Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.

ABSTRACT: The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

SUBMITTER: Mackay F

PROVIDER: S-EPMC2195729 | biostudies-literature | 1999 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.

Mackay F F Woodcock S A SA Lawton P P Ambrose C C Baetscher M M Schneider P P Tschopp J J Browning J L JL

The Journal of experimental medicine 19991201 11

The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complex ...[more]

PMID: 10587360

Similar Datasets

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAbeta knockout NOD mice.

Project description:A line of nonobese diabetic (NOD) mice expressing the human diabetes-associated HLA-DQ8 transgene in the absence of mouse IAbeta failed to show spontaneous insulitis or diabetes, but rather developed dilated cardiomyopathy, leading to early death from heart failure. Pathology in these animals results from an organ- and cell-specific autoimmune response against normal cardiomyoctes in the atrial and ventricular walls, as well as against very similar myocytes present in the outermost muscle layer surrounding the pulmonary veins. Progression of the autoimmune process could be followed by serial ECG measurements; irradiation of young animals significantly delayed disease progression, and this effect could be reversed by adoptive transfer of splenocytes taken from older animals with complete heart block. Disease progression could also be blocked by cyclosporin A treatment, but was accelerated by injection of complete Fruend's adjuvant. The constellation of findings of spontaneously arising destructive focal lymphocytic infiltrates within the myocardium, rising titers of circulating anticardiac autoantibodies, dilation of the cardiac chambers, and gradual progression to end-stage heart failure bears a striking resemblance to what is seen in humans with idiopathic dilated cardiomyopathy, a serious and often life-threatening medical condition. This transgenic strain provides a highly relevant animal model for human autoimmune myocarditis and postinflammatory dilated cardiomyopathy.

| S-EPMC263834 | biostudies-literature

Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy.

Project description:B cell activation factor of the TNF family (BAFF) is a potent B cell survival factor. BAFF overexpressing transgenic mice (BAFF-Tg mice) exhibit features of autoimmune disease, including B cell hyperplasia and hypergammaglobulinemia, and develop fatal nephritis with age. However, basal serum IgA levels are also elevated, suggesting that the pathology in these mice may be more complex than initially appreciated. Consistent with this, we demonstrate here that BAFF-Tg mice have mesangial deposits of IgA along with high circulating levels of polymeric IgA that is aberrantly glycosylated. Renal disease in BAFF-Tg mice was associated with IgA, because serum IgA was highly elevated in nephritic mice and BAFF-Tg mice with genetic deletion of IgA exhibited less renal pathology. The presence of commensal flora was essential for the elevated serum IgA phenotype, and, unexpectedly, commensal bacteria-reactive IgA antibodies were found in the blood. These data illustrate how excess B cell survival signaling perturbs the normal balance with the microbiota, leading to a breach in the normal mucosal-peripheral compartmentalization. Such breaches may predispose the nonmucosal system to certain immune diseases. Indeed, we found that a subset of patients with IgA nephropathy had elevated serum levels of a proliferation inducing ligand (APRIL), a cytokine related to BAFF. These parallels between BAFF-Tg mice and human IgA nephropathy may provide a new framework to explore connections between mucosal environments and renal pathology.

| S-EPMC3195458 | biostudies-other

Rheumatologic and autoimmune manifestations of primary immunodeficiency disorders.

