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Results for “Adaptive Immunity”

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PubMed2004

Acute alcohol consumption inhibits accessory cell function of monocytes and dendritic cells.

BACKGROUND: Alcohol affects both innate and acquired immune responses. Chronic alcoholics have reduced delayed-type hypersensitivity response and increased susceptibility to infections. In contrast, recent studies suggest that acute, moderate alcohol consumption has protective effects on mortality. Monocytes and dendritic cells (DC) play a central role in coordination of innate and adaptive immune responses and are pivotal in activation of T lymphocytes in an antigen-specific manner. In this study, we investigated the effects of acute, moderate alcohol consumption on antigen presenting cell function of blood monocytes and monocyte-derived myeloid dendritic cells. METHODS: Accessory cell function of human blood monocytes was tested before and after acute alcohol intake (2 ml vodka/kg body weight) by measuring T cell activation with alloantigen (mixed lymphocyte reaction, MLR), superantigen (staphylococcal enterotoxin B) and recall antigen (tetanus toxoid). Myeloid DCs were generated in vitro from monocytes obtained from these individuals using IL-4 and GM-CSF and their allostimulatory function was tested in an MLR. RESULTS: We found significantly reduced T cell proliferation in the presence of monocytes obtained 2 or 18 hr after alcohol consumption whether alloantigen, superantigen, or recall antigen was the stimuli (p < 0.01). The reduced T cell proliferation was due to the effects of acute alcohol on monocytes rather than on T cells as we found decreased proliferation only in the presence of alcohol-exposed accessory cells but not when T cells were exposed to alcohol. In addition, monocyte-derived dendritic cells showed significantly reduced allostimulatory capacity after alcohol consumption (p < 0.005). CONCLUSION: Acute alcohol consumption inhibits accessory cell function of both monocytes and myeloid dendritic cells. Impaired function of these key antigen-presenting cells may contribute to reduced adaptive immune responses and increased susceptibility to infections when acute alcohol intake coincides with exposure to pathogens.

Adult↗

PubMed2001

Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis.

The ability of dendritic cells (DCs) to shape the adaptive immune response to viral infection is mediated largely by their maturation and activation state as determined by the surface expression of HLA molecules, costimulatory molecules, and cytokine production. Dengue is an emerging arboviral disease where the severity of illness is influenced by the adaptive immune response to the virus. In this report, we have demonstrated that dengue virus infects and replicates in immature human myeloid DCs. Exposure to live dengue virus led to maturation and activation of both the infected and surrounding, uninfected DCs and stimulated production of tumor necrosis factor alpha (TNF-alpha) and alpha interferon (IFN-alpha). Activation of the dengue virus-infected DCs was blunted compared to the surrounding, uninfected DCs, and dengue virus infection induced low-level release of interleukin-12 p70 (IL-12 p70), a key cytokine in the development of cell-mediated immunity (CMI). Upon the addition of IFN-gamma, there was enhanced activation of dengue virus-infected DCs and enhanced dengue virus-induced IL-12 p70 release. The data suggest a model whereby DCs are the early, primary target of dengue virus in natural infection and the vigor of CMI is modulated by the relative presence or absence of IFN-gamma in the microenvironment surrounding the virus-infected DCs. These findings are relevant to understanding the pathogenesis of dengue hemorrhagic fever and the design of new vaccination and therapeutic strategies.

Antibodies, Viral↗

PubMed2005

Papillomavirus capsid mutation to escape dendritic cell-dependent innate immunity in cervical cancer.

Infection with oncogenic human papillomaviruses (HPVs), typified by HPV type 16 (HPV16), is a necessary cause of cervical cancer. Prophylactic vaccination with HPV16 L1 virus-like particles (VLPs) provides immunity. HPV16 VLPs activate dendritic cells and a potent neutralizing immunoglobulin G (IgG) response, yet many cervical cancer patients fail to generate detectable VLP-specific IgG. Therefore, we examined the role of the innate recognition of HPV16 L1 in VLP-induced immune responses and its evasion during carcinogenesis. Nonconservative mutations within HPV16 L1 have been described in isolates from cervical cancer and its precursor, high-grade cervical intraepithelial neoplasia (CIN). We determined the effect of mutations in L1 upon in vitro self-assembly into VLPs and their influence upon the induction of innate and adaptive immune responses in mice. Several nonconservative mutations in HPV16 L1 isolated from high-grade CIN or cervical carcinoma prevent self-assembly of L1 VLPs. Intact VLPs, but not assembly-defective L1, activate dendritic cells to produce proinflammatory factors, such as alpha interferon, that play a critical role in inducing adaptive immunity. Indeed, effective induction of L1-specific IgG1 and IgG2a was dependent upon intact VLP structure. Dendritic cell activation and production of virus-specific neutralizing IgG by VLPs requires MyD88-dependent signaling, although the L1 structure that initiates MyD88-mediated signaling is distinct from the neutralizing epitopes. We conclude that innate recognition of the intact L1 VLP structure via MyD88 is critical in the induction of high-titer neutralizing IgG. Tumor progression is associated with genetic instability and L1 mutants. Selection for assembly-deficient L1 mutations suggests the evasion of MyD88-dependent immune control during cervical carcinogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and prolongs the survival of mice with experimental brain tumors.

