Current Immunology Reviews (v.7, #1)

Within immunology, it is especially important to know the basic mechanisms of innate and adaptive immunity in the defence against infectious agents, the most important physiologic function of the immune system. The development of an infectious disease in a person involves complex interactions between the agents and the host. It starts with the entry of the microorganism, the colonization of the tissues and the invasion, after overcoming the host's defences, and the organic lesion or functional alteration of the tissues. Then some agents start spreading the disease through multiplication, liberation of toxins or events of hypersensitivity [1]. The immune system usually responds specifically against the infectious agents present and fights them with the highest efficiency possible, on the principle of all or nothing. The pathogenic capacity of the agents is linked to their capacity to elude or resist the effectors mechanisms of immunity, which are mainly adaptive, humoral or cellular. However, in many infections the disease can be the consequence of the host's response to the infection rather than the direct effect of the agent itself, through the hypersensitivity phenomena, which involve a more or less significant molecular mimetism. Some strains of Streptococcus pyogenes show similarity of capsular epitopes to the host connective tissue, its wall M protein shares epitopes with cardiac myosin; and streptolysin O binds to the erythrocyte membrane cholesterol altering its antigenic configuration. It may also form streptolysin O immunocomplexes and antibodies deposited on tissues, or the anti-streptolysin O may directly injure the cellular membranes [2]. On the contrary, and excluding molecular mimetism, other bacterian agents, such as mycobacteria, may cause granulomatous inflammation and histic destruction [3]. Finally, agents such as Mycoplasma pneumoniae may share mechanisms through the modification of the host antigens and direct tissular destruction [4]. Over the past years it has been stated that some diseases deriving from unknown causes, such as atherosclerosis [5], schizophrenia [6], multiple sclerosis [7] and periodontal disease [8], at least in a subgroup of patients, may be caused by sustained chronic infections, together with a genetic component, and perpetuated by the immune system. This hypothesis is based on epidemiologic and biologic evidence proving that these patients were exposed to infection risk factors during the pre- or post-natal period, such as Toxoplasma gondii, chlamydias, all the human herpesvirus, parvovirus B19, parotiditis virus or flu viruses. This list of microorganisms has increased with time and it will doubtlessly continue to grow, since there would only be the need to study agents with prevalences that are high enough to be significant risk factors. It is more complex to relate the infection with the clinical process because it first requires epidemiologic studies and then experimental animal studies. Some works have been done in relation to this. The belief is that the infection may distort the synthesis of neurotrophins by immune cells, with significant subsequent repercussions. On other occasions it is believed that maternal antibodies which are directed against infectious agents leave secondary injuries on foetal neuron tissues, which are the part of the anatomy affected by the subsequent lesion in subjects with the disease [9]. In any case, whether the infection is pre- or post-natal, the disease is immune-mediated: it generates an irreversible lesion, of greater or lower level which, with time, leads to the appearance of the disease. The hypothesis that foetal infections during gestation or during the first moments of post-partum may trigger the subsequent appearance of the disease, like an organic sequel, is based on the above. Nevertheless, it is also probable that a possibly unsolved very early chronic infection may exist through an agent able to perpetuate itself (such as DNA viruses, chlamydias or T. gondii), which facilitates the appearance or exacerbation of the disease by interacting with other factors. Thus, the subjects may be susceptible to symptomatic treatment of the disease, such as is currently done, but, in addition, in this last case, the subjects may also be susceptible to antimicrobial treatment that may improve their progress. One of the markers to show chronic infection status is the presence of the agent's DNA in leukocytes and an important synthesis of specific IgG and IgA. In principle, herpesviruses are important candidates, since they are cytotropic, they produce latent infection with exacerbations, they may block neuronal function and cause diseases that behave as if they are post-acute. The main criticism received by these studies centers on the fact that the infection and the antibodies against viruses of the Herpesviridae family, C. pneumoniae and T. gondii families are very frequent in the general population, and that most of the carriers are asymptomatic. Doubtlessly, the field of influence of different infectious agents related to diseases of unknown cause is in the midst of development, and, although conclusive results have still not been found, it is necessary to replicate the studies, start new ones and relate these factors with the different manifestations of the disease. As a result of all the above, it would be extremely interesting to show or to rule out whether there is a differential replication of the infectious agent, at least in some of the subjects studied. Thus a dynamic would be set in motion to detect a population that could be susceptible to treatment with specific antimicrobial agents, a better definition of the differential phenotype of the disease, and the possibility of prevention. With the foregoing facts and under the title and#x201C;Immune-Infectology Principlesand#x201D; we deem it opportune to run a monographic volume of the Current Immunology Reviews journal studying the relationship between infectious agents, human immunity mechanisms and disease, from different points of view.