Project description:Purpose of reviewAlthough it may seem paradoxical, primary immunodeficiency disorders are frequently complicated by autoimmune and inflammatory conditions. These conditions pose significant diagnostic and therapeutic challenges for clinicians caring for these patients. There have been a number of new insights into how immunodeficiencies can predispose to autoimmunity, and rheumatologists should understand the basis for and manifestations of autoimmunity in primary immunodeficiency disorders to more effectively care for these patients.Recent findingsA number of mechanisms have recently been found to link primary immunodeficiencies and autoimmunity, including increased homeostatic proliferation in primary immunodeficiencies associated with lymphopenia and defects in regulatory T cells in the Wiskott-Aldrich syndrome. Primary immunodeficiencies that affect the innate immune system can also lead to inappropriate inflammation through impairing negative regulatory mechanisms in innate immune cells.SummaryThe realization that primary immunodeficiencies can also impair negative regulation of immune responses has provided a new framework for the understanding of autoimmunity associated with these conditions. These insights may lead to new, more targeted therapies for autoimmune complications in primary immunodeficiency patients.

| S-EPMC2760066 | biostudies-literature

HMGA1-pseudogene7 transgenic mice develop B cell lymphomas.

Project description:We have recently identified and characterized two pseudogenes (HMGA1P6 and HMGA1P7) of the HMGA1 gene, which has a critical role in malignant cell transformation and cancer progression. HMGA1P6 and HMGAP17 act as microRNA decoy for HMGA1 and other cancer-related genes upregulating their protein levels. We have previously shown that they are upregulated in several human carcinomas, and their expression positively correlates with a poor prognosis and an advanced cancer stage. To evaluate in vivo oncogenic activity of HMGA1 pseudogenes, we have generated a HMGA1P7 transgenic mouse line overexpressing this pseudogene. By a mean age of 12 months, about 50% of the transgenic mice developed splenomegaly and accumulation of lymphoid cells in several body compartments. For these mice FACS and immunohistochemical analyses suggested the diagnosis of B-cell lymphoma that was further supported by clonality analyses and RNA expression profile of the pathological tissues of the HMGA1P7 transgenic tissues. Therefore, these results clearly demonstrate the oncogenic activity of HMGA1 pseudogenes in vivo.

| S-EPMC7184748 | biostudies-literature

Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities.

Project description:Dystrophic neurites are swollen dendrites or axons recognizable near amyloid plaques as a part of important pathological feature of Alzheimer's disease (AD). We report herein that reticulon 3 (RTN3) is accumulated in a distinct population of dystrophic neurites named as RTN3 immunoreactive dystrophic neurites (RIDNs). The occurrence of RIDNs is concomitant with the formation of high-molecular-weight RTN3 aggregates in brains of AD cases and mice expressing mutant APP. Ultrastructural analysis confirms accumulation of RTN3-containing aggregates in RIDNs. It appears that the protein level of RTN3 governs the formation of RIDNs because transgenic mice expressing RTN3 will develop RIDNs, initially in the hippocampal CA1 region, and later in other hippocampal and cortical regions. Importantly, we show that the presence of dystrophic neurites in Tg-RTN3 mice causes impairments in spatial learning and memory, as well as synaptic plasticity, implying that RIDNs potentially contribute to AD cognitive dysfunction. Together, we demonstrate that aggregation of RTN3 contributes to AD pathogenesis by inducing neuritic dystrophy. Inhibition of RTN3 aggregation is likely a therapeutic approach for reducing neuritic dystrophy.

| S-EPMC1888669 | biostudies-literature

Autoimmune manifestations in aged mice arise from early-life immune dysregulation.

Project description:Autoantibodies can be present years to decades before the onset of disease manifestations in autoimmunity. This finding suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. We show that Sjögren's syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren's pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks of age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology, including anti-muscarinic receptor antibodies. Microarray profiling of the salivary gland characterized the expression pattern of genes that increased with disease progression and showed that early anti-CD40L greatly repressed B cell function while having a broader effect on multiple biological pathways, including interleukin-12 and interferon signaling. A single prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and nonobese diabetic mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest that early peripheral immune dysregulation gives rise to autoimmune manifestations later in life, and for diseases predated by autoantibodies, early prophylactic intervention with biologics may prove efficacious.

| S-EPMC5291695 | biostudies-literature

Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome.

