bluuebunny/crossref_metadata_2025_split huggingface dataset:
TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis.
Authors: Zhang K , Gharaee-Kermani M , McGarry B , Remick D , Phan S H 
Published: December 2022

Abstract
Despite abundant evidence documenting the importance of TNF-alpha in the pathogenesis of pulmonary fibrosis, its actual role has not been fully elucidated. Recent observations also indicate that eosinophils found in fibrotic lung express elevated levels of cytokines known to be important in lung fibrosis. These findings suggest a possible role for TNF-alpha in eosinophil recruitment and cytokine expression in this disease. To examine this hypothesis, pulmonary fibrosis was induced in mice by endotracheal bleomycin treatment, and separate groups of animals were also treated with either anti-TNF-alpha Ab or control serum. On days 7 and 14 post-bleomycin treatment, lungs were harvested and analyzed for fibrosis, cytokine expression, and eosinophil influx. Anti-TNF-alpha caused a significant reduction in lung fibrosis, as indicated by a reduction in hydroxyproline content, which was accompanied by suppression of lung TGF-beta1, IL-5, and JE mRNA expression. Examination of tissue sections revealed a significant reduction in lung eosinophils and overall cellularity by anti-TNF-alpha treatment without a significant effect on the number of lung macrophages. The number of IL-5-expressing cells was also significantly reduced by anti-TNF-alpha treatment. Since IL-5 is important in eosinophil differentiation, activation, and recruitment, these findings suggest a novel mechanism by which TNF-alpha could mediate pulmonary fibrosis via induction of IL-5-mediated eosinophil recruitment and fibrogenic cytokine production. Since these eosinophil-derived cytokines include JE/monocyte chemotactic factor-1 and TGF-beta1, this cytokine networking orchestrated by TNF-alpha could, in turn, amplify the inflammatory response and drive the progression to fibrosis and end-stage lung disease.
Identification of a novel, spliced variant of CREB that is preferentially expressed in the thymus.
Authors: Yang L , Lanier E R , Kraig E 
Published: December 2022

Abstract
A conserved decamer sequence, AGTGA(T/C)(G/A)TCA, related to the cAMP response element (CRE), is found in the promoter regions of most TCR V beta gene segments. It has been shown to be a critical element for T cell-specific transcriptional regulation of the TCR genes. However, none of the decamer or CRE-binding proteins identified thus far is restricted in its expression to cells of the T cell lineage. Therefore, to find T cell-restricted decamer-binding proteins, we screened thymus cDNA expression libraries using the decamer probe. One of the thymus cDNAs identified, clone pmLY2, a novel spliced variant of CREB, was shown to be preferentially expressed in thymus. Therefore, clone pmLY2 is the first T cell-enriched decamer-binding sequence identified. We hypothesize that this CREB variant may play a role in the developmental regulation of TCR and of other T cell specific genes.
Thymic cortical epithelium is sufficient for the development of mature T cells in relB-deficient mice.
Authors: DeKoning J , DiMolfetto L , Reilly C , Wei Q , Havran W L , Lo D 
Published: December 2022

Abstract
Thymic development of T lymphocytes progresses as a consequence of both TCR-mediated and non-TCR-mediated interactions between thymocytes and stromal cells. As relB-deficient mice appear to lack thymic medullary epithelium and mature dendritic cells, we studied the effect of this "cortex-only" thymus on T cell development. Two major consequences were observed. First, in both relB mutant and TCR transgenic/relB mutant mice, positive selection of both TCR alpha beta and delta gamma T cells appeared to proceed normally, with export of fully functional T cells to the periphery, suggesting that the thymic medullary stromal cells are not required for full maturation of T cells nor is an organized medullary compartment required for accumulation of mature single positive CD4 and CD8 T cells. Second, thymic negative selection was impaired, as evidenced by significant autoreactive proliferative responses to normal spleen stimulators. Peripheral T cells in relB mutant mice showed an unusually high proportion of CD69+ and CD44high cells. While some of these cells may be autoreactive T cells, most of the cells appeared to be activated by cytokines produced by relB mutant nonlymphoid cells, as the effect is minimized in relB mutant bone marrow chimeras. In sum, while the TCR-mediated steps in T cell maturation require both thymic cortex and medulla (epithelium and dendritic cells) for normal positive and negative selection of the repertoire, non-TCR-mediated interactions in the thymic cortex alone are sufficient to generate mature functional T cells.
Abnormal CD40-mediated activation pathway in B lymphocytes from patients with hyper-IgM syndrome and normal CD40 ligand expression.
Authors: Durandy A , Hivroz C , Mazerolles F , Schiff C , Bernard F , Jouanguy E , Revy P , DiSanto J P , Gauchat J F , Bonnefoy J Y , Casanova J L , Fischer A 
Published: December 2022

