bluuebunny/crossref_metadata_2025_split huggingface dataset:
EBV induces the production and release of IL-8 and macrophage inflammatory protein-1 alpha in human neutrophils.
Authors: McColl S R , Roberge C J , Larochelle B , Gosselin J 
Published: January 2023

Abstract
As the first line of defense in the immune system, neutrophils may release a variety of potent agents upon exposure to infectious agents. In this study we have investigated the ability of human neutrophils to produce chemotactic cytokines, or chemokine in response to EBV. Exposure of neutrophils to EBV led to an increase in accumulation of mRNA for IL-8 and macrophage inflammatory protein-1alpha (MIP-1alpha). EBV stimulated a time-dependent production of immunoreactive IL-8 and MIP-1alpha by neutrophils. The ability of EBV to stimulate the synthesis of IL-8 and MIP-1alpha protein was reflected by both an accumulation of the protein in the intracellular compartment as well as increased secretion. A variety of control studies support the idea that infectious EBV is not required for induction of chemokine gene expression; however, the response is dependent on the interaction between the glycoprotein gp350 of the viral envelope and the neutrophil surface. Since both IL-8 and MIP-1alpha are reported to be chemoattractants in vitro for T cells and for T and B cells, respectively, the ability of EBV to induce their production by neutrophils may enhance the ability of this virus to infect B and T lymphocytes via increased recruitment to sites of infection.
Induction of biologically active IL-1 beta-converting enzyme and mature IL-1 beta in human keratinocytes by inflammatory and immunologic stimuli.
Authors: Zepter K , Häffner A , Soohoo L F , De Luca D , Tang H P , Fisher P , Chavinson J , Elmets C A 
Published: January 2023

Abstract
IL-1beta, a major mediator of inflammatory and immunologic skin disease, undergoes post-translational site-specific cleavage by a novel cysteine protease termed IL-1beta-converting enzyme (ICE). Although in human skin keratinocytes produce significant amounts of the 31-kDa IL-1beta precursor protein, they fail under nonpathologic conditions to convert it to the 17.5-kDa bioactive form. In this study, we examined whether haptens and inflammatory agents might serve as stimuli for ICE activity in human keratinocytes, and, if so, whether ICE activity might precipitate enzymatic processing of IL-1beta to its 17.5-kDa form. Baseline levels of ICE mRNA were detected in keratinocyte cultures devoid of Langerhans cells and were up-regulated by nontoxic concentrations of the reactive hapten urushiol and by the irritant chemicals sodium lauryl sulfate and PMA. Although untreated keratinocytes expressed the 31-kDa form of the protein, 17.5-kDa IL-1beta was easily detected in keratinocytes and keratinocyte supernatants treated with either urushiol or the irritant chemicals. Enzymatic conversion from the 31-kDa to the 17.5-kDa form of IL-1beta was blocked by addition of a highly specific aldehyde inhibitor that contained a tetrapeptide recognition sequence specific for ICE, but not by an aldehyde inhibitor of a related ICE-like cysteine protease. Induction of IL-1beta-converting enzyme by immunologic and inflammatory stimuli may be one of the key regulatory elements in the pathogenesis of allergic and irritant contact hypersensitivity.
Identification and characterization of multiple HLA-A24-restricted HIV-1 CTL epitopes: strong epitopes are derived from V regions of HIV-1.
Authors: Ikeda-Moore Y , Tomiyama H , Miwa K , Oka S , Iwamoto A , Kaneko Y , Takiguchi M 
Published: January 2023

Abstract
HIV-1-specific CTL has a crucial role in the elimination of the virus. However, a restricted number of common HLA class I alleles has been studied for their presentation of HIV-1 CTL epitopes. We have attempted to identify HIV-1 CTL epitopes presented by HLA-A*2402 using reverse immunogenetics. Fifty-three HLA-A*2402-binding HIV-1 peptides were used to induce specific CTL in PBL of four HIV-1-infected individuals carrying HLA-A24. Twelve peptides were strongly suggested to be HLA-A*2402-restricted HIV-1 CTL epitopes because these peptides induced the specific CTL that killed both the target cells pulsed with the specific peptides and those infected with the vaccinia HIV-1 recombinant virus in at least one HIV-1-infected individual. Of these epitopes, 11 were confirmed by the generation of the specific CTL clones. Six were the Env epitopes while three, one, and one were derived from Gag, Pol, and Nef proteins, respectively. Analysis of 12 HIV-1-infected individuals using these peptides showed that 5 derived from the Env protein and one from the Nef protein were strong epitopes. These strong epitopes were derived from the diverse region of HIV-1 while weak epitopes were conserved in the HIV-1 clade B strain. Analysis of CTL recognition of mutations in these strong epitopes suggested that the mutations in the Env epitopes may critically influence CTL recognition in vivo.
Demonstration and functional analysis of IL-10 receptors in human epidermal cells: decreased expression in psoriatic skin, down-modulation by IL-8, and up-regulation by an antipsoriatic glucocorticosteroid in normal cultured keratinocytes.
Authors: Michel G , Mirmohammadsadegh A , Olasz E , Jarzebska-Deussen B , Müschen A , Kemény L , Abts H F , Ruzicka T 
Published: January 2023

