Academic literature on the topic 'Regulation of innate immunity and inflammatory responses'

Innate immune cells monitor invading pathogens and pose the first-line inflammatory response to coordinate with adaptive immunity for infection removal. Innate immunity also plays pivotal roles in injury-induced tissue remodeling and the maintenance of tissue homeostasis in physiological and pathological conditions. Lipid metabolites are emerging as the key players in the regulation of innate immune responses, and recent work has highlighted the importance of the lipid metabolite palmitate as an essential component in this regulation. Palmitate modulates innate immunity not only by regulating the activation of pattern recognition receptors in local innate immune cells, but also via coordinating immunological activity in inflammatory tissues. Moreover, protein palmitoylation controls various cellular physiological processes. Herein, we review the updated evidence that palmitate catabolism contributes to innate immune cell-mediated inflammatory processes that result in immunometabolic disorders.

Pattern recognition receptors detect microbial components and induce innate immune responses, the first line of host defense against infectious agents. However, aberrant activation of immune responses often causes massive inflammation, leading to the development of autoimmune diseases. Therefore, both activation and inactivation of innate immune responses must be strictly controlled. Recent studies have shown that the cellular machinery associated with protein degradation, such as autophagy, is important for the regulation of innate immunity. These studies reveal that autophagy-related proteins are involved in the innate immune response and may contribute to the development of inflammatory disorders.

Inflammation plays an essential role in the control of pathogens and in shaping the ensuing adaptive immune responses. Traditionally, innate immunity has been described as a rapid response triggered through generic and nonspecific means that by definition lacks the ability to remember. Recently, it has become clear that some innate immune cells are epigenetically reprogrammed or “imprinted” by past experiences. These “trained” innate immune cells display altered inflammatory responses upon subsequent pathogen encounter. Remembrance of past pathogen encounters has classically been attributed to cohorts of antigen-specific memory T and B cells following the resolution of infection. During recall responses, memory T and B cells quickly respond by proliferating, producing effector cytokines, and performing various effector functions. An often-overlooked effector function of memory CD4 and CD8 T cells is the promotion of an inflammatory milieu at the initial site of infection that mirrors the primary encounter. This memory-conditioned inflammatory response, in conjunction with other secondary effector T cell functions, results in better control and more rapid resolution of both infection and the associated tissue pathology. Recent advancements in our understanding of inflammatory triggers, imprinting of the innate immune responses, and the role of T cell memory in regulating inflammation are discussed.

IL-27 is a pleiotropic cytokine capable of influencing both innate and adaptive immune responses. With anti- and pro-inflammatory activity, IL-27 exerts its opposing effects in a cell-dependent and infectious context-specific manner. Upon pathogenic stimuli, IL-27 regulates innate immune cells, such as monocytes, dendritic cells, macrophages and neutrophils. Immune responses involving these innate cells that are negatively regulated by IL-27 signaling include inflammatory cytokine production, phagolysosomal acidification following phagocytosis, oxidative burst and autophagy. IL-27 signaling is crucial in maintaining the subtle balance between Th1 and Th2 immunity, in which protective inflammation is upregulated within the early stages of infection and subsequently downregulated once microbial growth is controlled. The immunomodulatory effects of IL-27 provide promising therapeutic targets for multiple disease types.

Tyro3, Axl, MERTK (TAM) receptor tyrosine kinases are implicated in the regulation of the innate immune response through clearance of apoptotic cellular debris and control of cytokine signaling cascades. As a result they are pivotal in regulating the inflammatory response to tissue injury. Within the liver, immune regulatory signaling is employed to prevent the overactivation of innate immunity in response to continual antigenic challenge from the gastrointestinal tract. In this review we appraise current understanding of the role of TAM receptor function in the regulation of both innate and adaptive immunity, with a focus on its impact upon hepatic inflammatory pathology.