Immunity to Bacterial Infections by Maria Jimenez-Valera, Alfonso Ruiz-Bravo (3-12).
Co-evolution of pathogenic bacteria and hosts has led to the development of an array of virulence genes (the virulome) and a set of mechanisms of defense which constitute the immune system. Mechanisms of innate or non-specific immunity involve mucosal epithelial surface barriers, antibacterial peptides and enzymes, defensive molecules (collectins, complement), and cells (macrophages, dendritic cells, polymorphonuclear neutrophil leukocytes, natural killer cells). The presence of bacterial products in host tissues induces a complex series of non-specific responses which constitute the inflammatory reaction. Inflammation is critical to the resolution of infection, the key process being the ingestion and killing of bacteria by phagocytes, but inflammation also causes tissue damage and contributes to the pathology. The innate immunity is the initial step in the host defense against pathogens, but some pathogenic bacteria with appropriate virulence factors can overcome the innate immunity mechanisms. In these cases, the goal of innate immunity is to contain the infectious process until specific immunity is developed. The specific immune responses are performed by lymphocytes: B cells, T helper (TH) cells, and cytotoxic T lymphocytes (CTL). Specific antibodies are produced by B cells, usually with the cooperation of TH2 cells. In general terms, extracellular bacteria can be killed by antibodies and complement proteins, or cleared by phagocytosis after opsonization by antibodies, and bacterial exotoxins are neutralized by their specific antibodies. In contrast, resistance to intracellular bacteria requires the induction of TH1 and CTL responses. In this review, we will focus on current knowledge about the defensive mechanisms against bacterial infections. We will discuss the innate immunity mechanisms, connections between innate and specific immunity, the key role of T helper 1 (TH1) and TH2 cells, and the antibody and cell-mediated responses.

Immune Response to Mycobacteria by Maria del Mar Casal, Manuel Casal (13-18).
The immune response to mycobacteria is a complex process, varying according to the infection or disease involved and to its acute or chronic nature; it is not yet fully understood. A better understanding is essential for definitive diagnosis and the development of new vaccines. The immune response involves a wide range of molecular and Th1- model cellular components: antigen-presenting cells (macrophages and dendritic cells); T lymphocytes (CD4, CD8, NK and and#x3B3;and#x3B4;); cytokines such as IL-2, IFN-and#x3B3;, IL-18 and TNF-and#x3B1;; and the chemokines RANTES, MCP-1, MIP-1and#x3B1; and IL-8, which play a key role in granuloma formation in M. tuberculosis and atypical mycobacterial infection. The immune response also involves epithelial and natural killer (NK) cells, several signaling proteins (costimulatory molecules and transcription factors) that participate in regulating T-cell activation, toll-like receptors and major histocompatibility complex Class 1 molecules. M. tuberculosis-secreted antigens that reportedly induce the secretion of mediators associated with protection against M. tuberculosis infection include CPF-10, ESAT-6, 27kDa and 38 kDa, which induce production of IFN-and#x3B3;, TNF-and#x3B1; and nitric oxide. The immune response to M. leprae infection involves the Th-1 model in tuberculoid leprosy and the Th-2 model in lepromatous leprosy, with the production of IL-4, IL-5 and IL-13 or IL-10 (Th-3 response).

