bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen-specific inhibition of IgE binding to the high-affinity receptor.
Authors: Stämpfli M R , Rudolf M , Miescher S , Pachlopnik J M , Stadler B M 
Published: January 2023

Abstract
Since the beginning of this century, allergen immunotherapy has been widely used to treat allergic disorders. In addition to the long-term clinical efficacy of this therapy, there are immediate beneficial effects as observed in rush immunotherapy for which there is no clear mechanism. We investigated the direct impact of an Ag on its specific IgE in terms of IgE measurability in immunoassays and subsequent binding of IgE to the high-affinity receptor for IgE. As a model we used a chimeric IgE specific for NIP that exhibits similar biologic properties as serum or myeloma IgE. To mimic particulate and soluble allergens we coupled 15 NIP molecules to BSA. Using this "artificial allergen" we could show that the presence of the Ag reduced the IgE measurability in immune assays. Furthermore, IgE binding to the Fc epsilon RI was 60% inhibited in the presence of the Ag shown with an optical biosensor that monitors molecular interactions. In normal basophils passively sensitized with IgE that was preincubated with the Ag, no sulfidoleukotriene release could be induced. Rush immunotherapy may invoke a similar phenomenon, resulting in the short-term alteration of symptoms by blocking or substantially reducing binding of IgE to its high-affinity receptor. Thus, our result may explain some of the short-term beneficial effects observed in rush immunotherapy.
Human Ig S gamma regions and their participation in sequential switching to IgE.
Authors: Mills F C , Mitchell M P , Harindranath N , Max E E 
Published: January 2023

Abstract
The Ig isotype switch from IgM to IgE is accompanied by a DNA recombination that joins S mu, the highly repetitive "switch" region upstream of the C mu gene, to the S epsilon region upstream of C epsilon, thereby creating a composite S mu-S epsilon region. In human B cells cultured in vitro with IL-4 to promote the switch to IgE, we previously described evidence for S mu-S gamma-S epsilon structures, suggesting that some B cells can switch sequentially from mu to gamma and then to epsilon; similar sequential switching to epsilon occurs routinely in the mouse. To identify which of the four human gamma genes might be involved in this mu-gamma-epsilon switching pathway, we cloned and analyzed nine S mu-S gamma-S epsilon composite switch regions and studied S epsilon-S gamma junctions from reciprocal deletion circles. Since only the S gamma 4 sequence had previously been described, our investigation required determination of the germline S gamma 1, S gamma 2, and S gamma 3 sequences. This analysis showed that S gamma 1 is the longest and most highly repetitive switch region, including nearly identical 79-bp repeats partially homologous to the 49-bp repeat of murine S gamma sequences. Of nine cloned chromosomal S mu-S gamma-S epsilon junctions, seven were derived from S gamma 1, and one each from S gamma 3 and S gamma 4 (both of which were in inverted orientation). Analysis of reciprocal S epsilon-S gamma junctions demonstrated contributions of S gamma 1, S gamma 2, and S gamma 4. Thus, all four of the human gamma loci can participate in sequential switching to IgE, arguing against a model of directed switching from a specific subtype, such as was proposed in the murine system.
Analysis of anti-GM1 ganglioside IgM antibodies cloned from motor neuropathy patients demonstrates diverse V region gene usage with extensive somatic mutation.
Authors: Paterson G , Wilson G , Kennedy P G , Willison H J 
Published: January 2023

Abstract
Serum anti-GM1 ganglioside Abs are abnormally elevated in patients with chronic motor neuropathies and Guillain-Barré syndrome. We have cloned six anti-GM1 IgM Abs from PBMCs of five affected patients. VH and VL gene analysis demonstrated substantial somatic mutation, predominantly clustered around VH CDR2 and FR3 in all six Abs. The Abs SM1, DO1, and WO1, isolated from three different patients, are encoded by closely related VH gene segments with restricted canonical structures. The corresponding L chains are encoded by V lambda II and V lambda VIII genes and also share the same canonical structures, containing nucleotide deletions at the VL/JL boundary to form a VLCDR3 of 10 amino acids. DO1 and WO1 VH segments show nucleotide identities of 95.6% and 88.8%, respectively, to the VH3 member 1.9III, and SM1 shows 87.8% identity to the closely related VH3 member, Hv3005. The Abs BO1 and BO3, derived from a single patient and containing the same VH-D-JH and VL-JL rearrangements, are encoded by the VH3 gene, HHg19, with nucleotide identities of 92.2 and 91.2%, respectively, and have both common and unique somatic mutations. The VH sequence of BR1 has 91.3% identity to the VH4 member, V71-2. These data indicate that neuropathy-associated anti-GM1 IgM Abs can be encoded by both diverse and closely related V genes in association with restricted canonical structures, and that their V genes are somatically mutated, consistent with an origin through an Ag-driven immune response.
Role of the Leishmania surface protease gp63 in complement fixation, cell adhesion, and resistance to complement-mediated lysis.
Authors: Brittingham A , Morrison C J , McMaster W R , McGwire B S , Chang K P , Mosser D M 
Published: January 2023