RNA acts as an immunostimulatory molecule in the innate immune system to activate nucleic acid sensors. It functions as an intermediate, conveying genetic information to control inflammatory responses. A key mechanism for RNA sensing is discriminating self from non-self nucleic acids to initiate antiviral responses reliably, including the expression of type I interferon (IFN) and IFN-stimulated genes. Another important aspect of the RNA-mediated inflammatory response is posttranscriptional regulation of gene expression, where RNA-binding proteins (RBPs) have essential roles in various RNA metabolisms, including splicing, nuclear export, modification, and translation and mRNA degradation. Recent evidence suggests that the control of mRNA stability is closely involved in signal transduction and orchestrates immune responses. In this study, we review the current understanding of how RNA is sensed by host RNA sensing machinery and discuss self/non-self-discrimination in innate immunity focusing on mammalian species. Finally, we discuss how posttranscriptional regulation by RBPs shape immune reactions.

Mycobacterium tuberculosis and cancer are two diseases with proclivity for the development of resistance to the host immune system. Mechanisms behind resistance can be host derived or disease mediated, but they usually depend on the balance of pro-inflammatory to anti-inflammatory immune signals. Immunotherapies have been the focus of efforts to shift that balance and drive the response required for diseases eradication. The immune response to tuberculosis has widely been thought to be T cell dependent, with the majority of research focused on T cell responses. However, the past decade has seen greater recognition of the importance of the innate immune response, highlighting factors such as trained innate immunity and macrophage polarization to mycobacterial clearance. At the same time, there has been a renaissance of immunotherapy treatments for cancer since the first checkpoint inhibitor passed clinical trials, in addition to work highlighting the importance of innate immune responses to cancer. However, there is still much to learn about host-derived responses and the development of resistance to new cancer therapies. This review examines the similarities between the immune responses to cancer and tuberculosis with the hope that their commonalities will facilitate research collaboration and discovery.

Recent years have witnessed an emergence of interest in understanding metabolic changes associated with immune responses, termed immunometabolism. As oxygen is central to all aerobic metabolism, hypoxia is now recognized to contribute fundamentally to inflammatory and immune responses. Studies from a number of groups have implicated a prominent role for oxygen metabolism and hypoxia in innate immunity of healthy tissue (physiologic hypoxia) and during active inflammation (inflammatory hypoxia). This inflammatory hypoxia emanates from a combination of recruited inflammatory cells (e.g., neutrophils, eosinophils, and monocytes), high rates of oxidative metabolism, and the activation of multiple oxygen-consuming enzymes during inflammation. These localized shifts toward hypoxia have identified a prominent role for the transcription factor hypoxia-inducible factor (HIF) in the regulation of innate immunity. Such studies have provided new and enlightening insight into our basic understanding of immune mechanisms, and extensions of these findings have identified potential therapeutic targets. In this review, we summarize recent literature around the topic of innate immunity and mucosal hypoxia with a focus on transcriptional responses mediated by HIF.

ABSTRACT The control of lung inflammation is of paramount importance in a variety of acute pathologies, such as pneumonia, the acute respiratory distress syndrome, and sepsis. It is becoming increasingly apparent that local innate immune responses in the lung are negatively influenced by systemic inflammation. This is thought to be due to a local deficit in cytokine responses by alveolar macrophages and neutrophils following systemic bacterial infection and the development of a septic response. Recently, using an adenovirus-based strategy which overexpresses the human elastase inhibitor elafin locally in the lung, we showed that elafin is able to prime lung innate immune responses. In this study, we generated a novel transgenic mouse strain expressing human elafin and studied its response to bacterial lipopolysaccharide (LPS) when the LPS was administered locally in the lungs and systemically. When LPS was delivered to the lungs, we found that mice expressing elafin had lower serum-to-bronchoalveolar lavage ratios of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein 2, and monocyte chemoattractant protein 1, than wild-type mice. There was a concomitant increase in inflammatory cell influx, showing that there was potential priming of innate responses in the lungs. When LPS was given systemically, the mice expressing elafin had reduced levels of serum TNF-α compared to the levels in wild-type mice. These results indicate that elafin may have a dual function, promoting up-regulation of local lung innate immunity while simultaneously down-regulating potentially unwanted systemic inflammatory responses in the circulation.