Abstract
The CD40-mediated activation pathway of B cells from 10 patients with hyper-IgM syndrome and normal expression of CD40 ligand was studied. In all 10 cases, B cells were found to be defective for IgG, IgA, and IgE production after stimulation by anti-CD40 mAbs and cytokines. In the patients tested, neither B cell proliferation (n = 6) nor CD23 molecule expression (n = 5) were observed in cultures stimulated with anti-CD40 mAb. These results point to an intrinsic B cell deficiency and a defect in the CD40-triggered B cell activation pathway; this conclusion was supported by a lack of detectable germinal centers in the spleen of two patients. CD40-triggered activation events, i.e., phosphatidylinositol 3 (PI3) kinase activation and induction of transcription factors NF-kappaB and AP-1, were next analyzed in B cell lines derived from five patients. Three distinct patterns were observed: an absence of detectable abnormalities (n = 1), defective PI3 kinase activation with normal induction of NF-kappaB and AP-1 (n = 3), and defects in both PI3 kinase activation and induction of NF-kappaB and AP-1 (n = 1). In three B cell lines, each exhibiting one of the CD40-mediated activation patterns, sequences of CD40 and CD40 binding protein coding regions were normal. The coding region of TNF receptor-associated factor 2 (TRAF2), which is known to interact with CD40 for NF-kappaB induction, was also found to be normal in B cell lines deficient in NF-kappaB induction. Altogether, these results suggest that CD40 ligand-positive hyper-IgM syndrome could be genetically heterogeneous, although phenotypic variability is not excluded, and that an early defect in the CD40-triggered activation cascade can account for defective Ig class switching in some patients with CD40 ligand-positive hyper-IgM syndrome.
Antigenic phenotype and gene expression pattern of lymphohemopoietic progenitors during early mouse ontogeny.
Authors: Marcos M A , Morales-Alcelay S , Godin I E , Dieterlen-Lievre F , Copin S G , Gaspar M L 
Published: December 2022

Abstract
Hemopoiesis, initiated in the early embryo yolk sac (YS) (7.5-8 days postcoitum (pc) in mouse), takes place thereafter in sites successively seeded by extrinsic hemopoietic stem cells (HSC). Since the existence of intraembryonic HSC has been proven experimentally in some vertebrates, it is also likely that not all HSC originate in the YS in mammals, as previously thought. Candidate intraembryonic sites that may be active in producing HSC before liver colonization are the para-aortic splanchnopleura (P-Sp) and the aorta-gonads-mesonephros region (AGM). Here we explore these sites directly for the presence of cells with hemopoietic-specific surface molecules and gene activities. The Ags c-kit, AA4.1, Mac-1, and Sca-1 begin to be expressed on some P-Sp and AGM cells, making it possible to distinguish subpopulations that evolve according to reproducible developmental patterns. On the basis of RAG-1 gene transcription, the first lymphoid precursors in the mouse embryo appear to be present 9.5 to 10 days pc in P-Sp/AGM and YS. Starting B-cell lymphopoiesis (9-12 days pc) is characterized by nonexpression of the surrogate light chain lambda 5-encoding gene and biased usage of IgH DJ4 rearrangements. In the 12.5- to 13.5-day-pc fetal liver (FL), a switch occurs, characterized by the random use of all IgH DJ and the detection of lambda 5 gene transcripts.
Human T helper cell differentiation is regulated by the combined action of cytokines and accessory cell-dependent costimulatory signals.
Authors: Palmer E M , van Seventer G A 
Published: December 2022

