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Results for “Adaptive Immunity”

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PubMed2006

New insights to the immunopathology and autoimmune responses in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease with profound changes in different compartments of the immune system, including those involved in innate, and adaptive immunity. New data from epidemiological studies of PBC have reinforced the thesis that the cause for this relatively uncommon disease is likely to be a combination of both environmental factors and a susceptible genetic predisposition. Recent findings of abnormalities of the innate immune system in PBC suggest that they may serve as links between the environmental factors and the early events in PBC development. Viral and bacterial infections as well as xenobiotics are some of the potential environmental factors that have been implicated in this complex process. Identification of the etiological factors for PBC will point to new preventive or therapeutic treatments.

Adaptation, Biological↗

PubMed2006

The evolution of immune mechanisms.

From early on in evolution, organisms have had to protect themselves from pathogens. Mechanisms for discriminating "self" from "non-self" evolved to accomplish this task, launching a long history of host-pathogen co-evolution. Evolution of mechanisms of immune defense has resulted in a variety of strategies. Even unicellular organisms have rich arsenals of mechanisms for protection, such as restriction endonucleases, antimicrobial peptides, and RNA interference. In multicellular organisms, specialized immune cells have evolved, capable of recognition, phagocytosis, and killing of foreign cells as well as removing their own cells changed by damage, senescence, infection, or cancer. Additional humoral factors, such as the complement cascade, have developed that co-operate with cellular immunity in fighting infection and maintaining homeostasis. Defensive mechanisms based on germline-encoded receptors constitute a system known as innate immunity. In jaw vertebrates, this system is supplemented with a second system, adaptive immunity, which in contrast to innate immunity is based on diversification of immune receptors and on immunological memory in each individual.Usually, each newly evolved defense mechanism did not replace the previous one, but supplemented it, resulting in a layered structure of the immune system. The immune system is not one system but rather a sophisticated network of various defensive mechanisms operating on different levels, ranging from mechanisms common for every cell in the body to specialized immune cells and responses at the level of the whole organism. Adaptive changes in pathogens have shaped the evolution of the immune system at all levels.

Adaptation, Biological↗

PubMed2026

Building CRISPR immunity: evolution and mechanisms of spacer acquisition.

CRISPR-Cas systems in prokaryotes serve as adaptive immune systems that neutralize phage infections through RNA-guided nucleases. Immunization is achieved during the adaptation stage through Cas1-Cas2 integrase-mediated insertion of short foreign DNA snippets, termed spacers, into a CRISPR array in the host genome. This review examines the evolutionary origins of Cas1-Cas2 and the mechanisms of spacer acquisition in DNA-targeting CRISPR-Cas systems. Particular emphasis is placed on the recently characterized effector-assisted adaptation pathways, in which CRISPR effector proteins, such as Cascade and Cas9, typically involved in target interference, are repurposed for prespacer capture and integration into a CRISPR array.

CRISPR–Cas spacer acquisition↗

PubMed2006

Toll-like receptor recognition of Toxoplasma gondii.

Toxoplasma gondii potently stimulates IFN-gamma production by both the innate and adaptive immune system as part of its host adaptation. This response is known to be dependent on an Myeloid Differentiation factor 88 signaling pathway used by Toll-like receptors (TLRs), a family of proteins involved in the recognition of microbial molecular patterns. In the following review, we summarise the evidence for specific TLR function in host resistance to T. gondii focusing on the recent discovery in the parasite of a profilin-like ligand that potently stimulates TLR11 and regulates the production of IL-12, a cytokine necessary for the protective IFN-gamma response. In addition, we discuss the hypothesis that TLR11 may have evolved as a general pattern recognition receptor for apicomplexan protozoa and that as highly conserved proteins associated with actin-based motility, profilins are logical ligand targets for this form of pathogen detection. Finally, we review the evidence for involvement of other TLR and TLR ligands in host resistance to T. gondii and discuss how such receptors might synergise with TLR11 in the innate response to the parasite.

Animals↗

PubMedDate not supplied

Viruses as adjuvants for autoimmunity: evidence from Coxsackievirus-induced myocarditis.

Adjuvants historically are considered to stimulate immune responses 'non-specifically'. Recently, a renewed understanding of the critical role of innate immunity in influencing the development of an adaptive immune response has led researchers to a better understanding of 'the adjuvant effect'. Although innate immune cells do not respond to specific antigenic epitopes on pathogens, they do produce restricted responses to particular classes of pathogens via pattern recognition receptors such as Toll-like receptors (TLR). Coxsackievirus infection was found to upregulate TLR4 on mast cells and macrophages immediately following infection. Although both susceptible and resistant mice produce a mixture of Th1 and Th2 cytokines, susceptible mice have increased levels of key proinflammatory cytokines, increased numbers of mast cells, and go on to develop chronic autoimmune heart disease. TLR4 signalling also increases acute myocarditis and proinflammatory cytokines in the heart. Many similarities are described in the pathogenesis of Coxsackievirus and the adjuvant-induced model of myocarditis including upregulation of particular TLRs and cytokines soon after inoculation. Recent findings suggest that mast cell activation by viruses or adjuvants may be important in initiating autoimmune disease.