AbstractProgrammed death one (PD-1) is an inducible molecule belonging to the immunoglobulin superfamily. It is expressed on activated T and B lymphocytes and plays pivotal roles in the negative regulation of adaptive immune responses. We report here an unexpected finding: that PD-1 could also be induced on splenic dendritic cells (DCs) by various inflammatory stimuli. Adoptive transfer of PD-1–deficient DCs demonstrates their superior capacity to wild-type DCs in innate protection of mice against lethal infection by Listeria monocytogenes. Furthermore, PD-1–deficient mice are also more resistant to the infection than wild-type controls, even in the absence of T and B cells, accompanied by elevated production of DC-derived interleukin-12 and tumor necrosis factor-α. Our results reveal a novel role of PD-1 in the negative regulation of DC function during innate immune response.

IL-36 gamma is a proinflamatory cytokine which belongs to the IL-1 family of cytokines. It is expressed in the skin and by epithelial cells (ECs) lining lung and gut tissue. We used human 3-D organotypic cells, that recapitulate either in vivo human vaginal or cervical tissue, to explore the possible role of IL-36 gamma in host defense against pathogens in the human female reproductive tract (FRT). EC were exposed to compounds derived from virus or bacterial sources and induction and regulation of IL-36 gamma and its receptor was determined. Polyinosinic-polycytidylic acid (poly I:C), flagellin, and synthetic lipoprotein (FSL-1) significantly induced expression of IL-36 gamma in a dose-dependent manner, and appeared to be TLR-dependent. Recombinant IL-36 gamma treatment resulted in self amplification of IL-36 gamma and its receptor (IL-36R) via increased gene expression, and promoted other inflammatory signaling pathways. This is the first report to demonstrate that the IL-36 receptor and IL-36 gamma are present in the human FRT EC and that they are differentially induced by microbial products at this site. We conclude that IL-36 gamma is a driver for epithelial and immune activation following microbial insult and, as such, may play a critical role in host defense in the FRT.

La polyarthrite rhumatoïde (PR) est la maladie auto-immune la plus fréquente d'une prévalence de 1%. Les cellules résidentes de la cavité synoviale, les fibroblast-like synoviocytes (FLS), sont des acteurs majeurs de la PR. Leur activation par des récepteurs de l'immunité innée participe à l'acquisition d'un phénotype agressif menant à la destruction ostéo-articulaire. Dans cette étude, nous avons évalué le rôle régulateur de miARN sur les voies de signalisation des Toll-like receptors (TLR). L'activation de TLR2 et de TLR4 dans les FLS induit la diminution de l'expression de plusieurs miARN, dont miR-19a et b (miR-19), alors que TLR2 est surexprimé. Nous avons pu ainsi montrer que miR-19 régule Tlr2 et que la transfection de mir-19 dans les FLS activés induit une diminution de l'expression de TLR2 et de la synthèse d'IL-6 et de MMP-3. Mir-19 appartient au cluster miR-17~92, dont l'expression est abaissée dans les FLS. Il code pour 6 miARN dont miR-20a. miR-20a est également sous-régulé après activation de TLR2 et TLR4 dans les FLS et les THP-1. Nous avons montré que miR-20a régule directement l'expression d'Ask1, impliquée et surexprimée après activation de TLR4. La transfection de miR-20a in vitro nous a permis de montrer que miR-20a contrôle l'expression d'ASK1 et induit une inhibition de la synthèse de cytokines majeures de la PR dans les FLS et les THP-1. Des résultats équivalents ont été obtenus ex vivo chez la souris. Ces travaux ont permis d'identifier dans les FLS rhumatoïdes des miARN anti-inflammatoires dont la baisse d'expression permet une augmentation de l'expression de TLR2 et d'ASK1. Ces miARN pourraient donc constituer de nouvelles cibles thérapeutiques.