Abstract
The Leishmania surface protease gp63 has been identified as a parasite virulence factor. To better define the role of gp63 in Leishmania infectivity, the interaction of recombinant gp63 with complement and complement receptors was examined. On Leishmania, gp63 was not necessary for complement fixation. Complement activation occurred on transfected organisms expressing varying amounts of gp63 and on organisms expressing a mutant form of gp63 devoid of proteolytic activity. However, organisms expressing wild-type gp63 on their surface fixed only small amounts of the terminal complement components and were dramatically more resistant to lysis by complement than were those lacking functional gp63. Organisms expressing wild-type gp63 more rapidly converted C3b on their surface to a form that exhibited the neoantigen of iC3b and interacted avidly with cells expressing Mac-1, the receptor for iC3b. Complement fixation by transfected mammalian cells expressing recombinant Leishmania gp63 on their surface was also examined. The presence of Leishmania gp63 on the surface of these cells converted them into efficient activators of complement. Cells expressing gp63 on their surface fixed complement and bound avidly to the human complement receptors. The proteolytic activity of this molecule was not necessary for complement activation or adhesion to complement receptors. Thus, gp63 may contribute to parasite virulence by exerting a novel type of control over complement fixation. Organisms expressing gp63 can exploit the opsonic properties of complement while avoiding its lytic effects.
Aberrant antigen presentation by macrophages from tumor-bearing mice is involved in the down-regulation of their T cell responses.
Authors: Watson G A , Lopez D M 
Published: January 2023

Abstract
Splenic T cells from BALB/c mice bearing mammary adenocarcinomas initially demonstrate a primed response to tumor-associated Ags (TAA), which declines to presensitization levels within 4 wk after tumor implantation. Associated with this decline in responses to TAA is the expansion of a subpopulation of Mac-1+ 2+ splenic macrophages (M phi). These Mac-1+ 2+ cells present TAA inefficiently to normal T cells primed to TAA by footpad injection, as compared with the Ag presenting ability of M phi from normal mice. The addition of anti-I-Ed, but not anti-I-Ad, Ab blocked the ability of Ag-pulsed Mac-1+ 2+ cells to present TAA to primed T cells. The converse was observed with macrophages from normal mice. However, presentation of human gamma-globulin or OVA was restricted by I-Ad molecules when APC from normal mice or tumor bearers were used, although less efficiently in the latter. Using cell depletion techniques, it was determined that the I-Ed-restricted presentation preferentially expanded CD8+ T cells, and not CD4+ cells, as was the case for I-Ad-restricted normal macrophages. These CD8+ cells were poor effectors of cytotoxicity against tumor cells; instead they down-regulated the proliferative activity of T cells. Limiting dilution assays indicated that Mac-1+ 2+ macrophages preferentially present TAA to a low frequency inhibitory T cell population that expanded and inhibited further responses to TAA. Thus, alterations of Ag presentation in tumor bearers may help the tumor to subvert potential beneficial host responses and allow the progression of the neoplastic process.
Monocyte Fc gamma receptor cross-linking induces IL-8 production.
Authors: Marsh C B , Gadek J E , Kindt G C , Moore S A , Wewers M D 
Published: January 2023

