Lupus susceptibility loci map within regions of BXSB derived from the SB/Le parental strain

Maibaum, MA; Haywood, M; Walport, Mark J.; Morley, Bernard J

doi:10.1007/s002510050632

Cited by 23 publications

(24 citation statements)

References 12 publications

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“…Thus, the Ifi202 promoter region polymorphism may not be involved in lupus susceptibility in BXSB mice and in disease protection in our BXSB.␥ Ϫ/Ϫ mice as well. On the other hand, it is known that there are two SLAM/CD2 haplotypes (haplotypes 1 and 2) and that BXSB mice carry the parental SB/Le strain-derived haplotype 2 distinct from that of B6-derived haplotype 1 (41,45). These SLAM/CD2 family genes were reported to play a role in the modulation of cellular activation and signaling in the immune system (42)(43)(44), and B6 mice congenic for haplotype 2 show increased serum levels of IgG antichromatin Abs, suggesting that polymorphic SLAM/CD2 molecules are ideal candidates for autoimmune phenotype (41).…”

Section: Discussionmentioning

confidence: 99%

Genetic Dissection of the Effects of Stimulatory and Inhibitory IgG Fc Receptors on Murine Lupus

Lin

Xiu

Jiang

et al. 2006

The Journal of Immunology

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Immune complex (IC)-mediated tissue inflammation is controlled by stimulatory and inhibitory IgG Fc receptors (FcγRs). Systemic lupus erythematosus is a prototype of IC-mediated autoimmune disease; thus, imbalance of these two types of FcγRs is probably involved in pathogenesis. However, how and to what extent each FcγR contributes to the disease remains unclear. In lupus-prone BXSB mice, while stimulatory FcγRs are intact, inhibitory FcγRIIB expression is impaired because of promoter region polymorphism. To dissect roles of stimulatory and inhibitory FcγRs, we established two gene-manipulated BXSB strains: one deficient in stimulatory FcγRs (BXSB.γ−/−) and the other carrying wild-type Fcgr2b (BXSB.IIBB6/B6). The disease features were markedly suppressed in both mutant strains. Despite intact renal function, however, BXSB.γ−/− had IC deposition in glomeruli associated with high-serum IgG anti-DNA Ab levels, in contrast to BXSB.IIBB6/B6, which showed intact renal pathology and anti-DNA levels. Lymphocytes in BXSB.γ−/− were activated, as in wild-type BXSB, but not in BXSB.IIBB6/B6. Our results strongly suggest that both types of FcγRs in BXSB mice are differently involved in the process of disease progression, in which, while stimulatory FcγRs play roles in effecter phase of IC-mediated tissue inflammation, the BXSB-type impaired FcγRIIB promotes spontaneous activation of self-reactive lymphocytes and associated production of large amounts of autoantibodies and ICs.

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Section: Discussionmentioning

confidence: 99%

Genetic Dissection of the Effects of Stimulatory and Inhibitory IgG Fc Receptors on Murine Lupus

Lin

Xiu

Jiang

et al. 2006

The Journal of Immunology

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“…S3). Second, the major susceptibility loci associated with autoimmune disease in this model have been rigorously mapped and none are located near Il21r (23,24). IL-21 signaling is therefore fundamental to one or more critical steps in the pathogenesis of SLE in BXSB-Yaa mice.…”