Les azasulfurylpeptides sont des mimes peptidiques auxquels le carbone en position alpha et le carbonyle d’un acide aminé sont respectivement remplacés par un atome d’azote et un groupement sulfonyle (SO2). Le but premier de ce projet a été de développer une nouvelle méthode de synthèse de ces motifs, également appelés N-aminosulfamides. À cette fin, l’utilisation de sulfamidates de 4-nitrophénol s’est avérée importante dans la synthèse des azasulfuryltripeptides, permettant le couplage d’hydrazides avec l’aide d’irradiation aux micro-ondes (Chapitre 2). Par la suite, en quantité stoechiométrique d’une base et d’un halogénure d’alkyle, les azasulfurylglycines (AsG) formés peuvent être chimiosélectivement alkylés afin d’y insérer diverses chaînes latérales. Les propriétés conformationnelles des N-aminosulfamides à l’état solide ont été élucidées grâce à des études cristallographiques par rayons X : elles possèdent une structure tétraédrique autour de l’atome de soufre, des traits caractéristiques des azapeptides et des sulfonamides, ainsi que du potentiel à favoriser la formation de tours gamma (Chapitre 3). Après le développement d’une méthode de synthèse des N-aminosulfamides en solution, une approche combinatoire sur support solide a également été élaborée sur la résine amide de Rink afin de faciliter la génération d’une librairie d’azasulfurylpeptides. Cette étude a été réalisée en employant le growth hormone releasing peptide 6 (GHRP-6, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2). Ce dernier est un hexapeptide possédant une affinité pour deux récepteurs, le growth hormone secretagogue receptor 1a (GHS-R1a) et le récepteur cluster of differenciation 36 (CD36). Une affinité sélective envers le récepteur CD36 confère des propriétés thérapeutiques dans le traitement de la dégénérescence maculaire liée à l’âge (DMLA). Six analogues d’azasulfurylpeptides de GHRP-6 utilisés comme ligands du CD36 ont été synthétisés sur support solide, mettant en évidence le remplacement du tryptophane à la position 4 de GHRP-6 (Chapitre 4). Les analogues de GHRP-6 ont été ensuite analysés pour leur capacité à moduler les effets de la fonction et de la cascade de signalisation des ligands spécifiques au Toll-like receptor 2 (TLR2), en collaboration avec le Professeur Huy Ong du département de Pharmacologie à la Faculté de Pharmacie de l’Université de Montréal. Le complexe TLR2-TLR6 est reconnu pour être co-exprimé et modulé par CD36. En se liant au CD36, certains ligands de GHRP-6 ont eu un effet sur la signalisation du TLR2. Par exemple, les azasulfurylpeptides [AsF(4-F)4]- et [AsF(4-MeO)4]-GHRP-6 ont démontré une capacité à empêcher la surproduction du monoxyde d’azote (NO), un sous-produit réactif formé suite à l’induction d’un signal dans les macrophages par des ligands spécifiques liés au TLR2, tel le fibroblast-stimulating lipopeptide 1 (R-FSL-1) et l’acide lipotéichoïque (LTA). En addition, la sécrétion du tumor necrosis factor alpha (TNFa) et du monocyte chemoattractant protein 1 (MCP-1), ainsi que l’activation du nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), ont été réduites. Ces résultats démontrent le potentiel de ces azasulfurylpeptides à pouvoir réguler le rôle du TLR2 qui déclenche des réponses inflammatoires et immunitaires innées (Perspectives). Finalement, le potentiel des azasulfurylpeptides d’inhiber des métallo-bêta-lactamases, tels le New-Delhi Metallo-bêta-lactamase 1 (NDM-1), IMP-1 et le Verona Integron-encoded Metallo-bêta-lactamase 2 (VIM-2), a été étudié en collaboration avec le Professeur James Spencer de l’Université de Bristol (Royaumes-Unis). Certains analogues ont été des inhibiteurs micromolaires du IMP-1 (Perspectives). Ces nouvelles voies de synthèse des azasulfurylpeptides en solution et sur support solide devraient donc permettre leur utilisation dans des études de relations structure-activité avec différents peptides biologiquement actifs. En plus d'expandre l'application des azasulfurylpeptides comme inhibiteurs d'enzymes, cette thèse a révélé le potentiel de ces N-aminosulfamides à mimer les structures secondaires peptidiques, tels que les tours gamma. À cet égard, l’application des azasulfurylpeptides a été démontrée par la synthèse de ligands du CD36 présentant des effets modulateurs sur le TLR2. Compte tenu de leur synthèse efficace et de leur potentiel en tant qu’inhibiteurs, les azasulfurylpeptides devraient trouver une large utilisation dans les sciences de peptides pour des applications dans la médecine et de la chimie biologique.
The azasulfurylpeptides are peptide mimics in which the alpha carbon and the carbonyl of an amino acid residue are respectively replaced by a nitrogen atom and a sulfonyl group (SO2). The primary goal of this doctorate project was to develop a new effective method for the synthesis of these motifs, also called N-aminosulfamides. Towards this aim, the use of 4-nitrophenyl sulfamidates turned out to be important in the synthesis of azasulfuryltripeptides, allowing hydrazide couplings under micro-wave irradiation (Chapter 2). Side-chain diversity was then added using a stoichiometric amount of base and different alkyl halides to alkylate chemoselectively the azasulfurylglycine (AsG) residue. The conformational properties of the N-aminosulfamides in the solid state were studied using X-Ray crystallography, which showed a tetrahedral geometry about the sulfur atom, features of azapeptides and sulfonamides, as well as potential to favor the formation of gamma turns (Chapter 3). Following the development of the synthesis of these N-aminosulfamides in solution, a combinatorial approach on solid support was elaborated on Rink amide resin to generate a library of azasulfurylpeptides. The study was performed using the Growth Hormone Releasing Peptide 6 (GHRP-6, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2). The latter is a hexapeptide that has affinity for two receptors, the Growth Hormone Secretagogue Receptor 1a (GHS-R1a) and the Cluster of Differenciation 36 (CD36) receptor. Selective binding to the CD36 receptor has therapeutic potential in the treatment of age-related macular degeneration (AMD). Six azasulfurylpeptide analogs were synthesized on solid support by replacing tryptophan at the 4th position of GHRP-6 with different N-aminosulfamide residues (Chapter 4). The GHRP-6 analogs were tested for their ability to mediate the effects of receptor-specific ligands on the function and downstream signaling of the Toll-Like Receptor 2 (TLR2), in collaboration with Professor Huy Ong at the department of Pharmacology in the Faculty of Pharmacy at the Université de Montréal. The TLR2-TLR6 complex is known to be co-expressed and modulated by CD36. On binding to CD36, certain GHRP-6 ligands exhibited effects on the signaling of TLR2. For example, the azasulfurylpeptides [4-F-AsF4]- and [4-MeO-AsF4]-GHRP-6 prevented the overproduction of nitric oxide (NO), a reactive oxygen species formed following the induction of signal in macrophages on binding of TLR2-specific ligands, such as the Fibroblast-Stimulating Lipopeptide 1 (R-FSL-1) and lipoteichoic acid (LTA). Furthermore, the secretion of the Tumor Necrosis Factor Alpha (TNFa) and Monocyte Chemoattractant Protein 1 (MCP-1), as well as the activation of the Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NF-kB), all were reduced. These results offer promise for regulating Toll-like receptor roles in triggering innate immunity and inflammatory responses (Perspectives). Finally, the potential of the azasulfurylpeptides to inhibit metallo-bêta-lactamases, such as the New-Delhi Metallo-β-lactamase 1 (NDM-1), IMP-1 and the Verona Integron-encoded Metallo-bêta-lactamase 2 (VIM-2), has been studied in collaboration with Professor James Spencer at the University of Bristol (United-Kingdom). Some analogs were micromolar inhibitors of IMP-1 (Perspectives). These new approaches for the synthesis of azasulfurylpeptides in solution and on solid support should enable their use in studies of structure-activity relationships with different biologically active peptides. In addition to expanding the application of azasulfurylpeptides as enzyme inhibitors, this thesis has revealed the potential of these N-aminosulfamides to mimic the peptide secondary structures, such as gamma turns. Application of azasulfurylpeptides in this respect has been demonstrated by the synthesis of CD36 ligands exhibiting modulatory effects on the TLR2. Considering their effective synthesis and potential as inhibitors, azasulfurylpeptides should find broad use in peptide science for applications in medicine and chemical biology.

