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Results for “Adaptive Immunity”

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At least 847 records · Page 47Linked to original sources

PubMed2005

The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice.

OBJECTIVE: Cells of adaptive immunity have been implicated in atherogenesis. Though substantial information is available on immune cells in atherosclerotic lesions of the lamina intima, cells in the lamina adventitia have received less attention. METHODS AND RESULTS: The composition of immune cells in the innominate artery and abdominal aorta was examined in young, adult, and old apolipoprotein (apo) E(-/-) and wild-type mice on standard mouse chow. In the innominate artery of apoE(-/-) mice, adventitial T cells increased at 32, 52, and 78 weeks exceeding those of the intima by 6-, 24-, and 85-fold. Single T cells dominated in young mice, later T/B cell clusters emerged, and lymphoid-like structures reminiscent of inflammatory follicles formed preferentially in the abdominal aorta of old mice. Follicles contained organized sets of immune response-regulating cells: Interdigitating dendritic cells, T cell effectors, proliferating B cells, and plasma cells. Adventitial T cell inflammation was associated with a marked increase in transcripts of the chemokine MIP-1alpha in the aorta but not in spleen or liver. CONCLUSIONS: Adventitial lymphocyte infiltration and formation of inflammatory follicle-like structures in the abdominal aorta of old apoE(-/-) mice point to the adventitia as a site of local adaptive immune reactions during atherogenesis in hyperlipidemic mice.

Age Factors↗

PubMed2006

TLR7/8 agonists impair monocyte-derived dendritic cell differentiation and maturation.

Pathogen recognition by TLR activates the innate immune response and is typically followed by the development of an adaptive immune response initiated by antigen presentation. Dendritic cells (DC) are the most efficient APC and express diverse TLRs, including TLR7 and -8, which have been recently identified as targets for ssRNA recognition during viral infection. We have studied the effect of TLR7/8 agonists on DC differentiation and maturation from human monocytes. The synthetic agonist Resiquimod (R-848) or the physiological agonist ssRNA impaired monocyte differentiation to DC phenotypically and functionally. Induced expression of the nonclassical MHC molecules of the CD1 family in DC was inhibited at the protein and mRNA levels, and antigen acquisition was inhibited. Proinflammatory cytokine (including IL-6, IL-8, TNF-alpha, IL-1beta) and IL-10 production were induced during DC differentiation. Cross-talk between TLR4 and TLR7/8 was revealed as immature DC, which had been differentiated in the presence of R-848 were insensitive to LPS-mediated maturation and cytokine production but still induced allostimulation. These data lead us to suggest that ongoing viral activation of TLR7/8 could alter the adaptive immune response by modifying DC differentiation and by down-regulating DC responsiveness to a subsequent bacterial TLR4-mediated signal.

Antigen Presentation↗

PubMedDate not supplied

Toll-like receptor signaling and IRF transcription factors.

Interferon regulatory factors (IRFs) were originally discovered in the context of type I interferon (IFN-alpha/beta) gene induction, and subsequent studies on these transcription factors have revealed their remarkable functional diversity in regulating immune systems. Indeed, the critical involvement of IRF members in innate and adaptive immune responses has recently gained much attention, particularly with the recent discovery of Toll-like receptors (TLRs) and analyses of their critical functions in linking the innate and adaptive immune responses.

Animals↗

PubMed2005

The innate immune system and HIV pathogenesis.

Innate immunity represents the first line of defense against microbial infections. The innate immune system is activated by conserved structures present on most pathogens and profoundly regulates subsequent adaptive immune responses. HIV is notorious for evading and disrupting the immune system. Although HIV directly targets and gradually destroys the adaptive immunity, it has become clear that the virus also perturbs the components of the innate immune system. In this paper, we review the role of two innate lymphocyte subsets, natural killer and natural killer T cells, that are disrupted during HIV infection.

Animals↗

PubMed2006

Roles of glycans and glycopeptides in immune system and immune-related diseases.

Almost all of the key molecules in organisms involved in the innate and adaptive immune response (including immunoglobulins, cytokines and cytokine receptors, complements, CD molecules, adhesions, T-cell receptors and major histocompatibility complex molecules) are glycoproteins. Besides, foreign antigens, such as many viral envelope proteins, are glycoproteins too. Carbohydrates attached to proteins or peptides are classified by the nature of their linkages to the protein, mostly as either N-linked (N-acetylglucosamine to asparagines) or O-linked (N-acetylgalactosamine to serine or threonine) oligosaccharides. The glycans have three major roles: firstly, the sugars confer stability on the proteins to which they are attached, protecting them from proteases and non-specific protein-protein interactions. Secondly, glycans play key roles in signal transduction, control of cell development and differentiation. Thirdly, specific regions of the oligosaccharide chains provide recognition epitopes, which influence innate and adaptive immune responses. Glycopeptides not only provide specific oligosaccharides, but also have specific information of amino acids sequences. The glycans and glycopeptides not only influence the structure and functions of immune molecules, but also influence the immune response. In addition, changes in glycans or glycopeptides may have a significant role in a variety of human immune-related diseases, such as rheumatoid, autoimmune disease, Wiskott-Aldrich syndrome, infection disease, cancer, etc. In this article, the roles of N-, O-glycans and glycopeptides in immune system and immune-related diseases are discussed. The potential therapeutic significance of the information is also mentioned.