Toll-like receptors (TLRs) recognize a set of conserved molecular structures, so called pathogen-associated molecular patterns, which allow them to sense and initiate innate and adaptive immune responses. In this study, we examined the expression of TLRs in both human and murine glioma. We then analyzed the change in TLR expression after treatment with synthetic phosphorothioate oligodeoxynucleotides (ODNs) containing unmethylated CpG dinucleotides (CpG ODNs), strong activators of both innate and adaptive immunity. In addition, we investigated the in vivo effect of CpG injection into C57BL/6 mice implanted with syngeneic GL261 glioma. Our results indicate that TLR9 is overexpressed in human and murine glioma cell lines and CpG stimulation prolongs the survival of mice with experimental brain tumors. CpGs induce TLR9 down-regulation, followed by apoptosis of GL261 cells in vitro as well as in vivo. Furthermore, the effects of CpG stimulation appear to enhance the antigen presenting capacity of microglia, shift the immune response toward CD8(+) T cells, and decrease the number of CD4(+)CD25(+) regulatory T cells. Taken together, our data support the role of CpG in glioma immunotherapy and provide a rationale for further clinical development of CpG therapy in patients with malignant glioma.

Animals↗

PubMed2003

Effects of cold stress on immune responses and body weight of chicken lines divergently selected for antibody responses to sheep red blood cells.

Effects of cold stress (CS) on the immune system of chicken lines divergently selected for high (H line) and low (L line) antibody responses to SRBC next to a randombred control (C) line were studied. Three- to four-week-old growing chicks of the three lines were feed-restricted at 80% ad libitum and subjected to CS at 10 degrees C continuously for 7, 5, 3, 1, or 0 d prior to immunization with keyhole limpet hemocyanin (KLH). Specific and natural antibodies were measured in the three chicken lines subjected to or not subjected to various durations of CS prior to immunization. In addition to antibodies we also measured in vitro lymphocyte proliferation as a measure of cell-mediated immunity (CMI), zymosan-induced reactive oxygen intermediates (ROI) production as a measure of phagocytosis, and BW gain as a measure of production trait. In general, significantly higher antibody responses to KLH and natural antigens were found in the H line as compared to the other two lines. Specific antibody responses to KLH were not significantly affected by CS, but an acute transient increase in natural antibody titers to ovalbumin was found in H line birds subjected to 1 d of CS, which was not found in C or L line birds. On the other hand, an acute significant increase in natural antibody titers to lipopolysaccharide (LPS) was found in C and L line birds subjected to 1 d CS but not in H line birds. Cold stress enhanced the ROI production. In addition, 7 d of CS significantly enhanced cellular immunity in vitro, but no significant line effects with respect to cellular immunity were found. BW gain was negatively affected by CS, especially when CS was applied for longer periods. We concluded that birds responded immediately to CS with enhanced innate (phagocyte and natural antibody) immunity, irrespective of genetic background. When CS is prolonged, the cellular adaptive immune response is affected also. Although reallocation of energy was not measured, our data suggested that under limited conditions (e.g., restricted feeding) with simultaneous stress (e.g., CS), growth and cellular immunity were more sensitive than thermoregulation and humoral immunity. With respect to vital life traits, thermoregulation may have first priority followed by adaptive cellular immunity, humoral immunity, and BW gain. The relationships between immune responses and adaptation to stress are discussed.

Animals↗

PubMed2000

Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex.

The membrane protein complex CD19/CD21 couples the innate immune recognition of microbial antigens by the complement system to the activation of B cells. CD21 binds the C3d fragment of activated C3 that becomes covalently attached to targets of complement activation, and CD19 co-stimulates signaling through the antigen receptor, membrane immunoglobulin. CD21 is also expressed by follicular dendritic cells and mediates the long-term retention of antigen that is required for the maintenance of memory B cells. Understanding of the biology of this receptor complex has been enriched by analyses of genetically modified mice; these analyses have uncovered roles not only in positive responses to foreign antigens, but also in the development of tolerance to self-antigens. Studies of signal transduction have begun to determine the basis for the coreceptor activities of CD19. The integration of innate and adaptive immune recognition at this molecular site on the B cell guides the appropriate selection of antigen by adaptive immunity and emphasizes the importance of this coreceptor complex.

