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PubMed1992

Coevolution of hosts and microorganisms: an analysis of the involvement of cytokines in host-parasite interactions.

Parasites may employ particular strategies of eluding an immune response by taking advantage of those mechanisms that normally guarantee immunological self-tolerance. Much in the way as it occurs during the establishment of self-tolerance, live pathogens may induce clonal deletion, functional inactivation (anergy) and immunosuppression. At this latter level, it appears that certain pathogens produce immunosuppressive cytokine-like mediators or provoke the host to secrete cytokines that will compromise the anti-parasite immune response. It appears that immune responses that preferentially involve T helper 1 cells (secretors of interleukin-2-and interferon-gamma) tend to be protective, whereas T helper 2 cells (secretors of IL-4, IL-5, IL-6, and IL-10), a population that antagonizes T helper cells, mediate disease susceptibility and are involved in immunopathological reactions. Cytokines produced by T helper 2 cells mediate many symptoms of infection, including eosinophilia, mastocytosis, hyperimmunoglobulinemia, and elevated IgE levels. Administration of IL-2 and IFN-gamma has beneficial effects in many infections mediated by viruses, bacteria, and protozoa. The use of live vaccinia virus might be an avenue for the treatment of or the vaccination against infection. We have found that a vaccinia virus expressing the gene for human IL-2, though attenuated, precipitates autoimmune disease in immunodeficient, athymic mice. Thus, although T helper 1 cytokines may have desired immunostimulatory properties, they also may lead to unwarranted autoaggressive responses.

Animals↗
PubMed1992

V-region-related and -unrelated immunosuppression accompanying infections.

This paper discusses current evidence for the relationship between polyclonal lymphocyte activation, specific immunosuppression with decreased resistance, and autoimmune pathology, that are all often found associated with infections by a variety of virus, bacteria and parasites. The central question of class determination of immune effector activities is considered in the context of the cellular targets for nonspecific mitogenic activities associated with infection. A model is presented to integrate these findings: mitogens produced by the microorganism or the infected cells are preferentially active on CD5 B cells; the resulting over-production of IL-10 will tend to bias all immune activities into a Th2-mode of effector functions, with high titers of polyclonal antibodies and little or no production of gamma IFN and other "inflammatory" lymphokines that often mediate resistance. In turn, these conditions allow for parasite persistence and the corresponding long-term disregulation of self-directed immune reactivities, resulting in autoimmunity in the chronic phase. This model would predict that selective immunization with the mitogenic principles involved in deregulation, could stand better chances than strategies of vaccination based on immunopotentiation against other, functionally neutral antigenic epitopes. It is argued, however, that the complexity of immune responses and their regulation, together with our ignorance on the genetic controls of class-determination, offer poor prospects for a scientifically-based, rational development of vaccines in the near future. It is suggested that empirically-based and technologically developed vaccines might succeed, while basic scientific approaches are reinforced and given the time to provide a better understanding of those processes.

Animals↗
PubMed2022

Human Macrophages Exhibit GM-CSF Dependent Restriction of Mycobacterium tuberculosis Infection via Regulating Their Self-Survival, Differentiation and Metabolism.

GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of M. tuberculosis infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed between secreted levels of GM-CSF, survial of macrophages and intra-macrophage control of Mycobacterium tuberculosis bacilli. GM-CSF levels secreted by macrophages negatively correlated with the intra-macrophage M. tuberculosis burden, survival of infected host macrophages positively correlated with their GM-CSF levels. GM-CSF-dependent prolonged survival of human macrophages also correlated with significantly decreased bacterial burden and increased expression of self-renewal/cell-survival associated genes such as BCL-2 and HSP27. Antibody-mediated depletion of GM-CSF in macrophages resulted in induction of significantly elevated levels of apoptotic/necrotic cell death and a simultaneous decrease in autophagic flux. Additionally, protective macrophages against M. tuberculosis that produced more GM-CSF, induced a stronger granulomatous response and produced significantly increased levels of IL-1β, IL-12 and IL-10 and decreased levels of TNF-α and IL-6. In parallel, macrophages isolated from the peripheral blood of active TB patients exhibited reduced capacity to control the intracellular growth of M. tuberculosis and produced significantly lower levels of GM-CSF. Remarkably, as compared to healthy controls, macrophages of active TB patients exhibited significantly altered metabolic state correlating with their GM-CSF secretion levels. Altogether, these results suggest that relative levels of GM-CSF produced by human macrophages plays a critical role in preventing cell death and maintaining a protective differentiation and metabolic state of the host cell against M. tuberculosis infection.