Interleukins, cytokines secreted by leukocytes, are predominant messengers modulating immune responses. Interleukin-27 (IL-27), a key immunomodulatory cytokine, functions to induce both pro- and anti-inflammatory effects in various immune cells. IL-27 is a heterodimeric cytokine, composed of IL-27p28 and Epstein-Bar virus induced gene 3 (EBI3) subunits, and binds to a receptor composed of IL-27Rα (WSX-1) and gp130. Initial studies focused on describing IL-27 functions in skewing T helper cell development to a Th1 response, with few reports on functions in monocytes. Thus, in this thesis, I aimed to characterize novel functions of IL-27 in innate immune responses of monocytes. I initially established that IL-27 induced a pro-inflammatory cytokine profile (IL-6, IP-10, MIP-1α, MIP-1β, and TNF-α) mediated via STAT1/3 and NF-κB signaling pathways. Further investigation led to the discovery that IL-27 could enhance LPS responses via upregulation of TLR4 expression and NF-κB signaling. Together, these studies described novel signaling mechanisms (NF-κB and JAK/STAT crosstalk) and gene targets (cytokines and TLR4) of IL-27 that drive inflammatory responses. In continuing the quest for novel IL-27 functions in innate immunity, I reported IL-27 can upregulate expression of the IFN-responsive, antiviral protein called BST-2. My results showing IL-27-induced expression of BST-2 mRNA and cell surface protein were supported by previous studies reporting IL-27-induced expression of other antiviral molecules. Furthermore, previous studies showed IL-27 could inhibit HIV replication via antiviral gene induction, pointing to potential for IL-27 immunotherapies. In light of the posited role for IL-27 in therapeutics, it became inherently critical to describe how IL-27 functions in the setting of HIV infection. Thus, in my final thesis chapters, I described the effect of HIV infection on IL-27 expression and functions, addressing a substantial void in literature. Interestingly, a trend of decreased IL-27 expression and significant impairment of IL-27-induced gene expression was observed in HIV infection. Therefore, decreased circulating IL-27 and decreased IL-27 responsiveness may collectively dysregulate IL-27 function in HIV. This thesis describes novel, IL-27-driven, proinflammatory responses, and highlights impairment of IL-27 function in HIV infection. This work bridged a gap in knowledge of IL-27 functions in monocytes and highlighted multifaceted mechanisms underlying immunoregulation by IL-27.
Thesis (Ph.D, Microbiology & Immunology) -- Queen's University, 2012-04-12 13:07:50.588

