Monocytosis in BXSB mice is due to epistasis between Yaa and the telomeric region of Chromosome 1 but does not drive the disease process

Rogers, NJ; Gabriel, L; Nunes, CT; Rose, S.J.; Thiruudaian, Vasuky; Boyle, J; Morley, Bernard J

doi:10.1038/sj.gene.6364424

Cited by 11 publications

(8 citation statements)

References 23 publications

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“…Monocytosis might play an important role in the disease development of BXSB mice. 12–16 Our data revealed severe monocytosis developed (approximately 40% in the spleen), and decreased significantly after As 4 S 4 treatment. The result suggests that arsenic might play a pivotal role in cell apoptosis induction and autophagy, through which monocytes were the major target.…”

Section: Discussionmentioning

confidence: 52%

Effects of tetra-arsenic tetra-sulfide on BXSB lupus-prone mice: a pilot study

Zhao

Wen

Qiao

et al. 2013

Lupus

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Systemic lupus erythematosus (SLE) is an autoimmune disease of uncertain etiology that affects multiple tissues and organs. Arsenic trioxide (ATO) has been used in lupus-prone mice with a regulatory effect on immune abnormality. Tetra-arsenic tetra-sulfide (As4S4), a traditional Chinese medicine, is effective on acute promyelocytic leukemia with mild side effects than ATO. In this study, a pilot study was performed to investigate the effects and the mechanism of As4S4 on the lupus-prone BXSB mice. Improvement of monocytosis (p<0.05) in spleen and decreased serum interleukin-6 (IL-6) (p=0.0277) were observed with As4S4 treatment. As4S4-treated mice exhibited amelioration of skin, liver and renal disease with mild side effects. Histological analysis revealed that As4S4 suppressed immune complex deposition, mesangial proliferation and inflammatory cell infiltration in kidney and liver. Our study support that As4S4 selectively suppresses cutaneous lupus and nephritis in BXSB mice and might be a potential treatment for SLE.

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Section: Discussionmentioning

confidence: 52%

Effects of tetra-arsenic tetra-sulfide on BXSB lupus-prone mice: a pilot study

Zhao

Wen

Qiao

et al. 2013

Lupus

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“…In mice, Kikuchi et al (2006) found clear association between percentages of monocytes and serum levels of anti-nuclear antibodies; monocyte levels at 10 months of age and lethal nephritis by 18 months of age were correlated. Rogers et al (2007) observed that monocytosis was closely associated with autoantibody production in NZB but not BXSB mouse models. In our rabbit model, homozygosity for the Ig heavy chain haplotype with the VH1a1 allotype allele correlated with enhanced WBC and monocyte responses suggesting genetic influences of these traits.…”

Section: Discussionmentioning

confidence: 92%

Genetic contributions to the autoantibody profile in a rabbit model of systemic lupus erythematosus (SLE)

Puliyath

Ray

Milton

et al. 2008

Veterinary Immunology and Immunopathology

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For the development of rabbit models of Systemic Lupus Erythematosus (SLE), immunoglobulin allotype-defined pedigreed rabbits from the National Institute of Allergy and Infectious Diseases rabbit resource more closely approximate human populations due to their non-inbred pedigreed structure. In an initial study from this laboratory, peptides (SM and GR) from the spliceosomal Smith (Sm) and the NMDA glutamate receptor NR2b, on branched polylysine backbones (BB) elicited antinuclear and anti-dsDNA autoantibodies typical of SLE, as well as seizures and nystagmus sometimes observed as neurological manifestations in SLE patients. This suggested the feasibility of further selective breeding to develop a more reproducible rabbit model for investigations of SLE. Here we report the results of GR-MAP-8 and control BB immunization on autoantibody responses in a group of 24 rabbits specifically bred and developed from parents and ancestors tested for autoantibody responses. The changes in hematological profile and blood chemistry in the experimental rabbits were evaluated along with autoantibody responses. Elevations of total white blood cell (WBC), monocyte, eosinophil and basophil counts that developed following immunizations were moderately influenced by litter and presence of the antibody heavy chain allotype VH1a1. Autoantibody development followed a sequential pattern with anti-nuclear antibodies (ANA) followed by anti-dsDNA and subsequently anti-Sm and anti-RNP similar to SLE patients. High autoantibody levels to one autoantigen were not always associated with antibody response to another. Female rabbits had higher prevalence and levels of autoantibodies similar to human SLE. Higher autoantibody levels of anti-dsDNA and -ANA were observed among some full sibs and the presence of high responder ancestors in the pedigree was associated the augmented responses. We observed significant association between highest antibody responses to GR-MAP-8 and highest anti-dsDNA levels. Naturally occurring autoantibodies were found in some pre-immune sera and some unique ANA fluorescent staining patterns within the experimental group were observed. Background immunofluorescence in pre-immune sera, distinct patterns of programmed autoantibody responses unique among individual rabbits may have been modulated by genetic constitution, gender and environmental factors including exposure to antigens. The high incidence and intensity of autoantibody responses among descendants of high responders suggest that there may be an additive mode of inheritance with high heritability. It is conceivable that further rigorous pedigree selection for autoantibody responses could lead to development of rabbit models with spontaneous occurrence of SLE like serology and disease phenotypes.

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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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Monocytosis in BXSB mice is due to epistasis between Yaa and the telomeric region of Chromosome 1 but does not drive the disease process

Cited by 11 publications

References 23 publications

Effects of tetra-arsenic tetra-sulfide on BXSB lupus-prone mice: a pilot study

Effects of tetra-arsenic tetra-sulfide on BXSB lupus-prone mice: a pilot study

Genetic contributions to the autoantibody profile in a rabbit model of systemic lupus erythematosus (SLE)

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

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