Cell Differentiation↗
PubMed2026

Suggestive genome-wide associations with inflammatory biomarkers in an admixed population, including a missense variant in the OR6K6 olfactory receptor gene associated with MCP-1.

BACKGROUND: Chronic low-grade inflammation drives cardiometabolic diseases and has a strong genetic basis. Most genome-wide association studies (GWAS) have focused on European populations, limiting knowledge of the genetic influences on inflammation in admixed populations such as those in Brazil. METHODS: This study is part of the cross-sectional ISA Capital Health Survey. It uses data from the 2015 ISA Nutrition cohort, which measured biochemical, genetic, anthropometric, and lifestyle factors in a probabilistic sample of São Paulo residents. Genomic DNA was extracted from 841 individuals. Genotyping was performed using the Axiom 2.0 Precision Medicine Research Array. After quality control and missing data exclusion, 244,338 SNPs from 638 individuals remained for GWAS-based association analysis with eight inflammatory biomarkers. Models were adjusted for sex, age, age2, overweight, and the first two principal components of ancestry. RESULTS: Most participants were male (53%) and not overweight (55%). The median age was 49, and 38% were older adults. In the genome-wide analysis of TNF-α, IL-10, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and adiponectin, 12 SNPs were significantly associated, most of which were intronic. Notably, one signal mapped to the missense variant rs16841009 in the olfactory receptor gene OR6K6. This variant was associated with MCP-1, suggesting a possible involvement in inflammatory responses. CONCLUSIONS: We identified new SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population, including a missense variant in an olfactory receptor gene linked to MCP-1. This association may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.

Humans↗
PubMed2026

Protein Profiling Identifies Biomarkers for Predicting Disease Severity in Anti-NMDAR Encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neurological disorder characterized by pathogenic antibodies against the NMDAR. A systematic protein profiling approach is warranted to identify biomarkers capable of predicting disease status. An Olink proximity extension assay (PEA) profiled 91 inflammation-related proteins from anti-NMDAR encephalitis patients. Disease severity or prognosis were assessed by CASE score or mRS score at 6-month follow-up. Patients were stratified into distinct molecular clusters using unsupervised clustering. Logistic regression models incorporating selected biomarkers were developed to predict disease severity and prognosis, followed by absolute quantification using ELISA. Patients were classified into four consensus clusters. Clusters 1 and 2 corresponded to the mild group, while Cluster 3 represented the severe group, consistent with CASE score above 6. Cluster 4 showed heterogeneous clinical features. Elevated serum levels of IL-10, IL-6, and SIRT2, as well as increased CSF levels of CXCL10, CXCL11, and MMP10, were positively associated with severe disease. Conversely, several proteins including LTA and CCL11, CCL8, TGFB1, CXCL6 were associated with severe disease or unfavorable 6-month outcomes. A logistic regression model combining serum CXCL6 and CCL11 with CSF MMP10 achieved an area under the curve (AUC) of 0.95 for predicting disease severity. Serum CCL11 alone showed predictive value for 6-month prognosis, with an AUC of 0.79. These findings delineate distinct protein signatures associated with clinical heterogeneity of anti-NMDAR encephalitis. Prediction models incorporating multiple biomarkers may provide an approach for disease severity stratification and prognosis forecast.

Humans↗
PubMed2025

Intertypic Recombination Between Coxsackievirus A16 and Enterovirus A71 Structural and Non-Structural Genes Modulates Virulence and Protection Efficacy.

