The innate immune system and HIV pathogenesis

Innate immunity represents the first line of defense against microbial infections. The innate immune system is activated by conserved structures present on most pathogens and profoundly regulates subsequent adaptive immune responses. HIV is notorious for evading and disrupting the immune system. Although HIV directly targets and gradually destroys the adaptive immunity, it has become clear that the virus also perturbs the components of the innate immune system. In this paper, we review the role of two innate lymphocyte subsets, natural killer and natural killer T cells, that are disrupted during HIV infection.     

The innate immune system 'puzzle'

Detecting pathogen invasion and regulating homeostatic processes are two essential functions of myriad non-Toll-like innate immune proteins.     

The aging innate immune system

Advanced age is associated with a breakdown of the epithelial barriers of the skin, lung and gastrointestinal tract, which enables invasion of delicate mucosal tissues by pathogenic organisms. Thus, there is an increased challenge for the innate immune system in aged subjects, as the portal of pathogen entry becomes more readily disturbed. Because of the number of aging baby boomers and the added environmental stresses that bombard the immune system on a daily basis, gaining an understanding of the functional integrity of the innate immune system in aged subjects is of paramount importance. Evidence suggests that macrophages play a central role in both innate and adaptive immune responses. Intrinsic, as well as extrinsic (environmental), factors dictate macrophage function. In aged subjects, the influence of extrinsic factors becomes increasingly more important. This may override the innate immune balance--pro- versus anti-inflammatory signals--thus yielding an inappropriate (either inadequate or overabundant) response when the system is challenged.     

The importance of the innate immune system in controlling HIV infection and disease

The innate immune system is the first line of defense against invading pathogens and is particularly important in warding off bacterial and viral infections presenting at the mucosal cell surface. From this primitive immune response, the more sophisticated adaptive immune system was derived. Despite nearly two decades of research directed at inducing adaptive immune responses to HIV, no successful immunological therapy or vaccine has been developed. On the basis of recent observations, it is suggested that instead emphasis should now be placed on the alternative arm of the immune system, the innate immune response. Novel approaches should be developed to elicit this rapidly responding immune activity in HIV infection.     

The innate immune system in transplantation

The vertebrate innate immune system consists of inflammatory cells and soluble mediators that comprise the first line of defense against microbial infection and, importantly, trigger antigen-specific T and B cell responses that lead to lasting immunity. The molecular mechanisms responsible for microbial non-self recognition by the innate immune system have been elucidated for a large number of pathogens. How the innate immune system recognizes non-microbial non-self, such as organ transplants, is less clear. In this review, we approach this question by describing the principal mechanisms of non-self, or ‘damaged’ self, recognition by the innate immune system (pattern recognition receptors, the missing self theory, and the danger hypothesis) and discussing whether and how these mechanisms apply to allograft rejection.     

The innate immune system in demyelinating disease

Demyelinating diseases such as multiple sclerosis are chronic inflammatory autoimmune diseases with a heterogeneous clinical presentation and course. Both the adaptive and the innate immune systems have been suggested to contribute to their pathogenesis and recovery. In this review, we discuss the role of the innate immune system in mediating demyelinating diseases. In particular, we provide an overview of the anti-inflammatory or pro-inflammatory functions of dendritic cells, mast cells, natural killer (NK) cells, NK-T cells, γδ T cells, microglial cells, and astrocytes. We emphasize the interaction of astroctyes with the immune system and how this interaction relates to the demyelinating pathologies. Given the pivotal role of the innate immune system, it is possible that targeting these cells may provide an effective therapeutic approach for demyelinating diseases.     

The porcine innate immune system: An update

Over the last few years, we have seen an increasing interest and demand for pigs in biomedical research. Domestic pigs (Sus scrofa domesticus) are closely related to humans in terms of their anatomy, genetics, and physiology, and often are the model of choice for the assessment of novel vaccines and therapeutics in a preclinical stage. However, the pig as a model has much more to offer, and can serve as a model for many biomedical applications including aging research, medical imaging, and pharmaceutical studies to name a few. In this review, we will provide an overview of the innate immune system in pigs, describe its anatomical and physiological key features, and discuss the key players involved. In particular, we compare the porcine innate immune system to that of humans, and emphasize on the importance of the pig as model for human disease.     

