bluuebunny/crossref_metadata_2025_split huggingface dataset:
Urinary Bladder Epithelium Antigen Induces CD8+ T Cell Tolerance, Activation, and Autoimmune Response
Authors: Liu Wujiang , Evanoff David P. , Chen Xiaohong , Luo Yi 
Published: April 2014

Abstract
The effort to explore the specific autoimmune mechanisms of urinary bladder has long been hindered due to a lack of proper animal models. To better elucidate this issue, we developed a novel line of transgenic (Tg) mice, designated as URO-OVA mice, that express the model Ag OVA as a “self”-Ag on the bladder epithelium. URO-OVA mice are naturally tolerant to OVA and show no response to OVA stimulation. Adoptive transfer of naive OVA-specific T cells showed cell proliferation, activation, and infiltration but no bladder histopathology. In contrast, adoptive transfer of activated OVA-specific T cells induced OVA-mediated histological bladder inflammation. Increased mast cells and up-regulated mRNA expressions of TNF-α, nerve growth factor, and substance P precursor were also observed in the inflamed bladder. To further facilitate bladder autoimmunity study, we crossbred URO-OVA mice with OVA-specific CD8+ TCR Tg mice (OT-I mice) to generate a dual Tg line URO-OVA/OT-I mice. The latter mice naturally acquire clonal deletion for autoreactive OT-I CD8+ T cells (partial deletion in the thymus and severe deletion in the periphery). Despite this clonal deletion, URO-OVA/OT-I mice spontaneously develop autoimmune cystitis at 10 wk of age. Further studies demonstrated that the inflamed bladder contained infiltrating OT-I CD8+ T cells that had escaped clonal deletion and gained effector functions before developing histological bladder inflammation. Taken together, we demonstrate for the first time that the bladder epithelium actively presents self-Ag to the immune system and induces CD8+ T cell tolerance, activation, and autoimmune response.
A Local Antigen-Driven Humoral Response Is Present in the Inflammatory Myopathies
Authors: Bradshaw Elizabeth M. , Orihuela Ana , McArdel Shannon L. , Salajegheh Mohammad , Amato Anthony A. , Hafler David A. , Greenberg Steven A. , O’Connor Kevin C. 
Published: April 2014

Abstract
The inflammatory myopathies are putative autoimmune disorders characterized by muscle weakness and the presence of intramuscular inflammatory infiltrates. Although inclusion body myositis and polymyositis have been characterized as cytotoxic CD8+ T cell-mediated diseases, we recently demonstrated high frequencies of CD138+ plasma cells in the inflamed muscle tissue of patients with these diseases. To gain a deeper understanding of the role these B cell family members play in the disease pathology, we examined the molecular characteristics of the H chain portion of the Ag receptor. Biopsies of muscle tissue were sectioned and tissue regions and individual cells were isolated through laser capture microdissection. Ig H chain gene transcripts isolated from the sections, regions, and cells were used to determine the variable region gene sequences. Analysis of these sequences revealed clear evidence of affinity maturation in that significant somatic mutation, isotype switching, receptor revision, codon insertion/deletion, and oligoclonal expansion had occurred within the B and plasma cell populations. Moreover, analysis of tissue regions isolated by laser capture microdissection revealed both clonal expansion and variation, suggesting that local B cell maturation occurs within muscle. In contrast, sequences from control muscle tissues and peripheral blood revealed none of these characteristics found in inflammatory myopathy muscle tissue. Collectively, these data demonstrate that Ag drives a B cell Ag-specific response in muscle in patients with dermatomyositis, inclusion body myositis, and polymyositis. These findings highlight the need for a revision of the current paradigm of exclusively T cell-mediated intramuscular Ag-specific autoimmunity in inclusion body myositis and polymyositis.
B Cell Clonal Expansion and Somatic Hypermutation of Ig Variable Heavy Chain Genes in the Synovial Membrane of Patients with Osteoarthritis
Authors: Da Reng-Rong , Qin Yufen , Baeten Dominique , Zhang Yiping 
Published: April 2014