Background/Objectives: Enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) are major causative agents of hand, foot and mouth disease (HFMD), often co-circulating and occasionally undergoing genetic recombination. While natural recombinants often involve genomic regions encoding non-structural proteins, their effects on replication and pathogenesis remain unclear. Methods: To address this, four chimera viruses (Chi-CCE, Chi-ECE, Chi-EEC, and Chi-CEC) were constructed with 5'UTR, capsid P1, and non-structural P2 and P3 genes, from CVA16 (denoted as C) or EV-A71 (denoted as E). These chimeras were tested for replication kinetics and cytopathic effects in rhabdomyosarcoma cells while in vivo virulence and protection efficacy were evaluated using a newborn BALB/c mouse model. Results: All chimeric viruses remained viable and exhibited higher replication than CVA16. In vivo, all chimeric viruses were avirulent except Chi-CCE and CVA16, which showed high virulence and viral titres in the brains and limbs of infected newborn mice. This suggests that 5'UTR and capsid P1 genes of CVA16 are critical genetic determinants of virulence. Notably, only the anti-inflammatory cytokine IL-10 was elevated, suggesting potential immune modulation during infection. Inactivated Chi-CCE immunisation conferred 100% protection against lethal CVA16 or mouse-adapted EV-A71 challenge revealing its potential as a bivalent vaccine candidate. Conclusions: Our study demonstrates that recombination between CVA16 and EV-A71 influences viral virulence and protection efficacy with implications for future development of multivalent vaccines.

coxsackievirus A16↗
PubMed2026

Cytokines and Inflammatory Gene Polymorphisms Associated With Nosocomial Pulmonary Infection After Spontaneous Intracerebral Hemorrhage.

Nosocomial pulmonary infection is a frequent complication after spontaneous intracerebral hemorrhage and may worsen neurological recovery, prolong hospitalization, and increase clinical burden. This retrospective clinical-laboratory study presents a reproducible workflow for evaluating inflammatory biomarker and host immune-genetic profiles associated with nosocomial pulmonary infection after primary spontaneous intracerebral hemorrhage. Patients are classified according to whether nosocomial pulmonary infection occurs after admission. Peripheral venous blood is collected in the early post-admission period under standardized pre-analytical conditions. Serum is separated, aliquoted, and stored for enzyme-linked immunosorbent assay measurement of IL-1β, IL-6, IL-10, IL-17, IFN-γ, TNF-α, TLR2, TLR4, and TLR9. In parallel, genomic DNA is extracted from anticoagulated whole blood and used for polymerase chain reaction-restriction fragment length polymorphism genotyping of selected cytokine- and Toll-like receptor-related loci. The workflow also includes quality-control procedures for sample handling, duplicate ELISA measurements, DNA purity assessment, genotype calling, and repeat genotyping. Statistical analysis includes between-group comparison of clinical characteristics and biomarker levels, Hardy-Weinberg equilibrium testing, logistic regression analysis for genotype and allele associations, adjustment for relevant clinical covariates, and false-discovery-rate correction for multiple genetic comparisons. This combined clinical, inflammatory, and immune-genetic workflow may help characterize infection-risk profiles after spontaneous intracerebral hemorrhage, although prospective multicenter validation is still required before routine clinical application.

Humans↗
PubMed1992

Predominance of Th1 cells in ocular tissues during herpetic stromal keratitis.

Herpetic stromal keratitis (HSK) appears to represent an immunopathologic response in the cornea of the eye to HSV-1. T cells of the CD4+ subset were shown to be involved in the mediation of HSK, but how they subserve an immunopathologic role is uncertain. In the present report, we have isolated cells from eyes in the active phase of HSK and studied their cytokine profile after culture in vitro or stimulation with Ag or nonspecific mitogens. Inflammatory cells recovered from eyes consist of polymorphonuclear leukocytes, macrophages, and lymphocytes. As reported before, all the lymphocyte recovered were of the CD4+ phenotype. After stimulation in vitro with Ag or mitogen the cytokines IL-2, IFN-gamma, and TNF-alpha/beta were produced, but not the cytokines IL-4 and IL-10. Thus, on the basis of cytokine profile, ocular lymphocytes were identified as Th1 cells. Ocular cells were also stimulated with PMA and shown to produce IL-1. The results were discussed in terms of the possible means by which the Th1 cells induce tissue damage in HSK as well as in terms of the possible means by which a preferential accumulation of Th1 cell occurs in the eye.