Antiviral Immunity by Jose Maria Navarro, Mercedes Perez-Ruiz (19-24).
Viruses are obligate intracellular parasites that cause infection by invading cells of the body. Their life cycle comprises a relatively short extracellular period, and a longer intracellular period during which they undergo replication. The immune system has non-specific and specific mechanisms that attack the virus in both phases of its life cycle. Nonspecific immune response is mainly mediated by interferons and natural killer cells (NK). Type I interferons are produced by many cell types and lead to both inhibition of viral replication and cell proliferation; they also enhance the ability of NK to lyse infected cells. NK represent a different lineage of lymphocytes that recognize and lyse virally infected cells. They are mainly effective during an early stage of viral infection, since there is no lag phase of clonal expansion for NK as occurs with T and B lymphocytes. Specific immune antiviral mechanisms are both humoral and cellular. Specific antibodies protect against viral infections and play an important role in antiviral immunity, mainly during the early stage of the infection. The most effective antiviral antibodies are neutralizing antibodies which bind to the viral envelope or capsid proteins, and block the virus from entering into host cell. The main effectors involved in specific antiviral immunity are CD8+ cytotoxic T lymphocytes (CTL). These cells recognize viral antigens presented at the cell surface associated with class I MHC molecules. CTL response is not always beneficial, since the tissue destruction caused by CTL is sometimes greater than the damage done by the virus.

Immunity to Parasites by Nuria Tormo, Maria del Remedio Guna, Maria Teresa Fraile, Maria Dolores Ocete, Africa Garcia, David Navalpotro, Mercedes Chanza, Jose Luis Ramos, Concepcion Gimeno (25-43).
Parasites such as protozoa or helminths currently account for greater morbidity and mortality than any other class of infectious organisms, particularly in developing countries. The structural and antigenic diversity of pathogenic parasites is reflected in the heterogeneity of the adaptive immune responses that they elicit. Protozoa that live within host cells are destroyed by cell-mediated immunity, whereas helminths are eliminated by IgE antibody and eosinophil mediated killing as well as by other leukocytes. The principal innate immune response to protozoa is phagocytosis, but many of these parasites are resistant to phagocytic killing and may even replicate within macrophages. Phagocytes also attack helminthic parasites and secrete microbicidal substances to kill organisms that are too large to be phagocytosed. Some helminths may also activate the alternative pathway of complement. The principal defense mechanism against protozoa that survive within macrophages (e.g. Leishmania spp., Toxoplasma gondii) is cell-mediated immunity, particularly macrophage activation by TH1 cell-derived cytokines. Protozoa that replicate inside various host cells and lyse these cells stimulate specific antibody and cytotoxic T lymphocytes (CTL) responses (e.g. Plasmodium spp.). Defense against many helminthic infections is mediated by the activation of TH2 cells, which results in production of IgE antibodies and activation of eosinophils and mast cells. The combined actions of mast cells and eosinophils lead to expulsion and destruction of the parasites. Most parasitic infections are chronic because of weak innate immunity and the ability of parasites to evade or resist elimination by adaptive immune responses Parasites evade the immune system by varying their antigens during residence in vertebrate hosts, by acquiring resistance to immune effector mechanisms, and by masking and shedding their surface antigens.

New Vaccines and Delivery Strategies for Adult Immunization by Elisa Prieto-Lara, Manuel Carnero, Joaquin Fernandez-Crehuet (44-49).
A series of new vaccines have recently been licensed or are at advanced stages of development. Among the illnesses targeted are herpes zoster, meningococcal meningitis serogroup B and pneumococcal disease, which represent an important cause of morbidity and mortality in adults. Zoster is a localized, painful cutaneous eruption caused by reactivation of latent varicella zoster virus (VZV). Approximately one in three persons will develop zoster during their lifetime, occurring most frequently among older adults and immunocompromised persons. Possible complications of zoster are postherpetic neuralgia, facial scarring, and loss of vision. Licensed zoster vaccine is a lyophilized preparation of a live, attenuated strain of VZV recommended for all persons aged 60 years or more who have no contraindications. Serogroup B meningococci represent the main cause of meningococcal disease in developed countries. Previous efforts for the production of an effective and safe vaccine have focused on outer membrane vesicle vaccines, which have been implemented successfully during clonal outbreaks. Nevertheless, ongoing research is being directed towards a universal vaccine against endemic polyclonal serogroup B meningococcal disease. Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia in adults. The use of an adult 13-valent pneumococcal conjugate vaccine could optimize protection against pneumococcal disease over the lifetime of the individual overcoming some of the limitations of the 23-valent polysaccharide. In addition to these efforts, progress is being made on dose sparing strategies that use intradermal delivery with microneedles in order to simplify administration and face possible shortages of vaccines. Despite the established benefit of intramuscular influenza vaccination, intradermal administration with comparable or improved immunogenicity is being explored.

