No abstract

In an attempt to determine whether genes involved in T cell antigen recognition are structurally abnormal and thereby promote murine systemic lupus, we analyzed the structural integrity of the D, J, and C region elements of the T cell receptor alpha and beta chain genes in all major lupus strains and several normal strains. Within the limits of restriction fragment length polymorphism analysis, all strains had an identical genomic organization, except the NZW mice, in which a deletion of the C beta 1-D beta 2-J beta 2 elements was found. Sequence analysis of NZW genomic elements containing this deletion placed its probable origin within the first exon of C beta 1, and extending to a complementary region within the first exon of C beta 2. The significance of this abnormality in the pathogenesis of systemic autoimmune disease remains to be determined.

No 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.

We have analyzed the patterns of induced cytokine gene expression and cell cycle activity by CD4+ cells from mice, and have examined how these response patterns change during the aging process. CD4+ cells were isolated from spleens of young adult and old C57BL/6NNia mice and were stimulated in vitro with plate-bound anti-CD3 epsilon mAb. The cells were then assessed over time for the capacity to accumulate transcripts for IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, and TNF-beta; to secrete IL-2, IL-3, IL-4, IL-5, IL-6, and IFN-gamma; and to progress through S phase. Before the first major cell division in culture (< 32 h), stimulated CD4+ cells of the old group contained similar peak levels of IL-2, TNF-alpha, and TNF-beta transcripts relative to young adult controls, whereas IL-3, IL-4, IL-5, and IFN-gamma transcripts accumulated to significantly higher peak levels in the old group. These findings were consistent with the patterns of cytokine secretion later in culture (24 to 72 h): the peak IL-2 levels were similar between age groups, but the old group exhibited an enhanced capacity to release IL-3, IL-4, IL-5, and IFN-gamma. In contrast, CD4+ cells of the young group were superior in the hyper-expression of the housekeeping gene, rpL32, before cell division and in the levels of S phase activity throughout 3-day cultures. Similar analyses of CD4+ cells from mice of intermediate ages showed that the alterations in cytokine profiles occurred gradually from young adulthood to old age, whereas the reductions in proliferative capacity were late life changes. Consistent with previous reports, we found that the splenic CD4+ cell group also underwent a progressive, age-dependent increase in the proportions of cells expressing high levels of membrane CD44 (a phenotype associated with memory or effector cells). Moreover, the analysis of IL-3, IL-5, and IFN-gamma production by isolated CD4+CD44lo and CD4+CD44hi cells revealed that the capacity to produce these cytokines segregated predominantly with the CD44hi subset, regardless of donor age. Taken together, our data suggest that gradual age-associated shifts in the subset composition of the splenic CD4+ cell pool underlie progressive changes in the patterns of cytokine gene expression by this cell group.