Animals↗
PubMed1992

[Growth factors in hematology].

New experimental findings on the mutual regulation of growth, differentiation and function of human blood cells by growth factors offer the opportunity to use these factors in the treatment of haematological diseases. The hitherto known growth factors are divided into four basic groups: 1. haematopoietic growth factors proper [multi-CSF (IL-3), GM-CSF, G-CSF, M-CSF, erythropoietin, lymphopoietin (IL-7) and megakaryopoietin (IL-11)], 2. cytokines (IL-1 to IL-11, TFN)., 3. other growth factors (PDGF, FGF, MGF) and 4. so-called negative regulators of haematopoiesis (IFN, MIP, TGF beta and IL-10), some of which support the differentiation of stem cells. Before growth factors can be routinely used in clinical work, it is essential to acquire closer knowledge of their interrelations, the activity of their receptors and natural or acquired inhibitors in vivo.

Growth Substances↗
PubMed1992

Kinetic analysis of cytokine gene expression in the livers of naive and immune mice infected with Listeria monocytogenes. The immediate early phase in innate resistance and acquired immunity.

The anamnestic response to infection with Listeria monocytogenes is characterized by the rapid elimination of normally lethal doses of bacteria and accelerated granuloma formation. These phenomena are mediated by listeria-specific memory T cells within the first 24 h after reinfection. In order to elucidate the mechanisms operative during this decisive phase of infection, we conducted a comprehensive kinetic and quantitative analysis of cytokine gene expression in the livers of naive and immune mice. Organs were removed at 30 min, and 1, 2, 6, and 24 h after primary and secondary infections, and PCR3-assisted messenger RNA (mRNA) amplification was performed on matched samples using primers specific for IL-1 beta, IL-6, M-CSF, GM-CSF, TNF-alpha, IFN-gamma, IL-10, IL-4, IL-2, IL-3 and I1-2Rp55. The cytokine pattern characteristic of secondarily infected animals differed qualitatively by the expression of mRNA for IL-2, IL-2Rp55, IL-3, and IL-4, demonstrating the accumulation and activation of specific T cells in the livers as early as 1 to 2 h after reinfection. Combined in vivo depletion of both CD4+ and CD8+ T cells before reinfection almost completely abrogated the differentiated cytokine profile typical of the anamnestic response. Using competitive PCR for semiquantitative determination of mRNA levels, the amount of IL-1 beta and IL-6 mRNA was found to be very similar during primary and secondary infection, whereas TNF-alpha mRNA was found to be increased by approximately 10-fold 2 h and IFN-gamma mRNA by approximately 50 to 100-fold 6 h after reinfection when compared with a primary challenge. Combined in vivo depletion of both CD4+ and CD8+ T cells before reinfection resulted in a substantial (approximately 10-fold) decrease in IFN-gamma mRNA expression. To correlate these findings with cytokine secretion, spleen cells from naive and immune as well as normal and CD4+ and CD8+ cell depleted mice infected 6 h previously were cultured for 48 h, and supernatants were analyzed for the amount of the above mentioned cytokines. Semiquantitative PCR-assisted mRNA amplification is demonstrated to be a superior tool in dissociating the mediators of innate resistance from those operative in protective immunity and granuloma formation.

Animals↗
PubMed1992

Cytokine dysregulation and acute graft-versus-host disease.