Abstract
In response to bacterial cell wall products such as LPS, monocytes produce IL-8, a powerful neutrophil chemotaxin. However, in the absence of bacterial pathogens, immune complex-mediated diseases such as rheumatoid arthritis are associated with high levels of IL-8 in monocyte-rich compartments. Since it is known that IgG-containing immune complexes can recruit neutrophils via an Fc gamma R-dependent process, we hypothesized that cross-linking of monocyte Fc gamma receptors may induce IL-8. To test this hypothesis, peripheral blood mononuclear cells were evaluated for IL-8 induction in response to immobilized LPS-free pooled human IgG. Immobilized IgG, but not soluble IgG, induced IL-8 in a dose-dependent manner (p &lt; 0.05, r = 0.99). This induction corresponded with an up-regulation in IL-8 steady state mRNA levels that peaked at 4 h. The released IL-8 was functional, since supernatants induced concentration-dependent neutrophil migration that was inhibited by a monoclonal anti-IL-8 Ab. Evaluation of purified monocytes for IL-8 production, as well as FACS analysis of IgG-stimulated PBMC preparations, demonstrated that monocytes are the principal IL-8 producer cell. Thus, monocyte Fc gamma R cross-linking induces biologically active IL-8, which may participate in the pathogenesis of immune complex-mediated diseases.
Distinct immunohistochemical localization of IL-4 in human inflamed airway tissues. IL-4 is localized to eosinophils in vivo and is released by peripheral blood eosinophils.
Authors: Nonaka M , Nonaka R , Woolley K , Adelroth E , Miura K , Okhawara Y , Glibetic M , Nakano K , O'Byrne P , Dolovich J 
Published: January 2023

Abstract
Nasal polyposis and asthma are inflammatory conditions of the airways characterized by infiltration of activated inflammatory cells, particularly eosinophils. IL-4 is a multifunctional cytokine considered to play an important role in eosinophilic inflammation. We examined the cellular distribution of immunoreactive IL-4 in nasal polyps, as well as in the bronchial mucosa of both nonasthmatic control subjects (n = 6) and patients with well-characterized mild asthma (n = 6) subjected to a diluent or an allergen challenge. To determine eosinophilic contribution, tissue sections were counterstained with FITC after IL-4 immunostaining. No eosinophils were observed in the bronchial mucosa of nonasthmatic subjects. Nasal polyp tissues contained approximately 15 times more eosinophils per mm2 compared with bronchial tissues from asthmatics after a diluent challenge. Allergen challenge resulted in a marked increase in eosinophil density in bronchial tissues. A negligible number of cells immunostaining IL-4 was observed in bronchial tissues from nonasthmatic control subjects. The density of IL-4-positive cells in nasal polyp tissues was almost three times greater compared with asthmatics bronchial tissues after a diluent challenge. Approximately 90% of the IL-4-positive cells in bronchial tissues did not exhibit fluorescence after FITC counterstaining; in contrast, about 80% of the IL-4-positive cells in nasal polyp tissues did. We also show that peripheral blood eosinophils from allergic subjects express IL-4 mRNA by Northern blot analysis, particularly on stimulation with secretory IgA immune complexes. Finally, the supernatant of stimulated eosinophils contained approximately 50 pg/10(6) cells of IL-4 as determined by ELISA. These data demonstrate that eosinophils express the message and release IL-4 in vitro, and that these cells are the primary source of immunoreactive IL-4 in tissues undergoing chronic severe mucosal inflammation.
Perinuclear anti-neutrophil cytoplasmic antibodies are spontaneously produced by mucosal B cells of ulcerative colitis patients.
Authors: Targan S R , Landers C J , Cobb L , MacDermott R P , Vidrich A 
Published: January 2023

Abstract
Approximately 60% of sera from ulcerative colitis (UC) patients contains Igs reactive with neutrophil components, raising the question of the origin of these anti-neutrophil cytoplasmic Abs (ANCA). Our assertion that ANCA is a marker for a mucosal disease-related immune response predicts the existence of ANCA producing B cell clones in the lamina propria lymphocyte (LPL) fraction of UC patients. This hypothesis was tested by examining 12-day culture supernatants of LPL ANCA expression. LPL were isolated from surgically removed mucosa from patients with UC, Crohn's disease (CD), and diverticulitis. Normal mucosa was obtained from accident victims or normal margins of colon cancer resections. Supernatants were assayed by a fixed neutrophil ELISA. The ANCA staining pattern of supernatants expressing ANCA, as determined by ELISA, was assessed by indirect immunofluorescent staining of alcohol-fixed neutrophils. ANCA was found in 70% of culture supernatants from UC LPL fractions. In contrast, only approximately 11% of supernatants from CD and diverticulitis/normal (noninflammatory bowel disease (IBD)) LPL displayed ANCA binding. A perinuclear (pANCA) staining pattern was obtained with 70% of ANCA-expressing UC LPL supernatants, whereas ANCA-expressing CD and non-IBD LPL supernatants displayed a cytoplasmic reaction. PBL and mesenteric lymph node lymphocytes lacked spontaneous pANCA production, and pANCA production from PBL was not inducible. These findings indicate the existence of pANCA-producing B cell clones in mucosal lesions of UC patients and support our hypothesis that pANCA production is a consequence of a mucosal immune response specific to UC.
Polymorphic nucleotides within the human IL-4 promoter that mediate overexpression of the gene.
Authors: Song Z , Casolaro V , Chen R , Georas S N , Monos D , Ono S J 
Published: January 2023

