Memory in the innate and adaptive immune systems

Specific memory is a hallmark of the vertebrate adaptive immune system. However, recent experiments indicate that specific memory might also exist in the innate immune systems of invertebrates. At present, the underlying mechanisms are unknown; yet such phenomenological evidence is relevant for understanding the principles and evolution of immune defence.     

An emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis

Type I interferons are effector cytokines essential for the regulation of the innate immunity. A key effector of the type I interferon response that is dysregulated in autoimmunity and cancer is the cGAS-STING signalling axis. Recent work suggests that calcium and associated signalling proteins can regulate both cGAS-STING and autoimmunity. How calcium regulates STING activation is complex and involves both stimulatory and inhibitory mechanisms. One of these is calmodulin-mediated signalling that is necessary for STING activation. The alterations in calcium flux that occur during STING activation can also regulate autophagy, which in turn plays a role in innate immunity through the clearance of intracellular pathogens. Also connected to calcium signalling pathways is the cGAS inhibitor TREX1, a cytoplasmic exonuclease linked to several autoimmune diseases including systemic lupus erythematosus (SLE). In this review, we summarize these and other findings that indicate a regulatory role for calcium signalling in innate and autoimmunity through the cGAS-STING pathway.     

Shedding light on the immunomodulatory properties of galectins: novel regulators of innate and adaptive immune responses

Galectins are a large family of structurally related beta-galactoside-binding proteins that play a pivotal role in the control of cell differentiation, proliferation, activation and apoptosis of many different cell types including immune cells. By crosslinking specific glycoconjugates, different members of the galectin family behave as pro-inflammatory or anti-inflammatory "cytokine-like" mediators, acting at different levels of innate and adaptive immune responses. Here we will review recent advances on the role of galectins in key events of the immune and inflammatory response, such as tolerance induction, cell cycle progression, cell adhesion, chemotaxis, antigen presentation and apoptosis. In particular we will examine the influence of individual members of the galectin family in the physiology of different immune cell types involved in innate and adaptive immune responses. Moreover, we will discuss the importance of these sugar-binding proteins as therapeutic targets in Th1- and Th2-mediated immune disorders, an exciting area for future research.     

Shedding light on the immunomodulatory properties of galectins: Novel regulators of innate and adaptive immune responses

Galectins are a large family of structurally related β-galactoside-binding proteins that play a pivotal role in the control of cell differentiation, proliferation, activation and apoptosis of many different cell types including immune cells. By crosslinking specific glycoconjugates, different members of the galectin family behave as pro-inflammatory or anti-inflammatory “cytokine-like” mediators, acting at different levels of innate and adaptive immune responses. Here we will review recent advances on the role of galectins in key events of the immune and inflammatory response, such as tolerance induction, cell cycle progression, cell adhesion, chemotaxis, antigen presentation and apoptosis. In particular we will examine the influence of individual members of the galectin family in the physiology of different immune cell types involved in innate and adaptive immune responses. Moreover, we will discuss the importance of these sugar-binding proteins as therapeutic targets in Th1- and Th2-mediated immune disorders, an exciting area for future research. Published in 2004.     

Origins and evolutionary relationships between the innate and adaptive arms of immune systems

Long before vertebrates first appeared, protists, plants andanimals had evolved diverse, effective systems of innate immunity.Ancestors of the vertebrates utilized components of the complementsystem, protease-inhibitors, metal-binding proteins, carbohydrate-bindingproteins and other plasma-born molecules as humoral agents ofdefense. In these same animals, immunocytes endowed with a repertoireof defensive behaviors expressed Toll-like receptors. They madeNADPH oxidase, superoxide dismutase and other respiratory burstenzymes to produce toxic oxygen radicals, and nitric oxide synthaseto produce nitric oxide. Antimicrobial peptides and lytic enzymeswere in their armory. Immune responses were orchestrated bycytokines. Furthermore, genes within the immunoglobulin superfamilywere expressed to meet a variety of needs possibly includingdefense. However, recombination activating genes played no role.With the acquisition of one or more transposases and the resultingcapacity to generate diverse receptors from immunoglobulin genefragments, the adaptive (lymphoid) arm of the immune systemwas born. This may have coincided with the elaboration of theneural crest. Naturally, the role of the adaptive arm was initiallysubservient to the defensive functions of the pre-existing innatearm. The strong selective advantages that stemmed from having"sharp-shooters" (cells making antigen-specific receptors) onthe defense team ensured their retention. Refined through evolution,adaptive immunity, even in mammals, remains dependent upon cellsof the innate series (e.g., dendritic cells) for signals drivingtheir functional maturation. This paper calls for some freshthinking leading to a clearer vision of the origins and co-evolutionof the two arms of modern immune systems, and suggests a possibleneural origin for the adaptive immune system.     

