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Female Bias in Systemic Lupus Erythematosus is Associated with the Differential Expression of X-Linked Toll-Like Receptor 8.

McDonald G, Cabal N, Vannier A, Umiker B, Yin RH, Orjalo AV, Johansson HE, Han JH, Imanishi-Kari T - Front Immunol (2015)

Bottom Line: Here, we show the results of our investigation into the role of Tlr8 expression in SLE pathogenesis in 564Igi females.Bone marrow-derived macrophages from 564Igi females have a significant increase in Tlr8 expression compared to male-derived cells, and RNA fluorescence in situ hybridization data suggest that Tlr8 may escape X-inactivation in female-derived macrophages.These results propose a model by which females may be more susceptible to SLE pathogenesis due to inefficient inactivation of Tlr8.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Physiology and Pathobiology, Tufts University , Boston, MA , USA.

ABSTRACT
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of anti-nuclear antibodies. SLE is one of many autoimmune disorders that have a strong gender bias, with 70-90% of SLE patients being female. Several explanations have been postulated to account for the severity of autoimmune diseases in females, including hormonal, microbiota, and gene dosage differences. X-linked toll-like receptors (TLRs) have recently been implicated in disease progression in females. Our previous studies using the 564Igi mouse model of SLE on a Tlr7 and Tlr9 double knockout background showed that the presence of Tlr8 on both X chromosomes was required for the production of IgG autoantibodies, Ifn-I expression and granulopoiesis in females. Here, we show the results of our investigation into the role of Tlr8 expression in SLE pathogenesis in 564Igi females. Female mice have an increase in serum pathogenic anti-RNA IgG2a and IgG2b autoantibodies. 564Igi mice have also been shown to have an increase in neutrophils in vivo, which are major contributors to Ifn-α expression. Here, we show that neutrophils from C57BL/6 mice express Ifn-α in response to 564 immune complexes and TLR8 activation. Bone marrow-derived macrophages from 564Igi females have a significant increase in Tlr8 expression compared to male-derived cells, and RNA fluorescence in situ hybridization data suggest that Tlr8 may escape X-inactivation in female-derived macrophages. These results propose a model by which females may be more susceptible to SLE pathogenesis due to inefficient inactivation of Tlr8.

No MeSH data available.


Related in: MedlinePlus

564Igi females have more circulating pathogenic IgG autoantibodies. (A) Anti-RNA antibodies were detected using and isotype-specific anti-RNA ELISA. Shown is the mean O.D. 405 nm ± SEM at various serum dilutions. The number of mice is shown in the key. (B) Shown is the ratio of male:female offspring born to the dam in the indicated breeding pair. Each data point represents a single litter. The average ratio is shown with a horizontal line. (C) Pregnant C57BL/6 dams were given introperitoneal injections with 1.5 μg of the indicated antibody or media control at approximately embryonic days 13–15. Shown is the ratio of male:female offspring in each litter. Each data point represents a single litter. The average ratio is shown with a horizontal line. (D,E) The mean (D) anti-RNA and (E) anti-DNA reactivities of the indicated antibodies were tested by ELISA. Shown is the mean O.D. 405 nm ± SEM at the indicated antibody concentrations. The number of replicates is shown in the key. (F) Purified 564 and 2C10 antibodies were tested for anti-nuclear reactivity by HEp-2 staining. Shown are the staining representative staining patterns of at least four independent experiments.
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Figure 1: 564Igi females have more circulating pathogenic IgG autoantibodies. (A) Anti-RNA antibodies were detected using and isotype-specific anti-RNA ELISA. Shown is the mean O.D. 405 nm ± SEM at various serum dilutions. The number of mice is shown in the key. (B) Shown is the ratio of male:female offspring born to the dam in the indicated breeding pair. Each data point represents a single litter. The average ratio is shown with a horizontal line. (C) Pregnant C57BL/6 dams were given introperitoneal injections with 1.5 μg of the indicated antibody or media control at approximately embryonic days 13–15. Shown is the ratio of male:female offspring in each litter. Each data point represents a single litter. The average ratio is shown with a horizontal line. (D,E) The mean (D) anti-RNA and (E) anti-DNA reactivities of the indicated antibodies were tested by ELISA. Shown is the mean O.D. 405 nm ± SEM at the indicated antibody concentrations. The number of replicates is shown in the key. (F) Purified 564 and 2C10 antibodies were tested for anti-nuclear reactivity by HEp-2 staining. Shown are the staining representative staining patterns of at least four independent experiments.

Mentions: The production of autoantibodies is the characteristic symptom of SLE and mediates many of the pathologies associated with disease. To begin investigating the gender bias of SLE in 564Igi mice, we measured the RNA reactivity of serum antibodies in male and female mice. Female 564Igi mice have significantly more anti-RNA IgG2a antibodies than male 564Igi mice (Figure 1A).


