bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody Cross-Reactivity between Myelin Oligodendrocyte Glycoprotein and the Milk Protein Butyrophilin in Multiple Sclerosis
Authors: Guggenmos Johannes , Schubart Anna S. , Ogg Sherry , Andersson Magnus , Olsson Tomas , Mather Ian H. , Linington Christopher 
Published: April 2014

AbstractThe etiology of multiple sclerosis (MS) is believed to involve environmental factors, but their identity and mode of action are unknown. In this study, we demonstrate that Ab specific for the extracellular Ig-like domain of myelin oligodendrocyte glycoprotein (MOG) cross-reacts with a homologous N-terminal domain of the bovine milk protein butyrophilin (BTN). Analysis of paired samples of MS sera and cerebrospinal fluid (CSF) identified a BTN-specific Ab response in the CNS that differed in its epitope specificity from that in the periphery. This effect was statistically significant for the Ab response to BTN76–100 (p = 0.0026), which cosequestered in the CSF compartment with Ab to the homologous MOG peptide MOG76–100 in 34% of MS patients (n = 35). These observations suggested that intratheccal synthesis of Ab recognizing BTN peptide epitopes in the CNS was sustained by molecular mimicry with MOG. Formal evidence of molecular mimicry between the two proteins was obtained by analyzing MOG-specific autoantibodies immunopurified from MS sera. The MOG-specific Ab repertoire cross-reacts with multiple BTN peptide epitopes including a MOG/BTN76–100-specific component that occurred at a higher frequency in MS patients than in seropositive healthy controls, as well as responses to epitopes within MOG/BTN1–39 that occur at similar frequencies in both groups. The demonstration of molecular mimicry between MOG and BTN, along with sequestration of BTN-reactive Ab in CSF suggests that exposure to this common dietary Ag may influence the composition and function of the MOG-specific autoimmune repertoire during the course of MS.
A Major B Cell Epitope Present on the Apoptotic but Not the Intact Form of the U1-70-kDa Ribonucleoprotein Autoantigen
Authors: Greidinger Eric L. , Foecking Mark F. , Magee Joseph , Wilson Linda , Ranatunga Sriya , Ortmann Robert A. , Hoffman Robert W. 
Published: April 2014

Abstract
Apoptotically modified forms of autoantigens have been hypothesized to participate in lupus immunopathogenesis. This study identifies a major B cell epitope present on the apoptotic but not the intact form of the U1-70-kDa ribonucleoprotein lupus autoantigen (70k). Human autoimmune sera with strong recognition of apoptotic 70k and minimal recognition of intact 70k were identified and tested for reactivity to truncated forms of 70k by immunoblot and ELISA. Patient sera that preferentially recognized apoptotic 70k were specific for an epitope dependent on residues 180–205 of the protein. This epitope was also recognized by 19 of 28 (68%) intact anti-70k-positive autoimmune human sera with Abs also recognizing apoptotic but not the intact form 70k, but only 1 of 9 (11%) intact 70k-positive sera without such Abs (Fisher’s exact, p = 0.0055). Immunization of HLA-DR4-transgenic C57BL/6 mice with a peptide containing this epitope induced anti-70k immunity in 13 of 15 mice, including Abs recognizing apoptotic but not intact forms of autoantigens in 12 of 15 mice. Anti-70k responder mice also developed spreading of immunity to epitopes on the endogenous form of 70k, and proliferative lung lesions consistent with those described in patients with anti-70k autoimmunity. Thus, a major epitope in the B cell response to U1-70 kDa localizes to the RNA binding domain of the molecule, overlaps with the most common T cell epitope in the anti-70k response, and is not present on the intact form of the 70k molecule. Immunization of mice against this epitope induces an immune response with features seen in human anti-70k autoimmune disease.
DNA Acrobats of the Ig Class Switch
Authors: Wang Clifford L. , Wabl Matthias 
Published: April 2014