Collectin surfactant protein D binds antibodies and interlinks innate and adaptive immune systems

Innate immune collectins, such as surfactant protein D (SP-D), contain fibrillar collagen-like regions and globular carbohydrate-recognition domains (CRDs). SP-D recognizes carbohydrate arrays present on microbial surfaces via its CRDs, agglutinates microbes and enhances their phagocytosis. In contrast, adaptive immune proteins such as immunoglobulins (Igs) recognize pathogens via binding to specific antigens. Here we show that: SP-D binds various classes of immunoglobins, including IgG, IgM, IgE and secretory IgA, but not serum IgA; the globular domains of SP-D bind both the Fab and Fc domains of IgG; SP-D recognizes IgG via calcium-dependent protein-protein interactions, aggregates IgG-coated beads and enhances their phagocytosis by murine macrophage RAW 264.7 cells. Therefore, we propose that SP-D effectively interlinks innate and adaptive immune systems.     

Secretory IgA N- and O-glycans provide a link between the innate and adaptive immune systems

Secretory IgA (SIgA) is a multi-polypeptide complex consisting of a secretory component (SC) covalently attached to dimeric IgA containing one joining (J) chain. We present the analysis of both the N- and O-glycans on the individual peptides from this complex. Based on these data, we have constructed a molecular model of SIgA1 with all its glycans, in which the Fab arms form a T shape and the SC is wrapped around the heavy chains. The O-glycan regions on the heavy (H) chains and the SC N-glycans have adhesin-binding glycan epitopes including galactose-linked beta1-4 and beta1-3 to GlcNAc, fucose-linked alpha1-3 and alpha1-4 to GlcNAc and alpha1-2 to galactose, and alpha2-3 and alpha2-6-linked sialic acids. These glycan epitopes provide SIgA with further bacteria-binding sites in addition to the four Fab-binding sites, thus enabling SIgA to participate in both innate and adaptive immunity. We also show that the N-glycans on the H chains of both SIgA1 and SIgA2 present terminal GlcNAc and mannose residues that are normally masked by SC, but that can be unmasked and recognized by mannose-binding lectin, by disrupting the SC-H chain noncovalent interactions.     

模式识别受体介导的天然免疫反应调节获得性免疫的机理

模式识别受体（PRR）的发现推动了免疫学领域的迅速发展.在近15年时间里,揭示了PRR启动的天然免疫反应机制及信号转导途径,并对天然免疫反应调节获得性免疫产生的机制进行了广泛研究.本文综述该领域一些新的重要发现,集中讨论病原体激活抗原递呈细胞的天然免疫反应调节淋巴细胞介导的抗原特异性获得性免疫机理,以及不同天然免疫途径在宿主抵抗感染和修复组织损伤中的作用,并讨论该领域尚未解决的重要问题.     

Induction of immune activation by a novel immunomodulatory oligonucleotide without thymocyte apoptosis

Bacterial DNA and synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs (CpG DNA) can potently stimulate innate immunity. While the actions of CpG DNA resemble those of LPS, these molecules stimulate distinct Toll-like receptors as well as cell types. In a previous study, we showed that a CpG ODN could induce cytokine production but, unlike LPS, did not induce thymocyte apoptosis. In this study, we have further investigated these differences using as a model a second-generation immunostimulatory oligonucleotide called HYB2048. Following administration to normal BALB/c mice, HYB2048-induced IL-12 but not IL-6 production. Under conditions in which LPS induced thymocyte apoptosis, HYB2048 did not cause significant cell death and, furthermore, did not block apoptosis induced by LPS. The levels of corticosterone induced by HYB2048 were also significantly lower than those induced by LPS. This pattern of activation could distinguish CpG DNA from LPS in its effects on the immune system.     

IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms

Interleukin(IL)-18 is a pleiotrophic cytokine with functions in immune modulation, angiogenesis and bone metabolism. In this study, the potential of IL-18 as an immunotherapy for prostate cancer (PCa) was examined using the murine model of prostate carcinoma, RM1 and a bone metastatic variant RM1(BM)/B4H7-luc. RM1 and RM1(BM)/B4H7-luc cells were stably transfected to express bioactive IL-18. These cells were implanted into syngeneic immunocompetent mice, with or without an IL-18-neutralising antibody (αIL-18, SK113AE4). IL-18 significantly inhibited the growth of both subcutaneous and orthotopic RM1 tumors and the IL-18 neutralizing antibody abrogated the tumor growth-inhibition. In vivo neutralization of interferon-gamma (IFN-γ) completely eliminated the anti-tumor effects of IL-18 confirming an essential role of IFN-γ as a down-stream mediator of the anti-tumor activity of IL-18. Tumors from mice in which IL-18 and/or IFN-γ was neutralized contained significantly fewer CD4(+) and CD8(+) T cells than those with functional IL-18. The essential role of adaptive immunity was demonstrated as tumors grew more rapidly in RAG1(-/-) mice or in mice depleted of CD4(+) and/or CD8(+) cells than in normal mice. The tumors in RAG1(-/-) mice were also significantly smaller when IL-18 was present, indicating that innate immune mechanisms are involved. IL-18 also induced an increase in tumor infiltration of macrophages and neutrophils but not NK cells. In other experiments, direct injection of recombinant IL-18 into established tumors also inhibited tumor growth, which was associated with an increase in intratumoral macrophages, but not T cells. These results suggest that local IL-18 in the tumor environment can significantly potentiate anti-tumor immunity in the prostate and clearly demonstrate that this effect is mediated by innate and adaptive immune mechanisms.     

Yersinia's stratagem: targeting innate and adaptive immune defense

In contrast to Salmonella and Shigella, enteropathogenic Yersinia species are extracellular multiplying Gram-negative bacteria. This life style requires a sophisticated anti-host strategy, which is implemented by the Yersinia virulence plasmid. This plasmid encodes the type 3 secretion system (injectisome), at least six microinjected anti-host effector proteins, a trimeric coiled coil outer membrane protein (Yersinia adhesin) with cell adhesin and protective functions against complement and defensins, and the released V antigen, which has Toll-like receptor 2 agonist activity.     

The role of leptin in innate and adaptive immune responses

Leptin is produced primarily by adipocytes and functions in a feedback loop regulating body weight. Leptin deficiency results in severe obesity and a variety of endocrine abnormalities in animals and humans. Several studies indicated that leptin plays an important role in immune responses. It exerts protective anti-inflammatory effects in models of acute inflammation and during activation of innate immune responses. In contrast, leptin stimulates T lymphocyte responses, thus having rather a proinflammatory role in experimental models of autoimmune diseases. Clinical studies have so far yielded inconsistent results, suggesting a rather complex role for leptin in immune-mediated inflammatory conditions in humans.     

The role of alveolar epithelial cells in initiating and shaping pulmonary immune responses: communication between innate and adaptive immune systems

Macrophages and dendritic cells have been recognized as key players in the defense against mycobacterial infection. However, more recently, other cells in the lungs such as alveolar epithelial cells (AEC) have been found to play important roles in the defense and pathogenesis of infection. In the present study we first compared AEC with pulmonary macrophages (PuM) isolated from mice in their ability to internalize and control Bacillus Calmette-Guérin (BCG) growth and their capacity as APCs. AEC were able to internalize and control bacterial growth as well as present antigen to primed T cells. Secondly, we compared both cell types in their capacity to secrete cytokines and chemokines upon stimulation with various molecules including mycobacterial products. Activated PuM and AEC displayed different patterns of secretion. Finally, we analyzed the profile of response of AEC to diverse stimuli. AEC responded to both microbial and internal stimuli exemplified by TLR ligands and IFNs, respectively. The response included synthesis by AEC of several factors, known to have various effects in other cells. Interestingly, TNF could stimulate the production of CCL2/MCP-1. Since MCP-1 plays a role in the recruitment of monocytes and macrophages to sites of infection and macrophages are the main producers of TNF, we speculate that both cell types can stimulate each other. Also, another cell-cell interaction was suggested when IFNs (produced mainly by lymphocytes) were able to induce expression of chemokines (IP-10 and RANTES) by AEC involved in the recruitment of circulating lymphocytes to areas of injury, inflammation, or viral infection. In the current paper we confirm previous data on the capacity of AEC regarding internalization of mycobacteria and their role as APC, and extend the knowledge of AEC as a multifunctional cell type by assessing the secretion of a broad array of factors in response to several different types of stimuli.     