Population Diversity and its Relationship with Infectious and Tumor Diseases by Rosario Sabariegos, Antonio Mas, Pilar Clemente-Casares (50-56).
Evolution is based on mutation processes and the subsequent selection of the best-adapted individuals, i.e., and#x201C;survival of the fittestand#x201D;. Thus, diversity is a common feature in living things. Pathogens and their hosts, as well as tumoral processes are no exception. Changes in the genetic material of microorganisms allow them to colonize new ecological niches while hosts try to adapt to the new residents by either eliminating them or by establishing mutualistic interactions. The permanent coexistence of microorganisms and their hosts leads to continuous evolvement necessary for their survival, following a strategy that was initially proposed for coevolution models in predator-prey interactions known as the and#x201C;Red Queen Hypothesisand#x201D;. Similar conclusions can be established for tumoral processes. Thus, in general, tumors, microorganisms, and hosts can be considered at the population level as complex distributions of related although not identical individuals. Initially, these complex systems were described in a theoretical model that tried to explain the functioning of populations of primitive replicons during the origin of life. This theory was later experimentally confirmed by analyzing populations of positive-strand RNA viruses or RNA(+). In both cases, for replicons and RNA(+) viruses, the populations are described as quasispecies. Here, we will review the most recent discoveries regarding interactions between population diversity and pathogenicity, both in microorganisms and tumors.

The Role of Microbial Agents in the Etiology of Schizophrenia: An Infectious Hypothesis for Psychosis? by Blanca Gutierrez, Gabriel Heiber, Francisco Torres-Gonzalez, Jorge A. Cervilla (57-63).
The ultimate cause of schizophrenia remains to be found, but it clearly includes a significant genetic component with an estimated heritability up to 85and#x25;. This suggests that genes may act as a predisposing factor upon which a variety of environmental risk factors can exert their deleterious effects, determining the emergence of psychotic symptoms. A recently growing interest has re-arisen on perinatal brain infections, which may increase the risk for schizophrenia that can, in turn, be modified by hazardous genetic loading. This hypothesis is based on epidemiological evidence, which has shown a significant exposure of affected individuals to infections with different pathogens. Such results are supported by tests carried out on animals. Another possibility is that there may be a link between a primary maternal infection and the subsequent development of schizophrenia in offspring. It is also been hypothesized that maternal antibodies against microorganisms may damage the fetal neural tissue, the area which is later found to be affected by the lesion occurring in patients with schizophrenia. In the present chapter, we review recent evidence on the potential role of infectious agents in the etiology of schizophrenia and discuss possible implications on the future of diagnostic, preventive and therapeutic issues.

Microbial Agents, Immune Function and Atheromatosis: The Chlamydophila pneumoniae Role by Jose P. Linares-Palomino, Gonzalo Piedrola, Cristina Lopez-Espada, Eduardo Ros-Die (64-74).
Some pathogens have been associated with the pathogenesis of atherosclerosis. The best studied and characterized has been Chlamydophila pneumoniae. Over the last years, several reports in the literature have suggested that infection with C. pneumoniae may contribute to the pathogenesis of atherosclerosis. C. pneumoniae would need to persist within infected tissue for extended periods of time, thereby stimulating a chronic inflammatory response. C. pneumoniae has been shown to disseminate systemically from the lungs and alveolar macrophages through infected peripheral blood mononuclear cells and to localize in arteries where it may infect incipient atheromatous lesions and their cellular compounds (endothelial cells, vascular smooth muscle cells (SMC), monocytes/macrophages). This situation promotes inflammatory atherogenous process. The involvement of C. pneumoniae in atherosclerosis was investigated by seroepidemiological and pathological studies, in vivo and in vitro studies, and in clinical antibiotic treatment trials. C. pneumoniae has been demonstrate in atheromas by inmunohistochemical techniques, DNA isolation and even has been cultured from arterial walls. The immune system may interplay between C. pneumoniae infection and coronary artery disease. Major histocompatibility complex genes regulate innate and adaptive immunity. A recent analysis showed the HLA-B35 allele to be the strongest-risk gene for C. pneumoniae infection.