Abstract
The chronic skin disease psoriasis is characterized by epidermal hyperproliferation and inflammation. The exact etiology of the disease is still unknown. At the molecular level, overexpression of growth factors and proinflammatory cytokines such as IL-8 and the corresponding receptor has been described in psoriatic plaques. On the other hand, the loss of inhibitory control mechanisms is involved in the pathogenesis of the disease, as exemplified by the reduced mRNA levels for the cell cycle inhibitor p53 found in lesional skin. Here we extend these findings to a cytokine with negative regulatory functions, IL-10. Only under certain conditions are human keratinocytes able to synthesize IL-10. In skin, pathological overexpression of IL-10 was described om atopic dermatitis. IL-10 exerts its effects via a specific receptor (IL-10R). We show here for the first time the presence and functionality of IL-10R in epidermal cells and its dramatically decreased expression in acute exanthematic psoriatic epidermis by in vitro and in situ binding studies. These results were substantiated using semiquantitative reverse transcriptase-PCR, demonstrating decreased expression of the IL-10R gene in psoriatic skin, its down-modulation by the proinflammatory cytokine IL-8, and its pharmacological induction in cultured cells. Biological responsiveness of epidermal cells toward IL-10 could also be demonstrated by a reduction of the growth rate and inhibition of IFN-gamma-induced HLA-DR expression. Our results provide the first evidence for a role of the IL-10R gene in the homeostasis of the epidermis and substantiate the concept of a loss of negative regulatory peptides as a step in the eruption of psoriasis.
Lactate dehydrogenase-elevating virus (LDV): lifelong coexistence of virus and LDV-specific immunity.
Authors: van den Broek M F , Spörri R , Even C , Plagemann P G , Hänseler E , Hengartner H , Zinkernagel R M 
Published: January 2023

Abstract
Viruses have developed various strategies to coexist with vertebrate hosts. Lactate dehydrogenase-elevating virus (LDV) is a highly cytopathic virus exhibiting an extraordinary rate of replication; LDV nevertheless establishes a persistent infection without harming the host. The cytotoxic and helper T cell responses to LDV were monitored in mice with different genetic backgrounds. LDV-specific cytotoxic and helper T cells were found in all strains tested. These responses persisted for at least up to 250 days despite high levels of LDV in the blood. Thus, the cytopathic LDV induces and maintains an inefficient immune response that is not exhausted. LDV infection in mice reveals a special type of host-virus equilibrium where LDV quickly establishes persistence despite continuously induced LDV-specific helper and cytotoxic T cell responses, which apparently are too slow to control the highly cytopathic and extremely fast replicating virus.
Human monocytic cells contain high levels of intracellular Fas ligand: rapid release following cellular activation.
Authors: Kiener P A , Davis P M , Rankin B M , Klebanoff S J , Ledbetter J A , Starling G C , Liles W C 
Published: January 2023

Abstract
Human monocytes express both Fas and Fas ligand (FasL) on the cell surface, and the interaction of these molecules induces spontaneous apoptosis. In this report we present a study of monocytic cells by FACS and confocal microscopy using anti-FasL Abs that reveals high levels of preformed FasL within the intracellular compartment. Further analysis by immunoblotting of cell cytoplasmic proteins confirmed the presence of a 37-kDa protein recognized by anti-FasL Abs. Stimulation of the monocytic cells with immune complexes, PHA, or superantigen gave rise to the rapid release of soluble FasL from within the cells. The presence of high levels of FasL within human monocytes suggests that, upon stimulation, the cells can rapidly translocate intracellular FasL to the cell surface and release it into the extracellular milieu. These findings indicate a novel mechanism for monocytes to respond rapidly to environmental changes, resulting in the release of active, soluble FasL.
IL-12 production by central nervous system microglia is inhibited by astrocytes.
Authors: Aloisi F , Penna G , Cerase J , Menéndez Iglesias B , Adorini L 
Published: January 2023