AbstractSmall resting B lymphocytes all start out producing IgM Abs. Upon encountering Ag, the cells become activated and make a switch from IgM to other Ig classes. This class switch serves to distribute a particular V region to different Ig C regions. Each C region mediates a specialized effector function, and so, through switching, an organism can guide its Abs to various sites. Creating the new H chain requires loop-out and deletion of DNA between switch regions. These DNA acrobatics require transcription of the switch regions, presumably so that necessary factors can gain access to the DNA. These requisite switching factors include activation-induced cytidine deaminase and components of general DNA repair, including base excision repair, mismatch repair, and double-strand break repair. Despite much recent progress, not all important factors have been discovered, especially those that may guide recombination to a particular subclass.
Cutting Edge: The Natural Ligand for Glucocorticoid-Induced TNF Receptor-Related Protein Abrogates Regulatory T Cell Suppression
Authors: Ji Hong-bin , Liao Gongxian , Faubion William A. , Abadía-Molina Ana C. , Cozzo Cristina , Laroux F. Stephen , Caton Andrew , Terhorst Cox 
Published: April 2014

Abstract
CD4+25+ regulatory T (Treg) cells maintain immunological self-tolerance through mechanisms that are only in part understood. Previous studies suggest that the glucocorticoid-induced TNFR-related protein (GITR), which is preferentially expressed on the surface of Treg cells, potentially provides a signal that abrogates Treg suppression. In this study, we show that a soluble form of mouse GITR ligand (sGITR-L) induces GITR-dependent NF-κB activation and blocks in vitro suppression mediated by both resting and preactivated polyclonal and Ag-specific Treg cells. Since sGITR-L along with rIL-2 induces proliferation of CD4+25+ cells, it appears that sGITR-L can break the anergic state of Treg cells. Because sGITR-L also up-regulates IL-2 secretion by activated CD4+25 −T cells, these two sGITR-L induced signals synergize to interfere with suppressor activity by CD4+25+ Treg cells.
Shift from Systemic to Site-Specific Memory by Tumor-Targeted IL-2
Authors: Schrama David , Xiang Rong , Eggert Andreas O. , Andersen Mads Hald , Pedersen Lars Østergaard , Kämpgen Eckhart , Schumacher Ton N. , Reisfeld Ralph R. , Becker Jürgen C. 
Published: April 2014

Abstract
IL-2 has been approved for treatment of patients with cancer. Moreover, it has been used as a component of vaccines against cancer. In this regard, we have recently demonstrated that dendritic cell-based peptide vaccination in mice required IL-2 to mount an effective immune response against established melanoma metastases. In this study, we confirm this observation by use of tumor-targeted IL-2. However, the development of a protective systemic memory was substantially impaired by this measure, i.e., mice, which successfully rejected s.c. tumors of B16 melanoma after vaccination with dendritic cells pulsed with tyrosinase-related protein 2-derived peptides plus a boost with targeted IL-2, failed to reject a rechallenge with experimental pulmonary metastases. Detailed analysis revealed a change in the distribution of the tumor-reactive T cell population: although targeted IL-2 expanded the local effector population, tyrosinase-related protein 2-reactive T cells were almost completely depleted from lymphatic tissues.
Evolutionary Origins of Lymphocytes: Ensembles of T Cell and B Cell Transcriptional Regulators in a Cartilaginous Fish
Authors: Anderson Michele K. , Pant Rashmi , Miracle Ann L. , Sun Xiao , Luer Carl A. , Walsh Catherine J. , Telfer Janice C. , Litman Gary W. , Rothenberg Ellen V. 
Published: April 2014