Microbes, Immunity and Multiple Sclerosis by Ana Maria Fernandez, Marcos Papais-Alvarenga, Victoria Fernandez, Miguel Guerrero, Oscar Fernandez (75-82).
Multiple sclerosis (MS) can be considered a disease that appears in genetically predisposed persons who, by chance, are also affected by some unknown environmental factor, probably infectious, that sets in motion an abnormal immune response leading to an autoimmune disease. Infectious agents are involved in the appearance of autoreactive T cells against myelin via various mechanisms, such as molecular mimetism or acting as superantigens. Numerous possible microorganisms have been suggested, including bacteria like Chlamydophila pneumoniae and many viruses, e.g., canine distemper virus, measles, varicella zoster, human herpes virus 6 (HHV-6) and Epstein-Barr virus (EBV). The association with EBV is the best studied over recent years. The frequency (incidence and prevalence) of MS seems to be increasing, which is better explained by the effect of some environmental factor. In this study we analyze some of the infectious agents that have been associated with the disease and discuss the hygiene hypothesis, which is one of the possible explanations for the epidemiological changes reported over recent decades.

Oral Pathogens, Immunity, and Periodontal Diseases by Francisco Mesa, Jose Liebana, Pablo Galindo-Moreno, Francisco J. O'Valle (83-91).
The pathogenesis of periodontal disease is not fully understood. Subgingival bacterial pathogens are essential for the initiation and development of the disease, but it is the resulting host reaction that primarily mediates tissue damage. Complex inflammatory and immune responses are involved in the progression of periodontitis. Activated monocytes, macrophages, and fibroblasts all produce cytokines that orchestrate the cascade of destructive events in periodontal tissues. Cells from individuals with immune-mediated diseases exhibit different cytokine profiles, which may be due to genetic differences among individuals, causing hyper-responsiveness in some patients. Adaptive immunity, involving Bcells and subsets (B1, B2), plasma cells, and T-cell subsets, can be estimated by their cytokine profiles (Th1, Th2, Th17). Based on these data, it may be feasible to distinguish a protective from a destructive host response in periodontitis. Gene polymorphisms of inflammatory markers are also associated with the presence of viable periodontopathogenic bacteria. Lipopolysaccharides of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans are considered key factors in the development of chronic periodontitis. Lipopolysaccharides utilize toll-like receptor-2 and increase osteoblastic expression of RANKL, interleukin-1, interleukin-8, prostaglandin E2, and tumor necrosis factor-and#945;, which are all known to induce osteoclastic activity. The aforementioned findings support the hypothesis that complex interactions among microbiota, immune system, and host genome may underlie susceptibility to aggressive periodontitis. This article reviews research on periodontopathogens and provides an update on immunity paradigms in the pathogenesis of periodontal diseases.

