bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mast cells contribute to the changes in heart rate, but not hypotension or death, associated with active anaphylaxis in mice.
Authors: Martin T R , Ando A , Takeishi T , Katona I M , Drazen J M , Galli S J 
Published: December 2022

Abstract
The mast cell is widely thought to contribute importantly to the cardiopulmonary changes associated with anaphylaxis, but much of the evidence for this is indirect. We, therefore, performed a detailed assessment of heart rate and pulmonary function during active anaphylaxis in genetically mast cell-deficient W/Wv or S1/S1d mice, the congenic normal (+/+) mice, and W/Wv mice repaired of their mast cell deficiency by transplantation of bone marrow from the congenic +/+ mice (+/+ BM--&gt;W/Wv mice). For all five groups of mice, Ag challenge resulted in the death of more than two-thirds of the sensitized animals, whereas none of the nonsensitized control mice died as a result of Ag infusion. Sensitized normal (WBB6F1(-)+/+ or WCB6F1(-)+/+) mice and +/+BM--&gt;W/Wv mice developed increases in heart rate that were significantly greater than those of nonsensitized +/+ mice or those of sensitized mast cell-deficient mice, indicating that mast cells contribute to the tachycardia observed in this form of active anaphylaxis. By contrast, even though some of the pulmonary changes associated with active anaphylaxis were more severe in +/+ than in mast cell-deficient mice, it was not clear to what extent this difference was mast cell dependent. W/Wv mice undergoing active anaphylaxis developed decreases in systemic arterial blood pressure that occurred more rapidly and were more severe than those observed in the congenic +/+ mice, indicating that the hypotension associated with this model of anaphylaxis also can occur by mast cell-independent mechanisms. We conclude that in this model of anaphylaxis mast cells: 1) are required for the development of the tachycardia response; 2) may contribute to, but are not essential for, production of decreases in lung function; and 3) are not necessary for the development of hypotension or death.
IgE and IgG subclass regulation by IL-4 and IFN-gamma in human helminth infections. Assessment by B cell precursor frequencies.
Authors: King C L , Nutman T B 
Published: December 2022

Abstract
Helminth infections, like atopic disorders, show characteristic elevations of serum IgE and IgG4. To examine the mechanisms underlying the regulation of these two isotypes and of the other IgG subclasses, the frequency (Fo) of isotype-specific B lymphocytes (Bc) from 11 patients with helminth infections was compared by filter-spot ELISA using fresh peripheral blood-derived lymphocytes after 14-day Ag stimulation in vitro. The role of IL-4 and IFN-gamma in the generation and regulation of Ag-driven isotype responses was determined. The Fo of freshly obtained lymphocytes (expressed/10(5) Bc) secreting polyclonal Ig for the following isotypes was: IgE (geometric mean = 0.72; range, 0 to 17.7); IgG4 (geometric mean = 4.9; range, 1.8 to 24.4); IgG1 (geometric mean = 134.3; range, 16.7 to 318). The Fo of IgE correlated with IgG4-secreting Bc among study subjects (r = 0.8, p &lt; 0.01), however there was no association with the other isotypes. Parasite Ag added to cultured lymphocytes induced significant expansion in the number of Ig-secreting Bc for IgE and all IgG subclasses. In contrast, addition of a nonparasite Ag, tetanus toxoid, generated increased Fo of Ig-secreting Bc for IgG1, IgG2, and IgG3, and no expansion of IgG4 or IgE. The essential role of IL-4 in the expansion of IgE- and IgG4-secreting B cells in response to filarial Ag was demonstrated when simultaneous addition of neutralizing anti-IL-4 antibodies completely inhibited this response in all 11 patients studied. Neutralizing anti-IL-4 had no effect on either filarial or tetanus toxoid-driven expansion of IgG1-, IgG2-, or IgG3-secreting Bc. An inhibitory role of endogenously produced IFN-gamma was also shown when addition of neutralizing anti-IFN-gamma to cultures significantly augmented Ag-driven expansion of Bc-secreting IgE and all IgG subclasses; IgE, 0.4- to 9-fold; IgG4, 1.4- to 12-fold; IgG1, 1.6- to 13-fold; IgG2, 1.9- to 5-fold; and IgG3, 2.7- to 6-fold. This study demonstrates that parasite Ag stimulates Bc expansion in helminth-infected patients. Although this response for all five isotypes studied is down-regulated by IFN-gamma, the generation of only the IgE and IgG4 responses appears to be mediated selectively by IL-4. These findings support the concept that IgE and IgG4 production are linked and related to the quantities of IL-4 and IFN-gamma induced by Ag-specific T cells.
Human rheumatoid B-1a (CD5+ B) cells make somatically hypermutated high affinity IgM rheumatoid factors.
Authors: Mantovani L , Wilder R L , Casali P 
Published: December 2022