Abstract
We have developed an in vitro differentiation model for human Th cells to study the role of cytokines and accessory cell-dependent costimulatory signals in this process. Peripheral blood-derived CD4+ "naive" (CD45RA+ RO-) T cells were stimulated in weekly intervals with immobilized anti-CD3 mAb, accessory cells, and exogenous cytokines, and were analyzed for cytokine secretion pattern. With the B cell line JY (B7-1+ B7-2+), as source of accessory cells, we could generate distinct Th subsets. Coculture with the combination of recombinant human (rh) IL-1beta and rhIL-6 gave rise to Th0-like cells, which secreted low levels of IFN-gamma and IL-5. The addition of rhIL-12 led to the generation of Th1-like cells, which secreted high levels of IL-2, IFN-gamma, TNF-alpha, and upon multiple stimulations, significant levels of IL-10. The presence of rhIL-4 induced Th2-like cells that secreted high levels of IL-5 and IL-13, but undetectable levels of IL-4. Only after stimulation with phorbol ester and calcium ionophore could these Th2-like cells be induced to secrete significant levels of IL-4, indicating distinct stimulatory requirements for the induction of IL-5 and IL-13 compared with IL-4. The B7-1-negative monocytic cell line U937 could only provide accessory cell-dependent costimulatory signals for the generation of Th1-like cells, while B7-1-transfected U937 cells acquired the capacity to provide costimulation for the generation of Th2-like cells. These results indicate a differential dependence on CD28-mediated costimulation for the generation of human Th1-like and Th2-like cells.
TGF-beta differentially modulates epidermal growth factor-mediated increases in leukemia-inhibitory factor, IL-6, IL-1 alpha, and IL-1 beta in human thymic epithelial cells.
Authors: Schluns K S , Cook J E , Le P T 
Published: December 2022

Abstract
The regulation of cytokine production by thymic epithelial cells (TEC) in the thymus is under coordinated and temporal control and is important for the development of T cells. Human TEC express TGF-beta R and epidermal growth factor (EGF) receptor, and produce TGF-beta 3 in vitro and in vivo. Furthermore, EGF has been shown to increase IL-1 alpha, IL-1 beta, IL-6 mRNA and protein levels in human TEC. Since EGF has been shown to modulate TGF-beta effector functions, we determined whether TGF-beta can modulate EGF-mediated increases in cytokine gene expression in human TEC. We established that a single TEC expresses both EGF receptor and TGF-beta R. TGF-beta plus EGF synergistically increased leukemia-inhibitory factor (LIF), additively increased IL-6, but had little effect on IL-1 alpha and IL-1 beta mRNA levels. In contrast, TGF-beta alone increased LIF and IL-6, had little effect on IL-1 alpha, and slightly decreased IL-1 beta mRNA levels. The increases in LIF and IL-6 mRNA levels by TGF-beta plus EGF correlate with the increases in LIF and IL-6 concentrations in TEC culture supernatants as detected by ELISA. We also determined the mechanism responsible for the increases in cytokine mRNA levels. TGF-beta plus EGF did not affect transcription of LIF and IL-6 genes; this suggests that the increases in the steady state levels of cytokine mRNA were mediated post-transcriptionally, most likely at the level of mRNA stability. Our data demonstrate that TGF-beta modulates TEC cytokine production. We speculate that TGF-beta produced in situ plays a role in thymocyte development by directly affecting thymocyte differentiation and by indirectly modulating TEC cytokine production.
Role of costimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86.
Authors: Schweitzer A N , Borriello F , Wong R C , Abbas A K , Sharpe A H 
Published: December 2022

Abstract
For T cells to be optimally activated, recognition of Ag/MHC complexes by the TCR must be accompanied by a second, costimulatory signal that can be provided efficiently by the related costimulatory molecules CD80 (B7-1) and CD86 (B7-2). Recently, CD80 and CD86 have been implicated as differential determinants of Th1- vs Th2-type cytokine profiles. However, this remains a controversial issue since conflicting results have been obtained in different experimental models both in vivo and in vitro. To investigate the role of CD80 and CD86 in Th subset differentiation, we have examined the cytokine profiles induced in TCR transgenic T cells stimulated by peptide in association with splenic APCs obtained from knockout mice that selectively lack expression of either the CD80 or the CD86 molecule. Our data suggest that CD86, and to a lesser extent CD80, can make significant contributions to the production of both IL-4 and IFN-gamma. However, neither molecule plays an obligatory role in priming for the production of either effector cytokine. Furthermore, CD80 and CD86 contribute to the magnitude of T cell activation, but do not appear to selectively regulate Th1 vs Th2 differentiation.
Restoration of T cell-independent type 2 induction of Ig secretion by neonatal B cells in vitro.
Authors: Snapper C M , Rosas F R , Moorman M A , Mond J J 
Published: December 2022