AbstractThe evolutionary origins of lymphocytes can be traced by phylogenetic comparisons of key features. Homologs of rearranging TCR and Ig (B cell receptor) genes are present in jawed vertebrates, but have not been identified in other animal groups. In contrast, most of the transcription factors that are essential for the development of mammalian T and B lymphocytes belong to multigene families that are represented by members in the majority of the metazoans, providing a potential bridge to prevertebrate ancestral roles. This work investigates the structure and regulation of homologs of specific transcription factors known to regulate mammalian T and B cell development in a representative of the earliest diverging jawed vertebrates, the clearnose skate (Raja eglanteria). Skate orthologs of mammalian GATA-3, GATA-1, EBF-1, Pax-5, Pax-6, Runx2, and Runx3 have been characterized. GATA-3, Pax-5, Runx3, EBF-1, Spi-C, and most members of the Ikaros family are shown throughout ontogeny to be 1) coregulated with TCR or Ig expression, and 2) coexpressed with each other in combinations that for the most part correspond to known mouse T and B cell patterns, supporting conservation of function. These results indicate that multiple components of the gene regulatory networks that operate in mammalian T cell and B cell development were present in the common ancestor of the mammals and the cartilaginous fish. However, certain factors relevant to the B lineage differ in their tissue-specific expression patterns from their mouse counterparts, suggesting expanded or divergent B lineage characteristics or tissue specificity in these animals.
Differential Gene Expression Patterns by Oligonucleotide Microarray of Basal versus Lipopolysaccharide-Activated Monocytes from Cord Blood versus Adult Peripheral Blood
Authors: Jiang Hong , Van de Ven Carmella , Satwani Prakash , Baxi Laxmi V. , Cairo Mitchell S. 
Published: April 2014

Abstract
Monocytes (Mo) are critically important in the generation of inflammatory mediators, cytokines/chemokines, and regulation of innate and adaptive immune responses. We and others have previously demonstrated significant dysregulated cytokine gene expression and protein production and in vitro functional activities of activated cord blood (CB) vs adult peripheral blood (APB) mononuclear cells (MNC). In this study, we compared, by oligonucleotide microarray, the differential gene expression profiles of basal and LPS-activated APB vs CB Mo. We demonstrated a significant increase in the gene expression of several important functional groups of CB genes compared with basal levels including cytokine (IL-12p40, 5-fold), immunoregulatory (signaling lymphocytic activation molecule, 4-fold), signal transduction (Pim-2, 3-fold), and cell structure (Rho7, 4-fold) among others. Furthermore, there was significantly differentially amplified gene expression in LPS-activated APB vs LPS-activated CB Mo, including cytokine (G-CSF, 14-fold), chemokine (macrophage-inflammatory protein 1α, 5-fold), immunoregulatory (MHC DRB1, 5-fold), transcription factor (JunB, 4-fold), signal transduction (STAT4, 5-fold), apoptotic regulation (BAX, 5-fold), and cell structure (ladinin 1, 6-fold) among others. These results provide insight into the molecular basis for normal genetic regulation of Mo development and cellular function and differential inflammatory and innate and adaptive immune responses between activated CB and APB Mo.
Generation of Anergic and Regulatory T Cells following Prolonged Exposure to a Harmless Antigen
Authors: Chen Tse-Ching , Cobbold Stephen P. , Fairchild Paul J. , Waldmann Herman 
Published: April 2014

AbstractRegulatory CD4+ T cells are known to develop during the induction of donor-specific peripheral tolerance to transplanted tissues; it is proposed that such tolerance is a consequence of persistent, danger-free stimulation by Ag. To test this hypothesis, male RAG-1−/− mice were recolonized with small numbers of monospecific CD4+ T cells specific for the male H-2Ek-restricted Ag Dby. After 6 wk in the male environment, the monospecific CD4+ T cells, having recolonized the host, had become anergic to stimulation in vitro and had acquired a regulatory capacity. CD4+ T cells in these mice expressed higher levels of CTLA-4 and glucocorticoid-induced TNF-related receptor than naive CD4+ T cells, but only 3% of the recolonizing cells were CD25+ and did not express significant foxP3 mRNA. In vivo, these tolerant T cells could censor accumulation of, and IFN-γ production by, naive T cells, with only a slight inhibition of proliferation. This suppressive effect was not reversed by the addition of fresh bone marrow-derived male dendritic cells. These results suggest that persistent exposure to Ag in conditions that fail to evoke proinflammatory stimuli leads to the development of T cells that are both anergic and regulatory.
IL-2 Induces a Competitive Survival Advantage in T Lymphocytes
Authors: Dooms Hans , Kahn Estelle , Knoechel Birgit , Abbas Abul K. 
Published: April 2014

