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PubMed2006

Advances in the pathogenesis of inflammatory bowel disease.

Most people do not develop inflammatory bowel disease (IBD) in spite of the density of the commensal flora. In the past few years, several areas of gut mucosal immunology have emerged that will permit advances in the management of IBD at the bedside. The commensal flora is only beginning to be fully appreciated as another metabolic organ in the body. Innate immunity as it relates to the gut has complemented our understanding of the adaptive immune response. The most important susceptibility gene described for Crohn's disease, the NOD2 gene, participates in the innate immune response to pathogens. Patients carrying NOD2 mutations have an increased adaptive immune response to commensal organisms as measured by higher titers of antimicrobial antibodies, such as anti-CBir and anti-Saccharomyces cerevisiae antibodies. Toll-like receptors expressed by antigen-presenting cells (APCs) in the gut and intestinal epithelial cells also play a role in recognition of intestinal flora. Within the APC category, dendritic cells link the innate and adaptive immune systems and shape the nature of the adaptive immune response to commensal bacteria. With respect to adaptive immunity, a new signaling pathway involving a distinct helper CD4 T-cell subset producing interleukin-17 may become a target for the treatment of chronic inflammatory diseases. This review focuses on developments likely to culminate in advances in patient care.

Animals↗
PubMed2006

Natural killer cells in viral infection: more than just killers.

Innate immunity was believed originally to serve simply as the first-line defense against infection and malignancy, with adaptive immunity imposing specificity and ensuring that appropriate responses are mounted against chronic or reoccurring challenges. In this model of immunity, innate and adaptive immune responses are sequential, essentially non-overlapping, and interactions between components of each response limited or non-existent. Over the last 5 years, it has become increasingly evident that interactions between elements of the innate and adaptive immune systems are common. Indeed, it is now clear that the generation and maintenance of effective immunity require an extensive array of interactions between multiple components of the immune system. This review discusses recent advances in this area with particular emphasis on the role of natural killer cells in shaping the adaptive immune response to viral infection.

Animals↗
PubMed2003

Innate and adaptive mucosal immunity in protection against HIV infection.

Control of the HIV pandemic requires an effective vaccine. The difficulties in developing a preventive vaccine are generally believed to be due to the rapid rate of mutation of HIV that escapes cytotoxic lymphocytes (CTL) and the problems in induction of neutralising antibodies to wild strains of HIV. These difficulties should re-orientate vaccine strategy into four somewhat neglected areas of immunisation. Innate immunity, with its rapid protective response to infection that is independent of memory and relies on an optimal mucosal adjuvant. Targeting the genital and rectal mucosa, with the associated lymph nodes, as an immune response has to be elicited directly on encountering HIV during sexual intercourse. Stimulating a broadly based adaptive immune response that enhances the memory CD4(+) and CD8(+) T cells and B cells, induces maturation of dendritic cells and results in Th1 polarised immunity. Taking advantage of "experiments of nature", by utilising host antigens, as manifested by protection against HIV infection in homozygous Delta32 CCR5 individuals and in allo-immunity.

AIDS Vaccines↗
PubMed2003

Natural killer cells: emerging concepts in immunity to infection and implications for assessment of immunodeficiency.

PURPOSE OF REVIEW: As the molecular networks that connect innate and adaptive immunity are untangled, the prominence of natural killer (NK) cells in host defense continues to emerge. Herein we highlight recent findings pertaining to NK cell development, trafficking, and interactions with other innate and adaptive immune cells in the context of predicting how NK cells may be involved in a wider range of clinical immunodeficiency. RECENT FINDINGS: NK cells contribute vital roles in innate and adaptive immunity, especially in collaboration with dendritic cells (DC). Fascinating new details have been reported about cell surface integrins and receptors that regulate NK functions, as well as the cytokine/chemokine networks that provide for NK-DC interactions. Moreover, NK cells appear to play an important role in the attenuation or resolution of an immune response through either action against CD8 T cells or indirect control of certain DC. These findings shed important insights as to how NK cells and DC cooperate to control primary infections and shape the subsequent adaptive immune responses. SUMMARY: Natural killer cells are heterogeneous lymphocytes that provide an essential function in host defense. NK cells respond early to microbial assault and interact with other cells of the innate immune system, but they recognize and intercept pathogenic infections through highly specific mechanisms that are similar to T cells. Thus, NK cells are positioned as a cellular bridge between innate and adaptive immunity. It is imperative, then, to include a careful assessment of NK cell populations and functions in most cases of suspected immunodeficiency.

