bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antisense homology boxes in C5a receptor and C5a anaphylatoxin: a new method for identification of potentially active peptides.
Authors: Baranyi L , Campbell W , Okada H 
Published: December 2022

Abstract
A computer program was designed to locate regions termed antisense homology boxes (AHB), i.e., 8-15 amino acid regions corresponding to complementary DNA strands. Two AHBs were found in C5a and eight within the C5a receptor. The majority of intermolecular AHBs were found to overlap those found in the intramolecular AHBs. Several AHB peptides were synthesized and tested for their ability to interfere with C5a receptor functions. A peptide fragment of the C5a receptor corresponding to the loop between the fifth and sixth hypothetical transmembrane regions (amino acids 226-245) antisense to C5a and an intramolecular AHB in C5a receptor proved to be an antagonist of C5a when preincubated with C5a at high concentrations (&gt;0.5 microM). However, when U937 cells bearing the C5a receptor were preincubated with this peptide at a much lower concentration (even as little as 40 pmol), the AHB peptide behaved as an agonist. Another AHB peptide corresponding to region 10-27 in the C5a receptor bound to two of its corresponding antisense peptides derived from C5a anaphylatoxin, corresponding to amino acids 37-43 and 61-74. This observation raises the possibility that the C5a receptor may bind C5a with two distinct orientations. Two other AHB peptides derived from C5a, PL12 (amino acids 12-27), and PL61 (amino acids 61-74), were also shown to inhibit activity. Incubation of dibutyryl cyclic AMP-stimulated U937 cells with PL37 (amino acids 37-51) resulted in increased intracellular Ca2+ levels and an anergy to subsequent challenge with C5a. Locating regions with sense-antisense relationships in proteins might help in identification of peptides that can interfere with the function of target proteins.
Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus.
Authors: Berman M A , Sandborg C I , Wang Z , Imfeld K L , Zaldivar F , Dadufalza V , Buckingham B A 
Published: December 2022

Abstract
IL-4 has been shown to protect against diabetes development in rodent models of insulin-dependent (type I) diabetes mellitus (IDDM). To study IL-4 production in human IDDM, PBMC from IDDM patients and controls were stimulated in vitro with PHA, anti-CD3 mAb, or PMA and ionophore. IL-4 production by PBMC or T cells was strongly impaired in IDDM patients at diabetes onset (p &lt; 0.0001). The mean IL-4 response of patients in the honeymoon stage was higher than the mean of the new onset patients, but significantly lower than the control group (p = 0.01). Patients with IDDM of longer duration (&gt;2 yr) showed a wide range of IL-4 responses and their mean IL-4 response was lower than the controls; however, the difference was not statistically significant. IL-4 mRNA levels were measured using competitive reverse transcription PCR. The results showed greatly reduced mRNA levels in new onset IDDM. In contrast, IL-1 production (measured by ELISA) and IFN-gamma mRNA (measured by reverse transcription PCR) were not significantly different in IDDM. The results suggest an imbalance of inflammatory vs anti-inflammatory cytokine production at the onset of IDDM. Deficient IL-4 production as seen at the onset of IDDM may play a role in the development of diabetes by allowing the inflammatory/autoimmune process in pancreatic islets to progress.
Mitochondrial permeability transition triggers lymphocyte apoptosis.
Authors: Marchetti P , Hirsch T , Zamzami N , Castedo M , Decaudin D , Susin S A , Masse B , Kroemer G 
Published: December 2022

Abstract
In a number of experimental systems, the early stage of the apoptotic process, i.e., the stage that precedes nuclear disintegration, is characterized by the breakdown of the inner mitochondrial transmembrane potential (delta psi(m)). This delta psi(m) disruption may involve mitochondrial permeability transition (PT). Here, we address the question of whether PT transition would suffice to cause apoptosis or, rather, it would constitute a secondary event not causally involved in the apoptotic cascade. Protoporphyrin IX (PPIX), a ligand of the mitochondrial benzodiazepin receptor that is well known for its PT-triggering capacity, induces delta psi(m) disruption, enhanced generation of superoxide anions, as well as signs of nuclear apoptosis in thymocytes and in T cells. The sequence of events triggered by PPIX mimics that observed in natural apoptosis. The PT inhibitory compound bongkrekic acid, a specific ligand of the mitochondrial adenine nucleotide translocator, is an efficient inhibitor of protoporphyrin IX-induced delta psi(m) disruption. Bongkrekic acid prevents all PPIX-induced phenomena, including superoxide anion generation, chromatinolysis, and oligonucleosomal DNA fragmentation. In contrast, inhibitors of mRNA or protein synthesis fail to suppress PPIX-induced delta psi(m) disruption and apoptosis. Transfection-enforced hyperexpression of the apoptosis-inhibitory proto-oncogene bcl-2 also inhibits PPIX-induced delta psi(m) disruption, hyperproduction of reactive oxygen species, and nuclear DNA loss. The delta psi(m)-stabilizing effect of Bcl-2 is observed both in cells and in isolated mitochondria. In conclusion, these data are compatible with the hypotheses that mitochondrial PT is self-sufficient to trigger apoptosis and that Bcl-2 may directly regulate PT.
Altered TCR ligands affect antigen-presenting cell responses: up-regulation of IL-12 by an analogue peptide.
Authors: Matsuoka T , Kohrogi H , Ando M , Nishimura Y , Matsushita S 
Published: December 2022