We suggest that acute GVHD after marrow transplantation reflects (1) host injury due to the conditioning regimen followed by the production of inflammatory cytokines; (2) stimulation of mature donor T cells in the milieu of increased cell surface expression of leukocyte adhesion molecules and HLA molecules, followed by the autocrine production of IL-2; and, finally, (3) recruitment and activation of additional mononuclear effector cells from donor marrow progenitors, which produce additional inflammatory cytokines, thus sustaining the response. The second step is critical for the amplification of the systemic inflammatory response, and it is absence in autologous, syngeneic, and T-cell-depleted transplants. These T cells may also contribute to the inflammatory cytokine network. Acute GVHD can occur in the absence of primary tissue injury in such settings as transfusion-related GVHD; however, it is likely that a greater HLA disparity between donor and host is required. We propose that inflammatory cytokine production is the final common pathway of acute GVHD. If this model is correct, control of cytokine dysregulation at any of several points should control GVHD. Further studies of GVHD and investigations of cytokine antagonists (eg, IL-4 or IL-10) or combinations of antagonists such as IL-1ra and soluble TNF receptor or pentoxifylline will allow us to determine the validity of this hypothesis.

Animals↗
PubMed1992

Transcriptional regulation of the mucosal mast cell-specific protease gene, MMCP-2, by interleukin 10 and interleukin 3.

Although transcription of mast cell (MC) secretory granule neutral protease genes has been shown to distinguish MC subclasses in mucosal and serosal environments, the specific cytokines that regulate the expression of these genes have not been determined. To examine cytokine-mediated gene regulation, bone marrow-derived MC (BMMC) differentiated in vitro were obtained by culturing mouse bone marrow progenitor cells in the presence of WEHI-3 cell-conditioned medium, concanavalin A-stimulated splenocyte-conditioned medium (BMMCC), or recombinant (r) interleukin (IL)-3 (BMMCIL-3). All three populations of BMMC expressed the serosal MC-specific transcripts that encode mouse MC serine protease (MMCP)-5, MMCP-6, and MC carboxypeptidase A. However, only BMMCC contained MMCP-2 mRNA, a late expressed gene selectively transcribed by intestinal mucosal MC that proliferate during helminthic infestation in response to the T cell-derived cytokines IL-3, IL-4, and IL-10. When BMMCIL-3 were exposed to rIL-10 in the presence of either rIL-3 or rIL-4, they expressed MMCP-2 mRNA. Not only was the transcription of the MMCP-2 gene in BMMC dependent on continuous exposure of the cells to rIL-10, but the level of MMCP-2 mRNA in these cells could be down-regulated by rIL-3. These studies comparing the effects of two cytokines on the transcriptional regulation of secretory granule protease genes in MC demonstrate that rIL-10 induces BMMCIL-3 to express the mucosal MC protease MMCP-2, that rIL-3 attenuates the rIL-10-induced expression of this gene, and that transcription of the MMCP-2 gene is reversed in the absence of rIL-10.

Animals↗
PubMed1992

Expression of cytokine genes, cytokine receptor genes, and transcription factors in cultured Hodgkin and Reed-Sternberg cells.

In the present study, we show by Northern blot analysis and enzyme linked immunosorbent assay that the Hodgkin's disease (HD)-derived cell lines HDLM-2 and KM-H2 express a variety of cytokine genes either constitutively or upon induction with phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Cytokine genes expressed by HD-derived lines include granulocyte-macrophage colony-stimulating factor (CSF), macrophage-CSF, interleukin (IL)-1-alpha, IL-3, IL-5, IL-6, IL-8, leukemia inhibitory factor, tumor necrosis factor-alpha, tumor necrosis factor-beta, and transforming growth factor-beta, while transcripts and the corresponding proteins for granulocyte-CSF, IL-1-beta, IL-2, IL-4, IL-7, IL-10, and the JE/macrophage chemoattractant and activating factor gene were not detectable in cytoplasmic RNA and culture supernatants obtained from both lines. In addition, IL-2 receptor (R) p55 and macrophage-CSF R (c-fms) genes were expressed by both lines. HDLM-2, but not KM-H2 cells, exhibited the IL-6 R p80 and the IL-2 R p75 chain. Analysis of nuclear proteins that bind to oligonucleotides containing the consensus sequences of the transcription factors activation protein 1, nuclear factor (NF) kappa B, and NFAT 1 revealed a pattern for HD lines resembling that of activated T-cells: HDLM-2 and KM-H2 cells constitutively expressed NF binding to the NF of activated T-cells (type 1), previously described to be T-cell specific. In addition, NF kappa B-binding proteins obtained from both lines showed, in electrophoretic mobility shift assays, the same migration pattern as T-cell-derived proteins but differed from monocyte- and B-cell-derived proteins. UV cross-linking experiments confirmed that NF kappa B-binding proteins of M(r) 85,000, 75,000, and 50,000/55,000 were detectable in nuclear extracts obtained from T-cells and both HD lines, while monocytes and B-cells displayed the M(r) 50,000/55,000 and 75,000 NF kappa B complex only. Both HD lines also constitutively expressed transcripts for c-fos and c-jun, which are involved in heterodimeric formation of the transcription factor activation protein 1, as well as for the NF kappa B/KBF1 gene.