Heat shock proteins: the fountainhead of innate and adaptive immune responses

The ability of heat shock proteins to (1) chaperone peptides, including antigenic peptides; (2) interact with antigen-presenting cells through a receptor; (3) stimulate antigen-presenting cells to secrete inflammatory cytokines; and (4) mediate maturation of dendritic cells, makes them a unique starting point for generation of immune responses. These properties also permit the use of heat shock proteins for development of a new generation of prophylactic and therapeutic vaccines against cancers and infectious diseases.     

Genetic analysis of innate immunity: TIR adapter proteins in innate and adaptive immune responses

The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as "Toll-like receptors" (TLRs), of which 10 representatives are encoded in the human genome. Our understanding of the sensing role played by the TLRs began with the positional cloning of a spontaneous mutation (Lps(d)) in the gene encoding the mammalian lipopolysaccharide (LPS) receptor. Other key innate immunity proteins have been disclosed by germline mutagenesis, and are discussed in the present review.     

Influence of fiber detargeting on adenovirus-mediated innate and adaptive immune activation

The major adenovirus (Ad) capsid proteins hexon, penton, and fiber influence the efficiency and tropism of gene transduction by Ad vectors. Fiber is the high-affinity receptor binding protein that serves to mediate cell attachment in vitro when using coxsackie-adenovirus receptor (CAR)-containing cell lines. This contrasts with transduction efficiency in macrophages or dendritic cells that lack high concentrations of CAR. To determine how fiber influences gene transduction and immune activation in a murine model, we have characterized Ad type 5 (Ad5) vectors with two classes of chimeric fiber, CAR binding and non-CAR binding. In a systemic infection, Ad5 fiber contributes to DNA localization and vector transduction in hepatic tissue. However, the majority of vector localization is due to Ad5 fiber-specific functions distinct from CAR binding. CAR-directed transduction occurs but at a modest level. In contrast to CAR binding vectors, the F7 and F7F41S non-CAR-binding vectors demonstrate a 2-log decrease in hepatic transduction, with a 10-fold decrease in the amount of vector DNA localizing to the hepatic tissue. To characterize the innate response to early infection using fiber chimeric vectors, intrahepatic cytokine and chemokine mRNAs were quantified 5 hours postinfection. Tumor necrosis factor alpha mRNA levels resulting from Ad5 fiber infections were elevated compared to viruses expressing serotype 7 or 41 fiber. Levels of chemokine mRNA (gamma interferon-inducible protein 10, T-cell activation gene 3, and macrophage inflammatory protein 1beta) were 10- to 20-fold higher with CAR binding vectors (Ad5 and F41T) than with non-CAR-binding vectors (F7 and F7F41S). In spite of quantitative differences in vector localization and innate activation, fiber pseudotyping did not significantly change the outcome of anti-Ad adaptive immunity. All vectors were cleared with the same kinetics as wild-type Ad5 vectors, and each induced neutralizing antibody. Although non-CAR-binding vectors were impaired in transduction by nearly 2 orders of magnitude, the level of antitransgene immunity was the same for each of the vectors. Using primary bone marrow-derived macrophages and dendritic cells, we demonstrate that transduction, induction of cytokine/chemokine, and phenotypic maturation of these antigen-presenting cells are independent of fiber content. Our data support a model where fiber-mediated hepatic localization enhances innate responses to virus infection but minimally impacts on adaptive immunity.