bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tuberculosis generates a microenvironment enhancing the productive infection of local lymphocytes by HIV.
Authors: Garrait V , Cadranel J , Esvant H , Herry I , Morinet P , Mayaud C , Israël-Biet D 
Published: December 2022

Abstract
Tuberculosis (TB) contributes to the progression of HIV disease but, so far, the mechanism involved is not clear. Several cytokines accumulating in vivo at the site of mycobacterial infection up-regulate HIV expression in vitro. In this study, we assessed the role of pleural fluids recovered from seronegative patients with TB on HIV replication in acutely infected blast cells. Pleural fluids from subjects with congestive heart failure served as controls. In all cases, TB pleural fluids stimulated HIV replication in vitro. TNF-alpha, IL-6, IFN-gamma, and granulocyte/macrophage (GM)-CSF, as well as very low levels of IL-2, were detected in TB pleural fluids. An anti-IL-2 Ab preincubated with TB pleural fluids exhibited no blocking effect on HIV replication similarly to anti-IFN-gamma and anti-GM-CSF Abs. In contrast, anti-TNF-alpha and anti-IL-6 Abs decreased HIV replication by 60 and 90%, respectively. Recombinant TNF-alpha and IL-6 stimulated HIV replication, while IFN-gamma and GM-CSF had a more ambiguous role. The capacity of pleural fluids to stimulate HIV replication was specific for TB, since the capacity of control fluids was significantly lower. Finally, in contrast to PBL, which require in vitro activation for their productive infection by HIV, unstimulated tuberculous pleural lymphocytes were productively infectable by HIV. Taken together, our data suggest that the microenvironment generated by TB might increase the HIV burden in infected subjects, partly through cytokines other than IL-2, namely TNF-alpha and IL-6.
Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners.
Authors: Burns A R , Walker D C , Brown E S , Thurmon L T , Bowden R A , Keese C R , Simon S I , Entman M L , Smith C W 
Published: December 2022

Abstract
Since macromolecular permeability between endothelial cells is regulated by tight junctions (zonula occludens), we wished to determine whether they also regulate neutrophil transendothelial migration. HUVEC monolayers, a commonly used model for studying leukocyte transmigration, were characterized using electric cell substrate impedance sensing and transmission electron microscopy. We show that culture medium containing endothelial cell growth supplement (50 microg/ml) was sufficient and necessary for the development of endothelial tight junctions. The frequency with which tight junctions were observed by transmission electron microscopy was further increased (twofold) by culturing HUVEC monolayers in a 1:1 mixture of endothelial medium and astrocyte-conditioned medium. These astrocyte-conditioned HUVEC monolayers showed a &gt;1.5-fold increase in transcellular electrical resistance. The extent of neutrophil migration across IL-1-treated (10 U/ml for 4 h) HUVEC monolayers was the same whether tight junctions were present or absent, and the molecular requirements for neutrophil transmigration (CD18 and intercellular adhesion molecule-1) were unaffected by culturing in astrocyte-conditioned medium. Immunostaining for proteins associated with the intercellular junctional domain (occludin, ZO-1, cadherin, beta-catenin, gamma-catenin, and platelet-endothelial cell adhesion molecule-1) was localized to the endothelial borders, regardless of the culture conditions. Discontinuities were observed in the border staining for occludin, ZO-1, cadherin, and beta-catenin at the tricellular corner where the borders of three endothelial cells intersected. Significantly, 75% of neutrophil migration across IL-1-treated HUVEC monolayers occurred at tricellular corners. It appears that neutrophils preferentially migrate around endothelial tight junctions by crossing at tricellular corners rather than passing through the tight junctions that lie between two endothelial cells.
Human mast cells produce the CD4+ T lymphocyte chemoattractant factor, IL-16.
Authors: Rumsaeng V , Cruikshank W W , Foster B , Prussin C , Kirshenbaum A S , Davis T A , Kornfeld H , Center D M , Metcalfe D D 
Published: December 2022