Antigens, CD↗
PubMedDate not supplied

[New perspectives on the pathogenesis of rhinitis].

The division of T cells into distinct subsets (Th-1 and Th-2), based upon cytokine production, is a major advance in understanding the immune reactivities particularly those associated with allergy. This report summarizes some of the highlights on pathogenesis of allergic rhinitis. Th-2 cells, driven by IL-4, play an important role in allergic reactions inducing IgE switching in B cells and proliferation of mastocytes. In addition, by interaction with IL-5, Th-2 lymphocytes promotes eosinophil growth. By contrast, Th-1 cells antagonize Th-2 activity by IFN-gamma production. Finally IL-10, produced by Th-2, blocks the effects of the cytokines elaborated by Th-1. Recent results of this rapidly expanding area of research provide the background for this review. The intricate connections between Th-1, Th-2, the endothelial cells of the nose vessels and stromal cells are discussed.

Allergens↗
PubMed1992

Coculture of human peripheral blood mononuclear cells with Trypanosoma cruzi leads to proliferation of lymphocytes and cytokine production.

Trypanosoma cruzi, which causes Chagas' disease, has been shown to cause polyclonal proliferation of lymphocytes after infection in vivo. This paper demonstrates that coculture of human PBMC with T. cruzi CL strain leads to proliferation of lymphocytes, which peaks on days 5 to 7 after infection. Approximately 15% of lymphocytes in culture undergo blast transformation. The proliferation of lymphoblasts can be measured by [3H]TdR incorporation, because the parasites incorporate little TdR. Parasites derived from autologous PBMC cultures or xenogeneic rat fibroblasts stimulate lymphocyte transformation similarly. By immunofluorescent cytometry, lymphoblasts from these cultures are 23 to 46% B cells (CD19+) and 39 to 64% T cells (CD3+), and approximately half of the T cells are CD4+ and half CD8+. A high percentage of lymphoblasts express MHC class II and IL-2R p55, suggesting both B and T lymphoblasts express these molecules. Anti-MHC class II and anti-IL-2R p55 mAb significantly inhibit the proliferative response of PBMC to T. cruzi. The mRNA for cytokines IL-1 beta, IL-2, IL-5, IL-6, IFN-gamma, and TNF-alpha are detected after T. cruzi coculture with PBMC, peaking on day 3. No IL-4 or IL-10 mRNA are detected. Large quantities of bioactive IL-1 and IL-6 are found in the supernatants of these PBMC. Monocytes, infected in the apparent absence of lymphocytes, assume activated morphology and accumulate mRNA for IL-1 beta, TNF-alpha, and IL-6. T cells require accessory cells to proliferate and produce cytokine mRNA. A trypsin-sensitive activity in lysates of T. cruzi stimulates lymphocyte proliferation. The data presented demonstrate that T. cruzi coculture with PBMC leads to lymphocyte proliferation, monocyte activation, and cytokine production.

Animals↗
PubMed1991

Collagen-induced arthritis in mice. Relationship of collagen-specific and total IgE synthesis to disease.