Helicobacter pylori and the innate immune system

Since its discovery, Helicobacter pylori surprises us by its ability for life-long chronic persistence, proliferation, and probably active adaptation in the unfavourable niche of the human stomach, without being eliminated by the defence systems of the human body. This minireview highlights recent developments about the interaction of H. pylori with the innate immune system, and makes a case that evasion and possibly suppression of innate immune responses play an important role for the active survival in its local mucosal environment.     

The innate immune system and its role in allergic disorders

BACKGROUND: There has been an increasing prevalence of allergic diseases in the Western world over the last decades. The hygiene hypothesis has been proposed as a possible explanation for this epidemical trend in allergy. A key role in this theory is assigned to the reduced microbial stimulation of the Toll-like receptors (TLRs) in early life, which could lead to a weaker Th1 response and a stronger Th2 response to allergens. The individual immunological response is determined by the interplay between the dose and timing of exposure to endotoxins, other environmental factors and genetic predisposition. In the development and progression of allergic disorders, the innate immune system plays an important role. OBJECTIVE: In this review, we discuss the paradoxical effects that may appear when the innate immune components are triggered. We review the influence of changes in the gene sequence and TLR expression in relation to the overall pattern of commensals and pathogens. We explored the possibility of alternative stimulations of the immune system by CpG oligodeoxynucleotides and probiotics as therapeutic devices against this endemic disease in Western society. METHODS: Selection of papers was based on the importance of their contribution to the understanding of innate immunity and its implications. RESULTS AND CONCLUSION: The innate immune system plays an important role in both the protection against and the enhancement of allergic disorders, but the mechanisms are still unclear. Nevertheless, gene polymorphisms and triggers of the innate immune system provide therapeutic targets for protection against and treatment of allergic disorders.     

The innate immune system and the clearance of apoptotic cells

Removal of unwanted, effete, or damaged cells through apoptosis, an active cell death culminating in phagocytic removal of cell corpses, is an important process throughout the immune system in development, control, and homeostasis. For example, neutrophil apoptosis is central to the resolution of acute inflammation, whereas autoreactive and virus-infected cells are similarly deleted. The AC removal process functions not only to remove cell corpses but further, to control inappropriate immune responses so that ACs are removed in an anti-inflammatory manner. Such ″silent″ clearance is mediated by the innate immune system via polarized monocyte/macrophage populations that use a range of PRRs and soluble molecules to promote binding and phagocytosis of ACs. Additionally, attractive signals are released from dying cells to recruit phagocytes to sites of death. Here, we review the molecular mechanisms associated with innate immune removal of and responses to ACs and outline how these may impact on tissue homeostasis and age-associated pathology (e.g., cardiovascular disease). Furthermore, we discuss how an aging innate immune system may contribute to the inflammatory consequences of aging and why the study of an aging immune system may be a useful path to advance characterization of mechanisms mediating effective AC clearance.     

Role of immune activation in HIV pathogenesis

T-cell activation has long been considered a central mediator of HIV pathogenesis. High T-cell activation levels predict more rapid disease progression in untreated patients and decreased treatment-mediated CD4+ T-cell gains during antiretroviral therapy, independent of plasma HIV RNA levels, and may be the primary feature distinguishing pathogenic from nonpathogenic primate models of HIV infection. Studies in animal models and individuals with HIV infection continue to enhance our understanding of how T-cell activation causes immunodeficiency during HIV infection. The goal of these studies is to identify specific mechanisms that can be targeted by novel immune-based therapies for patients who have thus far been unable to recover normal immune function despite years of antiretroviral therapy. Although most immune-based therapies targeting T-cell activation have been unsuccessful to date, recent scientific developments have focused attention on specific pathways that may be exploited by future generations of immune-based therapies.     

Links between the innate immune system and sleep

Sleep is a fundamental physiologic process with unknown functions. It is divided into 2 distinct states: non-rapid-eye-movement sleep and rapid-eye-movement sleep. After acute infection with nonneurotropic agents, there are stereotypic changes in non-rapid-eye-movement sleep, particularly increased time spent in slow-wave sleep, and often a reduction of time spent in rapid-eye-movement sleep. It is now recognized that both infection-associated sleep and spontaneous sleep are regulated, in part, by immune mediators called cytokines. This review provides brief tutorials on the elements of the innate immune system that detect infection, how sleep is characterized in the laboratory, issues regarding the interpretation of sleep effects on immune function, the interaction of sleep with circadian rhythms and stress, and some of the microbial products, cytokines, and neuropeptides associated with sleep regulation. We also summarize our current understanding of the role of sleep in host defense and asthma exacerbation.