A significant overlap exists between spondyloarthritis (SpA) and inflammatory bowel disease (IBD), particularly in the IL-23/IL-17 pathway. Shared immunologic mechanisms include aberrant innate immune responses, an excess of Th1/Th17-mediated immunity, and inadequate immune regulation. Many genetic factors associated with IBD are involved in host–pathogen interactions and intestinal barrier function, and the intestinal microbiota do appear to play an important role in disease development. Hence the current hypothesis for IBD pathogenesis is that it stems from a dysregulated immune response to intestinal microbiota in a genetically susceptible host. In SpA, evidence for a role of intestinal microbiota is less abundant, but given the overlap with IBD, it is plausible that gut microbiota are important players in SpA pathogenesis as well. However, there are significant genetic differences between these two conditions, as well as differing responses to biologic therapy.

The chapter focuses on the role of immunity and inflammation in established cancer. From the evidence reviewed it is clear that immune and inflammatory responses, innate, humoral and adaptive, local and systemic, are intimately linked to the tumour and themselves and impact on cancer survival. It is also possible to identify key mediators that may be targeted in the cancer patient. However, further work is required to elucidate the mechanisms by which these immune and inflammatory responses are activated, maintained, and interact. Therapeutic intervention using non-selective anti-inflammatory agents is widely advocated and likely to become part of routine clinical practice in the near future. Selective therapeutic intervention directed at the immune and inflammatory responses in cancer is in its infancy. Therefore, it would appear that, at least in non-hereditary disease, immune and inflammatory responses are of key, if not of prime, importance in tumour progression and dissemination.