Abstract
CD4+ T cell infiltration is known to occur in tissues at sites of mast cell activation. The molecules produced and released by mast cells that account for this lymphocyte accumulation are poorly characterized. Here we report that a CD4+ T cell chemoattractant cytokine, IL-16, is stored preformed in bone marrow-cultured human mast cells and a human mast cell line, HMC-1, as demonstrated by intracytoplasmic cytokine staining and flow cytometry, and in human lung mast cells, as detected by immunohistochemistry. In response to the anaphylatoxin, C5a, or to PMA treatment, IL-16 mRNA transcripts detected by Northern blot analysis in HMC-1 cells increased 6- to 10-fold. HMC-1 cell lysates and activated supernatants contained IL-16 protein, as demonstrated by both ELISA and in vitro lymphocyte chemotaxis assays, the latter of which was blocked 59 to 88% by the addition of neutralizing Ab to recombinant human IL-16. IL-16 bioactivity was detected in the supernatants 2 to 4 h after PMA or C5a activation, and this activity remained elevated through 24 h. The capacity of human mast cells to synthesize and release biologically active IL-16 provides a possible link between mast cell activation and the accumulation of T cells in mast cell-dependent inflammation, thus amplifying the immune response and perpetuating the pathologic process.
Induction of TNF-alpha in human peripheral blood mononuclear cells by the mannoprotein of Cryptococcus neoformans involves human mannose binding protein.
Authors: Chaka W , Verheul A F , Vaishnav V V , Cherniak R , Scharringa J , Verhoef J , Snippe H , Hoepelman A I 
Published: December 2022

Abstract
We have shown previously that specific receptors on PBMCs and a serum factor other than Ab and complement are involved in the TNF-alpha response to cryptococcal mannoprotein (MP2). To characterize the mechanism of MP2 recognition by PBMCs, 10(6) PBMCs were incubated with 25 microg of FITC-labeled MP2 in 10% normal human serum (1 h). The cells were analyzed by flow cytometry. FITC-MP2 binding was CaCl2 and temperature dependent and was enhanced by prestimulating PBMCs with unlabeled MP2. Binding to PBMCs was specific, since unlabeled MP and mannan produced dose-dependent inhibition. Beta-Glucan laminarin produced background inhibition. mAbs against CD14, CD11b, and CD18 did not prevent FITC-MP2 binding to PBMCs, implying that these receptors are not involved in MP2 recognition by PBMCs. mAb against CD14 blocked (&gt;90%) MP2-induced TNF-alpha release by PBMCs, while mAbs against CD11b/CD18 caused no inhibition. Removal of human mannose binding protein (hMBP) by preincubation of serum with a specific mAb abrogated TNF-alpha induction by MP2 and strongly inhibited its binding to PBMCs. Recombinant hMBP enhanced TNF-alpha induction by MP2 as well as binding of FITC-MP2 to PBMCs. In addition, incubation of serum with MP2-coated beads and analysis by SDS-PAGE resulted in the detection of a protein of approximately 33/34 kDa that could be partially removed by preincubating the serum with hMBP mAb. We conclude that hMBP is involved in the binding of MP2 to PBMCs and the release of TNF-alpha.
Cytokine patterns in tuberculous and sarcoid granulomas: correlations with histopathologic features of the granulomatous response.
Authors: Bergeron A , Bonay M , Kambouchner M , Lecossier D , Riquet M , Soler P , Hance A , Tazi A 
Published: December 2022