AbstractThe acquisition of long-term survival potential by activated T lymphocytes is essential to ensure the successful development of a memory population in the competitive environment of the lymphoid system. The factors that grant competitiveness for survival to primed T cells are poorly defined. We examined the role of IL-2 signals during priming of CD4+ T cells in the induction of a long-lasting survival program. We show that Ag-induced cycling of CD4+ IL-2−/− T cells is independent of IL-2 in vitro. However, IL-2−/− T cells failed to accumulate in large numbers and develop in effector cells when primed in the absence of IL-2. More importantly, Ag-activated IL-2−/− T cells were unable to survive for prolonged periods of time after adoptive transfer in unmanipulated, syngeneic mice. IL-2−/− T cells exposed to IL-2 signals during priming, however, acquired a robust and long-lasting survival advantage over cells that cycled in the absence of IL-2. Interestingly, this IL-2-induced survival program was required for long-term persistence of primed IL-2−/− T cells in an intact lymphoid compartment, but was unnecessary in a lymphopenic environment. Therefore, IL-2 enhances competitiveness for survival in CD4+ T cells, thereby facilitating the development of a memory population.
Adult Human Liver Contains CD8pos T Cells with Naive Phenotype, but Is Not a Site for Conventional αβ T Cell Development
Authors: Golden-Mason Lucy , Douek Daniel C. , Koup Richard A. , Kelly Jacinta , Hegarty John E. , O’Farrelly Cliona 
Published: April 2014

Abstract
Normal adult human liver (AHL) contains populations of unconventional lymphocytes that have been shown in the mouse to mature locally. The presence of lymphoid progenitors together with IL-7, recombinase-activating gene, and pre-TCR-α expression in AHL suggests similar local T cell development activity in humans. Flow cytometry was used to characterize potentially naive hepatic αβ-T cells. We looked for evidence of TCR-αβ cell development in AHL by quantifying δ deletion TCR excision circles (TRECs) in CD3pos populations isolated from the liver and matched blood of eight individuals. Phenotypic analysis of hepatic T cells suggests the presence of Ag-inexperienced populations. TRECs were detected in all blood samples (mean, 164.10 TRECs/μg DNA), whereas only two hepatic samples were positive at low levels (59.40 and 1.92). The relatively high level of CD8pos T cells in these livers with a naive phenotype suggests that in addition to its role as a graveyard for Ag-specific activated CD8pos T cells, naive CD8pos T cells may enter the liver without prior activation. The almost complete absence of TRECs suggests that normal AHL is not a site for the development of conventional αβ T cells.
Thymic Expression of a Gastritogenic Epitope Results in Positive Selection of Self-Reactive Pathogenic T Cells
Authors: Laurie Karen L. , La Gruta Nicole L. , Koch Norbert , van Driel Ian R. , Gleeson Paul A. 
Published: April 2014

