Inflammation and immune response in atherosclerosis

Atherosclerosis is an inflammatory disease with a significant autoimmune component. Studies using transgenic murine models have clarified that recruitment of mononuclear leukocytes through vascular leukocyte-adhesion molecules and chemokines, differentiation of monocytes to macrophages, and endocytosis through scavenger receptors all are of decisive importance for atherosclerosis in hypercholesterolemic mice. T and B cells modulate disease progression and lesion development is reduced in mice lacking adaptive immunity. In particular, local immune responses eliciting Th1 effector mechanisms appear to be proatherogenic, whereas protective immune responses can be induced by immunization with oxidized low-density lipoprotein. Thus, innate immunity is necessary for atherosclerosis, whereas adaptive immunity is an important modulator of disease development.     

Basophils: a potential liaison between innate and adaptive immunity.

Activation of innate immunity is closely associated to development of protective adaptive immune response. Significant advances have been made to reveal such links between innate immunity and Th1 type adaptive immune responses. By contrast, the role of innate immunity in the development of Th2 type adaptive immune responses is still not well understood. Production of IL-4, a key cytokine in the induction of Th2 immunity, by innate type cells represents an attractive mechanism for such an innate link to Th2 immunity. We have recently reported that in the course of infection with the intestinal nematode, Nippostrongylus brasiliensis, a robust basophil accumulation in the liver/spleen occurs and that these basophils display enhanced IL-4 production. Thus, the basophils is an attractive candidate to mediate the innate-adaptive link for Th2 responses and understanding the control of the tissue homing patterns and cytokine responses of basophils in the course of infections may shed important light on the in vivo induction of Th2 adaptive immunity.     

Stress, cytokine patterns and susceptibility to disease

Recent evidence indicates that glucocorticoids and catecholamines, the end-products of the stress system, and histamine, a product of activated mast cells, might selectively suppress cellular immunity, and favour humoral immune responses. This is mediated by a differential effect of stress hormones and histamine, on T helper 1 (Th1)/Th2 patterns and type 1/type 2-cytokine production. Thus, systemically, stress might induce a Th2 shift, while, locally, under certain conditions, it might induce pro-inflammatory activities through neural activation of the peripheral corticotropin-releasing factor-mast cell-histamine axis. Through the above mechanisms, stress may influence the onset and/or course of infectious, autoimmune/inflammatory, allergic and neoplastic diseases.     

Stress Hormones,Th1/Th2 patterns,Pro/Anti-inflammatory Cytokines and Susceptibility to Disease

In general, stress has been regarded as immunosuppressive. Recent evidence, however, indicates that acute, subacute or chronic stress might suppress cellular immunity but boost humoral immunity. This is mediated by a differential effect of stress hormones, the glucocorticoids and catecholamines, on T helper 1 (Th1)/Th2 cells and type 1/type 2 cytokine production. Furthermore, acute stress might induce pro-inflammatory activities in certain tissues through neural activation of the peripheral corticotropin-releasing hormone–mast cell–histamine axis. Through the above mechanisms, stress might influence the onset and/or course of infectious, autoimmune/inflammatory, allergic and neoplastic diseases.     

Glucocorticoids suppress inflammation but spare innate immune responses in airway epithelium

Epithelial cells produce molecules that alter the growth and differentiation of mesenchymal cells, trigger the adhesion to endothelial cells and recruitment of inflammatory leukocytes, and regulate the activation of resident and infiltrating inflammatory cells. Recently, it has become clear that the airway epithelium also participates in innate immune responses. Accumulating evidence suggests that epithelial products such as complement, collectins, lysozyme, lactoferrin, secretory leukocyte protease inhibitor, and defensins can lead to localized destruction of microorganisms. While suppressing systemic adaptive immune responses, glucocorticoids exert little or no inhibitory effect on the ability of the epithelium to express these antimicrobial substances and, in some cases, may even elevate their production. Inhaled glucocorticoids generally profoundly inhibit epithelial cell expression of genes of inflammation, including chemokines, cytokines, and enzymes. Glucocorticoids may enhance the sensitivity of the epithelial surface to Toll-like receptor ligands, and they have been found to induce the expression of surfactant proteins A and D in several in vitro and in vivo model systems. Supporting the concept that glucocorticoids enhance innate immunity while suppressing adaptive immunity, these drugs enhance the survival and/or function of neutrophils and alveolar macrophages but induce the apoptosis of airway dendritic cells.     