Abstract
Cytokines play an important role in granuloma formation, but the extent that cytokine profiles are similar in different granulomatous diseases and whether differences in the histopathologic features of the granulomatous response results from differences in cytokine production have not been evaluated. To investigate these questions, we used RT-PCR to quantify the expression of mRNAs coding for 16 cytokines in granulomatous lymph nodes from patients with tuberculosis and sarcoidosis and from control tissues, and we sought correlations between the level of expression of these cytokines and the histopathologic features of the granulomas. Expression of mRNAs coding for a number of cytokines (IL-1beta, IFN-gamma, TNF-alpha, granulocyte-macrophage (GM)-CSF, IL-12 (p40), and lymphotoxin-beta) was increased in tuberculous and sarcoid granulomas compared with that of control tissues. All sarcoid granulomas were shown to express a Th1 pattern of cytokine mRNAs, while tuberculous lymph nodes expressed either a Th1 or a Th0 profile. GM-CSF and lymphotoxin-beta mRNAs were more abundant in sarcoid than in tuberculous granulomas, whereas IL-8 mRNA was strongly expressed only in tuberculous lymph nodes. Strong expression of GM-CSF, TNF-alpha, and IL-8 by granulomas was shown to be correlated, respectively, with the presence of florid granulomatous lesions, the absence of central necrosis, and the presence of neutrophil infiltration. These results demonstrate that the formation of tuberculous and sarcoid granulomas in humans is associated with the expression of characteristic cytokine profiles and indicate that the expression of certain cytokines is associated with the development of specific pathologic features in the resulting granulomas.
HLA-DR-triggered inhibition of hemopoiesis involves Fas/Fas ligand interactions and is prevented by c-kit ligand.
Authors: Lee J W , Gersuk G M , Kiener P A , Beckham C , Ledbetter J A , Deeg H J 
Published: December 2022

Abstract
The function of MHC class II (HLA-DR) Ags in hemopoiesis is not well defined. Here we investigated the effect of anti-HLA-DR mAb H81.9 on human marrow cells. mAb H81.9 inhibited colony formation from purified CD34+ marrow cells in long term culture-initiating cell assays. Inhibition was prevented, however, if c-kit ligand (stem cell factor (SCF)) was added to cultures concurrently with H81.9. DNA histograms from cultured untreated marrow mononuclear cells showed 2+/-1.2% apoptotic nuclei, whereas 14.1+/-5.4% were apoptotic after 12-h exposure to mAb H81.9. The apoptotic peak was reduced to 1.2+/-0.8% when SCF was added to cultures concurrently with mAb H81.9. The addition of Fas-Ig, a fusion protein that neutralizes Fas ligand (Fas-L), also prevented mAb H81.9-induced apoptosis. As determined by terminal deoxynucleotidyl transferase assays, agonistic anti-Fas mAb also induced apoptosis (in 13+/-4% of cells), and combined treatment with anti-Fas mAb and H81.9 was additive (27% apoptotic nuclei). The extent of apoptosis induced by anti-Fas mAb was significantly reduced by SCF. After H81.9 exposure, Fas was up-regulated on CD34+ cells, and Fas-L expression was 2.5-fold higher than in controls or CD34- cells, particularly within a small cell window with low orthogonal scatter (lymphocyte gate). These findings show that HLA-DR-mediated signals inhibit hemopoiesis in human marrow by a mechanism involving Fas/Fas-L-dependent signals that are blocked by c-kit ligand. These data suggest a possible role for MHC class II molecules in the regulation of hemopoiesis.
V alpha 3.2 selection in MHC class I mutant mice: evidence for an alternate orientation of TCR-MHC class I interaction.
Authors: Sim B C , Travers P J , Gascoigne N R 
Published: December 2022

Abstract
TCR V alpha elements are expressed preferentially in CD4 or CD8 subsets in a manner that is largely independent of MHC haplotype. It is likely that the V alphas interact preferentially with conserved regions of class I or class II molecules. To investigate the topology of binding of TCR to MHC-peptide complexes, we screened a panel of H-2Kbm mutants for differential V alpha expression. One strain, bm23, showed a consistent alteration in V alpha expression, with increased V alpha 3.2 expression in CD8 peripheral T cells. This overselection is manifest in CD8 single-positive thymocytes and appears to be due to enhanced positive selection on Kbm23. There is no apparent effect of V beta elements. The Kbm23 molecule is unique compared with Kb and the other Kbm molecules at residue 75 on the helix of the alpha 1 domain, suggesting an interaction between V alpha 3.2 and the alpha 1 helix at this point. Such an interaction is inconsistent with the orientation of TCR and MHC defined in two crystal structures, but is consistent with an orientation where the TCR is rotated by 180 degrees relative to MHC.
In vitro triggering of somatic mutation in human naive B cells.
Authors: Razanajaona D , Denépoux S , Blanchard D , de Bouteiller O , Liu Y J , Banchereau J , Lebecque S 
Published: December 2022