Animals↗

PubMed2005

Rapid emergence of escape mutants following infection with murine cytomegalovirus in immunodeficient mice.

Natural killer (NK) cells play a crucial role in the initial host defense against pathogens such as murine cytomegalovirus (MCMV). They respond rapidly and effectively control pathogen replication while the adaptive immune system is being activated. However, in the absence of an adaptive immune system, an effective initial NK cell response is not sufficient for long-term pathogen control as demonstrated by the late recrudescence of disease and mortality in immunodeficient mice infected with MCMV. In this setting, NK cells suppress the initial infection but exert enough selective pressure to drive the outgrowth of MCMV mutants that escape recognition by NK cells. Herein, we characterize the rapid emergence of escape mutants following infection with a plaque-purified MCMV isolate and demonstrate that these mutant viruses are no longer effectively controlled by NK cells. These findings suggest that late recrudescence of viral infections in certain clinical settings may also be due to viral escape from NK cells or other components of innate immunity.

Adoptive Transfer↗

PubMed2005

Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing.

In plants and invertebrate animals, RNA silencing is a form of nucleic acid-based adaptive immunity. By contrast, jawed vertebrates have evolved complex protein-based adaptive immunity. Although short interfering RNAs (siRNAs) have been used as artificial tools to silence viral infection in human cells, it remains unknown whether mammalian viruses naturally elicit such immunity in vertebral cells. Here, we report the evidence that HIV-1 encodes viral siRNA precursors in its genome and that natural HIV-1 infection provokes nucleic acid-based immunity in human cells. To combat this cellular defense, HIV-1 has evolved in its Tat protein a suppressor of RNA silencing (SRS) function. Tat abrogates the cell's RNA-silencing defense by subverting the ability of Dicer to process precursor double-stranded RNAs into siRNAs.

Animals↗

PubMed1995

Follicular dendritic cells, interdigitating cells, and cells of the monocyte-macrophage lineage are the C1q-producing sources in the spleen. Identification of specific cell types by in situ hybridization and immunohistochemical analysis.

In a mouse model, we have shown previously that macrophages are the principal source of complement C1q. Furthermore, spleen, heart, and brain were found to contain substantial levels of murine C1q-specific mRNA, whereas liver, kidney, lung, and small intestine contained only trace amounts of C1q-specific mRNA. This work addresses the identification of C1q-expressing spleen cells in the rat, using Northern blotting and in situ detection of rat C1q mRNA combined with immunohistochemical analysis. The complete sequence of mRNA encoding the B chain of rat C1q was established. The cloned cDNA was found to hybridize primarily with spleen-derived mRNA of 1.2 kb, and additionally with a novel mRNA species of 3 kb. In situ hybridization together with immunohistochemistry revealed most of the C1q-expressing cells to be located in the red pulp of the spleen, and to be mainly of the monocyte-macrophage lineage, as indicated by coexpression of ED-1, an established marker for this type of cell. In addition, C1q was expressed in S-100-positive but ED-1-negative cells, in germinal center follicular dendritic cells, and in some interdigitating dendritic cells of the periarteriolar lymphatic sheath (PALS). These results indicate that the spleen, containing the above APCs that are all involved to a major extent in the adaptive immune response and are all capable of synthesizing C1q that is involved intimately in the innate immune response, may provide the site at which the innate and adaptive immune systems merge.

Amino Acid Sequence↗

PubMed2005

Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis.

Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement-mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta were highly overexpressed, and immunohistochemistry for the interferon-alpha/beta inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon-alpha, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon-alpha/beta inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus.

Adult↗

PubMed2004

Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma.

Recognition of microbial components by APCs and their activation through Toll-like receptors (TLR) leads to the induction of adaptive immune responses. In this study, we show that activation of TLR2 by its synthetic ligand Pam3Cys, in contrast to activation of TLR9 by immunostimulatory DNA (ISS-ODN), induces a prominent Th2-biased immune response. Activation of APCs by Pam3Cys resulted in the induction of Th2-associated effector molecules like IL-13, and IL-1beta, GM-CSF and up-regulation of B7RP-1, but low levels of Th1-associated cytokines (IL-12, IFNalpha, IL-18, IL-27). Accordingly, TLR2 ligands aggravated experimental asthma. These data indicate that the type of TLR stimulation during the initial phase of immune activation determines the polarization of the adaptive immune response and may play a role in the initiation of Th2-mediated immune disorders, such as asthma.