Due to the and#x2018;baby boomersand#x2019; and health care advances, the aged population of Western countries is continuously growing [1]. Thus diagnosis and treatment of age-related diseases becomes an ever greater priority, for immune-mediated diseases translating into a need to better understand immunological dysfunction and its contribution to disease. The aging immune system, collectively termed immunosenescence, demonstrates a reduced capacity to mount a robust immune response and differentiate between self and foreign antigens. Immunosenescence manifests itself at several levels, from the whole organism to individual cells [2]: At the organism level, immunosenescence results in an increased susceptibility to age-related diseases including infections, cancer and autoimmune diseases. Besides, immunosenescence is associated with an impaired humoral response to vaccines, with suboptimal vaccination protection [3]. Biomarkers predicting the success of vaccination in aged individuals would improve current vaccination practice but such biomarkers have not been introduced into clinical routine yet. In this journal D. Herndler- Brandstetter et al. report that the presence of end-stage differentiated CD8+CD28- T-cells is associated with a reduced antibody production, whereas high levels of CD45RO+CD28+IL-2Rand#945;dimCD8+ T-cells may indicate preserved immuno-competence. As infectious diseases cause high morbidity and mortality in the elderly, this topic has to be considered as a major public health burden for the future [4]. At the cell population level, immune-aging is characterized by decreased function of progenitor and early differentiated cells as well as by the accumulation of highly specialized, senescent immune cells [5-7]. The involution of primary lymphoid organs and defects in the production of early lymphoid precursors contribute to these changes [8]. Other mechanisms such as lifelong encounter of the immune cells with acute and chronic pathogens further accelerate the progression of immunosenescence [4]. Age-associated thymic involution for example results in a significant loss of its capacity to generate and export new T-cells. Homeostatic equilibrium is then maintained by self-replication of T-cells in the periphery [8]. These peripheral mechanisms, however, are not unlimited: Telomere lengths decrease with each cell division and proliferative capacity of T-cells exhausts when telomere lengths are reduced to a critical level known as the and#x201C;Hayflick limitand#x201D; [9]. Chronic virus infections such as Human Immunodeficiency Virus (HIV) or Cytomegalovirus (CMV) accelerate peripheral proliferation of T-cells, and affected patients exhibit an aged T-cell population very early in life [4, 10]. M. Prelog and C. Duftner et al. discuss the role of early thymic failure for the development of autoimmune diseases, including juvenile idiopathic arthritis and rheumatoid arthritis [8, 11]. It is still a matter of debate, whether premature thymus dysfunction and T-cell senescence are the cause or consequence of autoimmunity. The observation that premature immune-aging also occurs in healthy individuals bearing the HLA-DR4 gene, the strongest genetic risk factor for rheumatoid arthritis, strongly supports the concept that immunosenescence precedes the onset of disease [12]. On this background immune-aging leads to phenotypical and functional changes of both, innate and adaptive immune cells. T-cell senescence for example is characterized by the down-regulation of the costimulatory molecule CD28, de-novo expression of innate immune receptors and gain of new effector functions [8]. Clinically, CD8+CD28- T-cells predict a low vaccine response (as outlined above) and are associated with an increased 2-year mortality in aged Swedish individuals [4]. Besides, higher prevalences of CD4+CD28- T-cells in the peripheral blood are linked with a worse outcome of autoimmune diseases and contribute to plaque instability in patients with coronary artery disease [8]. Concerning age-associated changes of innate immune cells, S. Mahbub et al. discuss functional changes of macrophages, neutrophils, dendritic cells, NK- and NKT-cells in aged compared to young individuals [13]. They report that aged innate immune cells have a lower capacity to clear invading pathogens as a result of lower chemotactic and phagocytosis activity. Besides, aged innate immune cells sub-optimally stimulate adaptive immune responses because of a decreased production of pro-inflammatory cytokines and defects in antigen presentation. Innate immune cells from aged individuals additionally show a lower activity after stimulation compared to young people, even though basal activation seems to be higher. The high basal activation of these cells possibly explains the common observation of high systemic levels of pro-inflammatory cytokines in the elderly. Depletion of CD28- T-cells in autoimmune diseases in order to interrupt chronic inflammation and increase homeostatic space for naive T-cells is proposed by C. Duftner et al. [8]. Such an approach, however, is critical and should be paralleled by increment of thymic output and survival of peripheral T-cells, as depletion of circulating aged T-cells drive into excessive autoproliferation aimed at re-filling-up peripheral niches. In summary, immunosenescence affects the innate and the adaptive immune system and manifests at different levels of the organism. Individuals with an aged immune system have a higher susceptibility to infections and autoimmune diseases and show a reduced immune response to vaccines. More detailed understanding of the underlying age-related alterations of the immune system should now pave the way to develop therapeutic strategies to delay, prevent or reverse immunosenescence; thereby improving quality of life in old age and new treatment regimens for patients with autoimmune diseases.