Female Bias in Systemic Lupus Erythematosus is Associated with the Differential Expression of X-Linked Toll-Like Receptor 8.

McDonald G, Cabal N, Vannier A, Umiker B, Yin RH, Orjalo AV, Johansson HE, Han JH, Imanishi-Kari T - Front Immunol (2015)

564Igi females have more circulating pathogenic IgG autoantibodies. (A) Anti-RNA antibodies were detected using and isotype-specific anti-RNA ELISA. Shown is the mean O.D. 405 nm ± SEM at various serum dilutions. The number of mice is shown in the key. (B) Shown is the ratio of male:female offspring born to the dam in the indicated breeding pair. Each data point represents a single litter. The average ratio is shown with a horizontal line. (C) Pregnant C57BL/6 dams were given introperitoneal injections with 1.5 μg of the indicated antibody or media control at approximately embryonic days 13–15. Shown is the ratio of male:female offspring in each litter. Each data point represents a single litter. The average ratio is shown with a horizontal line. (D,E) The mean (D) anti-RNA and (E) anti-DNA reactivities of the indicated antibodies were tested by ELISA. Shown is the mean O.D. 405 nm ± SEM at the indicated antibody concentrations. The number of replicates is shown in the key. (F) Purified 564 and 2C10 antibodies were tested for anti-nuclear reactivity by HEp-2 staining. Shown are the staining representative staining patterns of at least four independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4561825&req=5

Figure 1: 564Igi females have more circulating pathogenic IgG autoantibodies. (A) Anti-RNA antibodies were detected using and isotype-specific anti-RNA ELISA. Shown is the mean O.D. 405 nm ± SEM at various serum dilutions. The number of mice is shown in the key. (B) Shown is the ratio of male:female offspring born to the dam in the indicated breeding pair. Each data point represents a single litter. The average ratio is shown with a horizontal line. (C) Pregnant C57BL/6 dams were given introperitoneal injections with 1.5 μg of the indicated antibody or media control at approximately embryonic days 13–15. Shown is the ratio of male:female offspring in each litter. Each data point represents a single litter. The average ratio is shown with a horizontal line. (D,E) The mean (D) anti-RNA and (E) anti-DNA reactivities of the indicated antibodies were tested by ELISA. Shown is the mean O.D. 405 nm ± SEM at the indicated antibody concentrations. The number of replicates is shown in the key. (F) Purified 564 and 2C10 antibodies were tested for anti-nuclear reactivity by HEp-2 staining. Shown are the staining representative staining patterns of at least four independent experiments.
Mentions: The production of autoantibodies is the characteristic symptom of SLE and mediates many of the pathologies associated with disease. To begin investigating the gender bias of SLE in 564Igi mice, we measured the RNA reactivity of serum antibodies in male and female mice. Female 564Igi mice have significantly more anti-RNA IgG2a antibodies than male 564Igi mice (Figure 1A).

Bottom Line: Here, we show the results of our investigation into the role of Tlr8 expression in SLE pathogenesis in 564Igi females.Bone marrow-derived macrophages from 564Igi females have a significant increase in Tlr8 expression compared to male-derived cells, and RNA fluorescence in situ hybridization data suggest that Tlr8 may escape X-inactivation in female-derived macrophages.These results propose a model by which females may be more susceptible to SLE pathogenesis due to inefficient inactivation of Tlr8.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Physiology and Pathobiology, Tufts University , Boston, MA , USA.

ABSTRACT
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of anti-nuclear antibodies. SLE is one of many autoimmune disorders that have a strong gender bias, with 70-90% of SLE patients being female. Several explanations have been postulated to account for the severity of autoimmune diseases in females, including hormonal, microbiota, and gene dosage differences. X-linked toll-like receptors (TLRs) have recently been implicated in disease progression in females. Our previous studies using the 564Igi mouse model of SLE on a Tlr7 and Tlr9 double knockout background showed that the presence of Tlr8 on both X chromosomes was required for the production of IgG autoantibodies, Ifn-I expression and granulopoiesis in females. Here, we show the results of our investigation into the role of Tlr8 expression in SLE pathogenesis in 564Igi females. Female mice have an increase in serum pathogenic anti-RNA IgG2a and IgG2b autoantibodies. 564Igi mice have also been shown to have an increase in neutrophils in vivo, which are major contributors to Ifn-α expression. Here, we show that neutrophils from C57BL/6 mice express Ifn-α in response to 564 immune complexes and TLR8 activation. Bone marrow-derived macrophages from 564Igi females have a significant increase in Tlr8 expression compared to male-derived cells, and RNA fluorescence in situ hybridization data suggest that Tlr8 may escape X-inactivation in female-derived macrophages. These results propose a model by which females may be more susceptible to SLE pathogenesis due to inefficient inactivation of Tlr8.

No MeSH data available.


Related in: MedlinePlus