p53 is required for spontaneous autoantibody production in B6/lpr lupus mice

Kuan, Anita P.; Cohen, Philip L.

doi:10.1002/eji.200525982

Cited by 14 publications

(7 citation statements)

References 47 publications

(43 reference statements)

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“…Studies have provided evidence that p53 is required for spontaneous autoantibody production in B6/lpr lupus mice [82]. Generation of double mutant mice ( p53 −/− lpr ) having defects in both p53- and Fas-dependent pathways revealed that these mice have lower autoantibody levels than the single mutant lpr mice.…”

Section: The P202 Proteinsmentioning

confidence: 99%

Interferon-inducible Ifi200-family genes in systemic lupus erythematosus

2008

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Systemic lupus erythematosus (SLE) is the prototype of complex autoimmune diseases. Studies have suggested that genetic, hormonal, and environmental factors contribute to the development of the disease. Interestingly, several recent studies involving SLE patients and mouse models of the disease have suggested a role for interferon (IFN)-stimulated genes (ISGs) in the development of SLE. One family of ISGs is the Ifi200-family, which includes mouse (Ifi202a, Ifi202b, Ifi203, Ifi204, and Ifi205) and human (IFI16, MNDA, AIM2, and IFIX) genes. The mouse genes cluster between serum amyloid P-component (Apcs) and α-spectrin (Spna-1) genes on chromosome 1 and the human genes cluster in syntenic region 1q23. The Ifi200-family genes encode structurally and functionally-related proteins (the p200-family proteins). Increased expression of certain p200-family proteins in cells is associated with inhibition of cell proliferation, modulation of apoptosis, and cell differentiation. Our studies involving generation of B6.Nba2 congenic mice, coupled with gene expression analyses, identified the Ifi202 as a candidate lupus-susceptibility gene. Importantly, recent studies using different mouse models of SLE have suggested that increased expression of Ifi202 gene (encoding p202 protein) in immune cells contributes to lupus susceptibility. Consistent with a functional role for the p202 protein in lupus susceptibility, increased levels of IFI16 protein in human SLE patients are associated with the diseases. This review summarizes recent findings concerning the regulation and role of p200-family proteins in the development of SLE.

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Section: The P202 Proteinsmentioning

confidence: 99%

Interferon-inducible Ifi200-family genes in systemic lupus erythematosus

2008

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“…Given that type I IFNs increase p53 levels [27], which remain transcriptionally inactive, it remains unclear whether p53 in lymphocytes of SLE patients remains transcriptionally active or not. Moreover, p53 is required for spontaneous autoantibody production in B6/lpr lupus-prone mice [28]. In contrast, mice null for the Gadd45a gene develop lupus-like disease [29] and loss of expression of p21 WAF1 (encoded by the p21 gene), a known transcriptional target of p53, is also linked to the development of autoimmunity [30].…”

Section: P53 In B Cell Survival and Slementioning

confidence: 99%

Systemic lupus erythematosus and increased risk to develop B cell malignancies: Role of the p200-family proteins

Veeranki

Choubey

2010

Immunology Letters

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Systemic lupus erythematosus (SLE), an autoimmune disease, develops at a female-to-male ratio of 10:1. Increased serum levels of type I interferons (IFN-α/β) and induction of “IFN-signature” genes are associated with an active SLE disease in patients. Moreover, SLE patients exhibit three- to four-fold increase in the risk of developing malignancies involving B cells, including non-Hodgkin lymphoma (NHL) and Hodgkin's lymphoma (HL). Interestingly, homozygous mice expressing a deletion mutant (the proline-rich domain deleted) of the p53 develop various types of spontaneous tumors, particularly of B-cell origin upon aging. The deletion is associated with defects in transcriptional activation of genes by p53 and inhibition of DNA damage-induced apoptosis. Notably, increased levels of the p202 protein, which is encoded by the p53-repressible interferon-inducible Ifi202 gene, in B cells of female mice are associated with defects in B cell apoptosis, inhibition of the p53-mediated transcription of pro-apoptotic genes, and increased lupus susceptibility. In this review we discuss how increased levels of the p202 protein (and its human functional homologue IFI16 protein) in B cells increase lupus susceptibility and are likely to increase the risk of developing certain B cell malignancies. A complete understanding of the molecular mechanisms that regulate B cell homeostasis is necessary to identify SLE patients with an increased risk to develop B cell malignancies.

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“…Recently, the process of cell death has been suggested as the source of the antigenic stimulus that drives the production of anti-DNA antibodies in lupus [7-9]. Under normal conditions, the rapid and efficient clearance of apoptotic cells and their debris may prevent this form of self-immunization.…”

Section: Introductionmentioning

confidence: 99%

Disrupted Mer receptor tyrosine kinase expression leads to enhanced MZ B-cell responses

Shao

Kuan

Wang

et al. 2010

Journal of Autoimmunity

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Control of lymphocyte homeostasis is essential to ensure efficient immune responses and to prevent autoimmunity. Splenic marginal zone B-cells are important producers of autoantibodies, and are subject to stringent tolerance mechanisms to prevent autoimmunity. In this paper, we explore the role of the Mer tyrosine kinase (Mertk) in regulating autoreactive B cells. This receptor tyrosine kinase serves to bind apoptotic cells, to mediate their phagocytosis, and to regulate subsequent cytokine production. Mice lacking Mertk suffer from impaired apoptotic cell clearance and develop a lupus-like autoimmune syndrome. Here we show that such Mertk-KO mice have expanded numbers of splenic marginal zone B cells. Mertk-KO mice bearing a DNA-specific immunoglobulin heavychain transgene (3H9) produced anti-DNA antibodies that appeared to be secreted largely by marginal zone B cells. Finally, Mertk-KO mice developed greater antibody responses after NP-Ficoll immunization than their B6 counterparts. Taken together, our data show that Mertk has a major effect on the development of the marginal zone B-cell compartment. Mertk is also important in establishing DNA-specific B cell tolerance in 3H9 anti-DNA transgenic mice.

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p53 is required for spontaneous autoantibody production in B6/lpr lupus mice

Cited by 14 publications

References 47 publications

Interferon-inducible Ifi200-family genes in systemic lupus erythematosus

Interferon-inducible Ifi200-family genes in systemic lupus erythematosus

Systemic lupus erythematosus and increased risk to develop B cell malignancies: Role of the p200-family proteins

Disrupted Mer receptor tyrosine kinase expression leads to enhanced MZ B-cell responses

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