Animals↗
PubMed2003

Fever-like thermal conditions regulate the activation of maturing dendritic cells.

Fever is one of the most frequent clinical signs encountered in pathology, especially with respect to infectious diseases. It is currently thought that the role of fever on immunity is limited to activation of innate immunity; however, its relevance to activation of adaptive immunity remains unclear. Dendritic cells (DCs) that behave as sentinels of the immune system provide an important bridge between innate and adaptive immunity. To highlight the role of fever on adaptive immunity, we exposed murine bone marrow-derived lipopolysaccharide (LPS)- or live bacteria-maturing DCs over a 3-h period to 37 degrees C or to fever-like thermal conditions (39 degrees C or 40 degrees C). At these three temperatures, we measured the kinetics of cytokine production and the ability of DCs to induce an allogeneic mixed lymphocyte reaction. Our results show that short exposure of DCs to temperatures of 39 degrees C or 40 degrees C differentially increased the secretion of interleukin (IL)-12p70 and decreased the secretion of IL-10 and tumor necrosis factor alpha by maturing DCs. These fever-like conditions induced a regulation of cytokine production at the single-cell level. In addition, short-term exposed LPS-maturing DCs to 39 degrees C induced a stronger reaction with allogeneic CD4(+) T cells than maturing DCs incubated at 37 degrees C. These results provide evidence that temperature regulates cytokine secretion and DC functions, both of which are of particular importance in bacterial diseases.

Animals↗
PubMed2006

[Humoral and cellular responses in innate immunity].

The immune system is divided into innate and adaptive immunity. Either immunity consists of humoral and cellular responses, and immunity is maximized when both responses coordinately function. Adaptive immunity has been intensively studied, while it was only recently that we gained some understanding of innate immunity. In particular, cellular responses in innate immunity have been poorly understood compared with humoral responses. In addition, the mechanisms and roles of innate immune responses could be distinct between the organisms that possess both innate and adaptive immunity and those possessing only innate immunity. On the other hand, invading pathogenic microbes employ various strategies to inhibit the host immune system for their survival. I here summarize what needs to be known to gain a deeper understanding of the innate immune response. The readers are suggested to refer to the accompanying articles for more detailed description.

Animals↗
PubMed2005

Toll-like receptors and the eye.

PURPOSE OF REVIEW: This review will describe the structure, expression/distribution and functional activity of Toll-like receptors, in particular in the ocular structures. It will also discuss innate and adaptive immune responses, by exploring the possible modulation/regulation of innate and adaptive immunity by Toll-like receptors, in view of recent findings observed in the ocular surface. RECENT FINDINGS: Current knowledge indicates that Toll-like receptors represent essential elements in host defence against pathogens, a prerequisite to the induction of adaptive immune responses. The expression/distribution of Toll-like receptors in the healthy eye highlights the possible function of Toll-like receptors in both innate and adaptive responses during pathological conditions of the ocular surface. SUMMARY: Recent findings have greatly increased the knowledge of the possible role of Toll-like receptors in innate and adaptive immune responses. Toll-like receptors seem to play different roles in a wide range of activities of the immune system, and might represent an exclusive link between innate and adaptive responses under pathological conditions. Recent studies in ophthalmology have highlighted the role of Toll-like receptors in infections (keratitis) as well as in allergic states of the ocular surface. This review thus describes the relationship between Toll-like receptors and the main immune/structural cells taking part in inflammatory disorders. Understanding the complex mechanisms underlying Toll-like receptor localization and function will provide additional data that might help devise novel therapeutic approaches involving Toll-like receptors and their agonists, in an attempt to modulate the biased immune system.

Animals↗
PubMed2006

Immunity to fungi.