Abstract
To analyze the structure and formally ascertain the B-1a cellular origin of IgM rheumatoid factor (RF) autoantibodies, we generated 4 IgM RF mAb-producing cell lines using sorted (surface CD5+) B-1a cells from a patient with active rheumatoid arthritis. The RF mAb111, mAb112, mAb113, and mAb114 were monoreactive and displayed a relatively high affinity for human IgG Fc fragment (Kd, 3.1 x 10(-7) to 6.8 x 10(-7) M). The B-1a origin of the lymphocytes that gave rise to the IgM RF was confirmed by the expression of surface CD5 and specific CD5 mRNA by all mAb-producing cell lines. Analysis of the genes encoding the RF mAb VH and VL regions revealed that members of the VHI and VHIII families were utilized in conjunction with V kappa IIIa, V kappa IIIb, or V lambda I genes. JH3 and JH4 genes were each utilized twice. The H chain CDR3 sequences were divergent and variable in length. The RF mAb VH genes were identical or closely related to those expressed in the "restricted" fetal B cell repertoire and/or were JH-proximal. For instance, mAb111 VH gene likely constituted a mutated variant of the expressed fetal 20P3 which is the second most JH-proximal gene (125 kb from JH). In addition, the expressed VH and VL genes were among those that have been found to encode other RF, different autoantibodies, high affinity antibodies induced by exogenous Ag, and natural autoantibodies in the adult and neonatal B cell repertoires. When compared with those of known germline genes, the expressed V gene sequences displayed a number of differences. By cloning and sequencing DNA from PMN of the same patient whose B lymphocytes were used for the mAb generation, we showed that such differences resulted from somatic hypermutation in the RF mAb112 VH gene. The germline gene (112GL) that presumably gave rise to the RF mAb112 VH segment was identical to the expressed fetal 51P1 gene. The distribution and the high replacement to silent mutation ratio of the nucleotide mutations in RF mAb112 VH segment were highly consistent with their selection by Ag. RF mAb113 was clonally related to RF mAb112, as shown by the utilization of the same sets of VHI-D-JH4 and V kappa IIIb-J kappa 4 genes, displaying identical junctional sequences, and the presence of two identical replacement and one silent mutations.(ABSTRACT TRUNCATED AT 400 WORDS)
Characterization of CD7+CD19+ lymphoid cells after Epstein-Barr virus transformation.
Authors: Panzer-Grümayer E R , Panzer S , Wolf M , Majdic O , Haas O A , Kersey J H 
Published: December 2022

Abstract
The early stages of lymphoid differentiation preceding T and B lineage commitment remain poorly defined. We hypothesized that early lymphoid precursor cells are possibly common progenitors and would express a very early T cell-associated Ag (CD7) and a very early B cell-associated Ag (CD19) simultaneously. We therefore transformed CD7+CD19+ fetal bone marrow lymphoid cells using EBV. Extensive characterization of the resulting cell lines indicated that two cell lines corresponded to pre-B and early B cells co-expressing CD7. The third cell line resembled a thymocyte, which co-expressed a number of B cell-associated Ag including CD19 and the stem cell Ag CD34. The two predominantly B lineage cell lines have their Ig genes rearranged, whereas the predominantly T lineage cell line has TCR and Ig H chain genes rearranged. Cross-lineage Ag were not expressed any more after culturing for a prolonged period of time, i.e., B lineage cells became CD7 negative and the thymocyte lineage became negative for the B cell-associated Ag. However, in all three cell lines TCR and/or Ig gene rearrangements remained unchanged. These observations support the existence of a common lymphoid precursor co-expressing CD7 and CD19 that gives rise to either T or B cells.
Nucleotide sequences, polymorphism and gene deletion of T cell receptor beta-chain constant regions of Pan troglodytes and Macaca mulatta.
Authors: Jaeger E E , Bontrop R E , Lanchbury J S 
Published: December 2022

