F 1 hybrids of New Zealand black (NZB) and New Zealand white (NZW) mice are a model of human systemic lupus erythematosus. These mice develop a severe immune complex-mediated nephritis, in which antinuclear autoantibodies are believed to play the major role. We used a genetic analysis of (NZB ϫ NZW)F 1 ϫ NZW backcross mice to provide insight into whether different autoantibodies are subject to separate genetic influences and to determine which autoantibodies are most important in the development of lupus-like nephritis. The results showed one set of loci that coordinately regulated serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones, and chromatin, which overlapped with loci that were linked to the production of autoantibodies to the viral glycoprotein, gp70. Loci linked with anti-gp70 compared with antinuclear antibodies demonstrated the strongest linkage with renal disease, suggesting that autoantibodies to gp70 are the major pathogenic antibodies in this model of lupus nephritis. Interestingly, a distal chromosome 4 locus, Nba1, was linked with nephritis but not with any of the autoantibodies measured, suggesting that it contributes to renal disease at a checkpoint distal to autoantibody production. (J. Clin. Invest. 1996. 98:1762-1772.)

Several studies have described a role for type I interferons (IFNab) in the initiation and/or prolongation of autoimmune diseases. Most pronounced has been the association of disease activity with what is now known as 'the interferon signature' of gene expression in peripheral blood mononuclear cells from lupus patients. In correlation, studies have shown that inhibition of IFNab signaling abrogates disease in various mouse models of lupus. New Zealand black (NZB) and B6.Nba2 congenic mice spontaneously develop elevated levels of serum anti-nuclear autoantibodies (ANAs). Nevertheless, neither of these strains develop fatal renal disease. The female F1 offspring of NZB or B6.Nba2 crossed with New Zealand white (NZW) mice do, however, develop kidney disease. We have previously shown that increases in endogenous IFNab levels in (B6.Nba2 Â NZW)F1 mice leads to accelerated development of renal disease in an IFNab-dependent manner. We now show that B6.Nba2 and (B6.Nba2 Â NZW)F1 mice deficient for the IFNab-receptor fail to develop ANA and renal disease, although the mice have substantial immune complex deposition in the glomeruli. Thus, endogenous IFNab might influence disease by affecting B-cell activation and differentiation, as well as the kidneys' susceptibility to damage, the latter perhaps through induction of a local inflammatory milieu.

StlmmaryMice homozygous for the Ipr gene have a defect inJ~s (CD95), a cell surface receptor that belongs to the tumor necrosis factor receptor family and that mediates apoptosis. This genetic abnormality results in lymphoproliferation characterized by the accumulation of CD4-CDS-(double negative [DN]) T cells, autoantibody production, and background strain-dependent, end-organ disease. Our previous results suggested that major histocompatibility complex (MHC) class I may be involved in the development of DN cells. To test this hypothesis, we derived C57BL/6-1pr/Ipr (B6/Ipr) mice that were deficient for the 32-microglobulin gene (32m-lpr) and had no detectable class I expression. At 6 mo of age, compared with B6/lpr littermates with normal class I genes, these mice showed greatly reduced lymphadenopathy, mostly due to a dramatic decrease in the number of DN cells. Significant changes in the percentage of other T cell subsets were noted, but only "y/~+ T cells showed a marked increase in both percentage and absolute numbers. Analysis of T cell receptor V3 expression of the remaining DN T cells in 32m-Ipr mice showed a shift to a CD4-1ike repertoire from a CDS-like repertoire in control B6/Ipr mice, indicating that a small MHC class II selected DN population was unmasked in lpr mice lacking class I.We also found that the production of immunoglobulin G (IgG) autoantibodies (antichromatin and anti-single stranded DNA), total IgG and IgG2a, but not total IgM or IgM rheumatoid factor, was significantly reduced in the fl2m-lpr mice. This work suggests that >90% of DN T cells in lpr mice are derived from the CD8 lineage and are selected on class I. However, a T cell subset selected on class II and T cells expressing 3'/~ are also affected by the lpr defect and become minor components of the aberrant DN population.