Abstract
Intrathymic expression of tissue-specific self-Ags can mediate tolerance of self-reactive T cells. However, in this study we define circumstances by which thymic expression of a tissue-specific autoepitope enhances positive selection of disease-causing, self-reactive T cells. An immunodominant gastritogenic epitope, namely the gastric H/K ATPase β subunit253–277 (H/Kβ253–277), was attached to the C terminus of the invariant chain (Ii) and the hybrid Ii (Ii-H/Kβ253–277) expressed in mice under control of the Ii promoter. The Ii-H/Kβ253–277 fusion protein was localized to MHC class II-expressing cells in the thymus and periphery of Ii-H/Kβ253–277 transgenic mice. In one transgenic line the level of presentation in the periphery (spleen) was insufficient to activate naive, low affinity H/Kβ253–277-specific transgenic T cells (1E4-TCR), whereas thymic presentation of H/Kβ253–277 enhanced positive selection of 1E4-TCR cells in Ii-H/Kβ253–277/1E4-TCR double-transgenic mice. Furthermore, Ii-H/Kβ253–277/1E4-TCR double-transgenic mice had an increased incidence of autoimmune gastritis compared with 1E4-TCR single-transgenic mice, demonstrating that the 1E4 T cells that seeded the periphery of Ii-H/Kβ253–277 mice were pathogenic. Therefore, low levels of tissue-specific Ags in the thymus can result in positive selection of low avidity, self-reactive T cells. These findings also suggest that the precise level of tissue-specific Ags in the thymus may be an important consideration in protection against autoimmune disease and that perturbation of the levels of self-Ags may be detrimental.
The Role of IL-5 for Mature B-1 Cells in Homeostatic Proliferation, Cell Survival, and Ig Production
Authors: Moon Byoung-gon , Takaki Satoshi , Miyake Kensuke , Takatsu Kiyoshi 
Published: April 2014

AbstractB-1 cells, distinguishable from conventional B-2 cells by their cell surface marker, anatomical location, and self-replenishing activity, play an important role in innate immune responses. B-1 cells constitutively express the IL-5R α-chain (IL-5Rα) and give rise to Ab-producing cells in response to various stimuli, including IL-5 and LPS. Here we report that the IL-5/IL-5R system plays an important role in maintaining the number and the cell size as well as the functions of mature B-1 cells. The administration of anti-IL-5 mAb into wild-type mice, T cell-depleted mice, or mast cell-depleted mice resulted in reduction in the total number and cell size of B-1 cells to an extent similar to that of IL-5Rα-deficient (IL-5Rα−/−) mice. Cell transfer experiments have demonstrated that B-1 cell survival in wild-type mice and homeostatic proliferation in recombination-activating gene 2-deficient mice are impaired in the absence of IL-5Rα. IL-5 stimulation of wild-type B-1 cells, but not IL-5Rα−/− B-1 cells, enhances CD40 expression and augments IgM and IgG production after stimulation with anti-CD40 mAb. Enhanced IgA production in feces induced by the oral administration of LPS was not observed in IL-5Rα−/− mice. Our results illuminate the role of IL-5 in the homeostatic proliferation and survival of mature B-1 cells and in IgA production in the mucosal tissues.
The Ability of Two Listeria monocytogenes Vaccines Targeting Human Papillomavirus-16 E7 to Induce an Antitumor Response Correlates with Myeloid Dendritic Cell Function
Authors: Peng Xiaohui , Hussain S. Farzana , Paterson Yvonne 
Published: April 2014

Abstract
Previous work from our laboratory has shown that Lm-LLO-E7 induces complete regression of ∼75% of established TC-1 tumors, whereas Lm-E7 only slows the growth of such tumors. In this study, we examine the effects of Lm-LLO-E7 vs Lm-E7 on APCs. We hypothesize that the difference in antitumor efficacy of the two vaccines is due to the ability of each of these vectors to render immature dendritic cells (DCs) effective APCs in terms of MHC class II or costimulatory molecule expression. We also examine the ability of these vectors to stimulate cytokine production by DCs. Both vectors induced IL-12 and TNF-α, but only Lm-LLO-E7 induced IL-2 production by DCs. Lm-LLO-E7 also induced significantly higher levels of MHC class II molecules, CD40, and B7 costimulatory molecules (CD86, B7-H1, and B7-DC) on DCs than Lm-E7. Interestingly, a shift of CD11c+ cells from CD86low to CD86high is observed post-Lm-LLO-E7 infection. A similar shift is also observed for B7-H1 and B7-DC molecules. Moreover, Lm-LLO-E7, but not Lm-E7-pulsed DCs, stimulate naive T cell proliferation. These results indicate that Lm-LLO-E7 is more effective than Lm-E7 at inducing DC maturation. This effect is independent of the E7 Ag, because Lm-LLO-NP, and a mixture of Lm-LLO-NP and Lm-E7 induce the same changes in DC phenotype as Lm-LLO-E7. Taken together, the changes in DC expression correlate well with the differences in antitumor efficacy between these two vaccines.
T Cells Associated with Tumor Regression Recognize Frameshifted Products of the CDKN2A Tumor Suppressor Gene Locus and a Mutated HLA Class I Gene Product
Authors: Huang Jianping , El-Gamil Mona , Dudley Mark E. , Li Yong F. , Rosenberg Steven A. , Robbins Paul F. 
Published: April 2014