Abstract
Molecular studies in human, mouse, rat, and rabbit have demonstrated that the region of genomic DNA containing TCR C region genes has been strongly conserved during evolution. To investigate the degree of conservation of this region within the primate lineage we have undertaken analysis of the TCR constant region genes in two non-human primate species Pan troglodytes (chimpanzee) and Macaca mulatta (rhesus monkey). Constant regions of TCR beta-chains were cloned and sequenced from cDNA derived from peripheral blood T cells of healthy chimpanzees and rhesus monkeys. Two closely related C beta genes were characterized in each species corresponding to human C beta 1 and C beta 2. The chimpanzee/human similarity is greater than the rhesus monkey/human similarity as is expected from phylogenetic relationships. The amino acid sequences of corresponding C beta genes are identical between chimpanzee and human although synonymous substitutions are present at the nucleotide level. Two distinct monkey C beta 1 sequences were obtained. RFLP studies using genomic DNA from individuals of both species indicated the presence of only two C beta genes in each species. It is therefore likely that the rhesus monkey from which the sequence data are derived has a polymorphic C beta locus, which was also subsequently demonstrated in several other monkeys. Analysis of sequence data suggests that some nucleotide substitutions occurred after the chimpanzee/human line split from the rhesus monkey line approximately 25 million yr ago. These data also support the theory that specific mechanisms exist to reduce diversity in putative exon 1. Variable RFLP profiles indicated the presence of C beta polymorphism in chimpanzees and rhesus monkeys. There was also evidence for a homozygous deletion of a C beta gene in one monkey, represented by the absence of one band for each digest when compared to the band patterns of other monkeys. Variable intensities of the deletable band in other individuals suggest other monkeys may be heterozygous for this deletion. Thus rhesus monkeys demonstrate RFLP, coding sequence, and C beta gene deletion polymorphisms, with chimpanzees also demonstrating RFLP polymorphisms of C beta.
Characterization of platelet-activating factor receptors on canine T lymphocytes.
Authors: Mangino M J , Murphy M K , Weiss A , Anderson C B 
Published: December 2022

Abstract
The ability of purified canine T lymphocytes to selectively bind platelet activating factor (PAF) was characterized. Authentic radiolabeled PAF rapidly and selectively bound to T lymphocytes and reached saturation within 1 min. This binding was reversible and highly selective for (R) PAF because (S) PAF, lyso-PAF, and diacyl PAF did not displace the bound (R) PAF probe. Only increasing quantities of chemically pure (R) PAF displaced the radiolabeled (R) PAF probe. The binding maximum of PAF was determined to be 35 pM per 2 x 10(6) lymphocytes. Competitive radioligand binding studies and Scatchard analysis indicated a single class of high affinity receptors with a dissociation constant of 0.077 nM and a receptor density of 6419 receptors per cell. The ability of purified canine T lymphocytes to hydrolyze PAF to the biologically inactive metabolite lyso-PAF was also studied. Over a 30-min incubation period, about 5% of PAF was metabolized to lyso PAF. This rate of PAF hydrolysis was the same as the rate observed with the media without cells, suggesting a small degree of nonenzymatic hydrolysis. The effects of varying concentrations of authentic PAF on intracellular free Ca2+ release in purified T lymphocytes was evaluated using the fluorescent probe Fura-2 and excitation-emission spectrofluorometry. PAF below the concentration of 1.0 nM did not significantly increase intracellular Ca2+ in T lymphocytes. More than 1 nM PAF, intracellular-free Ca2+ modestly, but significantly, increased in T lymphocytes. In other experiments, canine PBMC proliferated in response to Con A and in the one way MLR. These proliferative responses were abolished when the selective PAF receptor antagonist SC-47014A was added to the culture medium. In the MLR, this inhibitory effect was dependent on the length of time that the antagonist was in the culture. Specifically, inhibition of proliferation was incrementally reversed when the PAF antagonist was introduced progressively later into the 7-day MLR stimulation period, suggesting that PAF receptor blockade prevents an MLR response from occurring, but is unable to suppress an existing MLR response. Although the Con A-induced mononuclear cell proliferation was abolished with PAF receptor antagonists, the addition of authentic biologically active PAF or PAF analogs did not alter the proliferative response to Con A. In conclusion, canine T lymphocytes possess high affinity receptors for PAF. These binding sites are highly selective and reversible. PAF binding slightly increases intracellular free Ca2+ in T lymphocytes and appears to be involved in lymphocyte proliferation in response to soluble plant mitogen and alloantigen.
Complement receptor type 3 (CD11b/CD18) involvement is essential for killing of Listeria monocytogenes by mouse macrophages.
Authors: Drevets D A , Leenen P J , Campbell P A 
Published: December 2022