The relationship between production of IgE and collagen-induced arthritis in mice was examined. Collagen-specific IgE was produced as a consequence of immunization of DBA/1 mice with chicken type II collagen emulsified in CFA. We observed a rise in collagen-specific IgE antibody levels at the onset of CIA clinical and histologic signs in DBA/1 mice. This rise in IgE paralleled that of IgG2a anticollagen antibodies, an isotype implicated in the pathogenesis of CIA by other laboratories. The collagen-specific IgE contained in the plasma of mice with CIA could arm basophils for Ag- (collagen) dependent degranulation. Collagen-specific IgE may thus contribute to CIA by promoting mast cell degranulation in the synovia of susceptible mice immunized with chick type II collagen; but, further work is required to establish such a role for IgE in CIA. However, genetic differences in disease susceptibility could not be accounted for by quantitative differences in collagen-specific IgE production. Further, comparable levels of IgE anticollagen antibodies were observed in animals with active CIA and after spontaneous remission, thereby confirming that the presence of such antibodies is insufficient for disease. Total IgE levels peaked just before spontaneous remission indicating active production of IL-4. IL-4 was administered to animals with CIA to determine if this lymphokine could be involved in the remission process. IL-4 facilitated remission of CIA. Enhanced total IgE production may thus be a marker for activation of Th2 cells that produce lymphokines such as IL-4 and IL-10, factors that may be involved in the spontaneous remission process.

Animals↗
PubMed1995

IgE-independent interleukin-4 expression and induction of a late phase of leukotriene C4 formation in human blood basophils.

T-helper cells can differentiate into at least two subtypes secreting distinct profiles of cytokines, Th1 and Th2, regulating immunoprotection and different immunopathologies. Interleukin-4 (IL-4) is both the product and the inducer of Th2 cells, raising the question whether IL-4 can be produced in response to antigen-independent stimuli. Here we show that human basophils produce IL-4 on stimulation with IL-3 and C5a or C5adesarg in similar amounts as induced by IgE-receptor-cross-linking. C5a-induced IL-4 production requires the presence of IL-3, with little effect of the sequence of stimuli addition. No "Th1-cytokines" (interferon-gamma and IL-2) and even no "Th2-cytokines" (IL-3, IL-5, IL-10, and granulocyte-macrophage colony-stimulating factor) are produced by basophils in response to either IgE-dependent or IgE-independent activation. The generation of leukotriene C4 (LTC4) is regulated in a similar manner. However, C5a induces a rapid, transient burst of leukotriene formation only if added after IL-3. Interestingly, upon prolonged culture, a late phase of continuous LTC4 production is observed, which also requires two signals (IL-3 and C5a), but rather depends on their continuous presence than on their sequence of action. These data describe an antigen-independent pathway of very restricted IL-4 expression. Thus, basophils must be considered as central immunoregulatory cells of the innate immune system. Furthermore, the results show that LTC4 can also be generated more continuously for many hours, a phenomenon that may be of particular importance in chornic allergic inflammation, such as asthma.

Basophils↗
PubMed1995

Critical involvement of transmembrane tumor necrosis factor-alpha in endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin.

In this report, we show that ionizing radiation (IR) at a clinically relevant dose (4 Gy) causes apoptosis in macrovascular and microvascular human endothelial cells. Treatment of irradiated cells with a low dose of bacterial endotoxin (LPS), similar to the levels observed in serum during endotoxemia, enhanced the rate of apoptosis, although LPS alone was unable to induce programmed cell death. The cytokine and endotoxin antagonist interleukin-10 (IL-10) reduced the rate of LPS + IR-induced apoptosis to levels obtained with irradiation alone. Using neutralizing antibodies against tumor necrosis factor-alpha (TNF), we could show crucial involvement of TNF in the LPS-mediated enhancement of IR-induced apoptosis, but not in the IR-induced apoptosis per se. However, further analysis strongly suggested the transmembrane form of TNF (mTNF), but not soluble TNF, to be accountable for the LPS-mediated cytotoxic effects. Studies with anatagonistic receptor specific antibodies clearly showed that TNF receptor type I (TR60) is essential and sufficient to elicit this effect. These findings are of potential clinical importance because they may disclose a relevant mechanism that leads to endothelial damage after radiotherapy or total body irradiation used for conditioning in bone marrow transplantation and that may thus contribute to transplant related complications, especially in association with endotoxemia or related inflammatory states.

Animals↗