The Aging of the Adaptive Immune System by Dietmar Herndler-Brandstetter, Birgit Weinberger, Gerald Pfister, Daniela Weiskopf, Beatrix Grubeck-Loebenstein (94-103).
Adaptive immune responses are severely affected by the aging process as reflected by an increased morbidity and mortality from infectious diseases and a low efficacy of vaccination in elderly persons. Age-related changes within the bone marrow and thymus lead to an impaired generation of new T and B cells severely compromising the maintenance of a diverse and balanced T and B cell repertoire in old age. The maintenance of a balanced T cell repertoire is further challenged by latent persistent infections, such as Cytomegalovirus. Understanding the mechanisms of age-related alterations of the adaptive immune response may help to facilitate the development of more efficient vaccines for elderly persons and to envisage strategies to overcome immunosenescence.

Aging of the Innate Immune System: An Update by Shegufta Mahbub, Aleah L. Brubaker, Elizabeth J. Kovacs (104-115).
The relationship between advanced age and immunologic deficits is becoming an area of rapidly advancing research. Many of the clinical hurdles in the elderly population result from dysregulation of the immune system leading to the inability of the elderly to swiftly combat infection and to the increased incidence of chronic disease states and autoimmune conditions. Herein, we address the crucial alterations in the innate immune system that occur with advancing age. Specifically, we discuss how the effects of advanced age may lead to functional changes in the neutrophil, macrophage, dendritic cell, natural killer cell, and natural killer T cell populations in human and murine models that translate into aberrant innate immune responses. Furthermore, we elucidate how these changes may contribute to documented deficits in adaptive immunity as well as the pathological conditions and the increased morbidity and mortality seen in the elderly population.

Several lines of evidence suggest that premature aging of the immune system may cause alterations in the peripheral T cell homeostasis making individuals vulnerable to triggers of autoimmunity. Childhood-onset autoimmunity may offer the investigation of these aspects in the setting of a young, relatively inexperienced immune system which is affected by an imbalance in thymic output, altered proportions of peripheral T cell subpopulations and proinflammatory cytokines. One hypothesis favors the idea that premature immunosenscence in childhood-onset autoimmunity is the primary defect causing breakdown of self-tolerance; another hypothesis postulates that premature immunosenescence in children with autoimmune disorders is secondary to chronic stimulation and activation of the immune system by inflammatory processes. Population-based longitudinal studies on risk factors for development of autoimmunity beginning at infancy are required to understand the pathogenetic factors, which lead to the breakdown of self-tolerance and perpetuation of inflammation, to allow the design of targeted therapy and preventive strategies.

Early Aged T-Cells in Immune-Mediated Diseases by Christina Duftner, Christian Dejaco, Michael Schirmer (124-132).
Early loss of thymic function may be crucial for the development of immune-mediated diseases. According to this concept premature collapse of thymic output is compensated by homeostatic proliferation of peripheral T-cells, driven by recognition of self antigens and finally resulting in the expansion of autoreactive, senescent T-cell clones. Such senescent T-cells are characterized by the loss of the co-stimulatory receptor CD28 and the gain of new immunomodulatory molecules such as natural killer cell receptors and toll-like receptors. The immune system may compensate for these changes by regulatory mechanisms, including the evolvement of regulatory T-cells. However, the aging process may also affect these regulatory T-cells leading to a second and#x201C;hitand#x201D; of the immune system. Current therapeutic approaches in patients with immune-mediated diseases target common end pathways of inflammation, driven by proinflammatory cytokines and effector cells. Future directions will include the aim to reset the immune system, by restoring the ability to repopulate the immune system with young and adaptable lymphocytes as well as by strengthening the effect of regulatory T-cells.

A Role for Glucocorticoids in Thymic Involution? by G. Jan Wiegers, Denise Tischner (133-134).
Aging of the immune system is characterized by a decline in adaptive immunity that leads to immune dysfunction in the elderly. The striking involution of the thymus with age is thought to be mainly responsible for the loss of immunocompetence. This involution process has been attributed not only to changes in the production of sex hormones but also to intrinsic defects in aged progenitor T-cells. Counteracting thymic involution is expected to contribute to restoration of immune function in the elderly. Here, we focus on recent evidence that glucocorticoid hormones might fulfil such a role.