Urothelial antigen-specific CD4+ T cells function as direct effector cells and induce bladder autoimmune inflammation independent of CD8+ T cells

Liu, Wujiang; Chen, Xiaohong; Evanoff, David P.; Luo, Yi

doi:10.1038/mi.2010.90

Cited by 9 publications

(6 citation statements)

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“…In present study, CD4 + Tcells had a larger scale in ltration in BLCA tissue from high-risk group than lowrisk group, but CD8 + had no difference. One study conducted by Liu W et al had revealed that urothelial antigen-speci c CD4 + T cells function as direct effector cells and induce bladder autoimmune in ammation independent of CD8 + T cells, which coincided with our nding [58].…”

Section: Discussionsupporting

confidence: 88%

Integrated Analysis Identifies and Validates a Novel Signature Based on Immune Related Gene Predicting Survival in Bladder Urothelial Carcinoma

Mao

Chen

2020

Preprint

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BackgroundThis study aimed to develop a prognostic signature based on immune related gene(IRG) predicting survival for patients with bladder urothelial carcinoma(BLCA).Methods1534 IRG’s expression data of 996 BLCA patients form Gene Expression Omnibus database and The Cancer Genome Atlas database were used for development and validation of the prognostic signature. Univariate Cox regression model and Random Survival Forest Variable Hunting algorithm were employed to achieve the variable selection. The independently prognostic ability of the signature was validated by Multivariate Cox model and Kaplan–Meier analysis in independent datasets. A nomogram was established to improve prognosis stratification. The relationship between tumor-infiltrating immune cells and the signature was analyzed using data retrieved from EPIC resource.FindingsA prognostic model consisting of 10 IRGs was developed as our immune signature. Based on this signature, patients were separated into low- and high- risk groups with different survival in both training and validation sets(HR : range from 1.1 [95% CI: 1–1.2; p = 0.038] to 1.3 [95% CI: 1.3–1.5; p <0.001]). Multivariable analyses demonstrated that this signature was an independent prognostic predictor and was strongly associated with important clinicopathological factors. The signature also showed a significantly positive correlation with immune checkpoint molecules, and had a superior prognostic value compared with some important targets. In addition, our signature was found to correlate the enhancement of tumor microenvironment positively.ConclusionsThis signature predicts prognosis for BLCA patients, which may promote individualized treatment and provide potential targets for immunotherapy.

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Section: Discussionsupporting

confidence: 88%

Integrated Analysis Identifies and Validates a Novel Signature Based on Immune Related Gene Predicting Survival in Bladder Urothelial Carcinoma

Mao

Chen

2020

Preprint

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“…In addition to CD8 + T cells, CD4 + T cells are capable of inducing EAC in the URO‐OVA mice. We observed that adoptive transfer of OT‐II CD4 + T cells that express the transgenic TCR specific for the I‐A b /OVA 323–339 epitope peptide induced EAC in the URO‐OVA mice 128 . Our studies showed that antigen‐specific CD4 + T cells functioned as direct effector cells and induced EAC independent of CD8 + T cells.…”

Section: Animal Modelsmentioning

confidence: 60%

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

et al. 2020

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Abbreviations & Acronyms BPS = bladder pain syndrome CCL2 = C-C motif ligand 2 CNS = central nervous system DMSO = dimethyl sulfoxide EAC = experimental autoimmune cystitis ESSIC = International Society for the Study of BPS FSS = functional somatic syndrome GAG = glycosaminoglycan IC = interstitial cystitis IFN-c = interferon-gamma IL = interleukin MC = mast cell NGF = nerve growth factor OVA = ovalbumin TCR = T-cell receptor TNF = tumor necrosis factor TLR = Toll-like receptor UCPPS = urological chronic pelvic pain syndrome UPK = uroplakin Upo = unpublished observation VEGF = vascular endothelial growth factor WAS = water avoidance stress Correspondence: Yoshiyuki Abstract: Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a noninflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition.