Adjuvants, Immunologic↗

PubMed2002

Dendritic cells are decreased in blood and accumulated in granuloma in tuberculosis.

Immunity against tuberculosis consists of innate and adaptive immune responses. In this study, we investigated the dynamics of dendritic cells (DC), which are known to elicit a variety of immune responses, in patients with tuberculosis. CD11c(+) peripheral blood DC were decreased in patients with tuberculosis. Immunohistochemical analyses demonstrated that a number of fascin(+), CD11c(+), HLA-DR(+) DC were infiltrating the lymphocyte areas of the tuberculous granulomas (tubercles). Immunohistochemical analyses also demonstrated that interferon-gamma-producing Th1 cells were increased in the tubercles of the patients, indicating the presence of Th1 polarization at least in the context of inflammatory tissues. In vitro coculture of autologous naive T cells with CD11c(+) or CD11c(-) DC pretreated with Bacillus Calmette Guérin augmented the production of Th1 cells. These findings suggested that the trafficking of DC from the peripheral blood into the tubercles causes a dominant Th1 balance and thus plays an essential role in the immunity against tuberculosis.

CD11c Antigen↗

PubMed2005

Role of immature myeloid cells in mechanisms of immune evasion in cancer.

Tumor affects myelopoiesis by inhibiting the process of differentiation/maturation of antigen-presenting cells from their myeloid precursors and by stimulating an accumulation of immature myeloid cells in cancer patients and tumor-bearing mice. These immature myeloid cells can contribute greatly to tumor progression and promote tumor evasion from immune attack: i) by inhibiting development of adaptive immune responses against tumor in lymphoid organs; ii) by migrating into tumor site and differentiating there into highly immune suppressive tumor-associated macrophages. Immature myeloid cells and tumor-associated macrophages utilize different JAK/STAT signaling pathways and different mechanisms to control T cell responses, which include increased production of TGF-beta, reactive oxygen species, peroxynitrites, as well as enhanced L-arginine metabolism. Understanding of precise mechanisms, which tumors use to affect differentiation of APC from myeloid cell precursors and inhibit T cell responses, could help to develop new approaches for cancer therapy and substantially improve efficiency of existing cancer vaccination strategies.

Animals↗

PubMed2005

Expression of complement protein C5a in a murine mammary cancer model: tumor regression by interference with the cell cycle.

The C5a anaphylatoxin protein plays a central role in inflammation associated with complement activation. This protein is commonly regarded as one of the most potent inducers of the inflammatory response and a C5a peptide agonist was used as a molecular adjuvant. However, the full length C5a protein has not been tested as a potential tumor therapy. In this report, we describe the creation of a mini-gene construct that directs C5a expression to any cell of interest. Functional expression could be demonstrated in the murine mammary sarcoma, EMT6. When C5a expressing cells were injected into syngeneic mice, most C5a-expressing clones had significantly reduced tumor growth. Further characterization of a clone expressing low levels of C5a demonstrated that one-third of mice injected with this line had complete tumor regression. The mice whose tumors regressed were immune to subsequent challenge with unmodified EMT6 cells, suggesting that a component of the innate immune response can be used to augment adaptive immunity. Cellular analyses demonstrated that a significant difference in actual tumor cell number could be detected as early as day 10. A block in cell cycle progression was evident at all time points and high levels of apoptosis were observed early in the regression event. These data demonstrate that the complement protein C5a can play a significant protective role in tumor immunity.

Amino Acid Sequence↗

PubMed2002

The role of cytokines in immunity and immunopathogenesis of pirolasmoses.

Cells involved in innate and adapted immunity produce cytokines capable of orchestrating the immune response to Babesia and Theileria infections. Thus, CD4-postive T cells recognise peptide fragments of the parasites in the context of the major histocompatibility complex (MHC) class II antigen and produce gamma interferon (IFN-gamma) to activate macrophages for enhanced phagocytosis and intracellular killing of the parasites. In addition, CD4-positive T cells produce interleukin 2 (IL-2) which is essential for the clonal expansion of CD8-positive T cells. The latter cells kill Theileria-infected host leucocytes in an MHC class I-dependent manner. On the other hand, the overproduction of proinflammatory cytokines contributes to disease progress.