Adjuvants, Immunologic↗

PubMed2004

Role of viral and host factors in HCV persistence: which lesson for therapeutic and preventive strategies?

Several lines of evidence support the view that hepatitis C virus is not directly cytopathic for infected host cells and that the immune response plays a central role in the pathogenesis of liver damage. Innate and adaptive immune responses are induced in most individuals infected with hepatitis C virus but are insufficient to eliminate the virus. The mechanisms responsible for this failure are largely unknown but the kinetics of hepatitis C virus replication relative to the priming of the adaptive responses may exert a profound influence on the balance between virus and host. Immediately after hepatitis C virus infection, the virus replicates efficiently, inducing the production of type I interferons. However, the rapid increase in viral replication seems to be ignored by the adaptive immune response, and after a short interval from exposure, viral load can reach levels comparable to those of patients with established persistent infection. The CD8-mediated response shows functional defects, with impaired production of interferon-gamma, low perforin content, decreased capacity of expansion and lysis of target cells. Late appearance and functional defects of T cells in hepatitis C virus infection might be the result of the rapid increase of the viral load that could create the conditions for exhaustion of the adaptive response or reflect an insufficient function of the innate immune response. This possibility is suggested by in vitro studies showing that hepatitis C virus gene products can interfere with the anti-viral activity of type I interferons and natural killer cells as well as with the maturation of dendritic cells. While T-cell defects are reversed in a minority of infected individuals who succeed in controlling the infection, the T-cell impairment becomes progressively more profound as infection progresses to chronicity. In this situation, therapeutic restoration of adaptive responses may represent a rational strategy to obtain resolution of infection and to complement available therapies. The peculiar kinetics of hepatitis C virus replication and T-cell induction soon after infection may have important implications also for the design of protective vaccines since memory responses may not be able to precede the early peak of viral replication. Therefore, vaccines against hepatitis C virus may be unable to prevent infection but may rather be effective in facilitating a self-limited evolution of infection.

Hepacivirus↗

PubMed2006

CD4+ T cells in the absence of the CD8+ cytotoxic T cells are critical and sufficient for NKT cell-dependent tumor rejection.

NKT cells perform crucial roles in tumor surveillance, functioning as regulators of early host response. In this study, we have assessed the effects of NKT activation at the time of tumor Ag immunization, and have evaluated the contributions of CD4+ and CD8+ T cells in tumor rejection during adaptive immune response against live tumor cells. Our data indicate that CD4+ T cells play critical roles, not only in assisting CTL, but also in the orchestration of host response against the tumor. The CD4+ T cells were found to reject the transplanted tumor cells very efficiently under conditions in which the CTLs were removed either genetically, or via the action of anti-CD8 Ab in mice that had been immunized with tumor extracts and alpha-galactosylceramide. Immunization resulted in an NKT cell-dependent antitumor adaptive immune response, which was associated with both CD4+ T cells and cytokine IFN-gamma.

Animals↗

PubMed2005

Liver immunobiology.

Tle liver has a number of important functions in innate and adaptive immunity. Contributions to the innate (nonspecific) immune system include production of acute phase proteins, nonspecific phagocytosis of particles, nonspecific pinocytosis of molecules, and nonspecific cell killing. Hepatic involvement in innate immunity contributes to the systemic response to local inflammation, clearance of particles and soluble molecules from the circulation, and killing of invading cells such as neoplastic cells. Liver involvement in the adaptive (specific) immune system includes deletion of activated T cells, induction of tolerance to ingested and self-antigens, extrathymic proliferation of T cells, and deletion of many of the signaling and effector molecules. Hepatic involvement in adaptive immunity allows clearance of activated T cells and signaling molecules following inflammatory reactions, and promotes immunologic tolerance toward potentially antigenic proteins that are absorbed from the intestinal tract. The liver is a major site of extrathymic T cell development, which assumes increasing significance with aging in mammals. Perturbations in hepatic structure or function can result in significant ramifications in both the innate and adaptive immune systems.

Acute-Phase Proteins↗

PubMed2004

Immunity to Salmonella from a dendritic point of view.