Abstract
Inflammatory mediators have been explored as possible factors in the initiation and/or progression of osteoarthritis (OA). This study shows that synovial infiltration by B lymphocytes is present in almost half of the knee OA cases. The degree of B lymphocyte infiltration is associated with more pronounced synovial inflammation and with the presence of plasma cells and lymphoid follicles in more severe cases. To examine whether these B cells are merely bystanders or could be involved in the pathogenesis of OA, we analyzed the Ig H chain variable region (VH) genes of B cells recovered from the synovial membrane of five OA patients with marked B cell infiltration. Sequence analysis of CDR3 regions of rearranged VDJ genes revealed clonal or oligoclonal B cell expansions in all cases. Expanded B cell clones in four of five OA patients showed clustered somatic mutations, occurring mainly in the CDRs and with a high replacement-to-silent ratio (&gt;2.9), indicating that these cells are postgerminal center B cells that had been positively selected through their Ag receptor. These data demonstrate the presence in inflamed knee OA synovium of clonally expanded, Ag-driven B cells that may contribute to the development or progression of the disease.
Elicitation of T Cell Responses to Histologically Unrelated Tumors by Immunization with the Novel Cancer-Testis Antigen, Brother of the Regulator of Imprinted Sites
Authors: Ghochikyan Anahit , Mkrtichyan Mikayel , Loukinov Dmitri , Mamikonyan Gregory , Pack Svetlana D. , Movsesyan Nina , Ichim Thomas E. , Cribbs David H. , Lobanenkov Victor V. , Agadjanyan Michael G. 
Published: April 2014

AbstractBrother of the regulator of imprinted sites (BORIS) was previously described as a transcription factor for epigenetic reprogramming the expression of which is strictly confined to germ cells of adult testes but is aberrantly activated in the vast majority of neoplastic cells. Considering the critical role of BORIS in cancerogenesis and the fact that its expression pattern may preclude thymic tolerance, we generated DNA- and protein-based mouse BORIS antitumor vaccines using a non-DNA-binding version of the BORIS molecule. Clinical use of BORIS as a vaccine Ag would require that certain safety concerns be met. Specifically, administration of the functional BORIS protein would hypothetically pose a risk of BORIS accelerating the progression of cancer. To alleviate such safety concerns, we have developed vaccines based on the BORIS molecule lacking the DNA-binding zinc fingers domain. To enhance anti-BORIS cellular immune responses, we used a standard molecular adjuvant approach. It consisted of plasmids encoding murine IL-12 and IL-18 for a DNA-based vaccine and conventional Th1 type adjuvant, Quil A, for a protein-based vaccine. Both DNA- and protein-based vaccines induced Ag-specific CD4+ T cell proliferation with Th1 and Th2 cytokine profiles, respectively. Protein-based, but not DNA-based, BORIS vaccine induced a significant level of Ab production in immunized animals. Importantly, potent anticancer CD8+-cytotoxic lymphocytes were generated after immunization with the DNA-based, but not protein-based, BORIS vaccine. These cytolytic responses were observed across a wide range of different mouse cancers including mammary adenocarcinoma, glioma, leukemia, and mastocytoma.
Suppression of Skin Lesions by Transdermal Application of CpG-Oligodeoxynucleotides in NC/Nga Mice, a Model of Human Atopic Dermatitis
Authors: Inoue Joe , Aramaki Yukihiko 
Published: April 2014

Abstract
Atopic dermatitis (AD) is a pruritic inflammatory skin disease characterized by an elevation of the total IgE level in plasma, the infiltration of mast cells and eosinophils, and the expression of cytokines by Th2 cells. NC/Nga mice kept in conventional conditions are known to develop skin lesions resembling human AD. We examined in this study the alterations of immune response in NC/Nga mice kept in conventional conditions, following transdermal application of CpG-oligodeoxynucleotides (ODN), which plays a critical role in immunity via the augmentation of Th1-type and suppression of Th2-type responses. CpG-ODN remarkably changed the immune response from type Th2 to Th1 as determined from cytokine mRNA and Ab levels. The serum IgE level was decreased and the expression of IgG2a was up-regulated. The application of CpG-ODN to the skin also decreased inflammatory infiltration of mast cells, and suppression in the skin lesions was observed. Furthermore, the generation of regulatory T cells, which are considered immune suppressive T cells, was observed in the skin on treatment with CpG-ODN. These results suggested CpG-ODN is effective for immunotherapy in patients with AD, which is characterized by Th2-dominated inflammation.
Regulation of Memory Antibody Levels: The Role of Persisting Antigen versus Plasma Cell Life Span
Authors: Gatto Dominique , Martin Stephen W. , Bessa Juliana , Pellicioli Erica , Saudan Philippe , Hinton Heather J. , Bachmann Martin F. 
Published: April 2014