Abstract
When examining the effects of analogue peptides on changes in response patterns of a human Th0 clone DT13.2 that recognizes a peptide fragment (18RSLRTVTPIRMQGG31) derived from a group I allergen in Dermatophagoides farinae in the context of HLA-DQ6 (DQA1*0102/DQB1*0602), we found that replacement of the 21st residue Arg to Lys resulted in a significant increase in IFN-gamma production, with no remarkable changes either in proliferative response or IL-4 production, at high doses of the peptide. Selective enhancement of IFN-gamma production by the analogue peptide was accompanied by an increased production of IL-12, which was suppressed by an anti-IL-12 Ab down to the level of IFN-gamma production induced by the wild-type peptide. On the contrary, co-incubation with neutralizing Abs to IFN-gamma and IFN-gamma receptor did not affect IL-12 production, indicating that increased production of IL-12 stimulated by the analogue peptide was not due to an effect of IFN-gamma from T cells. Peptide-induced up-regulation of CD40 ligand expression at high peptide concentrations showed no difference between the wild-type and analogue peptides. These data collectively indicate that certain T cell/APC interactions mediated through TCR and altered TCR ligands affect APC responses and that signals transmitted to APC are as indispensable as those to T cells in determining T cell response patterns.
Phosphatidylinositol 3-kinase participates in p56(lck)/CD4-dependent down-regulation of LFA-1-mediated T cell adhesion.
Authors: Mazerolles F , Barbat C , Hivroz C , Fischer A 
Published: December 2022

Abstract
The mechanism inducing cell detachment in Ag-independent adhesion between lymphocytes is poorly understood. Different putative CD4 ligands, anti-CD4 Ab, a DR35-46 peptide mimicking residues 35 to 46 of HLA class II beta1, and a DR134-148 peptide mimicking residues 134 to 148 of HLA class II beta2, were previously found to down-regulate LFA-1-dependent adhesion between CD4+ T cells and HLA class II+ B cells. This down-regulation was shown to be p56(lck) dependent. Here we show that binding of these ligands to CD4 induced the activation of the tyrosine kinase p56(lck) associated with CD4 and also the lipid kinase phosphatidylinositol-3 kinase (PI3-kinase) associated with the CD4-p56(lck) complex in the HUT78 cell line. These events were not detected when p56(lck) was dissociated from CD4 in cell lines expressing mutated forms of CD4. It was also shown, using different inhibitors of the PI3-kinase (wortmannin, Ly294002, and antisense oligonucleotides), that this lipid kinase was necessary for the down-regulation of LFA-1-mediated adhesion induced by CD4 binding. These results strongly suggest that CD4-induced PI3-kinase activation, in the absence of concomitant TCR/CD3 triggering, leads to down-regulation of LFA-1-mediated T cell adhesion to B cells. The mechanism by which PI3-kinase could exert its effect remains unknown. Since PI3-kinase has previously been found to participate in the regulation of cytoskeleton structure, we propose that p56(lck)-associated PI3-kinase activation leads to a cytoskeleton organization unfavorable for LFA-1 function.
CD40, but not lipopolysaccharide and anti-IgM stimulation of primary B lymphocytes, leads to a persistent nuclear accumulation of RelB.
Authors: Neumann M , Wohlleben G , Chuvpilo S , Kistler B , Wirth T , Serfling E , Schimpl A 
Published: December 2022