Abstract
IL-12, a 75-kDa heterodimeric cytokine composed of two chains (p35 and p40), is a central regulator of immune responses and may be implicated in the pathogenesis of certain inflammatory diseases of the central nervous system (CNS). We have examined the capacity of two CNS APC, microglia and astrocytes, to produce IL-12 upon stimulation with cytokines, LPS, or a neurotropic virus. In purified microglial cultures from neonatal mouse brains, expression of IL-12 p35 and p40 mRNA is induced by LPS and is stimulated maximally by combined IFN-gamma/LPS treatment, as detected by semiquantitative reverse-transcriptase PCR. LPS induces secretion of IL-12 p40, but not of IL-12 p75, as detected by specific ELISA. Combined stimulation with IFN-gamma/LPS enhances IL-12 p40 secretion and induces IL-12 p75 secretion by microglia. Conversely, mouse astrocytes do not express IL-12 p35 mRNA and do not secrete IL-12 p75 under any condition tested. IL-12 production by activated microglia is inhibited by IL-10, PGE2, and cAMP-elevating agents. Coculture of microglia with astrocytes or exposure of microglia to astrocyte-conditioned medium also results in marked reduction of IL-12 p75 and p40 secretion by IFN-gamma/LPS-stimulated microglia, indicating a regulatory role of astrocytes on IL-12 production. This novel mechanism of IL-12 regulation may play an important role in the control of immune responses during infection or in Th1 cell-mediated autoimmune diseases of the CNS.
Cot kinase regulation of IL-2 production in Jurkat T cells.
Authors: Ballester A , Tobeña R , Lisbona C , Calvo V , Alemany S 
Published: January 2023

Abstract
tpl-2 is a rat gene that encodes a serine/threonine protein kinase that can act as a novel mitogen-activated protein (MAP) kinase kinase kinase. Tpl-2 is activated in Moloney murine leukemia virus-induced rat T lymphomas, due to a truncation in the C-terminal region of the protein. cot is a very closely related gene, if not the human homologue. The truncated form of Cot has been shown to have a higher transforming activity than the nontruncated form. In this paper we show that an increase in truncated Cot kinase expression correlates with an increase in IL-2 production in anti-CD3-treated Jurkat cells. Truncated Cot expression also cooperates with PHA or phorbol 12,13-dibutyrate (PDBu) and calcium ionophore for IL-2 production in Jurkat cells. Both the truncated and nontruncated Cot forms increased IL-2 transcription because they enhanced transcription of a reporter gene linked to the IL-2 promoter. The expression of a dominant negative form of Cot inhibits transcription directed by the IL-2 promoter in Jurkat cells stimulated by PDBu and ionophore. These data suggest a role of Tpl-2/Cot kinase in IL-2 production during T lymphocyte activation and could also explain its role in Moloney murine leukemia virus-induced lymphomagenesis.
Modulation of lymphocyte interaction with endothelium and homing by HIV-1 gp120.
Authors: Bragardo M , Buonfiglio D , Feito M J , Bonissoni S , Redoglia V , Rojo J M , Ballester S , Portoles P , Garbarino G , Malavasi F , Dianzani U 
Published: January 2023

Abstract
We have previously shown that HIV-1 glycoprotein 120 (gp120) induces CD4 association with several molecules on the surface of CD4+ lymphocytes. Since one of these molecules was CD38, involved in lymphocyte/endothelium interaction, this article examines the possibility that gp120/CD4 binding alters CD4+ T cell interaction with vascular endothelium in vitro and in vivo. Cocapping experiments showed that gp120 induced CD4 association with CD38, CD29, CD49d, and CD11a in peripheral blood CD4+ T cells. Two in vitro binding assays were used to evaluate the effect of gp120. A static binding assay, performed at 37 degrees C, evaluated stable interactions mediated by integrins, and a dynamic binding assay, performed at 4 degrees C on a rocking shelf, evaluated weak interactions mediated by constitutively active molecules such as selectins and CD38. Gp120 increased dynamic binding and inhibited static binding to the endothelium of peripheral blood CD4+ T cells and SUPT-1 cells. Binding inhibition with mAbs suggested that the gp120 effect on dynamic binding involved CD38, CD31, and CD49d, whereas the effect on static binding involved CD11a and CD49d. In vivo experiments showed that treatment of 2D4 cells, a CD4- CD8- mouse T cell clone transfected with the human CD4, with gp120 increased their homing into the spleen, intestine, and mesenteric lymph nodes, whereas it decreased homing into peripheral lymph nodes. Alteration of lymphocyte homing may contribute to immune deficiency in HIV-1+ patients by decreasing the probability of an encounter between Ags and lymphocytes and inhibiting the spread of effector lymphocytes into tissues.
Introduction of soluble proteins into the MHC class I pathway by conjugation to an HIV tat peptide.
Authors: Kim D T , Mitchell D J , Brockstedt D G , Fong L , Nolan G P , Fathman C G , Engleman E G , Rothbard J B 
Published: January 2023