Section: Discussionmentioning

confidence: 99%

A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaamice

Bubier

Sproule

Foreman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

269

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Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor ␥ chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T H17) and follicular CD4 T helper cells (T FH), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T H17 cells and was not limited to conventional CXCR5 ؉ TFH but instead was produced broadly by ICOS ؉ CD4 ؉ splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.autoimmune disease ͉ autoantibodies ͉ B cells ͉ T cells S ystemic lupus erythematosus (SLE) in humans is a chronic, multigenic autoimmune disease characterized by a wide spectrum of clinical abnormalities, the production of multiple autoantibodies, and the generation of immune complexes that often lead to severe renal disease. The production of autoantibodies is indicative of a profound breakdown in humoral tolerance mechanisms and B cell hyperactivity caused either by B cell-intrinsic abnormalities or immunoregulatory defects of other cell types. Mouse models genetically programmed to develop characteristics of SLE have proven useful for characterizing this disease process and for identifying potential therapeutic targets. Among the most interesting models of SLE are the BXSB mice bearing the Y chromosome-linked autoimmune acceleration (Yaa) mutation (1). Affected animals develop a remarkably severe disease characterized by lymphoid hyperplasia, monocytosis, hypergammaglobulinemia, and severe immune complex-mediated glomerulonephritis. In contrast to the female prevalence of SLE in humans, this disease is male-biased because of the epistatic effects of BXSB-background autosomal alleles in combination with Yaa. This mutant locus is the result of the duplication of at least 17 genes in the X chromosome, including Toll-like receptor 7 (Tlr7), and their placement in the Y chromosome (2, 3). Remarkably, severe autoimmune disease results from the presence of an extra copy of these X-chromosome genes in Yaa mice in combination with BXSB-background autosomal alleles.IL-21 is a pleiotropic member of the ␥-chain family of cytokines, which engages the IL-21 receptor (IL-21R) and the common cytokine re...

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“…This locus was also associated with the production of anti-dsDNA and anti-ssDNA Ab. We have previously studied the derivation of the BXSB strain (21). The additional disease-associated locus identified in this study, Gp1, spans a region that is mainly derived from the B6 parental strain of BXSB.…”

Section: 03) Within the Context Of This Analysis This Does Not Rementioning

confidence: 99%

“…Furthermore, we have extensively studied the derivation of the BXSB strain and identified intervals that are B6-derived and therefore identical with the corresponding B10 intervals resulting from the backcross (21). Therefore, these intervals will not segregate in the crosses.…”

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confidence: 99%

Autoantigen Glycoprotein 70 Expression Is Regulated by a Single Locus, Which Acts as a Checkpoint for Pathogenic Anti-Glycoprotein 70 Autoantibody Production and Hence for the Corresponding Development of Severe Nephritis, in Lupus-Prone BXSB Mice1

Haywood

Vyse

McDermott

et al. 2001

The Journal of Immunology

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Retroviral envelope glycoprotein gp70 is present in the sera of immunologically normal and autoimmune-prone strains of mice. However, only lupus-prone mice spontaneously develop gp70-anti-gp70 immune complexes (gp70IC), and these have been implicated in the development of nephritis. We investigated the genetic factors that affect the production of both free serum gp70 and gp70IC in the lupus-prone BXSB mouse strain by analyzing (BXSB × (C57BL/10 × BXSB)F1)- and (C57BL/10 × (C57BL/10 × BXSB)F1)-backcrossed male mice. Production of gp70 mapped to a single major locus located on chromosome 13 (Bxs6) with a maximum log likelihood of the odds of 36.7 (p = 1.6 × 10−38). The level of gp70IC was highly dependent on Bxs6-related gp70 production, and high titer autoantibody production only occurred when serum gp70 levels were greater than a threshold value of ∼4.0 μg/ml. The subdivision of the (BXSB × (C57BL/10 × BXSB)F1)-backcrossed mice into those homozygous or heterozygous for Bxs6 enabled a remarkable association to be observed between high levels of gp70IC and severe nephritis in the Bxs6 homozygote population. A further mapping study in these two subgroups identified a previously unrecognized interval associated with the production of autoantibodies.

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Lupus susceptibility loci map within regions of BXSB derived from the SB/Le parental strain

Cited by 23 publications

References 12 publications

Genetic Dissection of the Effects of Stimulatory and Inhibitory IgG Fc Receptors on Murine Lupus

Genetic Dissection of the Effects of Stimulatory and Inhibitory IgG Fc Receptors on Murine Lupus

A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaamice

Autoantigen Glycoprotein 70 Expression Is Regulated by a Single Locus, Which Acts as a Checkpoint for Pathogenic Anti-Glycoprotein 70 Autoantibody Production and Hence for the Corresponding Development of Severe Nephritis, in Lupus-Prone BXSB Mice1

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