Innate and adaptive immune responses target pathogenic fungi and provide defense against fungal infections. Recent studies demonstrate that specific host receptors recognize ligands that are unique to fungi and activate signaling cascades that lead to phagocytosis of fungi, generation of pro-inflammatory mediators, formation of reactive oxygen species, trafficking of inflammatory cells to sites of infection, and initiation of adaptive immune responses. Greater understanding of the molecular mechanisms that underlie antifungal defense has provided a framework for the investigation of protective vaccines and strategies for therapeutic adoptive cell transfer.

Animals↗
PubMed2004

T cell immunity using transgenic B lymphocytes.

Adaptive immunity exists in all vertebrates and plays a defense role against microbial pathogens and tumors. T cell responses begin when precursor T cells recognize antigen on specialized antigen-presenting cells and differentiate into effector cells. Currently, dendritic cells are considered the only cells capable of stimulating T lymphocytes. Here, we show that mature naïve B lymphocytes can be genetically programmed by using nonviral DNA and turned into powerful antigen-presenting cells with a dual capacity of synthesis and presentation of antigen to T cells in vivo. A single i.v. injection of transgenic lymphocytes activates T cell responses reproducibly and specifically even at very low cell doses (approximately 10(2)). We also demonstrate that T cell priming can occur in the absence of dendritic cells and results in immunological memory with protective effector functions. These findings disclose aspects in the regulation of adaptive immunity and indicate possibilities for vaccination against viruses and cancer in humans.

Animals↗
PubMed2001

Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo.

The adaptive immune system has evolved distinct responses against different pathogens, but the mechanism(s) by which a particular response is initiated is poorly understood. In this study, we investigated the type of Ag-specific CD4(+) Th and CD8(+) T cell responses elicited in vivo, in response to soluble OVA, coinjected with LPS from two different pathogens. We used Escherichia coli LPS, which signals through Toll-like receptor 4 (TLR4) and LPS from the oral pathogen Porphyromonas gingivalis, which does not appear to require TLR4 for signaling. Coinjections of E. coli LPS + OVA or P. gingivalis LPS + OVA induced similar clonal expansions of OVA-specific CD4(+) and CD8(+) T cells, but strikingly different cytokine profiles. E. coli LPS induced a Th1-like response with abundant IFN-gamma, but little or no IL-4, IL-13, and IL-5. In contrast, P. gingivalis LPS induced Th and T cell responses characterized by significant levels of IL-13, IL-5, and IL-10, but lower levels of IFN-gamma. Consistent with these results, E. coli LPS induced IL-12(p70) in the CD8alpha(+) dendritic cell (DC) subset, while P. gingivalis LPS did not. Both LPS, however, activated the two DC subsets to up-regulate costimulatory molecules and produce IL-6 and TNF-alpha. Interestingly, these LPS appeared to have differences in their ability to signal through TLR4; proliferation of splenocytes and cytokine secretion by splenocytes or DCs from TLR4-deficient C3H/HeJ mice were greatly impaired in response to E. coli LPS, but not P. gingivalis LPS. Therefore, LPS from different bacteria activate DC subsets to produce different cytokines, and induce distinct types of adaptive immunity in vivo.

Animals↗
PubMed2003

Acute cold/restraint stress inhibits host resistance to Listeria monocytogenes via beta1-adrenergic receptors.

We previously reported that acute cold/restraint stress (ACRS) significantly inhibits host resistance to Listeria monocytogenes (LM) in BALB/c mice and that the sympathetic nervous system plays a major role in this inhibition. Here, we have further investigated the involvement of adrenergic receptor (ADR) subtypes. beta-ADR antagonist propranolol, but not alpha-ADR antagonist phentolamine significantly enhanced host resistance of ACRS mice. Pro-inflammatory cytokine (IL-6, IL-1beta, and TNFalpha) and IFNgamma levels positively correlated with the LM levels in all groups of mice. Furthermore, beta1-ADR antagonist atenolol but not beta2-ADR antagonist ICI118,551 significantly decreased LM burden in ACRS mice. In addition, SCID mice on the same genetic background (BALB/c), which have no adaptive immune potential, were used to assess the immune responses targeted by ACRS. ACRS-induced suppression of host resistance was not observed in SCID mice, and propranolol pretreatment provided no further improvement of host resistance, indicating that ACRS mainly affects adaptive immunity, which is less critical in mice with greater innate than adaptive immunity. In summary, the data suggest that ACRS inhibition of host resistance to LM is mediated through beta1-ADR stimulation, which appears to directly or indirectly modify activation of T cells or subsequent T cell functions involved in adaptive immunity, thus inhibiting overall host resistance. Interestingly, with heightened innate immunity and the absence of adaptive immunity, as observed in the SCID mice, ACRS does not affect host resistance, which emphasizes the importance of innate immunity in defense against bacterial infection.