Abstract
Recent work indicated that C receptor type 3 (CR3) mediates most phagocytosis of the facultative intracellular bacterium Listeria monocytogenes by mouse macrophages, which can kill it. In contrast, phagocytosis of Listeria by a population of nonlistericidal macrophages was largely CR3-independent. These findings suggested that CR3 binding during phagocytosis may be important in determining whether a macrophage kills Listeria, or is parasitized by the bacterium. The experiments reported here tested this hypothesis. When phagocytosis and killing were assayed separately, normally listericidal peritoneal macrophages still could phagocytose to some extent, but lost listericidal activity when CR3 was blocked by mAb. Anti-CR3 mAb inhibited killing in a dose-dependent fashion, and at high doses the cells became permissive hosts. Microbicidal function also was inhibited when active C components were absent during phagocytosis and during killing. Because Listeria are confined to phagosomes in listericidal macrophages but escape into the cytoplasm in nonlistericidal macrophages, we tested whether anti-CR3 mAb enhanced phagosomal escape. In fact, escape of Listeria into the cytoplasm was rare in both control and anti-CR3 mAb-treated macrophages. Moreover, electron microscopy of these cells demonstrated dividing intraphagosomal bacteria. Taken together, these results suggest that binding to CR3 during phagocytosis leads to bacterial killing, and that phagocytic pathways engaged when binding to CR3 is blocked do not trigger microbicidal activity. Furthermore, restriction of Listeria to the phagosome in the absence of CR3 engagement is not by itself sufficient for macrophage listericidal activity.
Tumor necrosis factor plays a role in Schistosoma mansoni egg-induced granulomatous inflammation.
Authors: Joseph A L , Boros D L 
Published: December 2022

Abstract
In murine schistosomiasis mansoni several proinflammatory lymphokines participate in the circumoval granulomatous inflammatory response. At the acute stage of the infection lymphokine secretion is maximal and coincides with the strong granulomatous reaction. With chronicity, Ag-elicited lymphokine production diminishes and the granulomatous inflammation is downmodulated. In this study the role of TNF in the granulomatous response was investigated. Macrophages isolated from vigorous liver granulomas of acute infection mice on LPS stimulation produced significantly more TNF than their counterparts obtained from the downmodulated granulomas of chronic infection animals. Endotoxin-injected, acutely infected mice had higher TNF serum levels than those with chronic infection. Repeated injections of polyclonal anti-TNF-alpha antiserum given to acutely infected mice significantly suppressed the size of developing liver granulomas. Administration of graded dosages of recombinant murine TNF-alpha to mice with chronic infection restored the size of the downmodulated liver and lung granulomas to the level of the vigorous lesions. Repeated injections of rIL-2 to chronically infected mice augmented the downmodulated liver granulomatous response, induced enhanced production of TNF by the liver granuloma macrophages, and elevated cytokine levels in the sera of treated mice. Enhanced TNF production was also observed in vitro in monolayers of murine rIFN-gamma-treated granuloma macrophages. These findings indicate that focally and systemically produced TNF influences the development of the schistosome egg-induced granulomatous response. Moreover, in vivo manipulation of cytokine levels can modify the intensity of the inflammatory response.
HLA-A2 presents shared tumor-associated antigens derived from endogenous proteins in ovarian cancer.
Authors: Peoples G E , Goedegebuure P S , Andrews J V , Schoof D D , Eberlein T J 
Published: December 2022

Abstract
Tumor-associated lymphocytes (TAL) from the malignant ascites and tumor-infiltrating lymphocytes (TIL) from the solid tumor were isolated from six consecutive untreated ovarian cancer patients. Tumor-specific CTL were generated from both TAL and TIL using solid phase anti-CD3, low dose IL-2 (50 IU/ml), and repeated tumor stimulation. The specificity of TAL and TIL was tested in standard cytotoxicity assays using autologous tumor, several allogeneic ovarian tumors, and the NK-sensitive cell line, K562. Anti-HLA-A-B-C mAb, W6/32, was used to demonstrate that these tumor-specific TAL and TIL were HLA class I-restricted. The ability of the ascitic and solid tumor to present Ag by HLA class I was assessed using Brefeldin A, a fungal metabolite that blocks the endogenous Ag-processing pathway in the viral model. Brefeldin A significantly inhibited tumor-specific cytotoxicity as well as HLA class I expression on the cell surface, suggesting an endogenous source of tumor-associated Ag. Despite previous reports of antigenic heterogeneity in ovarian cancer, shared tumor-associated Ag were shown to exist in this disease as demonstrated by significant allogeneic recognition of HLA-A2-matched patients as opposed to unmatched controls. Specifically, CTL from HLA-A2+ patients lysed HLA-A2+ allogeneic targets significantly better than HLA-A2- allogeneic or HLA-A2+ melanoma targets. There was no such difference with HLA-A2- effectors. Furthermore, HLA-A2 was confirmed to be a major restriction element in ovarian cancer by the blocking of HLA-A2+ effectors against both autologous and allogeneic HLA-A2+ targets with the anti-HLA-A2 mAb, BB7.2. These findings verify a similar lymphocyte/tumor interaction as has been documented in melanoma, suggesting a common mechanism of recognition of these human tumors by lymphocytes.
Suppressor macrophages in African trypanosomiasis inhibit T cell proliferative responses by nitric oxide and prostaglandins.
Authors: Schleifer K W , Mansfield J M 
Published: December 2022