Abstract
Atopy, which predisposes individuals to develop asthma, severe systemic anaphylaxis, and atopic dermatitis, is usually associated with dramatically elevated total serum IgE levels and is thought to be controlled by a major susceptibility gene and multiple minor susceptibility genes. A recent sib-pair analysis revealed a tight linkage between markers on 5q31.1 and a major susceptibility gene controlling total serum IgE levels. Due to its location within this cluster and its biologic role in Ig class switching and Th2 cell differentiation, the IL-4 gene has emerged as one major candidate for the atopy gene. In one model, polymorphisms within IL-4 regulatory elements might result in overexpression of the gene, amplifying Th2 cell differentiation and class switching to IgE. In support of this model, we report that the human IL-4 promoter exists in multiple allelic forms that exhibit distinct transcriptional activities in IL-4-positive T cells. A particular allele has an unusually high transcriptional activity. A nucleotide substitution within a recently described OAP40 element located just upstream of an NF-AT site (P sequence) appears to be largely responsible for the increased promotor strength of this particular allelic form of the IL-4 promoter. In EMSAs, this substitution results in a markedly enhanced affinity for sequence-specific complexes exhibiting an AP-1 specificity. The identification of allelic nucleotides, which results in overexpression of the IL-4 gene, provides specific targets for a comprehensive screening of atopic and nonatopic individuals and may provide a clue for genetic predisposition for atopy.
alpha-Melanocyte-stimulating hormone induces hapten-specific tolerance in mice.
Authors: Grabbe S , Bhardwaj R S , Mahnke K , Simon M M , Schwarz T , Luger T A 
Published: January 2023

Abstract
alpha-Melanocyte-stimulating hormone (alpha-MSH) is a proopiomelanocortin-derived peptide with known immunoregulatory effects, acting mainly via modulation of cytokine secretion by lymphocytes and monocytes. When applied epicutaneously, alpha-MSH inhibits both induction as well as elicitation of contact hypersensitivity (CHS) responses in mice. We questioned whether systemically administered alpha-MSH leads to the induction of hapten-specific tolerance. For this purpose, mice were injected i.v. with 75 microgram/kg synthetic bioactive alpha-MSH 2 h before sensitization (day 0) or challenge (day 6) with the hapten, trinitrochlorobenzene (TNCB). Intravenous administration of alpha-MSH 2 h before sensitization or 2 h before challenge resulted in a markedly reduced CHS response. To distinguish between unresponsiveness and tolerance, these mice were sensitized and challenged a second time, but in the absence of alpha-MSH. Mice that had been injected with alpha-MSH before the first sensitization (day 0), but not before challenge (day 6), were also unable to develop a significant CHS response after an additional sensitization and challenge with the same Ag 10 to 14 days later. In contrast, sensitization to the unrelated hapten, dinitrofluorobenzene, was unaffected in these mice, indicating the induction of hapten-specific tolerance by alpha-MSH. Moreover, regional lymph node cells obtained from alpha-MSH-treated mice 5 days after resensitization failed to produce IL-2 in response to trinitrobenzosulfonic acid, the water-soluble analogue of TNCB, whereas lymph node cells from TNCB-sensitized, not alpha-MSH-treated, mice as well as from mice treated with alpha-MSH before challenge readily exhibited trinitrobenzosulfonic acid-specific IL-2 production in this assay. Finally, in vivo tolerance induction by alpha-MSH could be abrogated by the administration of anti-IL-10 Ab at the site of sensitization. These data indicate that alpha-MSH, in addition to its suppressive effect on induction and elicitation of CHS, is able to induce hapten-specific tolerance in mice. Thus, alpha-MSH may be a significant regulatory mediator of cutaneous immune responses in vivo.
A dual role for both CD40-ligand and TNF-alpha in controlling human B cell death.
Authors: Lens S M , Tesselaar K , den Drijver B F , van Oers M H , van Lier R A 
Published: January 2023