Abstract
Protection against most intracellular pathogens requires T cells that recognize pathogen-derived peptides in association with MHC class I molecules on the surface of infected cells. However, because exogenous proteins do not ordinarily enter the cytosol and access the MHC class I-processing pathway, protein-based vaccines that induce class I-restricted CTL responses have proved difficult to design. We have addressed this problem by conjugating proteins, such as OVA, to a short cationic peptide derived from HIV-1 tat (residues 49-57). When APC were exposed in vitro to such protein conjugates, they processed and presented the peptides in association with MHC class I molecules and stimulated CD8+ Ag-specific T cells. Moreover, Ag-specific CTLs were generated in vivo by immunizing mice with histocompatible dendritic cells that had been exposed to protein-tat conjugates.
A solution to the rheumatoid factor paradox: pathologic rheumatoid factors can be tolerized by competition with natural rheumatoid factors.
Authors: Stewart J J , Agosto H , Litwin S , Welsh J D , Shlomchik M , Weigert M , Seiden P E 
Published: January 2023

Abstract
Rheumatoid factors (RF) associated with arthritic joint erosion are only seen transiently, if at all, in nondiseased individuals. Therefore, a tolerance mechanism must exist that prevents pathologic RF B cells from expressing Abs. Surprisingly, it has been shown that pathologic RF B cells are not tolerized by any previously established tolerance mechanism such as deletion, receptor editing, anergy, or prevention of memory establishment. How are pathologic RF cells tolerized? By simulating the RF response with a cellular automaton model immune system, we demonstrate that pathologic RFs can be tolerized by the novel mechanism of "competitive tolerance" with natural, nonpathologic RFs. We then demonstrate that competitive tolerance can be broken when a sequestered pool of expanding B cells are inappropriately subjected to chronic stimulation (as appears to occur in MRL/lpr mice and in patients with rheumatoid arthritis).
The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction.
Authors: Sudo N , Sawamura S , Tanaka K , Aiba Y , Kubo C , Koga Y 
Published: January 2023

Abstract
The role of intestinal bacterial flora in oral tolerance induction to the IgE response was investigated using germfree (GF) mice. When GF mice were orally administered 20 mg of OVA as tolerogen before a systemic challenge with OVA, the Th1-mediated responses, such as the production of IgG2a and IFN-gamma, were abrogated, while the Th2-mediated immune responses, such as the production of IgE, IgG1, and IL-4, were maintained. Moreover, the basal level of IL-4 production in vitro was significantly higher in the GF mice than that of IL-4 in specific pathogen-free mice when challenged systemically with OVA. On the other hand, both Th1 and Th2 responses were fully sensitive to such tolerance induction in specific pathogen-free mice. The reconstitution of intestinal flora of GF mice with Bifidobacterium infantis, one of the predominant bacteria in the intestinal flora, restored the susceptibility of these Th2 responses to oral tolerance induction; however, this was only effective when such reconstitution was performed in neonates, but not in mice at an older age. These results thus suggested that intestinal bacterial flora play a crucial role in generating a Th2 cell population whose size and response are adequately regulated and, consequently, fully susceptible to oral tolerance induction, probably by affecting the development of gut-associated lymphoid tissue at the neonatal stage.
T cell receptor engagement induces tyrosine phosphorylation of FAK and Pyk2 and their association with Lck.
Authors: Berg N N , Ostergaard H L 
Published: January 2023