New roles for estrogens in rheumatoid arthritis

Sex hormones appear to play an important role as modulators of autoimmune disease onset/perpetuation. Steroid hormones are implicated in the immune response, with estrogens as enhancers at least of humoral immunity, and androgens and progesterone (and glucocorticoids) as natural immune suppressors. Serum levels of estrogens have been found to be normal in rheumatoid arthritis (RA) patients. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female RA patients as compared to controls, which is most probably due to an increase in local aromatase activity. Thus, available steroid pre-hormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e. TNF alpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular 16 alpha-hydroxyestrone, showing a mitogenic stimulating role. Indeed, recent studies by us indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase in markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on the immune/inflammatory response is exerted by activating the NFkB complex. In conclusion, locally increased estrogens may exert activating effects on synovial cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in RA.     

Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity

Sex hormones seem to play an important role as modulators of the autoimmune disease onset/perpetuation. Generally, steroid hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immunosuppressors. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female rheumatoid arthritis (RA) patients, as compared to controls, which is most probably due to increase of local enzymatic aromatase activity. Serum levels of estrogens have been found altered in RA patients, particularly estradiol in man. Thus, available steroid prehormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e., TNFalpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular, 16alpha-hydroxyestrone, showing a mitogenic tumor growth stimulating role. Altered serum hydroxylated estrogens have been found also in serum of systemic lupus erythematosus (SLE) patients. As a matter of fact, our recent studies indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase of markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on immune/inflammatory response is exerted by activating the NFkB complex pathway. In conclusion, locally increased estrogens (i.e., synovial tissue in RA or skin in SLE) might exert activating effects on cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in autoimmunity.     

Regulation by innate immune T lymphocytes in the host defense against pulmonary infection with Cryptococcus neoformans

Recently, innate immune lymphocytes, such as natural killer (NK) T cells and gamma/delta antigen receptor-bearing T (gamma delta T) cells, have garnered much attention, and their biological significance in the tumor immunity, allergic diseases and infectious diseases is extensively exploited. We have addressed the role of these cells in the host defense using a mouse model of pulmonary infection with Cryptococcus neoformans, which frequently causes fatal meningoencephalitis in AIDS patients. Host defense to this fungal pathogen is largely mediated by cellular immunity, and type-1 helper T (Th1) cells play a central role in this process. This infection causes a prompt accumulation of both NKT and gamma delta T cells in the lung tissues in a monocyte chemoattractant protein (MCP)-1-dependent or -independent manner, respectively. Genetic deletion of V alpha 14+ NKT cells ameliorates the Th1 response and clearance of microorganisms in the lungs, whereas these host protective responses are rather enhanced in mice lacking gamma delta T cells. Thus, in some aspect, these innate immune lymphocytes may co-regulate the Th1-mediated response for induction of the moderate host defense. gamma delta T cells may act to keep the balance of Th1-Th2 responses in a proper manner by suppressing the exaggerated Th1 response caused by NKT cells. In this review, I describe the recent research development in the innate immune host defense against cryptococcal infection in respiratory organs with emphasis on our data in the regulatory role of NKT cells and gamma/delta T cells.     

动脉粥样硬化中的免疫调节

目前已经认识到,动脉粥样硬化是一个由各种免疫细胞启动的炎症反应过程。参与其中的有固有免疫中的单核细胞、巨噬细胞,也有适应性免疫中的T细胞和B细胞,还包括其中的细胞因子。各种免疫细胞在动脉粥样硬化过程中起到的作用是不同的,有的会促进病变的发展,有的会抑制病变的发展。人类单核细胞中的CD14+CD16+细胞具有促炎作用,而有的CD14+CD16-细胞具有抑制炎症的作用;T细胞中的Th1和Th17细胞促进病变的发展,而Th2,CD4+CD25+调节性T细胞则作用相反。近年研究还发现,针对ox-LDL的抗体,对动脉粥样硬化的发生也具有保护作用。因此,深入研究免疫机制会对有效地的防治动脉粥样硬化有指导作用。     

Pulmonary defenses against fungi

Pulmonary immunity to fungal pathogens requires both innate and adaptive immune responses. Alveolar macrophages, dendritic cells, and neutrophils are the phagocytic cells of the lung innate system. These cells produce early inflammatory mediators (i.e., reactive oxygen species, cytokines, and chemokines) in response to fungal infection. The production of early cytokines by innate cells, namely tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-12, plays a central role in the development of protective cell-mediated immunity against fungi. T helper 1 (Th1) cell-mediated immunity is essential for limiting a pulmonary fungal infection. Virulence factors produced by the fungi can also modulate the host immune response. Fungal virulence factors include the production of prostaglandins and a polysaccharide capsule. The type of adaptive immune response (T1 vs T2) generated determines whether the fungi are cleared from the lungs or a chronic fungal infection prevails.     