Abstract
Members of the TNF-R family are instrumental in controlling lymphoid cell death and survival. A major role in the regulation of murine and human B cell survival and differentiation has been attributed to CD40/CD40-ligand (CD40-L) interactions, but recent in vitro and in vivo data implicate that other receptor-ligand pairs might also be involved. We have used the human Burkitt lymphoma cell line Ramos as a model system to identify additional TNF-R/TNF family members that are implicated in the regulation of B cell apoptosis. Ligation of B cell receptor (BCR) with anti-IgM mAb for 48 h induced apoptosis in approximately 68% of the Ramos B cells. Interestingly, not only CD40 mAb but also rTNF-alpha could efficiently inhibit BCR-induced B cell death. In addition, activated T cells also prevented BCR-triggered apoptosis, and this effect was inhibited completely by a combination of blocking Abs against CD40-L and TNF-alpha. In contrast to the strong effect of BCR ligation, APO-1 mAb induced apoptosis in only +/- 18% of the Ramos cells after 48 h. Noticeably, addition of CD40 mAb or rTNF-alpha increased the percentage of cells (+/- 46%) undergoing apoptosis, which correlated with an increase of Fas/APO-1 membrane expression induced by CD40 or TNF-R ligation. Taken together, we show that CD40/CD40-L and TNF-R/TNF-alpha interactions not only postpone or prevent B cell death, but are also involved in sensitizing B cells for Fas-ligand (Fas-L)-dependent death.
IL-2 rescues antigen-specific T cells from radiation or dexamethasone-induced apoptosis. Correlation with induction of Bcl-2.
Authors: Mor F , Cohen I R 
Published: January 2023

Abstract
Most studies of apoptosis on T lymphocytes have examined the effects of various stimuli on immature T cells from the thymus. Previous work has indicated that apoptosis of mature memory T cells may be an important pathophysiologic mechanism in diseases such as AIDS, cancer, and autoimmunity. The effect of IL-2 on apoptosis of T cells is not clear. Therefore, we studied the ability of IL-2 to rescue Ag-specific T cells from apoptosis. We found that IL-2, in a dose-dependent manner, prevented T cells from entering apoptosis induced by gamma-irradiation, mitomycin C, or dexamethasone. This effect was specific for IL-2; IL-1 beta, IL-6, or IFN-gamma could not reproduce it. In contrast to Ag-specific T cells, immature T cells and naive mature peripheral T cells could not be rescued by IL-2 from radiation-induced apoptosis. Apoptosis rescue by IL-2 was associated with the induction of bcl-2 mRNA and protein. This induction could not be attributed to the effects of IL-2 on the cell cycle, as T cells that were prevented from cell cycle progression by irradiation showed a similar induction of bcl-2. Rescued cells retained their Ag-specific proliferative capacity and in vivo functions. These findings demonstrate that the apoptotic death of Ag-specific T cell lines, cells which can be regarded as a model for memory T cells, can be prevented with IL-2. This effect may have important therapeutic implications for patients receiving chemotherapy or radiotherapy, and for patients with AIDS who develop immunodeficiency primarily as a result of loss of Ag-specific memory T cells.
pim-1 proto-oncogene expression in anti-CD3-mediated T cell activation is associated with protein kinase C activation and is independent of Raf-1.
Authors: Wingett D , Long A , Kelleher D , Magnuson N S 
Published: January 2023

Abstract
We have studied pim-1 proto-oncogene expression in human T cell responses to Ag receptor-generated signals. The pim-1 gene encodes a serine/threonine protein kinase that is expressed primarily in cells of hematopoietic lineage and is implicated in the intracellular signaling processes accompanying lymphocyte activation. We show here that pim-1 mRNA expression is rapidly induced after receptor cross-linking with anti-CD3 Abs. We examined the linkage of pim-1 expression to known signaling pathways generated through the T cell Ag receptor. pim-1 mRNA was not substantially induced after elevation of intracellular free Ca2+. In contrast, PMA, which directly activates PKC, induced rapid pim-1 expression. Further, anti-CD3- or PMA-induced pim-1 expression was markedly reduced by various PKC inhibitors and by deficiency of the PKC epsilon isoform in a mutant T cell line. Thus, T cell Ag receptor-linked pim-1 expression appears to be coupled to the PKC component of transmembrane signaling. Because the activation of protein kinase C has been shown to activate Raf-1 kinase activity, the involvement of Raf-1 in pim-1 expression was also investigated using a human T cell line stably transfected with an inducible Raf expression vector. Although the overexpression of activated Raf was shown to cause a substantial increase in IL-2 expression, no discernible effects on pim-1 were apparent. In addition, we examined transcriptional and post-transcriptional mechanisms involved in PKC-mediated pim-1 expression and observed that both transcriptional and post-transcriptional mechanisms are coordinately involved in the up-regulation of the pim-1 proto-oncogene.