Abstract
During T cell-dependent immune response, germinal center B cells accumulate somatic mutations in their Ig V(D)J genes and give rise to affinity-selected B cells. We tested several culture conditions for triggering somatic mutation in human tonsillar naive slgD+CD23+ cells after cross-linking their membrane Igs. CD40 activation, in the presence of exogenous cytokines (IL-2, IL-4, and IL-10), induced proliferation and isotype switch without somatic mutation. In contrast, after coculture with anti-CD3-activated cloned T cells, somatic mutation accumulated in a fraction of naive B cells. Mutations included shared as well as independent events in clonally related sequences, allowing reconstitution of genealogic trees generated in vitro. Naive tonsillar B cells sorted for slgD expression can be induced to mutate their Ig V(H) gene upon coculture with activated T cells, thereby providing a model to study somatic hypermutation in vitro.
Complete protective immunity induced in mice by immunization with the 19-kilodalton carboxyl-terminal fragment of the merozoite surface protein-1 (MSP1[19]) of Plasmodium yoelii expressed in Saccharomyces cerevisiae: correlation of protection with antigen-specific antibody titer, but not with effector CD4+ T cells.
Authors: Hirunpetcharat C , Tian J H , Kaslow D C , van Rooijen N , Kumar S , Berzofsky J A , Miller L H , Good M F 
Published: December 2022

Abstract
The 19-kDa carboxyl-terminal fragment of the merozoite surface protein-1 (MSP1) is a leading malaria vaccine candidate but is unable to induce immunity in all monkeys or all strains of mice. The mechanism of immunity is unclear, although data show that cell-mediated immunity plays a critical role following immunization with the larger mature MSP1 protein. We optimized a vaccine protocol using the MSP1(19) fragment of Plasmodium yoelii expressed in Saccharomyces cerevisiae, such that following exposure of mice to parasites, they remained undetectable in peripheral blood, whereas control animals all died at very high parasitemia within 10 days. We then depleted the vaccinated mice of &gt;99% of CD4+ T cells by anti-CD4 mAb treatment and could show that infections in most animals remained subpatent following challenge. Furthermore, mice in which the gene for the mu-chain of Ig had been disrupted could not be immunized with MSP1(19). Immunity in normal mice did not depend on the presence of an intact spleen nor production of nitric oxide, persisting unabated when &gt;70% of splenic macrophages were depleted. Thus, while effector CD4+ T cells may contribute to immunity, neither they nor factors associated with a Th1-type cell mediated immune response appeared to play the major role in MSP1(19)-induced protection in normal mice. Furthermore, T cells were not sufficient for immunity in mice lacking B cells. In normal mice, protection correlated with a very high titer of MSP1(19)-specific Abs (&gt;6,400,000), predominantly G1 and G2b, which may function by merozoite neutralization.
Influenza infection of beta 2-microglobulin-deficient (beta 2m-/-) mice reveals a loss of CD4+ T cell functions with aging.
Authors: Taylor S F , Cottey R J , Zander D S , Bender B S 
Published: December 2022

