To examine how specificity for foreign and self-antigens influence immune repertoire formation, we have studied mice transgenic (Tg) for the influenza virus hemagglutinin (HA; HA104 and HACII mice). Expression of the neo-self HA in HA104 mice (driven under the control of the SV40 promoter) is ubiquitous, and causes a population of HA-specific B cells that dominates the primary response following influenza virus immunization of BALB/c mice to be negatively selected in HA104 mice. Here we show that HA-specific memory response B cells developed equivalently in HA104 and non-Tg mice, despite evidence that the neo-self HA can be recognized by HA-specific memory B cells in HA104 mice. Furthermore, HA-specific autoantibodies were induced in the absence of virus immunization by mating HA104 mice with mice transgenic for a T cell receptor (TCR) specific for the major I-Ed determinant of HA, S1 (TS1 mice). Thus, work indicates that specificity for a self-antigen does not prevent maturation of autoreactive memory B cells through the germinal center pathway. The studies carried out in HA104 mice suggested that T cells play a critical role in regulating the B cell response to the neo-self HA. Indeed, TS1xHA104 mice developed high titers of autoantibodies to the neo-self HA even though the majority of HA-specific T cells were eliminated in the thymus. Surprisingly, when TS1 mice were mated with a lineage of HA Tg mice engineered to express HA under the control of the MHC class II promoter (HACII mice), the resultant offspring (TS1xHACII mice) developed severe autoimmunity with manifestations closely resembling human rheumatoid arthritis (RA) despite enhanced thymic deletion of HA-specific T cells. The autoimmunity in TS1xHACII mice was accompanied by the activation of peripheral HA-specific T cells concomitant with a reduction in the frequency of HA-specific T cells bearing a regulatory phenotype (CD25+) relative to TS1xHA104 mice. Additionally, TS1xHACII mice displayed evidence of systemic antigen presenting cell (APC) activation and expansion that was not seen in TS1xHA104 mice. In summary, this thesis demonstrates that there can be distinct consequences of B and T cell recognition of a systemically expressed, single neo-self antigen ranging from systemic to organ-targeted autoimmunity. Furthermore, this thesis proposes a new murine model for RA, TS1xHACII mice, that arises a consequence of T cell recognition of a self-antigen expressed endogenously by APCs.
Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 2002. Source: Dissertation Abstracts International, Volume: 63-11, Section: B, page: 5149. Supervisor: Andrew J. Caton.