Abstract
The humoral immune response of neonates to T cell-independent type 2 (TI-2) Ags is markedly defective. We previously demonstrated that multivalent membrane Ig cross-linking, using dextran-conjugated anti-Ig Abs (anti-Ig-dextran), is an in vitro model for membrane Ig-dependent TI-2 induction of Ig secretion. In this work, we demonstrate that highly purified neonatal B cells are intrinsically defective in IgM secretion in response to anti-Ig-dextran and cytokines in vitro, as well as other modes of B cell activation, relative to adult B cells. However, costimulation of anti-Ig-dextran-activated neonatal B cells with either CD40-ligand, a recombinant bacterial lipoprotein, or LPS restores the IgM secretory response of neonatal B cells to adult levels. Analysis of Ig isotype secretion indicates that neonatal B cells have an enhanced capacity to secrete IgE and IgA relative to other Ig isotypes. These data suggest that neonatal B cells are competent to secrete Ig in response to TI-2 Ags if adequate costimuli are provided, and thus may have particular relevance for the design of vaccine strategies in the immunodeficient host. The data also suggest that neonatal B cells are programmed to secrete relatively enhanced amounts of IgE and IgA, which may be relevant for antimicrobial resistance at mucosal surfaces.
Analysis of the frequency and pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes.
Authors: Dörner T , Brezinschek H P , Brezinschek R I , Foster S J , Domiati-Saad R , Lipsky P E 
Published: December 2022

Abstract
Somatic hypermutation plays an essential role in avidity maturation of Ab. To characterize the effects of hypermutation without the imposed bias of Ag-mediated selection, the mutational pattern of 37 nonproductively rearranged VH genes amplified from individual human B cells was analyzed. A high frequency of mutations as well as frequent replacement mutations were observed in the complementarity-determining regions (CDR) and in the framework regions of nonproductive VHDJH rearrangements. Comparison with 57 productive VH rearrangements indicated that replacement mutations, especially those occurring in the framework regions, were less frequent in productively rearranged VH genes, suggesting that they were deleted from the expressed repertoire. A number of factors contributed to the nonrandom localization of mutations, including: the targeting of specific motifs, such as AGY, GCY, GTA, TAY, and RGYW; an increased frequency of some commonly mutated motifs in the CDRs; and an apparent increased likelihood of mutations of CDR nucleotides. Each of these appeared to bias the mutational machinery, resulting in an increased frequency of replacement mutations in the CDRs of nonproductive VH rearrangements.
Requirement of glycosylation of the human thyrotropin receptor ectodomain for its reactivity with autoantibodies in patients' sera.
Authors: Seetharamaiah G S , Dallas J S , Patibandla S A , Thotakura N R , Prabhakar B S 
Published: December 2022

Abstract
To understand the role of glycosylation on autoantibody reactivity, we expressed cDNA encoding amino acid residues 22 to 416 of the human thyrotropin receptor (TSHR), along with the baculovirus-encoded glycoprotein 67 signal sequence (ETSHR-gp) in insect cells. N-terminal sequence analysis revealed that the signal peptide was cleaved and confirmed the identity of ETSHR-gp protein. The molecular mass of the ETSHR-gp protein was 63 kDa and was higher than the expected molecular mass of 45 kDa, suggesting that the protein was glycosylated. Carbohydrate analysis showed that the protein was glycosylated and that mannose was the major oligosaccharide. A nonglycosylated recombinant ETSHR protein expressed earlier in our laboratory neutralized TSH-binding-inhibitory Ig (TBII) activity in the sera of rabbits immunized with the protein but did not neutralize TBII activity in the sera of patients. In contrast, the glycosylated ETSHR-gp protein neutralized TBII activity in the sera of both experimental animals and patients with autoimmune thyroid disorders. Furthermore, only the ETSHR-gp protein completely neutralized the activities of stimulatory and blocking Abs in the sera of patients with hyperthyroidism and hypothyroidism, respectively. These data clearly show that glycosylated ETSHR-gp, but not the nonglycosylated ETSHR protein, can react with autoantibodies in patients' sera and that it has the epitopes required for the binding of TBII, thyroid stimulatory Abs, and thyroid stimulatory blocking Abs. Moreover, these data suggest that glycosylation might be an important determinant of autoantigenicity of human TSHR.
Precursor frequency analysis of cytotoxic T lymphocytes to pre-erythrocytic antigens of Plasmodium falciparum in West Africa.
Authors: Plebanski M , Aidoo M , Whittle H C , Hill A V 
Published: December 2022