High-Risk Human Papillomavirus Targets Crossroads in Immune Signaling

Persistent infections with a high-risk type human papillomavirus (hrHPV) can progress to cancer. High-risk HPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses to invading pathogens. Viral persistence is achieved by active interference with KCs innate and adaptive immune mechanisms. To this end hrHPV utilizes proteins encoded by its viral genome, as well as exploits cellular proteins to interfere with signaling of innate and adaptive immune pathways. This results in impairment of interferon and pro-inflammatory cytokine production and subsequent immune cell attraction, as well as resistance to incoming signals from the immune system. Furthermore, hrHPV avoids the killing of infected cells by interfering with antigen presentation to antigen-specific cytotoxic T lymphocytes. Thus, hrHPV has evolved multiple mechanisms to avoid detection and clearance by both the innate and adaptive immune system, the molecular mechanisms of which will be dealt with in detail in this review.     

Toll-like receptor-3 and the regulation of intrahepatic immunity: implications for interferon-alpha therapy

The liver is known to be a classical immunoprivileged site with a relatively high resistance against immune responses. Here we demonstrate that highly activated liver-specific effector CD8+ T cells alone were not sufficient to trigger immune destruction of the liver in mice. Only additional innate immune signals orchestrated by TLR3 provoked liver damage. While TLR3 activation did not directly alter liver-specific CD8+ T cell function, it induced IFN-alpha and TNF-alpha release. These cytokines generated expression of the chemokine CXCL9 in the liver, thereby enhancing CD8+ T cell infiltration and liver disease in mice. Thus, nonspecific activation of innate immunity can drastically enhance susceptibility to immune destruction of a solid organ.     

TNF-alpha -dependent maturation of local dendritic cells is critical for activating the adaptive immune response to virus infection

Tumor necrosis factor-alpha (TNF-alpha) is well recognized for its role in mediating innate immune responses. However, the mechanisms of TNF-alpha that influence the adaptive immune response to virus infections are not well understood. In this study, we have investigated the role of TNF-alpha in activating the cellular and humoral responses to systemic viral challenge with recombinant replication-defective adenovirus (rAd). Evaluation of T cell function in TNF-alpha-deficient (TNFKO) mice revealed impaired virus-specific proliferation of T cells derived from the draining lymph nodes of the liver. Analysis of dendritic cells (DC) isolated from local draining lymph nodes after systemic challenge showed that DC from TNFKO mice were relatively immature compared with those from strain-matched wild-type mice. In vitro, TNF-alpha was required to mature DC efficiently during virus-mediated stimulation. Adoptive transfer of primed, mature DC into TNFKO mice restored T cell responses and reconstituted anti-adenovirus antibody responses. Thus, TNF-alpha plays a significant role in the maturation of DC after adenovirus challenge both in vitro and in vivo, highlighting the importance of this innate cytokine in activating adaptive immunity to viral challenge.     

New insights into the cellular immunology of the intestine in relation to the pathophysiology of inflammatory bowel diseases

The authors review advances about altered immunological cellular mechanisms in inflammatory bowel diseases (IBD). The innate immune response might play a role in the inductive phase : epithelial barrier defect, production of inflammatory cytokines and defective neutrophil function. Dendritic cells have a pivotal role, since they sense the nature of the micro-organisms in the intestine in order to drive either adaptive immune responses through IL-12 or IL-4 and co-stimulatory molecules, or immunotolerance through regulatory T cells (Tr). T helper(Th)1 cytokines (IFNgamma, TNF-alpha, IL-12) are secreted in excess in Crohn's disease (CD) whereas in ulcerative colitis an atypical Th2 immune response (IL-4, TGFbeta) has been reported. However, activation of Th can only lead to effective immune response if co-stimulatory molecules expressed on activated T cells bind to their specific ligands on the antigen-presenting-cells, mesenchymal and endothe-, lial cells. This binding is necessary to generate an effective immune response, to enhance expression of adhesion molecules and T cell recruitment, promoting chronic inflammation in IBD. A defective function of Tr might contribute to excessive T cell response. Innate CD4 + CD25 + Tr derived from the thymus represent 5-10% of T cells in peripheral lymphoid organs. Acquired peripheral Tr downregulate the immune response through IL-10 and TGF-beta production. In IBD effector T cells might downregulate the development of Tr cells in the thymus. Another defective mechanism in CD is T cell resistance to apoptosis, leading to inappropriate immune homeostasis and accumulation of T cells in the tissues. New therapeutic agents have been proposed for correcting deficiencies of innate immunity or reducing excessive immune responses, with promising results confirmed by randomized controlled trials.     

Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses

The C-type lectin receptor dectin-1 functions as a pattern recognition receptor for beta-glucans and signals via Syk kinase but independently of the Toll-like receptor (TLR) pathway to regulate expression of innate response genes. Dectin-1 signaling can promote activation of dendritic cells (DCs), rendering them competent to prime Th1 and Th17 responses. Here we show that dectin-1-activated DCs can also prime cytotoxic T-lymphocyte (CTL) responses. DCs exposed to a dectin-1 agonist induced antigen-specific expansion of TCR transgenic CD8(+) T cells and their differentiation into CTLs in vitro. Dectin-1 agonist also acted as an adjuvant for CTL crosspriming in vivo, eliciting potent CTL responses that protected mice from tumor challenge. In vitro but not in vivo, CTL crosspriming was dependent on IL-12 p70, which was produced by dectin-1-activated DCs in response to IFN-gamma secreted by newly activated CD8(+) T cells. The dectin-1/Syk pathway is thus able to couple innate immune recognition of beta-glucans to all branches of the adaptive immune system, including CD4(+) T-helper cells, B cells, and CD8(+) cytotoxic T cells. These data highlight the ability of non-TLR receptors to bridge innate and adaptive immunity and suggest that dectin-1 agonists may constitute useful adjuvants for immunotherapy and vaccination.     

Modulating macrophage function with IgG immune complexes

Macrophages respond to bacterial products by releasing a large array of inflammatory mediators. We demonstrate that, in the presence of IgG immune complexes, macrophages produce high levels of IL-10 and virtually no IL-12, when they are exposed to bacterial products. The production of IL-10 by these cells can dampen innate inflammatory responses to microbial products, such as LPS. This alteration in macrophage cytokine production can also influence an adaptive immune response, preferentially inducing Th2-type immunity. Thus, immune complexes change the physiology of activated macrophages, converting them to anti-inflammatory cells that induce Th2-like immune responses. We have termed these cells type II activated macrophages.     

Discovery of immunostimulatory CpG-DNA and its application to tuberculosis vaccine development

DNA containing an unmethylated CpG motif has a potent immunostimulatory effect on the vertebrate immune system. Because such CpG motifs are relatively common in bacterial DNA, but rare in mammalian animal and plant DNA, they may be an evolutionary adaptation augmenting innate immunity, most likely in response to pathogens that replicate within the host cells, such as viruses and intracellular bacteria. Microbial infection induces innate immunity by triggering pattern-recognition systems. The infected cells produce proinflammatory cytokines that directly combat microbial invaders and express costimulating surface molecules, which develop adaptive immunity by inducing distinct T cell differentiation. Bacterial DNA with unmethylated CpG-DNA stimulates vertebrate immature immune cells to induce maturation and to produce TNF-alpha as well as Th1-type cytokines, IL-12 and IFN-gamma. Therefore, CpG-DNA functions as an adjuvant for regulating the initiation of Th1 differentiation. The roles of immunostimulatory CpG motifs in DNA vaccine developments and in therapeutic applications have been discussed.     

Research advances of vasoactive intestinal peptide in the pathogenesis of ulcerative colitis by regulating interleukin-10 expression in regulatory B cells

Ulcerative colitis (UC) is a chronic relapsed intestinal disease with an increasing incidence around the world. The pathophysiology of UC remains unclear. However, the role of the interaction between the enteric nervous system and the immune system in the pathogenesis of UC has been the focus of attention and has become a research hotspot. Vasoactive intestinal peptide (VIP) is a kind of endogenous neuropeptide with regulatory activity on intestinal immunity. It has been shown to regulate immune disorders in animal and human experiments and has become an effective anti-inflammatory and immune modulator that affects the innate immune system and adaptive immune system. Regulatory B cells (Bregs) are a new group of B cells that negatively regulate the immunity and have received extensive attention in immune circles. Bregs can regulate immune tolerance by producing interleukin (IL)-10, IL-35, and transforming growth factor-β, suppressing autoimmune diseases or excessive inflammatory responses. The secretion of IL-10 by Bregs induces the development of T helper (Th) 0 and Th2 cells. It also induces Th2 cytokines and inhibits Th1 cytokines, thereby inhibiting Th1 cells and the Th1/Th2 balance. With further clarity on the mechanism of the regulation of IL-10 expression by VIP in Bregs in colitis patients, we believe that Bregs can provide a novel strategy for the clinical treatment of UC. Thus, we aim to review the current literature on this evolving topic.