Animals↗

PubMed2005

Functional diversity and plasticity of human dendritic cell subsets.

The induction of different types of innate and adaptive immune responses, depending on the nature of the antigens and the environmental context, is crucial to cope with a variety of pathogens and concurrently to avoid pathologic reaction to self antigens. Recent studies have elucidated that the diversity of immune responses is critically controlled by dendritic cells (DCs). Two DC subsets, myeloid DCs and plasmacytoid DCs, have been identified in humans. The DC subsets recognize different microbial pathogens by expressing distinct repertoires of Toll-like receptors and induce different types of innate and adaptive immune responses, depending on the environmental factors. In particular, plasmacytoid DC precursors produce vast amounts of type I interferons in response to viruses and thus play an important role in antiviral immunity. Elucidating the cellular and molecular mechanisms that modulate the functions of the 2 DC subsets will lead to an understanding of the pathogenesis of various immune-related diseases and to the development of novel immunologic therapies.

Animals↗

PubMed2005

Spring brings breezes, wheezes, and pollen oxidases.

While the release of pollen into the air is essential for the reproduction of plants, the accidental yet inevitable uptake of pollen into human airways can cause symptoms of seasonal allergies and asthma. The symptomatic response to pollen is caused by granulocytes that produce inflammation, which is due in part to oxidative stress through the action of NADPH oxidases. The recruitment of these inflammatory granulocytes was previously thought to depend entirely on the activation of an adaptive immune response. In this issue of the JCI, Boldogh et al. demonstrate that pollens contain endogenous NADPH oxidase activity, which functions to generate local "danger signals" in nearby airway epithelium. These signals in turn trigger the early recruitment of granulocytes, even in the absence of the adaptive immune response. These findings suggest that inhibition of the pollen oxidase may provide a way to antagonize allergic inflammation at a very early step.

Allergens↗

PubMed2006

Protective immune responses against West Nile virus are primed by distinct complement activation pathways.

West Nile virus (WNV) causes a severe infection of the central nervous system in several vertebrate animals including humans. Prior studies have shown that complement plays a critical role in controlling WNV infection in complement (C) 3(-/-) and complement receptor 1/2(-/-) mice. Here, we dissect the contributions of the individual complement activation pathways to the protection from WNV disease. Genetic deficiencies in C1q, C4, factor B, or factor D all resulted in increased mortality in mice, suggesting that all activation pathways function together to limit WNV spread. In the absence of alternative pathway complement activation, WNV disseminated into the central nervous system at earlier times and was associated with reduced CD8+ T cell responses yet near normal anti-WNV antibody profiles. Animals lacking the classical and lectin pathways had deficits in both B and T cell responses to WNV. Finally, and somewhat surprisingly, C1q was required for productive infection in the spleen but not for development of adaptive immune responses after WNV infection. Our results suggest that individual pathways of complement activation control WNV infection by priming adaptive immune responses through distinct mechanisms.

Animals↗

PubMed2006

Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of viral arthritis and myositis.

Mosquito-borne alphaviruses are a significant cause of both encephalitic and arthritic disease in humans worldwide. In contrast to the encephalitic alphaviruses, the pathogenesis of alphavirus-induced arthritic disease is not well understood. Utilizing a mouse model of Ross River virus (RRV) disease, we found that the primary targets of RRV infection are bone, joint, and skeletal muscle tissues of the hind limbs in both outbred CD-1 mice and adult C57BL/6J mice. Moreover, histological analyses demonstrated that RRV infection resulted in severe inflammation of these tissues. Characterization of the inflammatory infiltrate within the skeletal muscle tissue identified inflammatory macrophages, NK cells, and CD4+ and CD8+ T lymphocytes. To determine the contribution of the adaptive immune system, the outcome of RRV-induced disease was examined in C57BL/6J RAG-1(-/-) mice, which lack functional T and B lymphocytes. RAG-1(-/-) and wild-type mice developed similar disease signs, infiltration of inflammatory macrophages and NK cells, and muscle pathology, suggesting that the adaptive immune response does not play a critical role in the development of disease. These results establish the mouse model of RRV disease as a useful system for the identification of viral and host factors that contribute to alphavirus-induced arthritis and myositis.

