Sex-Defined T-Cell Responses to Cardiac Self Determine Differential Outcomes of Murine Dilated Cardiomyopathy

Jane‐wit, Dan; Altuntas, Cengiz Z.; Monti, Jennifer; Johnson, Justin M.; Forsthuber, Thomas G.; Tuohy, Vincent K.

doi:10.2353/ajpath.2008.070324

Cited by 10 publications

(6 citation statements)

References 47 publications

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“…However, future studies using von Frey filaments to assess the severity of response to mechanical stimulation (tactile allodynia) could be performed to compare values before immunization and progression over time. Further analysis using a device recently developed by our group, bladder sensory perception threshold [30], integrated with the Neurometer diagnostic neurostimulator (Neurotron, Baltimore, MD, USA), could be used to measure afferent sensory function as a phenotyping measure of pelvic pain in rmUPK2-immunized mice with EAC [18]. Overall, we have demonstrated the organ-specific autoimmune nature of rmUPK2-immunized mice with EAC and suggest this is a potentially useful model for the future investigation of pathogenesis and therapeutic intervention of IC/PBS.…”

Section: Discussionmentioning

confidence: 99%

“…As described previously [11,12,17,18], to determine immunogenicity, inguinal and axillary lymph node cells (LNCs) were removed from 10 mice 10 d after immunization with rmUPK2 and cultured as a single-cell suspension in 96-well flat-bottom microtiter Falcon plates (BD Biosciences, San Jose, CA, USA) at 3 × 10 5 cells per well in Dulbecco modified Eagle medium (DMEM) (Mediatech CellGro, Herndon, VA, USA) with 10% fetal bovine serum (HyClone), 5% HEPES buffer, 2% L-glutamine, and 1% penicillin/streptomycin (Invitrogen Life Technologies) added. Then rmUPK2 and recombinant mouse anti-Müllerian hormone (AMH) (as a control) were added in serial 10-fold dilutions to triplicate wells with positive control wells containing 2 µg/ml antimouse CD3 (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

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Autoimmunity to Uroplakin II Causes Cystitis in Mice: A Novel Model of Interstitial Cystitis

et al. 2012

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Background The pathophysiology of interstitial cystitis (IC) is unknown. Deficits in urothelial cell layers and autoimmune mechanisms may play a role. Objective To examine whether immunization of mice with recombinant mouse uroplakin II (rmUPK2), a bladder-specific protein, would provoke an autoimmune response sufficient to create an IC phenotype. Design, setting, and participants RmUPK2 complementary DNA was generated, transferred into a bacterial expression vector, and the generated protein was purified. Eight-week-old SWXJ female mice were immunized with rmUPK2 protein via subcutaneous injection of 200 µg of rmUPK2 protein in 200 µl of an emulsion. Measurements Mice were euthanized 5 wk after immunization. Axillary and inguinal lymph node cells were tested for antigen-specific responsiveness and cytokine production, serum isotype antibody titers against rmUPK2 were determined, and gene expression of inflammatory mediators was measured in the bladder and other organs. For functional analysis, mice were placed in urodynamic chambers for 24-h micturition frequency and total voided urine measurements. Results and limitations Immunization with rmUPK2 resulted in T-cell infiltration of the bladder urothelium and increased rmUPK2-specific serum antibody responses in the experimental autoimmune cystitis (EAC) mice models compared with controls. The ratio of bladder to body weight was increased in EAC mice. Quantitative reverse transcriptase polymerase chain reaction analysis showed elevated gene expression of tumor necrosis factor α, interferon γ, interleukin (IL)-17A, and IL-1β in bladder urothelium but not in other organs. Evaluation of 24-h micturition habits of EAC mice showed significantly increased urinary frequency (p < 0.02) and significantly decreased urine output per void (p < 0.021) when compared with control mice. Conclusions Our study showed that a bladder-specific autoimmune response sufficient to induce inflammation and EAC occurs in mice following immunization with rmUPK2. EAC mice displayed significant evidence of urinary frequency and decreased urine output per void. Further phenotype characterization of EAC mice should include evidence for pain and/or afferent hypersensitivity, and evidence of urothelial cell layer damage.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Autoimmunity to Uroplakin II Causes Cystitis in Mice: A Novel Model of Interstitial Cystitis

et al. 2012

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“…It is a primary indication for heart transplantation and is associated with high morbidity and mortality . The prevalence of DCM is estimated to be as high as 1/2500 adults, and it is reported to affect an estimated two to three times as many women as men . Moreover, approximately 20%‐50% of affected patients have a family history, suggesting that heredity is an important cause of this disease .…”