Abstract
Following influenza infection, aged mice have prolonged viral shedding that is presumably due to lower anti-influenza class I-restricted CD8+ CTL activity. To examine alternative viral clearance mechanisms in immunosenescense, we infected young (1.5-2.5 month) and aged (15-18 month) class I and CD8+-deficient beta 2m-/- mice with influenza A/Port Chalmers/1/73 (H3N2). We found that 40% of young beta 2m-/- mice were shedding virus from the lung on day 9 (mean titer of 0.3 log10 TCID[50]), with a maximal anti-influenza class II CTL activity of 68+/-2% on day 7. In contrast, 100% of aged beta 2m-/- mice were still shedding virus (mean titer of 3.0 log10 TCID[50]) from the lung on day 9 with a peak CTL activity of 15+/-6%. Aged beta 2m-/- mice also had significantly lower pulmonary IFN-gamma levels, serum anti-influenza neutralizing Ab, and anti-influenza mucosal IgA titers, as well as a less intense pulmonary inflammatory response on early days of infection. Th2-mediated cytokines were dysregulated. We conclude that there are multiple mechanisms responsible for the age-related delay in recovery from influenza. These include decreased anti-influenza class II-restricted CTL activity, pulmonary IFN-gamma levels, and serum neutralizing Ab. Taken together, these findings show a loss of CD4+ T cell functions with aging.
The role of IFN regulatory factor-1 in synovitis and nitric oxide production.
Authors: Shiraishi A , Dudler J , Lotz M 
Published: December 2022

Abstract
The IFN regulatory factor-1 (IRF-1) DNA binding protein regulates expression of genes that are involved with the induction of immune and inflammatory responses. The present study used mice with a targeted disruption of the IFN regulatory factor-1 gene (IRF-1-/-) to examine the role of this transcription factor in synovial inflammation and nitric oxide production. Intraarticular injection of IL-1 or LPS was associated with a significantly reduced intensity of synovial lining hyperplasia and leukocyte infiltration in the IRF-1-/- mice as compared with wild-type mice of the same parental lineage C57BL/6. Nitric oxide (NO) is involved with the pathogenesis of arthritis, and IRF-1 regulates expression of inducible NO synthase (iNOS) in mononuclear phagocytes. Articular chondrocytes from IRF-1-/- mice produced similar levels of NO in response to IL-1 or LPS. Furthermore, the synergistic induction of NO by IFN-gamma and IL-1 or LPS was almost identical in chondrocytes from wild-type and IRF-1-/- mice. This was in contrast to the expected decrease in NO production by peritoneal macrophages from IRF-1-/- mice, suggesting that IRF-1 is not required for iNOS expression in chondrocytes. These results indicate that IRF-1 has a tissue-specific role in the induction of iNOS. Inhibition of this transcription factor may represent a novel approach in controlling inflammatory diseases such as arthritis.
Mycobacterial and schistosomal antigen-elicited granuloma formation in IFN-gamma and IL-4 knockout mice: analysis of local and regional cytokine and chemokine networks.
Authors: Chensue S W , Warmington K , Ruth J H , Lukacs N , Kunkel S L 
Published: December 2022

Abstract
Type 1 (IFN-gamma/TNF-dominant) and 2 (IL-4/IL-5-dominant) granulomatous inflammation were analyzed in mice with knockout of IFN-gamma or IL-4 genes. Lung granulomas were elicited by beads coated with purified protein derivative (PPD) of Mycobacteria bovis or soluble Schistosoma mansoni egg Ags. Parameters included granuloma size, composition, and macrophage function; white blood cell differentials; lymph node cytokine profiles; and cytokine/chemokine mRNA expression by lungs. Type 1 (PPD) and 2 (soluble Schistosoma mansoni egg Ags) responses showed characteristic cytokine and chemokine profiles in control mice. IFN-gamma knockout converted the PPD response to a type 2-like pattern with eosinophil infiltration and decreased TNF and RANTES, but increased IL-4, IL-5, IL-10, IL-13, monocyte chemoattractant protein-3 (MCP-3), and eotaxin expression. IL-4 knockout exacerbated type 1 inflammation with increased IL-2/IFN-gamma production by lymph nodes and IL-1 production by granuloma macrophages, but unexpectedly, IFN-gamma transcripts were reduced in lungs. Regarding the type 2 response, IL-4 was needed for maximal blood eosinophilia, but surprisingly, its absence had a minimal effect on type 2 granuloma size and composition despite regional reductions of IL-5 and IL-10 as well as local reductions of TNF-alpha, MCP-1, MCP-3, and eotaxin. Thus, the type 2 granuloma was not converted to a type 1 composition with IL-4 knockout, but showed persistent expression of IL-13 and some degree of IL-5 and MCP-3, suggesting that these cytokines could potentially support a compensatory type 2 response. IFN-gamma knockout did not augment type 2 granuloma size or Th2 cytokines in lymph nodes and unexpectedly reduced IL-4 transcripts in lungs. This study offers important implications regarding inflammation and its relationship to local and regional cytokine expression.
Human IgG2 variants of chimeric anti-CD3 are nonmitogenic to T cells.
Authors: Cole M S , Anasetti C , Tso J Y 
Published: December 2022