Dendritic cells (DC) are the key link between innate and adaptive immunity. Features of DC, including their presence at sites of antigen entry, their ability to migrate from peripheral sites to secondary lymphoid organs, and their superior capacity to stimulate naïve T cells places them in this pivotal role in the immune system. DC also produce cytokines, particularly IL-12, upon antigen encounter and can thus influence the ensuing adaptive immune response. As DC are phagocytic antigen-presenting cells located at sites exposed to bacterial invaders, studies have been performed to gain insight into the role of DC in combating bacterial infections. Indeed, studies with Salmonella have shown that DC can internalize and process this bacterium for peptide presentation on MHC-II as well as MHC-I. DC can also act as bystander antigen--presenting cells by presenting Salmonella antigens after internalizing neighbouring cells that have undergone Salmonella-induced apoptotic death. DC also produce IL-12 and TNF-alpha upon Salmonella encounter. Moreover, studies in a murine infection model have shown that splenic DC increase surface expression of co-stimulatory molecules during infection, and DC contain intracellular bacteria. In addition, quantitative changes occur in splenic DC numbers in the early stages of oral Salmonella infection, and this is accompanied by redistribution of the defined DC subsets in the spleen of infected mice. DC from Salmonella-infected mice also produce cytokines and can stimulate bacteria-specific T cells upon ex vivo co-culture. In addition, DC may play a role in the traversal of bacteria from the intestinal lumen. Studying the function of DC during Salmonella infection provides insight into the capacity of this sophisticated antigen-presenting cell to initiate and modulate the immune response to bacteria.

Animals↗

PubMed2006

Toll-like receptors in human infectious diseases.

Toll-like receptors (TLRs) have emerged as critical players in immunity. They are capable of sensing organisms ranging from protozoa to bacteria, fungi or viruses upon detection of the pathogen as well as recognizing endogenous ligands, and triggering transduction pathways. Following activation of the innate immune system, strong inflammatory signals are generated inducing inflammation and activation of the adaptive immune response. However, the deregulation of TLRs signaling pathways may be conducive to the pathogenesis of many infectious diseases. Therefore, innate and adaptive immunity are not simply sequential and complementary mechanisms of resistance to pathogen, they regulate each other through cellular contacts and the secretion of soluble mediators. Herein, we summarize recent findings on TLRs signaling in infectious diseases and how pathogens have developed strategies to evade these pathways. In this context, a potential modulation of the innate immune response could have therapeutic benefit through the development of new drugs as well as vaccination strategies to be employed in infectious diseases.

Communicable Diseases↗

PubMed2006

Translating innate immunity into immunological memory: implications for vaccine development.

Vaccination is the most effective means of preventing infectious diseases. Despite the success of many vaccines, there is presently little knowledge of the immunological mechanisms that mediate their efficacy. Such information will be critical in the design of future vaccines against old and new infectious diseases. Recent advances in immunology are beginning to provide an intellectual framework with which to address fundamental questions about how the innate immune system shapes adaptive immunity. In this review, we summarize current knowledge about how the innate immune system modulates the quantity and quality of long-term T and B cell memory and protective immune responses to pathogens. In addition, we point out unanswered questions and identify critical challenges, the solution of which, we believe, will greatly facilitate the rational design of novel vaccines against a multitude of emerging infections.

Adjuvants, Immunologic↗

PubMed2003

Skin immune responses to peptide and protein antigen are TLR4 independent.

Little is known about the innate immune mechanisms regulating adaptive immune responses elicited through the skin. Tissue injury is postulated to liberate Toll like receptor 4 (TLR4) ligands. In this study, we determined whether TLR4 signaling modulates the response to epidermal injury induced by tape stripping (TS) and whether it alters humoral and cellular immune responses generated through epicutaneous immunization with peptide+cholera toxin (CT). The combined use of cholera toxin and TS with antigen promoted optimal antigen-specific CD4(+) and CD8(+) T cell proliferation in Balb/c and C57BL/6 mice, respectively. TLR4 mutant mice had similar T cell responses to wild type mice. Further, OVA-protein specific IgG, IgG(1), IgG(2a), and IgE titers were similar in wild type and TLR4 mutant mice. Thus, TLR4 signaling was not required for the generation of epicutaneous T cell or antibody mediated immune responses and did not alter the quality of the immune responses elicited.

Adoptive Transfer↗

PubMed2006

Current and future drugs targeting one class of innate immunity receptors: the Toll-like receptors.

Innate immunity receptors are germline-encoded receptors that can sense molecular signatures of pathogens and cancer cells. Recent advances in immunology demonstrate the key role of these receptors in inflammation and initiation of subsequent immune responses, including adaptive immunity. Pharmaceutical interest in this field has grown with the retrospective demonstration that some marketed drugs targeting cancer or infectious diseases act via those receptors. In this review, I present an update on the scientific rationale for targeting one class of innate immunity receptor, the Toll-like receptors, and an update on the development status of corresponding drug candidates in infectious diseases, cancer, allergy and vaccines.

Animals↗