Abstract
Some individuals living in malaria-endemic areas have CTL to Plasmodium falciparum liver stage Ags. We have quantified these CTL responses using limiting dilution analysis studies on the peripheral blood cells of naturally exposed Gambian donors. CTL precursor frequencies were determined to a wide range of epitopes derived from different liver stage Ags (liver stage protein 1, circumsporozoite protein, thrombospondin-related anonymous protein, and sporozoite threonine/asparagine-rich protein) restricted through common HLA alleles present in this population (HLA-A2.1, -A2.2, -B7, -B8, -B35, and B53). Precursor frequencies were between 17 and 98/million PBMC and correlated with the levels of specific lysis in parallel bulk cultures. The quantitative nature of limiting dilution assay analysis revealed varying degrees of immunodominance in the CTL responses to different epitopes within single proteins (thrombospondin related anonymous protein: tr42, tr43, tr26, tr29, and tr39; circumsporozoite protein: cp6, cp26, and cp29) and within individual donors. The temporal stability of some of these CTL responses was determined over a 4-yr period. This is the first quantitative study of CTL specific for any plasmodial species or nonviral pathogen in humans and provides a basis for a multiepitope approach to malaria vaccination.
In vitro prevention and reversal of lipopolysaccharide desensitization by IFN-gamma, IL-12, and granulocyte-macrophage colony-stimulating factor.
Authors: Randow F , Döcke W D , Bundschuh D S , Hartung T , Wendel A , Volk H D 
Published: December 2022

Abstract
LPS tolerance is characterized by a diminished monocytic synthesis of TNF-alpha and, interestingly, IL-10 after LPS restimulation. We wondered whether granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12, and IFN-gamma can prevent or reverse this down-regulation of TNF-alpha and IL-10 production. The LPS-induced TNF-alpha amounts in desensitized PBMC treated with GM-CSF, IFN-gamma, or IL-12 and in naive, non-cytokine-primed cultures were similar, while much more TNF-alpha was induced in cytokine-primed naive cells. The effect of IL-12 was dependent on the presence of nonmonocytic cells and could be completely blocked with an IFN-gamma antiserum. Treatment of LPS-desensitized pure monocytes with IFN-gamma or GM-CSF resulted in a very high TNF-alpha expression and no difference to cytokine-primed naive monocytes was evident any longer. While IFN-gamma and IL-12 decreased IL-10 expression in naive PBMC, it was increased by both and by GM-CSF in LPS-tolerant cultures. Again, only IL-12 was dependent on the presence of nonmonocytic cells. For prevention of LPS tolerance, similar results were obtained. Recently, we have shown that IL-10 and TGF-beta mediate LPS desensitization in vitro and can be used to establish LPS hyporesponsiveness in the absence of LPS. IFN-gamma and GM-CSF prevented and reversed down-regulation of TNF-alpha and IL-10 synthesis also in the model of IL-10/TGF-beta1-induced LPS hyporesponsiveness, while IL-12 was ineffective because of its obvious inability to induce IFN-gamma. In summary, after LPS desensitization/hyporesponsiveness, IFN-gamma and GM-CSF tended to normalize pro- and anti-inflammatory monocytic behavior. Our results suggest that during LPS desensitization/hyporesponsiveness, monocytes acquire a hitherto unknown functional state with an altered reaction to biologic response modifiers.
Lack of chronic immune activation in HIV-infected chimpanzees correlates with the resistance of T cells to Fas/Apo-1 (CD95)-induced apoptosis and preservation of a T helper 1 phenotype.
Authors: Gougeon M L , Lecoeur H , Boudet F , Ledru E , Marzabal S , Boullier S , Roué R , Nagata S , Heeney J 
Published: December 2022

Abstract
Chimpanzees are one of the few species, along with humans, susceptible to persistent HIV-1 infection. However, HIV-infected chimpanzees do not exhibit the marked immune system alterations seen in humans and remain relatively resistant to AIDS. In humans, HIV infection leads to unresponsiveness of T cells in response to TCR stimulation, associated with increased T cell death by apoptosis. In an effort to understand some of the mechanisms used to limit lentivirus infection in African nonhuman primates, we compared apoptosis in infected humans vs chimpanzees in CD4 and CD8 T cells in relation with the expression of Bcl-2 and Fas molecules. The intensity of apoptosis in CD4 and CD8 T cells from infected chimpanzees was very low, was not inducible by several TCR-dependent activators, and was comparable to that detected in noninfected chimpanzees. Moreover, CD45RO+ and HLA-DR+ subsets, which were shown to exhibit ex vivo a high propensity to undergo apoptosis in infected humans, were not modified in infected chimpanzees. Interestingly, in contrast to the situation found in infected humans, Fas ligation by agonistic Abs or recombinant human Fas ligand on CD4 and CD8 T cells from infected chimpanzees did not induce apoptosis in these subsets even when Bcl-2 was down-regulated. Finally, this resistance to apoptosis was associated with the predominance of CD3 T cells with a Th1 phenotype. Together these observations argue for a strong relationship among the absence of chronic immune stimulation in HIV-1-infected chimpanzees, the normal control of lymphocyte survival, and the resistance to disease progression.