Abstract
Protective Ab levels can be maintained for years upon infection or vaccination. In this study, we studied the duration of Ab responses as a function of the life span of plasma cells and tested the role of persisting Ag in maintaining B cell memory. Our analysis of B cell responses induced in mice immunized with virus-like particles demonstrates the following: 1) Ab titers are long-lived, but decline continuously with a t1/2 of ∼80 days, which corresponds to the life span of plasma cells; 2) the germinal center (GC) reaction, which lasts for up to 100 days, is dependent on Ag associated with follicular dendritic cells; and 3) early GCs produce massive numbers of plasma and memory B cell precursors, whereas the late Ag-dependent GCs are dispensable for the maintenance of Ab levels and B cell memory.
Immune Regulation by Microvascular Endothelial Cells: Directing Innate and Adaptive Immunity, Coagulation, and Inflammation
Authors: Danese Silvio , Dejana Elisabetta , Fiocchi Claudio 
Published: April 2014

Abstract
An effective immune response depends not only on the proper activation, regulation, and function of immune cells, but also on their distribution and retention in diverse tissue microenvironments where they encounter a number of stimuli and other cell types. These activities are mediated by endothelial cells, which form specialized microcirculatory networks used by immune cells under both physiological and pathological circumstances. Endothelial cells represent a highly heterogeneous population of cells with the ability to interact with and modulate the function of immune cells. This review is focused on the role of microvascular endothelial cells in innate and adaptive immunity, inflammation, coagulation, angiogenesis, and the therapeutic implications of targeting endothelial cells in selected autoimmune and chronic inflammatory disorders.
Cutting Edge: IPSE/alpha-1, a Glycoprotein fromSchistosoma mansoniEggs, Induces IgE-Dependent, Antigen-Independent IL-4 Production by Murine Basophils In Vivo
Authors: Schramm Gabriele , Mohrs Katja , Wodrich Maren , Doenhoff Michael J. , Pearce Edward J. , Haas Helmut , Mohrs Markus 
Published: April 2014

AbstractDuring infection with the helminth parasite Schistosoma mansoni, the deposition of eggs coincides with the onset of IL-4 production and Th2 development. Although IL-4 is known as a potent inducer of Th2 differentiation, the mechanism by which schistosome eggs induce IL-4 production is not clear. In this study, we demonstrate that the S. mansoni egg Ag (SmEA) induces IgE-dependent IL-4 production by basophils derived from Heligmosomoides polygyrus-infected or OVA/alum-immunized mice in the absence of pathogen-specific IgE. The effect is mediated by the secretory glycoprotein IPSE/alpha-1, because IPSE/alpha-1-depleted SmEA no longer induces cytokine production. Conversely, recombinant IPSE/alpha-1 is sufficient to induce IL-4 production. Importantly, the injection of SmEA or recombinant IPSE/alpha-1 into H. polygyrus-infected 4get/KN2 IL-4 reporter mice rapidly induces the dose-dependent IL-4 production by basophils in the liver, a major site of egg deposition. Thus, IPSE/alpha-1 induces basophils to produce IL-4 even in the absence of Ag-specific IgE.
Cutting Edge: Conventional Dendritic Cells Are the Critical APC Required for the Induction of Experimental Cerebral Malaria
Authors: deWalick Saskia , Amante Fiona H. , McSweeney Karli A. , Randall Louise M. , Stanley Amanda C. , Haque Ashraful , Kuns Rachel D. , MacDonald Kelli P. A. , Hill Geoff R. , Engwerda Christian R. 
Published: April 2014

AbstractCerebral malaria (CM) is a serious complication of Plasmodium falciparum infection, causing significant morbidity and mortality among young children and nonimmune adults in the developing world. Although previous work on experimental CM has identified T cells as key mediators of pathology, the APCs and subsets therein required to initiate immunopathology remain unknown. In this study, we show that conventional dendritic cells but not plasmacytoid dendritic cells are required for the induction of malaria parasite-specific CD4+ T cell responses and subsequent experimental CM. These data have important implications for the development of malaria vaccines and the therapeutic management of CM.
Cutting Edge: Cross-Presented Intracranial Antigen Primes CD8+ T Cells
Authors: Walter Lisa , Albert Matthew L. 
Published: April 2014