The adaptive T-cell response represents the most sophisticated component of the immune response. Foreign invaders are recognized first by cells of the innate immune system. This leads to a rapid and non-specific inflammatory response, followed by induction of the adaptive and specific immune response. Different adaptive responses can be promoted, depending on the predominant effector cells that are involved, which themselves depend on the microbial/antigen stimuli. As examples, Th1 cells contribute to cell-mediated immunity against intracellular pathogens, Th2 cells protect against parasites, and Th17 cells act against extracellular bacteria and fungi that are not cleared by Th1 and Th2 cells. Among the new subsets, Th22 cells protect against disruption of epithelial layers secondary to invading pathogens. Finally these effector subsets are regulated by regulatory T cells. These T helper subsets counteract each other to maintain the homeostasis of the immune system, but this balance can be easily disrupted, leading to chronic inflammation or autoimmune diseases. The challenge is to detect early changes in this balance, prior to its clinical expression. New molecular tools such as microarrays could be used to determine the predominant profile of the immune effector cells involved in a disease process. Such understanding should provide better therapeutic tools to counteract deregulated effector cells.

Advances in modern medicine, such as organ transplantations and the appearance of HIV (human immunodeficiency virus), have significantly increased the patient cohort at risk of developing chronic superficial and life-threatening invasive fungal infections. To tackle this major healthcare problem, there is an urgent need to understand immunity against fungal infections for the purposes of vaccine design or immune-mediated interventions. In this chapter, we give an overview of the components of the innate and adaptive immune system and how they contribute to host defence against fungi. The various cell types contributing to fungal recognition and the subsequent stimulation of phagocytosis, the activation of inflammatory and B- and T-cell responses, and fungal clearance are discussed using the major fungal pathogens as model systems.

Toll-like receptors (TLRs) are the most essential pattern recognition receptors in mediating the effects of innate immunity. It plays a pivotal role in inducing immune response against a number of pathogens, various diseases conditions including pathogenesis of cancer. Inflammation is often associated with the development and progression of most of cancer, where TLRs interplay very crucial roles. Moreover, TLRs activation can impact the initiation, progression and treatment of cancer by modulating the inflammatory microenvironment. Rapidly growing number of evidences related to TLRs function and expression in cancer cells, suggests its critical association with chemoresistance and tumourigenesis. The current chapter describes the development of various agonist and antagosist for TLRs and their application in cancer therapeutics. The aim of this book chapter is to highlights basic features of TLRs, and its role in cancer progression. It also addresses, how a defect in the TLRs signaling pathway can contributes towards carcinogenesis and recent development of cancer therapeutics that target TLR signaling pathways.

The chapter focuses on the role of immunity and inflammation in established cancer. From the evidence reviewed it is clear that immune and inflammatory responses, innate, humoral and adaptive, local and systemic, are intimately linked to the tumour and themselves and impact on cancer survival. It is also possible to identify key mediators that may be targeted in the cancer patient. However, further work is required to elucidate the mechanisms by which these immune and inflammatory responses are activated, maintained, and interact. Therapeutic intervention using non-selective anti-inflammatory agents is widely advocated and likely to become part of routine clinical practice in the near future. Selective therapeutic intervention directed at the immune and inflammatory responses in cancer is in its infancy. Therefore, it would appear that, at least in non-hereditary disease, immune and inflammatory responses are of key, if not of prime, importance in tumour progression and dissemination.

Cytological diagnosis of infectious diseases is as important as the cytodiagnosis of malignancies, because the detection of pathogens in cytological specimens is crucially valuable for prompt and appropriate patients’ treatment. When compared with histological diagnosis, cytology is strong at detecting microbes under Papanicolaou and Giemsa stains. Host response against the infectious agent can be estimated by the type of background inflammatory cells. Patterns of the inflammatory cellular responses against extracellular and intracellular pathogens should be recognized. Immunocytochemical and molecular approaches can be applied, even when we have only one cytology specimen in hand. The cell transfer technique is useful to create plural material from one glass slide for immunocytochemistry and other techniques. In case of transmissible disorders including sexually transmitted diseases, the prompt and appropriate diagnosis will avoid avoidable transmission of infectious agents among people, and eventually contribute to the safety of the human society.