Acute Disease↗
PubMed1998

Bacterial DNA as immune cell activator.

Pattern recognition receptors of the innate and adaptive immune systems apparently recognize unmethylated CpG motifs of bacterial DNA. Cells of the innate immune system are activated directly by CpG motifs, and the resulting response dictates a Th1 bias to the developing adaptive immune response. Interestingly, antigen receptor occupancy of cells of the adaptive immune system augments their responsiveness to CpG motifs, suggesting that co-stimulatory mechanisms are operative.

Animals↗
PubMed2000

The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice.

During influenza virus infection innate and adaptive immune defenses are activated to eliminate the virus and thereby bring about recovery from illness. Both arms of the adaptive immune system, antibody neutralization of free virus and termination of intracellular virus replication by antiviral cytotoxic T cells (CTLs), play pivotal roles in virus elimination and protection from disease. Innate cytokine responses, such as alpha/beta interferon (IFN-alpha/beta) or IFN-gamma, can have roles in determining the rate of virus replication in the initial stages of infection and in shaping the initial inflammatory and downstream adaptive immune responses. The effect of these cytokines on the replication of pneumotropic influenza A virus in the respiratory tract and in the regulation of adaptive antiviral immunity was examined after intranasal infection of mice with null mutations in receptors for IFN-alpha/beta, IFN-gamma, and both IFNs. Virus titers in the lungs of mice unable to respond to IFNs were not significantly different from congenic controls for both primary and secondary infection. Likewise the mice were comparably susceptible to X31 (H3N2) influenza virus infection. No significant disruption to the development of normal antiviral CTL or antibody responses was observed. In contrast, mice bearing the disrupted IFN-alpha/beta receptor exhibited accelerated kinetics and significantly higher levels of neutralizing antibody activity during primary or secondary heterosubtypic influenza virus infection. Thus, these observations reveal no significant contribution for IFN-controlled pathways in shaping acute or memory T-cell responses to pneumotropic influenza virus infection but do indicate some role for IFN-alpha/beta in the regulation of antibody responses. Recognizing the pivotal role of CTLs and antibody in virus clearance, it is reasonable to assume a redundancy in IFN-mediated antiviral effects in pulmonary influenza. However, IFN-alpha/beta seems to be a valid factor in determining tissue tropism and replicative rates of highly virulent influenza virus strains as reported previously by others, and this aspect is discussed here.

Animals↗
PubMed2005

LL-37 enhances adaptive antitumor immune response in a murine model when genetically fused with M-CSFR (J6-1) DNA vaccine.

DNA vaccine against M-CSFR(J6-1) (macrophage colony-stimulating factor receptor cloned from the J6-1 leukemic cell line) has shown both protective and therapeutic effects. In this study, to explore the adjuvant effects of LL-37 to M-CSFR(J6-1) DNA vaccines, we constructed genetically fused vaccines encoding M-CSFR(J6-1) and LL-37(pF). After immunizing BALB/c mice, specific humoral and cellular immune responses were detected. Compared with pR (encoding the extracellular region of M-CSFR(J6-1)), pF was more effective in inducing humoral and cytotoxic immune response, prolonging survival of mice challenged with SP2/0-CSFR(J6-1) tumor cells, and inducing IFN-gamma and IL-4 release by splenocytes. In this study, we also constructed pLL37 (encoding the mature LL-37) and coadministrated pLL37 and pR to see whether the genetic fusion was necessary. We found that compared with pR alone, pLL37+pR could not prolong survival of mice challenged with SP2/0-CSFR(J6-1) tumor cells. Our results suggest that when genetically fused with M-CSFR(J6-1), LL-37 could enhance adaptive immune response against M-CSFR(J6-1) in a murine model challenged with tumor cells bearing M-CSFR(J6-1).

Adaptation, Physiological↗
PubMed2005

Silica and the immune system.

