The Y chromosome from autoimmune BXSB/MpJ mice induces a lupus‐like syndrome in (NZW × C57BL/6)F₁ male mice, but not in C57BL/6 male mice

Abstract

The Y chromosome of the BXSB mouse has been shown to be responsible for the acceleration of lupus-like autoimmune syndrome in inbred BXSB mice and in their F1 hybrids with NZB or NZW mice. To further define the role of this as yet unidentified gene linked to the BXSB Y chromosome, designated Yaa (Y chromosome-linked autoimmune acceleration), the Y chromosome was transferred from the BXSB strain to nonautoimmune C57BL/6 (B6) mice. The effect of the Yaa gene on the autoantibody formation and the development of glomerulonephritis was investigated in B6 mice and in their F1 hybrids with NZW mice. The presence of the BXSB Y chromosome was not able to induce significant autoimmune responses in B6 mice. However, (NZW x B6)F1 males bearing the BXSB Y chromosome developed a severe lupus-like autoimmune syndrome, as documented by the production of anti-DNA antibodies and gp70-anti-gp70 immune complexes and the development of lethal lupus nephritis. Both sexes of (NZW x B6)F1 hybrids without the BXSB Y chromosome were essentially normal. Our results suggest that (a) the BXSB Y chromosome by itself is not sufficient to initiate autoimmune responses in nonautoimmune B6 mice, and (b) it is able to induce autoimmune responses in mice potentially capable of developing the disease, but whose autosomal abnormality by itself is not sufficient to develop autoimmune diseases.

Enforced Bcl‐2 expression in B lymphocytes induces rheumatoid factor and anti‐DNA production, but the Yaa mutation promotes only anti‐DNA production

“…B6.Yaa mice (IgG2a b ) bearing the Yaa gene and BXSB.Igh a mice bearing the Igh a allotype (IgG2a a ), but lacking the Yaa mutation, were developed by backcross procedures, and established at the 12th backcross generations as described [36,37]. The (NZW×B6)F1 hybrids used in this study were obtained in our animal facilities.…”

“…Glomerulonephritis was scored on a 0-4 scale based on the intensity and extent of histopathological changes, as described previously [36,37]. Glomerulonephritis of grades 3 and 4 was considered significant contributor to clinical disease or death.…”

Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

“…[12][13][14] Not surprisingly important effects of the genetic background on the expression of autoimmunity have also been reported in gene-targeted mice. 5,15,16 For example, C1q deficiency, a condition that in humans is strongly associated with the development of a lupus-like disease, 17 in mice appears to have a disease-accelerating effect only in lupus-prone strains, including the (129 Â B6) genetic background.…”

C1q Deficiency and Autoimmunity: The Effects of Genetic Background on Disease Expression

“…In contrast, homozygosity of the lpr gene in other strains such as C57BL/6, AKR, LG/J, and C3H leads only to autoantibody production and lymphoproliferation; GN is largely absent (6). The Y-chromosome-linked Yaa gene in BXSB and MRL/Mp ϩ/ϩ males enhances the rapid development of autoantibodies and GN (7,8). However, in the C57BL/6 background, the Yaa gene does not lead to an autoimmune phenotype (7).…”

“…The Y-chromosome-linked Yaa gene in BXSB and MRL/Mp ϩ/ϩ males enhances the rapid development of autoantibodies and GN (7,8). However, in the C57BL/6 background, the Yaa gene does not lead to an autoimmune phenotype (7). Extensive mapping analyses of (New Zealand Black ϫ New Zealand White)-derived cohorts of mice have provided insights into the genetic aspects of disease inheritance in murine models of SLE.…”