Allospecific CD8ϩ T lymphocytes are an important component of the cellular response in allograft rejection. These cells recognize and engage MHC class I antigens, leading to allospecific cytolytic responses and graft rejection. In mouse kidney allografts that survive to 3 wk after transplantation, we noted that the majority of CD8

The effect of estrogens on the renin-angiotensin system (RAS) have been well delineated. Thus, in both humans (1) and rats (2) estrogens stimulate the synthesis of angiotensinogen, the renin substrate (RS). Consequently there ensues an increase in plasma renin activity (PRA) in both species (1, 3). The resulting increase in plasma angiotensin I1 (4) has a negative feedback effect on the renal secretion of renin ( 5 ) , and plasma renin concentration (PRC) falls significantly in both species (3, 4). This results in a final PRA during estrogen treatment which is not significantly different from control levels in the rat (3). In the human, however, the negative feedback system is apparently not as effective since PRA during estrogen therapy remains somewhat elevated (1, 4, 6).Androgens have the opposite effects from estrogens on the level of the special-function proteins made in the liver, such as thyroxine binding globulin (7) and corticosteroid binding globulin (8). The effect of androgens on RS and the rest of the RAS, however, has not been extensively studied. Nasjletti et al.(9) reported that castration had no effect on RS levels in male rats and that 10 mg of testosterone given for 21 days had no effect on RS in ovariectomized rats. A preliminary report showed a temporary reduction in PRA with testosterone treatment in men

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A post-ovulatory peak of fasting supine plasma aldosterone (PA) preceded or accompanied by an increase in plasma renin activity (PRA) was previously reported. These studies have now been extended in 4 additional normal menstruating women and 4 women taking oestrogen\x=req-\ progestogen oral contraceptive pills (OCP), all studied daily for an entire cycle. Distinct luteal phase increases in PRA were seen in the 4 normals, with 2 also demonstrating a rise in PA. Plasma renin substrate (PRS) was usually unvarying throughout the control cycles. The women taking OCP, on the other hand, all had PA and PRA peaks that were apparent by the fourth or fifth day of taking "the pill". All 4 of the treated women had elevated PRS levels but only one woman showed an increase which preceded the elevation of PRA and PA. Plasma cortisol levels were usually above the normal range in the women taking OCP. This study thus indicates that factors other than oestrogen-induced increased substrate production may be responsible for the PRA and PA rise during OCP treatment Such factors might be the natri-uretic effects of oestrogens and progestogens or a direct effect on renin secretion by one of these steroids.

The development of double-negative (CD4-, CD8-) T cells and other T cells subsets in lymphoproliferation (lpr) mice continues to be poorly defined. Recent studies indicate that lpr is a mutation of a receptor mediating apoptosis. It has thus been hypothesized that T cell development in the thymus should be abnormally affected. In this study, we analyzed the TCR V beta repertoire of double-negative T cells as well as CD4+ and CD8+ single-positive subsets in various lpr and matched non-lpr strains. Particular comparisons were made to determine the influence of different class I and class II molecules on repertoire formation. The data demonstrate that positive and negative selection of the CD4+ and CD8+ subsets are normal in lpr mice when compared with non-lpr congenic mice. Surprisingly, the result also suggest that double-negative T cells are mostly selected on class I MHC molecules in a pattern similar to the CD8+ population, and that T cells positively selected on class II MHC antigens may be absent from the double-negative population. In all lpr strains, we also found an increased percentage of double-negative V beta 8.3+ cells out of proportion to levels in the CD4+ or CD8+ subsets. Longitudinal studies and studies in thymectomized animals showed that this increase reflects a peripheral process selectively affecting V beta 8.3+ double-negative T cells. Together, these repertoire data provide new insight into the effect of the lpr genetic defect on T cell development and the derivation of double-negative T cells. Despite the role of Fas in apoptosis and the abnormal expression of this gene in lpr mice, the present results support the hypothesis that thymic events are relatively normal in lpr mice, and that the double-negative T cells are mostly class I MHC selected and expanded by abnormal peripheral processes.