Abstract
The dramatic tumor regression observed following adoptive T cell transfer in some patients has led to attempts to identify novel Ags to understand the nature of these responses. Nearly complete regression of multiple metastatic melanoma lesions was observed in patient 1913 following adoptive transfer of autologous tumor-infiltrating lymphocytes. The autologous 1913 melanoma cell line expressed a mutated HLA-A11 class I gene product that was recognized by the bulk tumor-infiltrating lymphocytes as well as a dominant T cell clone derived from this line. A second dominant T cell clone, T1D1, did not recognize the mutated HLA-A11 product, but recognized an allogeneic melanoma cell line that shared expression of HLA-A11 with the parental tumor cell line. Screening of an autologous melanoma cDNA library with clone T1D1 T cells in a cell line expressing the mutated HLA-A11 gene product resulted in the isolation of a p14ARF transcript containing a 2-bp deletion in exon 2. The T cell epitope recognized by T1D1, which was encoded within the frameshifted region of the deleted p14ARF transcript, was also generated from frameshifted p14ARF or p16INK4a transcripts that were isolated from two additional melanoma cell lines. The results of monitoring studies indicated that T cell clones reactive with the mutated HLA-A11 gene product and the mutated p14ARF product were highly represented in the peripheral blood of patient 1913 1 wk following adoptive transfer, indicating that they may have played a role in the nearly complete tumor regression that was observed following this treatment.
Toll-Like Receptor Ligands Directly Promote Activated CD4+ T Cell Survival
Authors: Gelman Andrew E. , Zhang Jidong , Choi Yongwon , Turka Laurence A. 
Published: April 2014

AbstractToll-like receptor (TLR) engagement by pathogen-associated molecular patterns (PAMPs) is an important mechanism for optimal cellular immune responses. APC TLR engagement indirectly enhances activated CD4+ T cell proliferation, differentiation, and survival by promoting the up-regulation of costimulatory molecules and the secretion of proinflammatory cytokines. However, TLRs are also expressed on CD4+ T cells, suggesting that PAMPs may also act directly on activated CD4+ T cells to mediate functional responses. In this study, we show that activated mouse CD4+ T cells express TLR-3 and TLR-9 but not TLR-2 and TLR-4. Treatment of highly purified activated CD4+ T cells with the dsRNA synthetic analog poly(I:C) and CpG oligodeoxynucleotides (CpG DNA), respective ligands for TLR-3 and TLR-9, directly enhanced their survival without augmenting proliferation. In contrast, peptidoglycan and LPS, respective ligands for TLR-2 and TLR-4 had no effect. Enhanced survival mediated by either poly(I:C) or CpG DNA required NF-κB activation and was associated with Bcl-xL up-regulation. However, only CpG DNA, but not poly(I:C)-mediated effects on activated CD4+ T cells required the TLR/IL-1R domain containing adaptor molecule myeloid differentiation factor 88. Collectively, our results demonstrate that PAMPs can directly promote activated CD4+ T cell survival, suggesting that TLRs on T cells can directly modulate adaptive immune responses.