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“…Recently, several studies using transgenic mouse models that expressed various model autoantigens demonstrated that autoantigen‐specific T cells induced autoimmune diseases. For example, OVA‐specific CD4 + T cells induced bladder autoimmune inflammation in transgenic URO‐OVA mice that express the model self‐antigen OVA on the bladder urothelium . A study using skin‐directed expression of OVA demonstrated that GVHD‐like inflammatory skin disease was induced by transferring OVA‐specific OT‐I CD8 + T cells .…”

Section: Discussionmentioning

confidence: 99%

“…For example, OVA-specific CD4 1 T cells induced bladder autoimmune inflammation in transgenic URO-OVA mice that express the model self-antigen OVA on the bladder urothelium. 29 A study using skin-directed expression of OVA demonstrated that GVHD-like inflammatory skin disease was induced by transferring OVA-specific OT-I CD8 1 T cells. 30 Furthermore, transfer of OT-I T cells led to cholangitis in the liver of transgenic mouse in which the model antigen OVA was expressed in cholangiocytes.…”

Section: Discussionmentioning

confidence: 99%

Clonality, activated antigen-specific CD8⁺T cells, and development of autoimmune cholangitis in dnTGFβRII mice

et al. 2013

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There are several murine models described with features similar to human primary biliary cirrhosis (PBC). Amongst these models, the one which has the closest serologic features to PBC is a mouse with a T cell-restricted expression of the dominant negative transforming growth factor β receptor type II (dnTGFβRII). Our work has demonstrated that CD8+ T cells from dnTGFβRII mice transfer autoimmune cholangitis to Rag1-/- recipients. However, it remained unclear whether the autoimmune cholangitis was secondary to an intrinsic function within CD8+ T cells or due to the abnormal TGFβR environment within which CD8+ T cells were generated. To address this mechanistic issue, we utilized our dnTGFβRII, OT-I/Rag1-/-, OT-II/Rag1-/- mice and in addition generated OT-I/dnTGFβRII/Rag1-/-, and OT-II/dnTGFβRII/Rag1-/- mice in which the entire T cell repertoire was replaced with ovalbumin (OVA) specific CD8+ or CD4+ T cells, respectively. Importantly, neither the parental OT-I/dnTGFβRII/Rag1-/- mice and/or OT-II/dnTGFβRII/Rag1-/- mice developed cholangitis. However, adoptive transfer demonstrated that only transfer of CD8+ T cells from dnTGFβRII mice but not CD8+ T cells from OT-I/Rag -/- mice or from OT-I/dnTGFβRII/Rag1-/- mice transferred disease. These data were not secondary to absence of CD4+ T cell help since a combination of CD8+ T cells from OT-I/dnTGFβRII/Rag1-/- and CD4+ T cells from OT II/dnTGFβRII/Rag1-/- or CD8+ T cells from OT-I/dnTGFβRII/Rag1-/- with CD4+ T cells from OT-II/Rag1-/- mice failed to transfer disease. In conclusion, defective TGFβRII signaling, in addition to clonal CD8+ T cells that target biliary cells, are required for induction of autoimmune cholangitis.

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Urothelial antigen-specific CD4+ T cells function as direct effector cells and induce bladder autoimmune inflammation independent of CD8+ T cells

Cited by 9 publications

References 50 publications

Integrated Analysis Identifies and Validates a Novel Signature Based on Immune Related Gene Predicting Survival in Bladder Urothelial Carcinoma

Integrated Analysis Identifies and Validates a Novel Signature Based on Immune Related Gene Predicting Survival in Bladder Urothelial Carcinoma

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

Clonality, activated antigen-specific CD8⁺T cells, and development of autoimmune cholangitis in dnTGFβRII mice

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Urothelial antigen-specific CD4+ T cells function as direct effector cells and induce bladder autoimmune inflammation independent of CD8+ T cells

Cited by 9 publications

References 50 publications

Integrated Analysis Identifies and Validates a Novel Signature Based on Immune Related Gene Predicting Survival in Bladder Urothelial Carcinoma

Integrated Analysis Identifies and Validates a Novel Signature Based on Immune Related Gene Predicting Survival in Bladder Urothelial Carcinoma

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

Clonality, activated antigen-specific CD8+T cells, and development of autoimmune cholangitis in dnTGFβRII mice

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Clonality, activated antigen-specific CD8⁺T cells, and development of autoimmune cholangitis in dnTGFβRII mice