Alphavirus Infections↗

PubMed2004

Burn injury initiates a shift in superantigen-induced T cell responses and host survival.

Severe injury induces a temporal shift in immune reactivity that can cause serious complications or even death. We previously reported that mice exposed to bacterial superantigen (SAg) early after injury undergo a strong SAg response with lethal consequences. This study compares the early and late effects of burn injury on SAg reactivity in vivo to establish how injury influences adaptive immune responses. We found that mice challenged with ordinarily sublethal doses of staphylococcal enterotoxin A or staphylococcal enterotoxin B at 1 day after burn injury exhibited high mortality, whereas no mortality occurred at 7 days after injury. This shift in mortality correlated with higher Th2-type cytokines (IL-4 and IL-10) being expressed by CD4(+) and CD8(+) T cells from burn as opposed to sham mice at 7 days after injury. Lymph node cells from burn-injured mice also produced higher levels of Th2-type cytokines at 7 days after injury. The results of cell-mixing studies using CD4(+) and CD8(+) T cells mixed with APCs from sham or burn mice suggested that changes in both T cells and APCs are involved in the altered SAg response. Finally, the biological significance of altered SAg reactivity following injury was shown by demonstrating that blocking IL-10 activity in vivo caused higher SAg-induced mortality at 7 days after injury. These findings support the idea that injury promotes a Th2-type shift in adaptive immune reactivity. Although prior studies link this counterinflammatory-type response to lowered resistance to infection, the present results suggest it may sometimes benefit the injured host.

Animals↗

PubMed2006

Are increased frequency of macrophage-like and natural killer (NK) cells, together with high levels of NKT and CD4+CD25high T cells balancing activated CD8+ T cells, the key to control Chagas' disease morbidity?

The immunological response during early human Trypanosoma cruzi infection is not completely understood, despite its role in driving the development of distinct clinical manifestations of chronic infection. Herein we report the results of a descriptive flow cytometric immunophenotyping investigation of major and minor peripheral blood leucocyte subpopulations in T. cruzi-infected children, characterizing the early stages of the indeterminate clinical form of Chagas' disease. Our results indicated significant alterations by comparison with uninfected children, including increased values of pre-natural killer (NK)-cells (CD3- CD16+ CD56-), and higher values of proinflammatory monocytes (CD14+ CD16+ HLA-DR++). The higher values of activated B lymphocytes (CD19+ CD23+) contrasted with impaired T cell activation, indicated by lower values of CD4+ CD38+ and CD4+ HLA-DR+ lymphocytes, a lower frequency of CD8+ CD38+ and CD8+ HLA-DR+ cells; a decreased frequency of CD4+ CD25HIGH regulatory T cells was also observed. These findings reinforce the hypothesis that simultaneous activation of innate and adaptive immunity mechanisms in addition to suppression of adaptive cellular immune response occur during early events of Chagas' disease. Comparative cross-sectional analysis of these immunophenotypes with those exhibited by patients with late chronic indeterminate and cardiac forms of disease suggested that a shift toward high values of macrophage-like cells extended to basal levels of proinflammatory monocytes as well as high values of mature NK cells, NKT and regulatory T cells, may account for limited tissue damage during chronic infection favouring the establishment/maintenance of a lifelong indeterminate clinical form of the disease. On the other hand, development of an adaptive cell-mediated inflammatory immunoprofile characterized by high levels of activated CD8+ cells and basal levels of mature NK cells, NKT and CD4+ CD25HIGH cells might lead to late chronic pathologies associated with chagasic heart disease.

ADP-ribosyl Cyclase 1↗

PubMed2006

Interleukin-23 drives innate and T cell-mediated intestinal inflammation.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract involving aberrant activation of innate and adaptive immune responses. We have used two complementary models of IBD to examine the roles of interleukin (IL)-12 family cytokines in bacterially induced intestinal inflammation. Our results clearly show that IL-23, but not IL-12, is essential for the induction of chronic intestinal inflammation mediated by innate or adaptive immune mechanisms. Depletion of IL-23 was associated with decreased proinflammatory responses in the intestine but had little impact on systemic T cell inflammatory responses. These results newly identify IL-23 as a driver of innate immune pathology in the intestine and suggest that selective targeting of IL-23 represents an attractive therapeutic approach in human IBD.

Animals↗

PubMed2004

Neuronal apoptosis in immunodeficient mice infected with the challenge virus standard strain of rabies virus by intracerebral inoculation.

