Correlations of autoimmunity with H2 and T cell receptor β chain genotypesin (NZB x NZW) F₂ mice

Abstract

Accelerated autoimmunity as expressed by the classical autoimmune strain mouse (NZB x NZW)F1 is thought to be the result of major histocompatibility complex (MHC)-associated NZW genes acting on a genetic predisposition for autoimmunity as expressed by the NZB mouse. To evaluate more accurately both H-2 and T cell receptor (TcR) beta chain involvement in F1 disease, we studied the segregation of NZB (H-2d, TcRB) and NZW (H-2z, TcRW) haplotypes of these genetic elements and the development of autoimmunity in (NZB x NZW)F2 generation mice. F2 mice with the H-2d/z genotype lived shorter average life-spans and expressed elevated levels of antibodies to gp70, ssDNA and dsDNA, while those with the TcRW/W genotype (homozgous for the NZW TcR deletion) expressed elevated levels of autoantibodies but had relatively long life-spans. On the other hand, mice with the TcRB/B genotype (homozygous for the NZB TcR) produced consistently low levels of autoantibodies but died at an early age. The most severely affected F2 population were the mice carrying both the TcRB/B and H-2d/z alleles. These mice died on an average within the first 5 months of life, but produced the lowest levels of antibodies to gp70, single-stranded DNA and double-stranded DNA. These data confirm the contribution of NZW H-2-linked genes to accelerated autoimmunity in the F1 hybrid and, furthermore, define NZB TcR-linked components as primary developers of this phenomenon. They also suggest a limited, if any, contribution of both the NZW TcR deletion and traditional autoantibodies to F1 accelerated autoimmunity.

Role of the major histocompatibility complex class IIEagene in lupus susceptibility in mice

“…However, this does not imply that the Ea gene is the only gene encoded within MHC that determines the genetic susceptibility to murine SLE. Studies in New Zealand mice have demonstrated the association of the H-2 d/z heterozygosity or the bm12 mutation in the I-A␤ chain, independently of the expression of I-E molecules, with the development of SLE (27)(28)(29)(30). In view of particular sequence homologies of the A␤ ) failed to promote the development of SLE in (BALB.H-2 z ϫ NZB) ϫ NZB backcross mice (33).…”

A genetically determined insertion/deletion related polymorphism in human T cell receptor beta chain (TCRB) includes functional variable gene segments.

“…While gross differences in immune function were not observed in these strains, functional consequences of these deletions have been reported. Some studies have concluded that the TCR deletions correlate with susceptibility or resistance to autoimmune diseases (27,28). Another study showed that deletions in TCR have an impact in specific immune responses (12).…”

The Yaa Gene Model of Systemic Lupus Erythematosus

“…Extensive studies in New Zealand mice using (NZBxW)xNZB backcross, NZBXW E2, and H-2 congenic NZBXW mice by several groups have consistently demonstrated that the H-2''^^ hybrid MHC class II molecules produced in NZBxW mice are likely to act as restriction elements for their autoimmune disease (Hirose et al 1986, Kotzin & Palmer 1987, Noonan et al 1990). The role of hybrid class II molecules in the development of murine lupus was also suggested in studies on (NZWxBXSB)Ei and (NZWxSWR)Fi hybrid mice (Kawano et al 1992, Ghatak et al 1987.…”