Abstract
Suppression of host T cell responses is one of the hallmarks of infection with the African trypanosomes. The cellular basis for immunosuppression includes the generation of suppressor macrophages that down-regulate T cell proliferative but not necessarily cytokine responses to both mitogen and trypanosome Ag. Since macrophages from infected animals display activation characteristics, we have asked whether products of activated cells, specifically nitric oxide (NO) and PG, may mediate the suppressor cell effects and immunosuppression observed. We demonstrate that cells isolated from B10.BR mice infected with Trypanosoma brucei rhodesiense exhibited transcriptional up-regulation of inducible NO synthase and released significant amounts of NO. The levels of NO released were elevated further after stimulation of cells with T cell mitogens or specific parasite Ag; antibody blocking experiments demonstrated that this up-regulation of NO synthesis was at least partially dependent upon IFN-gamma and TNF-alpha. The addition of inducible NO synthase substrate analogues such as NG-monomethyl-L-arginine to cell cultures inhibited NO release and also partially reversed the suppressor cell activity and immunosuppression displayed by such cultures. PG levels also were elevated in cell cultures from infected mice, but the PG inhibitor indomethacin had no effect on suppressor cells or suppression when added alone to the cultures. However, the concurrent inhibition of NO and PG synthesis by the addition of both NG-monomethyl-L-arginine and indomethacin completely blocked suppressor cell activity associated with infected macrophages and also resulted in further recovery of infected cells from immunosuppression, thus revealing an epistatic effect between these two mediators. We conclude that macrophage activation in trypanosomiasis induces the release of reactive nitrogen intermediates and PG, which down-regulate proliferative responses by T cells during infection.
Mechanisms of the inflammatory response induced by extracts of Schistosoma mansoni larvae in guinea pig skin.
Authors: Teixeira M M , Doenhoff M J , McNeice C , Williams T J , Hellewell P G 
Published: December 2022

Abstract
Penetration of skin by cercariae of Schistosoma mansoni is associated with a local inflammatory response characterised by leukocyte accumulation and tissue swelling. The significance of the inflammation and its relevance to infection of the host is unknown. In this study, we have investigated the mechanisms of the local inflammatory response induced by injecting extracts of Schistosoma mansoni cercariae into guinea pig skin. Intradermal injection of cercarial homogenate or cercarial transformation fluid induced a dose-dependent increase in local edema formation and accumulation of intravenously injected 111In-labeled eosinophils and neutrophils. The responses were rapid in onset and independent of new protein synthesis. The capacity of extracts to induce edema formation and leukocyte accumulation correlated significantly with their proteolytic activity. In addition, extract-induced inflammation was reduced by co-injection with Trasylol, soybean trypsin inhibitor, PMSF, or heparin. A combination of PMSF and heparin virtually abolished extract-induced inflammation. The known inhibitory effect of Trasylol on kallikrein prompted an investigation into the role of kinins in inducing local edema formation. The bradykinin antagonist HOE 140 substantially reduced extract-induced edema whereas bradykinin itself was weak at inducing leukocyte accumulation. The cyclooxygenase inhibitor ibuprofen, the platelet-activating factor antagonist WEB 2086, and the 5-lipoxygenase inhibitor PF5901 had no effect on edema formation. In contrast, extract-induced eosinophil accumulation was reduced by WEB 2086 and PF5901, suggesting that endogenous PAF and leukotriene B4 were involved in recruiting these cells to inflammatory sites. Thus, cercarial proteases induce a local inflammatory response in guinea pig skin that can be attributed, in part, to known mediators of inflammation. It remains to be established whether the response is protective for the host or whether it is beneficial for the parasite. Further understanding of the underlying mechanisms may provide a target for the pharmacologic control of infection in schistosomiasis.