Abstract
In this study we analyzed the effect of CD40 stimulation on the activity and nuclear appearance of Rel/nuclear factor kappaB (NF-kappaB) factors in primary murine B lymphocytes. We show that triggering of CD40 signaling pathway(s) by CD40 ligands expressed on L cells led to strong activation of an NF-kappaB-controlled beta-globin reporter gene in primary B lymphocytes from transgenic mice. Analyses of nuclear translocation of individual members of Rel proteins after CD40 induction of primary B cells showed a strong and long-lasting accumulation of RelB and, less pronounced, of c-Rel. LPS stimulation did not give rise to a persistent nuclear accumulation of RelB and c-Rel, whereas nuclear c-Rel, but not RelB, accumulated after B cell receptor stimulation. CD40 induced not only nuclear translocation but also de novo synthesis of RelB RNA and protein. S107 plasmacytoma cells, which express CD40 but are defective for the nuclear appearance of p50/p65-NF-kappaB, do not express RelB after CD40 stimulation. In S107 cells stably transfected with relB genes, stimulation of nuclear RelB translocation by CD40 was observed. These results indicate that stimulation of CD40 signaling pathways exerts a long-lasting stimulatory effect on both the transcription and nuclear translocation of RelB. Since LPS and anti-IgM were unable to activate RelB, CD40 appears to trigger a special program of gene expression involved in the proliferation and/or differentiation of B lymphocytes.
Differential regulation of metalloelastase activity in murine peritoneal macrophages by granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor.
Authors: Kumar R , Dong Z , Fidler I J 
Published: December 2022

Abstract
We investigated the regulation of elastase activity in murine peritoneal macrophages by different cytokines and bacterial LPS. Thioglycolate-elicited mouse peritoneal exudate macrophages secrete a metalloproteinase that degrades elastin. Incubation of peritoneal exudate macrophages with LPS and IFN-gamma significantly inhibited the production of elastase by a mechanism independent of nitric oxide, superoxide, and hydrogen peroxide. The cytokines IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, TNF, TGF-alpha and -beta, basic fibroblast growth factor, monocyte chemotactic factor-1, and granulocyte CSF (G-CSF) had no significant effect on the production of elastase by macrophages. In contrast, granulocyte-macrophage CSF (GM-CSF) increased the production of elastase in a dose-dependent manner, and with macrophage CSF (M-CSF) inhibited it. Elastin zymography demonstrated that the modulation of elastolytic activity in macrophages was associated with changes in the level of metalloelastase protein. The stimulation of elastase activity by GM-CSF and the inhibition of elastase activity by LPS, IFN-gamma, and M-CSF occurred at the level of transcription. LPS and M-CSF also augmented the expression level of tissue inhibitors of metalloproteinase mRNA. The increased mRNA steady state level of murine macrophage elastase induced by GM-CSF resulted from both increased transcription and enhanced stability. The modulation of metalloelastase activity in macrophages by IFN-gamma, M-CSF, and GM-CSF suggests that these molecules may control the degradation of elastin fibers in lungs or blood vessels.
Leukotriene-deficient mice manifest enhanced lethality from Klebsiella pneumonia in association with decreased alveolar macrophage phagocytic and bactericidal activities.
Authors: Bailie M B , Standiford T J , Laichalk L L , Coffey M J , Strieter R , Peters-Golden M 
Published: December 2022

Abstract
Leukotrienes (LTs) are potent mediators of inflammation derived from the 5-lipoxygenase pathway of arachidonic acid metabolism. Although they are known to enhance leukocyte recruitment and function, their role in antimicrobial host defense has not been established. To determine the role of endogenous LTs in the host response to pulmonary infection, wild-type mice and mice rendered LT-deficient by targeted disruption of the 5-lipoxygenase gene (knockout mice) were studied following intratracheal challenge with Klebsiella pneumoniae. Wild-type mice demonstrated a marked increase in lung LT levels and neutrophil numbers following bacterial challenge. As compared with wild-type animals, knockout animals manifested a greater degree of lethality as well as bacteremia following challenge. Interestingly, they displayed no defect in neutrophil recruitment to the lung. However, alveolar macrophages from knockout animals exhibited impairments in bacterial phagocytosis and killing, and these defects were overcome by in vitro addition of exogenous LTB4. We conclude that endogenous LTs play a critical role in the defense against bacterial pneumonia in this murine model.
Induction of nonpathologic, humoral autoimmunity in lupus-prone mice by a class II-restricted, transgenic alpha beta T cell. Separation of autoantigen-specific and -nonspecific help.
Authors: Peng S L , Fatenejad S , Craft J 
Published: December 2022