Abstract
The mouse anti-human CD3 mAb OKT3 is a potent immunosuppressive agent used for the treatment of acute transplant rejection. OKT3 therapy is associated with acute toxicity resulting from in vivo T cell activation and systemic cytokine release, and a human anti-mouse Ab response. T cell activation is thought to be triggered by CD3 cross-linking mediated by the Abs bridging T cells and Fc receptor-bearing cells. Recent studies in a mouse model indicate that anti-mouse CD3 Abs with low affinity for Fc receptors can achieve immunosuppression without T cell activation, toxicity, or an anti-Ab response. To obtain an analogous Ab to improve the current anti-human CD3 therapy, a humanized Ab with low affinity for Fc receptors is needed. In this study, we introduced mutations into the upper CH2 region of IgG2 and expressed the altered Fc as chimeric OKT3 Abs. Compared with chimeric OKT3 IgG1, IgG2, IgG3, and IgG4, the IgG2 mutants were less mitogenic to T cells, and they did not induce the release of TNF-alpha, IFN-gamma, or IL-2. In parallel, we observed no functional interaction of the IgG2 mutant Abs with K562 cells, which express the IgG2-binding Fc receptor on their surface. Despite no measurable T cell activation, the mutant Abs could still modulate the CD3 complex. When coupled to a humanized anti-CD3, the IgG2 variant may provide a drug with less acute toxicity and immunogenicity, but may still retain potent immunosuppressive properties.
HIV-1 reverse transcriptase-specific CTL against conserved epitopes do not protect against progression to AIDS.
Authors: van der Burg S H , Klein M R , Pontesilli O , Holwerda A M , Drijfhout J W , Kast W M , Miedema F , Melief C J 
Published: December 2022

Abstract
A small group of HIV-1-infected subjects who either do not progress to AIDS or progress only slowly have sustained HIV-1-specific CTL responses. It has been suggested that the specificities of these responses differ from the CTL responses of rapid progressors due to recognition of epitopes that are under structural or functional constraints. We have, in this respect, studied the CTL response to reverse transcriptase (RT) in long term survivors (LTS) and in HIV-1-infected individuals who progressed to AIDS within 3 to 6 yr. Both LTS and progressors displayed vigorous RT-specific CTL responses of comparable magnitude during the asymptomatic phase. From each individual at least two CTL lines were obtained from blood samples drawn at different time points during follow-up. A total of 19 CTL lines recognized nine different RT-derived epitopes. CTL obtained from progressors recognized epitopes with a similar degree of amino acid conservation as epitopes targeted by CTL from LTS. Furthermore, five of seven epitopes were recognized by both LTS and progressors. Moreover, one of the epitopes recognized by progressors contained the highly conserved YMDD motif that is essential for RT activity. In conclusion, our data imply that neither the magnitude nor the specificity of HIV-1-specific CTL against RT is a major cause of a more protracted course of disease.