Section: Introductionmentioning

confidence: 99%

LTBP2 knockdown by siRNA reverses myocardial oxidative stress injury, fibrosis and remodelling during dilated cardiomyopathy

Xuefeng

Xue

et al. 2019

Acta Physiologica

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Aim Dilated cardiomyopathy (DCM) is characterised by left ventricular dilation and associated with systolic dysfunction. Recent evidence has reported the high expression of latent transforming growth factor beta binding protein 2 (LTBP2) in heart diseases, which may play a role in regulating multiple biological functions of myocardial cells. Thus, this study set out to investigate the molecular mechanism and effects of LTBP2 in myocardial oxidative stress injury, fibrosis and remodelling in a rat model of DCM, with the involvement of NF‐κB signalling pathway. Methods The rat model of DCM was treated with si‐LTBP2 and/or activator of NF‐κB signalling pathway to examine the haemodynamic indexes, cardiac functions, oxidative stress injury, fibrosis and remodelling. Moreover, in vitro experiments were conducted to verify the regulatory role of LTBP2 and NF‐κB signalling pathway in DCM. Results LTBP2 was up‐regulated in DCM rats. After LTBP2 was knocked down, haemodynamic indexes, HW/BW ratio, collagen volume fraction (CVF) level, positive expression of LTBP2, levels of reactive oxygen species (ROS), malondialdehyde (MDA), interleukin‐6 (IL‐6), tumour necrosis factor‐alpha (TNF‐α), tumour necrosis factor beta 1 (TGF‐β1) and brain natriuretic peptide (BNP) were all decreased. Meanwhile, levels of LTBP2, Col‐I, Col‐III, p65 and p52 were also reduced, while HW, BW and levels of SOD and TAOC were increased. In contrast, activation of NF‐κB signalling pathway reversed effects of LTBP2 gene silencing. These findings were confirmed by in vivo experiments. Conclusions LTBP2 silencing can attenuate myocardial oxidative stress injury, myocardial fibrosis and myocardial remodelling in DCM rats by down‐regulating the NF‐κB signalling pathway.

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“…Idiopathic DCM represents the substrate for approximately 10% of sudden cardiac deaths in the adult population [3] and there was increasing evidence for the participation of cellular and humoral autoimmunity in the pathological process of DCM, such as antibodies directed against the second extracellular loop of β1‐adrenergic (β1) receptors, antibodies against muscarinic M2‐acetylcholine (M2) receptors and antibodies against the catalytic α‐subunit of sarcolemmal Na‐K‐ATPase, which were known to play a role in the pathophysiology of DCM [4–6]. Recent studies also showed that T cell was an important determinant in the development of idiopathic DCM [7]. Moreover, Yi et al.…”

Section: Introductionmentioning

confidence: 99%

The Treg/Th17 Imbalance in Patients with Idiopathic Dilated Cardiomyopathy

Li¹,

Wang²,

Wang³

et al. 2010

Scandinavian Journal of Immunology

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To assess whether Treg/Th17 balance was broken in patients with idiopathic dilated cardiomyopathy (DCM). We studied 25 patients who were diagnosed as idiopathic DCM (18 men and seven women, mean age 35.6 ± 5.2) and 25 normal persons (18 men and seven women, mean age 33.8 ± 4.9). Then, we detected Treg/Th17 functions on different levels including cell frequencies, related cytokine secretion and key transcription factors in patients with idiopathic DCM and controls. The results demonstrated that patients with idiopathic DCM revealed significant increase in peripheral Th17 number, Th17‐related cytokines (IL‐17, IL‐6, IL‐23) and transcription factor (RORγt) levels and obvious decrease in Treg number, Treg‐related cytokines (TGF‐β1 and IL‐10) and transcription factor (Foxp3) levels when compared to normal persons. Results indicated that Treg/Th17 functional imbalance existed in patients with idiopathic DCM, suggesting a potential role for Treg/Th17 imbalance in the development of idiopathic DCM.

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Sex-Defined T-Cell Responses to Cardiac Self Determine Differential Outcomes of Murine Dilated Cardiomyopathy

Cited by 10 publications

References 47 publications

Autoimmunity to Uroplakin II Causes Cystitis in Mice: A Novel Model of Interstitial Cystitis

Autoimmunity to Uroplakin II Causes Cystitis in Mice: A Novel Model of Interstitial Cystitis

LTBP2 knockdown by siRNA reverses myocardial oxidative stress injury, fibrosis and remodelling during dilated cardiomyopathy

The Treg/Th17 Imbalance in Patients with Idiopathic Dilated Cardiomyopathy

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