To protect the male germ cells from adverse immune reaction, the male reproductive system adopts special immune environment such as immunoprivileged status. The male genital organs can be infected by various microorganisms via hematogenous dissemination and ascending genitourinary tracts. To overcome the immunoprivileged status, the male genital organs also adopt their own innate defense against microbial infection. The tissue-specific cells in the male reproductive system are well equipped with innate immune machineries, including pattern recognition receptors (PRRs) and their negatively regulatory system. PRR-initiated immune responses must be tightly regulated by the negative regulatory system for the maintenance of immune homeostasis. The immune homeostasis can be disrupted by unrestrictive innate immune response, which may lead to inflammatory conditions in the male genital tracts, an important etiological factor contributing to male infertility. This chapter describes the current understanding of the innate immune responses in the male reproductive system and their effects on male fertility.

Apart from its traditional role in disease control, recent body of evidence has implicated a role of the immune system in regulating metabolic homeostasis. Owing to the importance of this “immune-metabolic alignment” in dictating a state of health or disease, a proper mechanistic understanding of this alignment is crucial in opening up for promising therapeutic approaches against a broad range of chronic, metabolic, and inflammatory disorders like obesity, diabetes, and inflammatory bowel syndrome. In this project, we addressed the role of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) innate immune pathway in regulating different metabolic parameters using the Drosophila melanogaster (DM) fruit fly model organism. Mutant JAK/STAT pathway flies with a systemic knockdown of either Domeless (Dome) [domeG0282], the receptor that activates JAK/STAT signaling, or the signal-transducer and activator of transcription protein at 92E (Stat92E) [stat92EEY10528], were used. The results of the study revealed that blocking JAK/STAT signaling alters the metabolic profile of mutant flies. Both domeG0282 and stat92EEY10528 mutants had an increase in body weight, lipid deprivation from their fat body (lipid storage organ in flies), irregular accumulation of lipid droplets in the gut, systemic elevation of glucose and triglyceride levels, and differential down-regulation in the relative gene expression of different peptide hormones (Tachykinin, Allatostatin C, and Diuretic hormone 31) known to regulate metabolic homeostasis in flies. Because the JAK/STAT pathway is evolutionary conserved between invertebrates and vertebrates, our potential findings in the fruit fly serves as a platform for further immune-metabolic translational studies in more complex mammalian systems including humans.

Due to the anatomical and physiological similarities to humans that include similar heart size, flow rate, skin, liver enzymes and bone healing, porcine models as a powerful investigational platform have been widely used in research areas such as diabetes, obesity and islet transplantation [1]. The advantages of relative low cost, ease in handling and comparatively short period of breeding time may make swine provide a promising solution to the shortage of human donors and difficulty in isolating purified islets from adult human in future. Porcine cytokines play a significant role in innate immunity, apoptosis, angiogenesis, cell growth and differentiation. They are involved in cellular responses, maintenance of homeostasis, and disease states such as inflammatory disease, cardiovascular disease, and cancer. Thus, the technologies to analyze the expression of cytokines are developed rapidly and are still hot topics. The traditional approach for cytokine detection and quantification is the use of an enzyme-linked immunosorbent assay (ELISA). However, its inability to do multiplex test calls for more robust detection system. Biochip-based assay for the detection of biological agents using giant magnetoresistive (GMR) sensors and magnetic nanoparticles have emerged recently [2, 3]. It is proved that the nanomagnetic biosensor technology has advantages of low cost, high sensitivity, multiplexity, and real-time signal readout. The integration of GMR biosensor and use of weak magnetic fields allow to eventually realize point-of-care and portability. In addition, interferon gamma (IFNγ) is one of the most important porcine cytokines, and is associated with a number of autoinflammatory and autoimmune diseases. In this work, IFNγ is selected as a model target for the detection of porcine cytokine using nanomagnetic GMR biosensor.