Project description:Asparaginyl endopeptidase (AEP or legumain) is a lysosomal cysteine protease that cleaves protein substrates on the C-terminal side of asparagine. AEP plays a pivotal role in the endosome/lysosomal degradation system and is implicated in antigen processing. The processing of the lysosomal proteases cathepsins in kidney is completely defective in AEP-deficient mice with accumulation of macromolecules in the lysosomes, which is typically seen in lysosomal disorders. Here we show that mutant mice lacking AEP develop fever, cytopenia, hepatosplenomegaly, and hemophagocytosis, which are primary pathological manifestations of hemophagocytic syndrome/hemophagocytic lymphohistiocytosis (HLH). Moreover, AEP deficiency provokes extramedullary hematopoiesis in the spleen and abnormally enlarged histiocytes with ingested red blood cells (RBCs) in bone marrow. Interestingly, RBCs from AEP-null mice are defective in plasma membrane components. Further, AEP-null mice display lower natural killer cell activity, but none of the major cytokines is substantially abnormal. These results indicate that AEP might be a previously unrecognized component in HLH pathophysiology.

| S-EPMC2626726 | biostudies-literature

miR-145 transgenic mice develop cardiopulmonary complications leading to postnatal death.

Project description:BackgroundBoth downregulation and elevation of microRNA miR-145 has been linked to an array of cardiopulmonary phenotypes, and a host of studies suggest that it is an important contributor in governing the differentiation of cardiac and vascular smooth muscle cell types.Methods and resultsTo better understand the role of elevated miR-145 in utero within the cardiopulmonary system, we utilized a transgene to overexpress miR-145 embryonically in mice and examined the consequences of this lineage-restricted enhanced expression. Overexpression of miR-145 has detrimental effects that manifest after birth as overexpressor mice are unable to survive beyond postnatal day 18. The miR-145 expressing mice exhibit respiratory distress and fail to thrive. Gross analysis revealed an enlarged right ventricle, and pulmonary dysplasia with vascular hypertrophy. Single cell sequencing of RNA derived from lungs of control and miR-145 transgenic mice demonstrated that miR-145 overexpression had global effects on the lung with an increase in immune cells and evidence of leukocyte extravasation associated with vascular inflammation.ConclusionsThese data provide novel findings that demonstrate a pathological role for miR-145 in the cardiopulmonary system that extends beyond its normal function in governing smooth muscle differentiation.

| S-EPMC8440944 | biostudies-literature

E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia.

Project description:Transgenic mice with lymphoid-restricted overexpression of the double bromodomain protein bromodomain-containing 2 (Brd2) develop splenic B-cell lymphoma and, upon transplantation, B-cell leukemia with leukemic infiltrates in liver and lung. Brd2 is a nuclear-localized transcription factor kinase that is most closely related to TATA box binding protein-associated factor, 250 kDa (TAF(II)250) and the Drosophila developmental protein female sterile homeotic. Constitutive expression of BRD2 in the lymphoid compartment increases cyclin A transcription, "priming" transgenic B cells for proliferation. Mice stochastically develop an aggressive B-cell lymphoma with the features of B-1 cells, including CD5 and surface IgM expression. The B-cell lymphoma is monoclonal for immunoglobulin gene rearrangement and is phenotypically stable. The lymphoblasts are very large and express a transcriptome that is similar to human non-Hodgkin lymphomas. Both a wild-type BRD2 transgene and a kinase-null point mutant drive lymphomagenesis; therefore we propose that, rather than kinase activity, Brd2-mediated recruitment of E2 promoter binding factors (E2Fs) and a specific histone acetyltransferase to the cyclin A promoter by both types of transgene is a mechanistic basis for neoplasia. This report is the first to describe a transgenic mouse model for constitutive expression of a protein with more than one bromodomain.

| S-EPMC2825482 | biostudies-literature

TCL1 transgenic mice as a model for CD49d-high chronic lymphocytic leukemia.

Project description: Not available

| S-EPMC7449868 | biostudies-literature