This article collects the evidence that shows that the biological reactions to Silica are due to the stimulation of the Immune System. Both Innate and Adaptive Immunity are involved. The following sets of events take place sequentially: (1) Silica is recognized as a PAMP (pathogen-associated molecular pattern) by the Receptors of Innate Immunity; (2) This causes the stimulation first and then the death of the key cells of Innate Immunity (the macrophages); (3) While stimulated, macrophages produce cytokines (IL-1 and TNF) that stimulate fibroblasts; (4) The same and possibly other cytokines produced by silica- activated macrophages induce the maturation of dendritic cells, which are the connecting elements between the Innate and the Adaptive (lymphoid) Immune Systems; (5) It follows a polyclonal activation of the Adaptive Immunity; (6) The end result is the formation of fibro-hyaline tissue. In view of the double involvement of the Innate and the Adaptive Immune Systems and their cooperation in the stimulation of fibrosis, Silicosis can be considered as a "Collagen" Disease, related to other diseases of that group like Rheumatoid Arthritis, Lupus erythematosus and Scleroderma. Not surprisingly the incidence of these Diseases has been shown to be significantly increased in human exposed to Silica.

Animals↗
PubMed1998

Bacterial DNA as an evolutionary conserved ligand signalling danger of infection to immune cells.

During infection, the innate limb of the immune system senses danger (pathogens) via constitutively expressed pattern-recognition receptors, and responds with activation and secretion of pro-inflammatory cytokines. Cell-wall components of gram-positive and gram-negative bacteria, such as peptidoglycan, endotoxin or lipoteichoic acid, activate via CD14, a prototypic pattern-recognition receptor for carbohydrates. This review article focuses on an alternative recognition system of the innate immune system for the recognition of bacterial DNA. Bacterial DNA differs from eukaryotic DNA in its frequency of the dinucleotides CG and its lack of methylation. These structural differences appear to be sensed by cells of the innate immune system such as antigen-presenting cells. As a consequence bacterial DNA serves as an alternate ligand to signal danger of infection. Bacterial DNA and (synthetic) oligonucleotides (ODN) derived thereof are as efficient as endotoxin in activating macrophages and dendritic cells and in triggering release of pro-inflammatory cytokines. In mice sensitized with D-galactosamine (D-GalN), high doses of bacterial DNA from either gram-positive or gram-negative pathogens induce a lethal cytokine syndrome (lethal shock). Therefore, bacterial DNA may represent a hitherto unrecognized pathophysiological entity in host-parasite interactions. Moreover, recent evidence suggests that bacterial DNA or immunostimulating ODN triggers the immunostimulation of antigen-presenting cells, and can be utilized as adjuvant to enhance immune responses of the adaptive immune system towards poorly immunogenic antigens. In fact, foreign DNA might be useful as immunotherapeutically active adjuvant to direct adaptive immune responses towards Thl-dominated immune reactions. If these findings are operative in humans, immunostimulating ODN might be used to influence Th2-dominated diseases such as allergy.

Animals↗
PubMed2006

Innate and adaptive cellular immunity in flavivirus-naïve human recipients of a live-attenuated dengue serotype 3 vaccine produced in Vero cells (VDV3).

VDV3, a clonal derivative of the Mahidol live-attenuated dengue 3 vaccine was prepared in Vero cells. Despite satisfactory preclinical evaluation, VDV3 was reactogenic in humans. We explored whether immunological mechanisms contributed to this outcome by monitoring innate and adaptive cellular immune responses for 28 days after vaccination. While no variations were seen in serum IL12 or TNFalpha levels, a high IFNgamma secretion was detected from Day 8, concomitant to IFNalpha, followed by IL10. Specific Th1 and CD8 responses were detected on Day 28, with high IFNgamma/TNFalpha ratios. Vaccinees exhibited very homogeneous class I HLA profiles, and a new HLA B60-restricted CD8 epitope was identified in NS3. We propose that, among other factors, adaptive immunity may have contributed to reactogenicity, even after this primary vaccination. In addition, the unexpected discordance observed between preclinical results and clinical outcome in humans led us to reconsider some of our preclinical acceptance criteria. Lessons learned from these results will help us to pursue the development of safe and immunogenic vaccines.

Adult↗