Abstract
Stimulation through the TCR is known to induce tyrosine phosphorylation of a number of proteins, which leads to functional activation of T cells. Identification of the substrates that become phosphorylated and defining their interactions with other signaling molecules will provide insight into the mechanisms controlling T cell activation. Focal adhesion kinase (FAK) and the recently described Pyk2 kinase are homologous members of a non-receptor protein tyrosine kinase family. FAK has been shown to become phosphorylated upon TCR stimulation, but its role, if any, in T cell activation remains to be defined. Although Pyk2 has been shown to play a role in neuronal cell activation stimulated through G-protein-coupled receptors, a role in T cell activation has not been described. In this study we show that FAK and Pyk2 are two of the major 115-to-120-kDa proteins that become tyrosine phosphorylated in T cells following TCR complex stimulation. Furthermore, coincident with the increase in tyrosine phosphorylation, we show an association of these kinases with the SH2 domain of the tyrosine kinase Lck in vivo. The increase in tyrosine phosphorylation of both FAK and Pyk2, however, occurs in Lck-deficient cells suggesting that phosphorylation of both of these kinases does not require Lck. Taken together, these results suggest that FAK and Pyk2, perhaps in coordination with Lck, play a role in T cell activation.
TCR expression in human fetal intestine and identification of an early T cell receptor beta-chain transcript.
Authors: Koningsberger J C , Chott A , Logtenberg T , Wiegman L J , Blumberg R S , van Berge Henegouwen G P , Balk S P 
Published: January 2023

Abstract
TCR expression by human fetal intestinal intraepithelial lymphocytes (ilELs) and intestinal lamina propria lymphocytes was analyzed to address whether T cell development occurs in human fetal intestine, the diversity of human fetal iIELs, and whether human fetal iIELs may contribute to the adult iIEL repertoire. ilELs and intestinal lamina propria lymphocytes from second trimester human fetal intestine were analyzed for TCR-alphabeta transcripts. Rearranged TCR-alpha transcripts were undetectable at 14 wk in the intraepithelial lymphocytes (IELs), whereas multiple TCR-beta transcripts were found at this stage. The TCR-alpha repertoire remained restricted relative to TCR-beta at later stages, and the IEL repertoire was restricted relative to the lamina propria lymphocytes at all stages. A previously reported T early alpha message was the major transcript from the TCR-alpha locus early in gestation. A previously undescribed TCR-beta transcript initiating upstream of the Dbeta1 locus and spliced to Cbeta1 or Cbeta2 was also identified and may represent a T early beta message. These results provide evidence for ongoing TCR gene rearrangement in human fetal intestine and suggest that transcription from the TCR-beta locus initiates with a T early beta transcript. The TCR-alpha repertoire (and hence the repertoire of potentially functional IELs) was limited through the second trimester.
B cell responses to a peptide epitope: IV. Subtle sequence changes in flanking residues modulate immunogenicity.
Authors: Vijayakrishnan L , Sarkar S , Roy R P , Rao K V 
Published: January 2023

Abstract
We examined modulation of primary humoral responses to a model synthetic peptide immunogen, peptide PS1CT3, as a consequence of single amino acid substitutions. Two analogues were employed, one in which the amino-terminal histidine (His1, peptide G28CT3) and another in which an internal proline (Pro14, peptide G41CT3) were replaced with glycine residues. Peptide G28CT3 displayed markedly enhanced immunogenicity relative to peptide PS1CT3 in BALB/c mice, whereas peptide G41CT3 was only poorly immunogenic. Nevertheless, in all three cases the mature polyclonal IgG response was predominantly directed against a tetrapeptide segment of sequence Asp-Pro-Ala-Phe between positions 4 and 7 of the sequence. While all three peptides proved equally capable of priming Ag-specific Th cells, they, however, displayed significant differences in their abilities to recall T cell responses. Regardless of the priming immunogen, in vitro challenge with either PS1CT3 or its analogues consistently gave a hierarchy of potencies as G28CT3 &gt; PS1CT3 &gt; G41CT3. This could also be correlated with B cell recall responses in which an identical hierarchy was obtained on restimulation of G41CT3-primed B cells in adoptive transfer experiments. Subsequent studies revealed that peptide-mediated modulation of Th cell recruitment by Ag-primed B cells was probably due to differences in on-rates for engagement of B cell Ag receptor by these analogues. This was despite the fact that all three peptides displayed equally randomized conformations in solution. These studies indicate that even subtle variations in the flanking sequences can markedly influence the immunogenicity of B cell epitopes.