Abstract
Murine lupus predominantly requires alpha beta T cells, which provide pathogenic help for autoantibody production and immune complex-associated end-organ disease. Autoantigen-specific, pathogenic alpha beta T cells have been isolated from some lupus-prone mice, but a requirement for such T cells in disease has not been clearly demonstrated. To address alpha beta T cell specificity in murine lupus, lupus-prone mice were generated that contained only a single population of alpha beta T cells of foreign specificity by generating anti-pigeon cytochrome c (AND) TCR transgenic TCRalpha -/- TCRbeta -/- MRL/Mp-lpr/lpr (MRL/lpr) mice, which lacked the ability to express endogenous TCRalpha or -beta genes. These AND alpha beta T cells induced hypergammaglobulinemia and autoantibody production, as seen in serum Ig, anti-DNA, anti-small nuclear ribonucleoprotein (snRNP) and rheumatoid factor titers, but failed to promote the development of lymphadenopathy or pathogenic immune-complex disease, as assayed by cutaneous, renal, and salivary gland lesions. Thus, antigen-nonspecific alpha beta T cell help can promote generalized autoimmunity, but autoantigen-specific alpha beta T cells are required to cause overt disease.
Reversal of immunosuppression inducible through ultraviolet-exposed skin by in vivo anti-CD11b treatment.
Authors: Hammerberg C , Duraiswamy N , Cooper K D 
Published: December 2022

Abstract
In both human in vitro models and murine in vivo adoptive transfer studies, UV-induced class II MHC+ CD11b+ leukocytes that infiltrate the epidermis appear to mediate UV-induced immunosuppression. In the present study, their role is further probed using an anti-CD11b mAb (clone 5C6), which is effective in vivo in blocking CD11b+ monocyte/macrophage diapedesis into inflammatory lesions. A single exposure, low dose UV protocol (72 mJ/cm2) that resulted in tolerance only when dinitroflurobenzene was applied 48 h later through the UV-irradiated skin, but not through a distant non-UV-irradiated site, was used. In vivo anti-CD11b treatment in non-UV-irradiated mice did not block contact sensitivity responses. However, the ability to induce a primary contact sensitivity response was completely restored in UV-irradiated mice receiving anti-CD11b. This restoration was associated with partial restoration of papillary dermal class II MHC+ NLDC-145- cells. In vivo anti-CD11b treatment also blocked tolerance induction, which was associated with a 50% reduction in the infiltration of class II MHC+ CD11b+ Gr-1+ monocyte/macrophages into UV-irradiated skin. In addition, anti-CD11b treatment partially protected against epidermal UV injury, in that the epidermal structure was better preserved and the keratinocytes were less severely damaged. CD11b+ leukocytes may thus affect UV-irradiated skin through at least two mechanisms: 1) a class II MHC+ CD11b+ Gr-1+ monocyte/macrophage population inducing a state of tolerance to Ag(s) acquired in UV-irradiated skin, and 2) CD11b+ leukocytes capable of inflicting additional injury to both keratinocytes and constitutive APC damaged by UV photons.
Memory T cell development in the absence of specific antigen priming.
Authors: Lee W T , Cole-Calkins J , Street N E 
Published: December 2022

Abstract
Numerous studies have shown that memory T cell development is Ag dependent and specific. In the present study, we show that memory responses can be made against an Ag to which there has been no prior exposure. In unimmunized DO11.10 mice, which carry alpha and beta transgenes that encode a TCR specific for OVA, CD45RB(low) memory cells express the transgenic TCR. These cells can be stimulated by OVA to proliferate and perform typical memory functions, such as secrete diverse lymphokines and provide cognate help to B cells, despite the fact that the mice were never exposed to OVA. Thus, memory cells can be generated in the absence of specific Ag. The data also demonstrate that the transgenic TCR-bearing memory T cells possess endogenous TCR alpha-chains, which permit the expression of a second TCR. In DO11.10/RAG(-/-) mice, the endogenous alpha-chains are eliminated, and the T cells can only express the transgenic TCR. In these mice, no memory cells were observed. Thus, it is the additional TCR that appears to drive memory cell generation. Once induced, memory function may be triggered through the transgenic receptor. Since dual TCR-bearing cells have been shown to exist in nontransgenic mice and humans, our results provide evidence that one mechanism for the maintenance of memory responses to a specific Ag is through stimulation of the second TCR by another Ag. Further, these findings have important implications for understanding aberrant immune responses, such as those that occur in autoimmunity.
Identification of a heparin binding domain in the seventh short consensus repeat of complement factor H.
Authors: Blackmore T K , Sadlon T A , Ward H M , Lublin D M , Gordon D L 
Published: December 2022