Animals↗

PubMed2004

Vaginal Immunity in Bacterial Vaginosis.

Vaginal immunity in response to microbial perturbation is still poorly understood and may be crucial for protection from adverse outcomes associated with bacterial vaginosis (BV). BV is the most prevalent vaginal disorder in adult women worldwide. However, its pathogenesis is still elusive. In BV-positive women, inflammatory signs are scant--approximately 50% of women are asymptomatic. The number of vaginal neutrophils in the BV-positive patient is not increased with respect to healthy women. In contrast, vaginal interleukin (IL)-1beta levels are largely increased. Recent findings indicate that microbial hydrolytic enzymes could be responsible for dampening the expected proinflammatory response cascade after IL-1beta increase. In other words, BV causes a large increase of vaginal IL-1beta, which is not paralleled by an increase of IL-8 levels, suggesting that BV-associated factors specifically dampen IL-8. The impairment of IL-8 increase may explain the absence of neutrophil increase in most women exposed to a massive abnormal anaerobic vaginal colonization (BV). Among BV-positive women, vaginal innate immunity is strongly correlated to a specific adaptive immune response: the immunoglobulin A (IgA) against the hemolysin produced by Gardnerella vaginalis (anti-Gvh IgA), which is the main bacterium present in BV. High anti-Gvh IgA levels are protective for adverse pregnancy outcomes. However, an exaggerated inflammatory response, mainly attributed to genetic polymorphisms, is also implicated in BV-associated adverse outcomes.

Journal Article↗

PubMed2005

NK-DC interaction: on the usefulness of auto-aggression.

In recent years a number of studies have highlighted the novel concept that the actual role of natural killer (NK) cells is not only confined to the destruction of virus-infected cells or tumors. Indeed NK cells, by interacting with myeloid DCs during the early phases of inflammation, appear to play a crucial role in shaping both innate immune reactions (within inflamed peripheral tissues) and adaptive immune responses (in secondary lymphoid compartments). Interestingly, this novel function assigned to NK cells is essentially mediated through the aggression of normal immature myeloid DCs. Only DCs undergoing optimal maturation become refractory to NK cell killing and will obtain the permission to prime Th1 cells after migration to lymph nodes.

Animals↗

PubMed2005

FLT3 ligand administration after hematopoietic cell transplantation increases circulating dendritic cell precursors that can be activated by CpG oligodeoxynucleotides to enhance T-cell and natural killer cell function.

Dendritic cells (DCs) are key effectors in innate immunity and play critical roles in triggering adaptive immune responses. FLT3 ligand (FLT3-L) is essential for DC development from hematopoietic progenitors. In a phase I clinical trial, we demonstrated that immunotherapy with subcutaneous injection of FLT3-L is safe and well tolerated in cancer patients recovering from autologous hematopoietic cell transplantation (HCT). FLT3-L administration significantly increased the frequency and absolute number of blood DC precursors without affecting other mature cell lineages during the 6-week course of FLT3-L therapy. After 14 days of FLT3-L administration, the number of blood CD11c + DCs, plasmacytoid DCs (PDCs), and CD14 + monocytes increased by 5.3-, 2.9-, 3.8-fold, respectively, and was maintained at increased levels throughout FLT3-L therapy. FLT3-L-increased blood DCs in HCT patients were immature and had modest enhancing effects on in vitro T-cell proliferation to antigens and natural killer (NK) cell function. The addition of type B CpG oligodeoxynucleotides (ODNs) to peripheral blood mononuclear cells obtained from HCT patients receiving FLT3-L therapy induced rapid maturation of both CD11c + DCs and PDCs and enhanced T-cell proliferative responses. In addition, CpG ODN induced potent activation of NK cells from FLT3-L-treated patients with increased surface CD69 expression and augmented cytotoxicity. CpG ODN-induced activation of NK cells was primarily via an indirect mechanism through PDCs. These findings suggest that FLT3-L mobilization of DC precursors followed by a specific DC stimulus such as CpG ODN may provide a novel strategy to manipulate antitumor immunity in patients after HCT.

Adult↗

PubMed2006

Expression and function of Toll-like receptors in T lymphocytes.

Toll-like receptors (TLRs) are widely expressed in the innate immune system. They recognize conserved microbial ligands such as bacterial lipopolysaccharide, lipopeptides or viral and bacterial RNA and DNA. TLRs play an essential role in innate immune responses and in the initiation of adaptive immune responses. However, certain TLRs are also expressed in T lymphocytes, and the respective ligands can directly modulate T cell function. TLR2, TLR3, TLR5 and TLR9 act as co-stimulatory receptors to enhance proliferation and/or cytokine production of T-cell receptor-stimulated T lymphocytes. In addition, TLR2, TLR5 and TLR8 modulate the suppressive activity of naturally occurring CD25(+)CD4(+) regulatory T cells. The direct responsiveness of T lymphocytes to TLR ligands offers new perspectives for the immunotherapeutic manipulation of T cell responses.

