Prolidase deficiency causes spontaneous T cell activation and lupus-like autoimmunity
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PROVIDER: PRJNA914261 | ENA |
REPOSITORIES: ENA
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Project description:Prolidase deficiency causes spontaneous T cell activation and lupus-like autoimmunity
| PRJNA915013 | ENA
Project description:Prolidase Deficiency (PD) is a multi-system disorder caused by mutations in the PEPD gene, which encodes a ubiquitously-expressed metallopeptidase essential for the hydrolysis of dipeptides containing C-terminal proline or hydroxyproline. PD typically presents in childhood with developmental delay, skin ulcers, recurrent infections and in some patients, autoimmune features which can mimic systemic lupus erythematosus (SLE). The basis for the autoimmune association is uncertain, but might be due to self-antigen exposure with tissue damage, or indirectly driven by chronic infection and microbial burden. Here we address the question of causation and show that Pepd null mice have increased anti-nuclear autoantibodies and raised serum IgA, accompanied by kidney immune complex deposition, consistent with an SLE-like disease. These features are associated with an accumulation of CD4 and CD8 effector T cells in the spleen and liver. Pepd deficiency leads to spontaneous T cell activation and proliferation into the effector subset, which is cell intrinsic and independent of antigen receptor specificity or antigenic stimulation. However, an increase in KLRG1+ effector CD8 cells is not observed in mixed chimeras, in which the autoimmune phenotype is also absent. Our findings link autoimmune susceptibility in PD to spontaneous T cell dysfunction, likely to be acting in combination with immune activators that lie outside the haemopoietic system but result from the abnormal metabolism or loss of non-enzymatic prolidase function. This knowledge provides insight into the role of prolidase in the maintenance of self-tolerance and highlights the importance of treatment to control T cell activation.
2022-12-22 | GSE221569 | GEO
Project description:Prolidase Deficiency (PD) is a multi-system disorder caused by mutations in the PEPD gene, which encodes a ubiquitously-expressed metallopeptidase essential for the hydrolysis of dipeptides containing C-terminal proline or hydroxyproline. PD typically presents in childhood with developmental delay, skin ulcers, recurrent infections and in some patients, autoimmune features which can mimic systemic lupus erythematosus (SLE). The basis for the autoimmune association is uncertain, but might be due to self-antigen exposure with tissue damage, or indirectly driven by chronic infection and microbial burden. Here we address the question of causation and show that Pepd null mice have increased anti-nuclear autoantibodies and raised serum IgA, accompanied by kidney immune complex deposition, consistent with an SLE-like disease. These features are associated with an accumulation of CD4 and CD8 effector T cells in the spleen and liver. Pepd deficiency leads to spontaneous T cell activation and proliferation into the effector subset, which is cell intrinsic and independent of antigen receptor specificity or antigenic stimulation. However, an increase in KLRG1+ effector CD8 cells is not observed in mixed chimeras, in which the autoimmune phenotype is also absent. Our findings link autoimmune susceptibility in PD to spontaneous T cell dysfunction, likely to be acting in combination with immune activators that lie outside the haemopoietic system but result from the abnormal metabolism or loss of non-enzymatic prolidase function. This knowledge provides insight into the role of prolidase in the maintenance of self-tolerance and highlights the importance of treatment to control T cell activation.
2022-12-20 | GSE221410 | GEO
Project description:Prolidase deficiency (PD) is a multisystem disorder caused by mutations in the PEPD gene, which encodes a ubiquitously expressed metallopeptidase essential for the hydrolysis of dipeptides containing C-terminal proline or hydroxyproline. PD typically presents in childhood with developmental delay, skin ulcers, recurrent infections, and, in some patients, autoimmune features that can mimic systemic lupus erythematosus. The basis for the autoimmune association is uncertain, but might be due to self-antigen exposure with tissue damage, or indirectly driven by chronic infection and microbial burden. In this study, we address the question of causation and show that Pepd-null mice have increased antinuclear autoantibodies and raised serum IgA, accompanied by kidney immune complex deposition, consistent with a systemic lupus erythematosus-like disease. These features are associated with an accumulation of CD4 and CD8 effector T cells in the spleen and liver. Pepd deficiency leads to spontaneous T cell activation and proliferation into the effector subset, which is cell intrinsic and independent of Ag receptor specificity or antigenic stimulation. However, an increase in KLRG1+ effector CD8 cells is not observed in mixed chimeras, in which the autoimmune phenotype is also absent. Our findings link autoimmune susceptibility in PD to spontaneous T cell dysfunction, likely to be acting in combination with immune activators that lie outside the hemopoietic system but result from the abnormal metabolism or loss of nonenzymatic prolidase function. This knowledge provides insight into the role of prolidase in the maintenance of self-tolerance and highlights the importance of treatment to control T cell activation.
| S-EPMC9946897 | biostudies-literature
Project description:We performed a comparative immunology case study of client-owned dogs to determine if immune and skin gene expression profiles in spontaneous canine chronic cutaneous lupus erythematosus (CCLE) with concomitant systemic autoimmunity mirror those observed in human CCLE.
2022-02-11 | GSE180276 | GEO
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| PRJNA557414 | ENA
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Project description:Intercellular transmission of the second messenger 2′,3′‐cGAMP, synthesized by the viral DNA sensor cGAMP synthase (cGAS), is a potent mode of bystander activation during host defense. However, whether this mechanism also contributes to cGAS-dependent autoimmunity remains unknown. Here, using a murine bone marrow transplantation strategy, we demonstrate that, in Trex1-/--associated autoimmunity, cGAMP shuttling from radioresistant to immune cells induces NF-κB activation, interferon regulatory protein 3 (IRF3) phosphorylation and subsequent interferon signaling. cGAMP travel prevented myeloid cell and lymphocyte death, promoting their accumulation in secondary lymphoid tissue. Nonetheless, it did not stimulate B cell differentiation into autoantibody-producing plasmablasts or aberrant T cell priming in the steady state. Although cGAMP-mediated bystander activation did not induce spontaneous organ disease, it did trigger interface dermatitis after UV light exposure, similar to cutaneous lupus erythematosus. These findings reveal that, in Trex1-deficiency, intercellular cGAMP transfer propagates cGAS signaling and, under conducive conditions, causes tissue inflammation.
2021-07-09 | GSE176225 | GEO
Project description:Dominant GNAI2 mutants causes human immunodeficiency and autoimmunity
| PRJNA807792 | ENA
Project description:Dominant GNAI2 mutants causes human immunodeficiency and autoimmunity
| PRJNA807793 | ENA