Abstract
Surface polyanions such as sialic acid and heparin are thought to enhance the binding of complement factor H (fH) to C3b deposited on particles and cell surfaces, thereby reducing complement activation. fH contains 20 short consensus repeat (SCR) domains, and it has been proposed that SCR 13 contains a heparin binding site. We used recombinant proteins to determine the heparin binding site on fH. Full-length fH (H20) and truncated and SCR deletion mutant proteins were cloned and expressed in Chinese hamster ovary cells. Supernatants were applied to heparin-agarose affinity columns to determine their binding and elution profiles. Deletion of SCR 13 from H20 did not prevent heparin binding nor alter its salt elution profile, indicating that SCR 13 does not contain an essential heparin binding site. We found that SCR 7 contains a heparin binding site, as SCRs 1 through 7 were the smallest truncated proteins to bind heparin (89 +/- 3%). Furthermore, deletion of SCR 7 from a protein containing SCRs 1 through 9 reduced heparin binding, whereas deletion of SCR 6 did not (17 +/- 13 vs 81 +/- 13%; p = 0.02). It is likely that other heparin binding sites exist within SCRs 10 through 20; an SCR 7 deletion mutant of H20 eluted earlier than H20, but still showed &gt;99% binding to immobilized heparin. SCR 13 does not contain such a site because a double deletion of SCRs 7 and 13 from H20 showed &gt;97% heparin binding and had an elution profile smilar to that of a single deletion of SCR 7.
Analysis of cytotoxic T cell responses to dominant and subdominant epitopes during acute and chronic lymphocytic choriomeningitis virus infection.
Authors: van der Most R G , Sette A , Oseroff C , Alexander J , Murali-Krishna K , Lau L L , Southwood S , Sidney J , Chesnut R W , Matloubian M , Ahmed R 
Published: December 2022

Abstract
The cytotoxic T cell response against lymphocytic choriomeningitis virus (LCMV) in BALB/c (H-2d) mice is predominantly directed against a single immunodominant Ld-restricted epitope in the viral nucleoprotein (NP118-126). Here we report that the immunodominance of this peptide can be in part attributed to its very high affinity for Ld class I molecules. By employing motif searches and sensitive MHC class I binding assays, we also identified 5 Kd-binding peptides in the viral nucleoprotein and glycoprotein among 16 Kd motif-fitting peptides. The nucleoprotein and glycoprotein sequences also contained 18 Dd motif-fitting peptides, three of which bound Dd with weak affinity. Two of the Kd-binding peptides, residues 99-108 and residues 283-291 from the viral glycoprotein, are subdominant epitopes. Although these peptides did not sensitize target cells for direct ex vivo killing by primary antiviral CTL, secondary responses against these peptides were readily detected in BALB/c mice after acute LCMV infection. BALB/c mice that had cleared a long-term LCMV infection showed more sustained CTL responses against these subdominant epitopes, suggesting that subdominant responses might play a role in clearance of chronic infections. One of the subdominant epitopes, GP283-291, conferred partial protection against persistent viral infection after peptide vaccination.
Human monocyte chemoattractant protein (MCP)-4 is a novel CC chemokine with activities on monocytes, eosinophils, and basophils induced in allergic and nonallergic inflammation that signals through the CC chemokine receptors (CCR)-2 and -3.
Authors: Garcia-Zepeda E A , Combadiere C , Rothenberg M E , Sarafi M N , Lavigne F , Hamid Q , Murphy P M , Luster A D 
Published: December 2022

Abstract
The chemokines are a large family of cytokines that regulate the complex and precise recruitment of immune cells into inflammatory foci. To fully appreciate their role in the pathogenesis of human diseases, the entire spectrum of chemokines, their receptors, their cellular targets, and mechanisms of regulation need to be delineated. Using eotaxin as a probe, we isolated a cDNA for a novel human beta (or CC) chemokine that, based on its biological and structural features, we have named monocyte chemoattractant protein (MCP)-4. Purified recombinant MCP-4 protein was a potent chemoattractant for monocytes and eosinophils and stimulated histamine release from basophils. MCP-4 induced a calcium flux in HEK-293 cells transfected with the monocyte selective MCP-1 receptor (CCR-2B) and the eosinophil selective eotaxin receptor (CCR-3), but not in the more widely expressed CCR-1 or CCR-5. This novel chemokine is expressed in TNF-alpha and IL-1 activated epithelial and endothelial cells in vitro, and in the epithelial mucosa of patients with both Th2-type allergic and Th1-type nonallergic sinusitis. Furthermore, both IFN-gamma and IL-4, products of Th1 and Th2 cells, respectively, synergized with TNF-alpha and IL-1 in inducing MCP-4 mRNA accumulation. These properties of MCP-4 offer a molecular explanation for the observed accumulation of monocytes, eosinophils and basophils in both Th1- and Th2-type immune responses.