Animals↗

PubMed2006

Advances in basic and clinical immunology.

This review comments on basic and clinical immunology articles that were published in 2005, with a focus on those that appeared in the Journal of Allergy and Clinical Immunology. In the area of basic immunology, mechanisms of the innate immune system and its interaction with the adaptive immune system were described, with special consideration to applications in biodefense strategies. T regulatory cells were further characterized in their role for the control of allergic, autoimmune, and neoplastic disorders. The function of the thymus Hassall's corpuscles was reported to be the generation of T regulatory cells. Flavonoid molecules obtained from medicinal herbs, including astilbin and epigallocatechin gallate, were discovered to have immunomodulatory properties. Advances in clinical immunology resulted from efforts to develop a newborn screening test for severe combined immunodeficiency and the elucidation of the crystal structure of the IL-2 receptor gamma chain. Mutations in the membrane receptor transmembrane activator and calcium modulator and cyclophilin ligand interactor were found in patients with common variable immunodeficiency. New therapeutic options are described, such as the use of infliximab for granulomas and GM-CSF for chronic ulcers in patients with common variable immunodeficiency. The importance of mucosal immunity in acute HIV infection is cited, as is the role of CD8+ T-cell activation in HIV disease progression in children.

Allergy and Immunology↗

PubMed2004

Rapid and inexpensive real-time PCR for genotyping functional polymorphisms within the Toll-like receptor -2, -4, and -9 genes.

The discovery of the human Toll-like receptors (TLRs) and the recognition of their pivotal role in sensing microbial pathogens during the last 5 years have resulted in a renewed appreciation of innate immunity. Due to their central role in both, triggering innate immunity as well as linking innate and adaptive immunity, genetic variations within the TLR genes, known to be associated with a variety of infectious diseases, are currently of great interest. Several single nucleotide polymorphisms (SNPs) within TLR genes have been described and seem to be associated with susceptibility to inflammatory diseases. However, methods for genotyping SNPs within the TLR genes, e.g. direct sequencing or polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) analysis, are time-consuming. In this work, we report novel real-time PCR methods for genotyping five TLR SNPs within TLR-2, TLR-4 and TLR-9 that have been associated with various diseases using fluorescence labeled hybridization probes and the LightCycler instrument. In addition, we provide protocols employing a standard Taq polymerase in order to reduce substantially the costs for real-time PCR.

DNA Primers↗

PubMed2006

Immune control by endocannabinoids - new mechanisms of neuroprotection?

The endocannabinoid system consists of cannabinoid receptors, their endogenous ligands and enzymes for synthesis and degradation of endocannabinoids and represents a local messenger system within and between the nervous and immune system. Apparently, the endocannabinoid system is involved in immune control and neuoprotection. In this review, we discuss possible mechanisms of immune control by endocannabinoids, which include the modulation of innate immunity, effects on cytokin networks, downregulation of adaptive immune response and apoptosis in immune cells.

Animals↗

PubMed2005

The role of atrial natriuretic peptide in the immune system.

Atrial natriuretic peptide (ANP) is a hormone predominately produced by the heart atria which regulates the water and salt balance as well as blood pressure homeostasis. Being expressed in various parts of the immune system a link of the peptide to the immune system has been proposed. In fact, this review focus on effects of ANP in the immune system and reports about the role of the peptide in innate immune functions as well as in the adaptive immune response.

Animals↗

PubMed2002

Three-step purification of gp96 from human liver tumor tissues suitable for isolation of gp96-bound peptides.

Glycoprotein 96 (gp96), a member of heat shock protein (HSP) family, plays important roles in both innate immunity by itself and in T cell adaptive immunity in complex with antigenic-specific peptides. Using ammonium sulfate precipitation, ConA-Sepharose affinity chromatography and anion exchange chromatography, we have successfully purified gp96 from human liver tumor tissues. Subsequently, the gp96-associated peptides were successfully isolated from the gp96 preparation in quantities sufficient for micro-sequencing and identification of the peptides [Lancet 357 (2001) 528]. This three-step purification method might be used as a universal technique for the easy and reproducible isolation of antigenic heat shock protein gp96 from liver tissue or even other tissues of different sources. This will inevitably trigger the search for antigenic-specific peptides bound to gp96. Here, we report the method in detail.

Ammonium Sulfate↗