Abstract
The CNS is considered immune privileged due to the blood-brain barrier and the absence of conventional lymphatics. Nonetheless, T cell immune responses specific for CNS Ag have been documented. Where these events are initiated and what cellular mechanisms are involved remain unknown. In this study, we established an experimental mouse model to evaluate the requirements for priming CD8+ T cells following the cross-presentation of intracranial Ag. Surprisingly, we find that even with a damaged blood-brain barrier, Ag presentation occurs in regional lymph nodes and not within the CNS itself. Only once the responding cells have expanded can they traffic to the site of CNS injury. Cross-presentation of intracranial Ag is efficient and the subsequent priming of CD8+ T cells is dependent on CD4+ T cell help and CD40 signaling in host APCs. Our findings have important implications for the initiation of T cell immune responses toward CNS Ags.
Nasal Cholera Toxin Elicits IL-5 and IL-5 Receptor α-Chain Expressing B-1a B Cells for Innate Mucosal IgA Antibody Responses
Authors: Kataoka Kosuke , Fujihashi Keiko , Sekine Shinichi , Fukuiwa Tatsuya , Kobayashi Ryoki , Suzuki Hideaki , Nagata Hideki , Takatsu Kiyoshi , Shizukuishi Satoshi , McGhee Jerry R. , Fujihashi Kohtaro 
Published: April 2014

Abstract
In this study, we examine whether native cholera toxin (nCT) as a mucosal adjuvant can support trinitrophenyl (TNP)-LPS-specific mucosal immune responses. C57BL/6 mice were given nasal TNP-LPS in the presence or absence of nCT. Five days later, significantly higher levels of TNP-specific mucosal IgA Ab responses were induced in the nasal washes, saliva, and plasma of mice given nCT plus TNP-LPS than in those given TNP-LPS alone. High numbers of TNP-specific IgA Ab-forming cells were also detected in mucosal tissues such as the nasal passages (NPs), the submandibular glands (SMGs), and nasopharyngeal-associated lymphoreticular tissue of mice given nCT. Flow cytometric analysis showed that higher numbers of surface IgA+, CD5+ B cells (B-1a B cells) in SMGs and NPs of mice given nasal TNP-LPS plus nCT than in those given TNP-LPS alone. Furthermore, increased levels of IL-5R α-chain were expressed by B-1a B cells in SMGs and NPs of mice given nasal TNP-LPS plus nCT. Thus, CD4+ T cells from these mucosal effector lymphoid tissues produce high levels of IL-5 at both protein and mRNA levels. When mice were treated with anti-IL-5 mAb, significant reductions in TNP-specific mucosal IgA Ab responses were noted in external secretions. These findings show that nasal nCT as an adjuvant enhances mucosal immune responses to a T cell-independent Ag due to the cross-talk between IL-5Rα+ B-1a B cells and IL-5-producing CD4+ T cells in the mucosal effector lymphoid tissues.
Allosuppressive Donor CD4+CD25+ Regulatory T Cells Detach from the Graft and Circulate in Recipients after Liver Transplantation
Authors: Demirkiran Ahmet , Bosma Brenda M. , Kok Alice , Baan Carla C. , Metselaar Herold J. , IJzermans Jan N. M. , Tilanus Hugo W. , Kwekkeboom Jaap , van der Laan Luc J. W. 
Published: April 2014

Abstract
Organ transplantation (Tx) results in a transfer of donor leukocytes from the graft to the recipient, which can lead to chimerism and may promote tolerance. It remains unclear whether this tolerance involves donor-derived regulatory T cells (Tregs). In this study, we examined the presence and allosuppressive activity of CD4+CD25+Foxp3+ Tregs in perfusates of human liver grafts and monitored the cells presence in the circulation of recipients after liver Tx. Vascular perfusions of 22 liver grafts were performed with University of Wisconsin preservation and albumin solutions. Flow cytometric analysis revealed that perfusate T cells had high LFA-1 integrin expression and had a reversed CD4 to CD8 ratio compared with control blood of healthy individuals. These findings indicate that perfusate cells are of liver origin and not derived from residual donor blood. Further characterization of perfusate mononuclear cells showed an increased proportion of CD4+CD25+CTLA4+ T cells compared with healthy control blood. Increased percentages of Foxp3+ cells, which were negative for CD127, confirmed the enrichment of Tregs in perfusates. In MLR, CD4+CD25+ T cells from perfusates suppressed proliferation and IFN-γ production of donor and recipient T cells. In vivo within the first weeks after Tx, up to 5% of CD4+CD25+CTLA4+ T cells in recipient blood were derived from the donor liver. In conclusion, a substantial number of donor Tregs detach from the liver graft during perfusion and continue to migrate into the recipient after Tx. These donor Tregs suppress the direct pathway alloresponses and may in vivo contribute to chimerism-associated tolerance early after liver Tx.
Unrestrained Glycogen Synthase Kinase-3β Activity Leads to Activated T Cell Death and Can Be Inhibited by Natural Adjuvant
Authors: Sengupta Sadhak , Jayaraman Padmini , Chilton Paula M. , Casella Carolyn R. , Mitchell Thomas C. 
Published: April 2014