The challenge virus standard-11 strain (CVS) of fixed rabies virus produces neuronal apoptosis in widespread areas of the brain of mice after intracerebral inoculation. The role of the adaptive immune response in producing neuronal apoptosis in this model was evaluated by comparing the infections in adult C57BL/6J mice with nude mice (T cell deficient) and Rag1 mice (T and B cell deficient). Both strains of immunodeficient mice showed very similar clinical disease and neuropathological findings, including marked neuronal apoptosis. The adaptive immune response is unlikely of fundamental importance in producing neuronal apoptosis in the brains of mice in this model.

Animals↗

PubMed2007

Toll-like receptors and innate immunity in gut homeostasis and pathology.

PURPOSE OF REVIEW: Immune responses to commensal bacteria and resulting chronic inflammation are hallmarks of inflammatory bowel disease. Considerable evidence has accumulated to suggest that innate immune defense mechanisms interact with pro-inflammatory pathways and exacerbate or perhaps even initiate development of inflammatory bowel disease. RECENT FINDINGS: Recent cellular and mouse studies now show Toll-like receptor responses in intestinal epithelial cells are polarized and their activation by commensal bacteria plays an essential role in maintaining colonic homeostasis and controlling tolerance in the gut. Recent data also implicate signaling by Toll-like receptors and the common adaptor molecule MyD88 in intestinal epithelial homeostasis as well as the pathogenesis of inflammatory bowel disease, establishing a key link between the innate and adaptive immune defenses. SUMMARY: We review recent progresses in the understanding of the role of Toll-like receptors and other pattern recognition receptors in the host defense against gastrointestinal pathogens and maintenance of immune tolerance to commensal bacteria, highlighting areas that should provide fertile ground for future studies aimed at a more comprehensive understanding of the interplay between innate and adaptive immune defense mechanisms and inflammatory bowel disease.

Animals↗

PubMed2004

Regulation of immune responses by CD1d-restricted natural killer T cells.

Natural killer T (NKT) cells are a unique subset of T lymphocytes that share receptor structures and properties with conventional T lymphocytes and natural killer (NK) cells. NKT cells are specific for glycolipid antigens such as the marine sponge-derived agent alpha-galactosylceramide (alpha-GalCer) presented by the major histocompatibility complex (MHC) class I-like molecule CD1d. My laboratory has evaluated the function of NKT cells by generating and analyzing CD1d-deficient mice. These studies showed that CD1d expression is required for NKT cell development, but not absolutely necessary for the generation of polarized T helper (Th) cell responses. Further, we have studied the in vivo response of NKT cells to alpha-GalCer stimulation and the capacity of alpha-GalCer to modulate innate and adaptive immune responses. Our results revealed that, quickly following administration of alpha-GalCer, NKT cells expand and produce cytokines, trans-activate a variety of innate and adaptive immune cells, and promote Th2 responses that are capable of suppressing Th1-dominant autoimmunity. Our findings indicate that NKT cells play a regulatory role in the immune response and that specific activation of these cells may be exploited for therapeutic purposes.

Animals↗

PubMed2025

Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East respiratory syndrome coronavirus disease severity.

Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoVs from the past 20 years (SARS-CoV, SARS-CoV-2, and MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers, and acute lung injury among lethal and sub-lethal virus doses. Virus-induced apoptosis of type I and II alveolar epithelial cells suggests that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness.IMPORTANCEEmerging coronaviruses like SARS-CoV, SARS-CoV-2, and MERS-CoV cause a range of disease outcomes in humans from an asymptomatic, moderate, and severe respiratory disease that can progress to death but the factors causing these disparate outcomes remain unclear. Understanding host responses to mild and life-threatening infections provides insight into virus-host networks within and across organ systems that contribute to disease outcomes. We used multi-omics approaches to comprehensively define the host response to moderate and severe MERS-CoV infection. Severe respiratory disease was associated with dysregulation of the immune response. Key lung epithelial cell populations that are essential for lung function get infected and die. Mice lacking key immune cell populations experienced greater virus replication but decreased disease severity implicating the immune system in both protective and pathogenic roles in response to MERS-CoV. These data could be utilized to design new therapeutic strategies targeting specific pathways that contribute to severe disease.

Animals↗

PubMed2004

Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity.

There are no studies so far linking molecular regulation of lymphangiogenesis and induction of adaptive immunity. Here, we show that blockade of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling significantly suppresses corneal antigen-presenting (dendritic) cell trafficking to draining lymph nodes, induction of delayed-type hypersensitivity and rejection of corneal transplants. Regulating the function of VEGFR-3 may therefore be a mechanism for modulating adaptive immunity in the periphery.

Animals↗