}\sb1{dollar} mice. In one set of studies, mice were manipulated to upregulate V{dollar}\sb{lcub}\rm H{rcub}{dollar}11 usage using an anti-idiotypic reagent in a variety of immunization protocols. In another, the primary and secondary immune responses to influenza A virus were compared between the NZB/W F{dollar}\sb1{dollar} animals and non-autoimmune Balb/c mice. Finally, the expression of V{dollar}\sb{lcub}\rm H{rcub}{dollar}11-encoded antibodies was studied at the molecular level by capturing V{dollar}\sb{lcub}\rm H{rcub}{dollar}11 gene-expressing B cells as hybridomas from the spleen of a sick NZB/W F{dollar}\sb1{dollar} mouse that had been immunized and boosted with influenza A virus.;The results of these studies demonstrate that the immune response to influenza A virus is essentially normal in an autoimmune strain of mice--with respect to both the serological response and the molecular structure of secondary response antibodies. If there is an underlying B cell defect in these mice, it does not appear to extend into the realm of the response to foreign pathogens. Furthermore, the response to HA in the NZB/W F{dollar}\sb1{dollar} animal was not observed to directly stimulate the production of V{dollar}\sb{lcub}\rm H{rcub}{dollar}11-encoded autoantibodies. The question remains as to the nature of the eliciting antigen and the level at which tolerance breaks down to allow the expression of anti-DNA antibodies in lupus. ftn*All degree requirements completed in 1992, but degree with be granted in 1993.