AbstractActivated T cell death (ATCD) after peak clonal expansion is required for effective homeostasis of the immune system. Using a mouse model of T cell clonal expansion and contraction, we found that regulation of the proapoptotic kinase glycogen synthase kinase (GSK)-3β plays a decisive role in determining the extent to which T cells are eliminated after activation. Involvement of GSK-3β in ATCD was tested by measuring T cell survival after GSK-3β inhibition, either ex vivo with chemical and pharmacological inhibitors or in vivo by retroviral expression of a dominant-negative form of GSK-3. We also measured amounts of inactivating phosphorylation of GSK-3β (Ser9) in T cells primed in the presence or absence of LPS. Our results show that GSK-3β activity is required for ATCD and that its inhibition promoted T cell survival. Adjuvant treatment in vivo maintained GSK-3β (Ser9) phosphorylation in activated T cells, whereas with adjuvant-free stimulation it peaked and then decayed as the cells became susceptible to ATCD. We conclude that the duration of GSK-3β inactivation determines activated T cell survival and that natural adjuvant stimulation decreases the severity of clonal contraction in part by keeping a critical proapoptotic regulatory factor, GSK-3β, inactivated.
Involvement of Heat Shock Protein (Hsp)90β but Not Hsp90α in Antiapoptotic Effect of CpG-B Oligodeoxynucleotide
Authors: Kuo Cheng-Chin , Liang Chi-Ming , Lai Chen-Yen , Liang Shu-Mei 
Published: April 2014

Abstract
Unmethylated CpG oligodeoxynucleotides (CpG ODNs) activate immune responses in a TLR9-dependent manner. In this study, we found that stimulation of mouse macrophages and dendritic cells with B-type CpG ODN (CpG-B ODN) increased the cellular level of heat shock protein (Hsp) 90β but not Hsp90α and prevented apoptosis induced by serum starvation or staurosporine treatment. The CpG-B ODN-induced Hsp90β expression depended on TLR9, MyD88, and PI3K. Inhibition of Hsp90β level by expressing small-interfering RNA suppressed not only Hsp90β expression but also PI3K-dependent phosphorylation of Akt and CpG-B ODN-mediated antiapoptosis. Additional studies demonstrated that as described by other group in mast cells, Hsp90β but not Hsp90α was associated with Bcl-2. Inhibition of Hsp90β suppressed the CpG-B ODN-induced association of Hsp90β with Bcl-2 and impaired the inhibitory effect of CpG-B ODN in the release of cytochrome c and activation of caspase-3. This study thus reveals the involvement of Hsp90β but not Hsp90α in CpG-B ODN-mediated antiapoptotic response and that Hsp90β is distinct from Hsp90α in regulation of the cellular function of immune cells.
TCRβ Chain That Forms Peptide-Independent Alloreactive TCR Transfers Reduced Reactivity with Irrelevant Peptide/MHC Complex
Authors: Santori Fabio R. , Popmihajlov Zoran , Badovinac Vladimir P. , Smith Courtney , Radoja Sasa , Harty John T. , Vukmanović Stanislav 
Published: April 2014

AbstractA major feature of the TCR repertoire is strong alloreactivity. Peptides presented by allogeneic MHC are irrelevant for recognition by a subset of alloreactive T cells. To characterize peptide-independent TCRs at the molecular level, we forced the expression of a TCRβ chain isolated from a peptide-independent alloreactive CD8+ T cell line. The alloreactive TCR repertoire in the transgenic mouse was peptide dependent. However, analysis of essential TCR contacts formed during the recognition of self-MHC-restricted Ag showed that fewer contacts with peptide were established by the transgenic TCRβ chain, and that this was compensated by additional contacts formed by endogenous TCRα chains. Thus, reduced interaction with the peptide appears to be a transferable feature of the peptide-independent TCRβ chain. In addition, these findings demonstrate that reactivity to peptides is preferred over the reactivity to MHC during the formation of the TCR repertoire.