Numerical alterations of ageing B lymphocyte subsets

The global population is ageing. Elderly people suffer from more severe infections than younger persons. The major reason for the increased susceptibility to infections in the elderly is the deregulated functions of the immune system. Immunosenescence affects both innate and adaptive immune reactions. Among these, quantitative alterations of B lymphocyte subsets determine outcome of infections and vaccination. The overall number of B cells seems to be stable or the decrease is moderate. Reduced input of naive B lymphocytes is compensated by anergic, exhausted memory cells. Concerning B lymphocyte subsets, experimental data obtained in the mouse model and in vivo studies conducted in old-age humans are frequently controversial. Further analysis of human B lymphocyte subpopulations is required that could be regarded as an important biomarker of human life span.     

NK and NKT cell functions in immunosenescence

Immunosenescence is defined as the state of dysregulated immune function that contributes to the increased susceptibility to infection, cancer and autoimmune diseases observed in old organisms, including humans. However, dysregulations in the immune functions are normally counterbalanced by continuous adaptation of the body to the deteriorations that occur over time. These adaptive changes are likely to occur in healthy human centenarians. Both innate (natural) and adaptive (acquired) immune responses decline with advancing age. Natural killer (NK) and natural killer T (NKT) cells represent the best model to describe innate and adaptive immune response in aging. NK and NKT cell cytotoxicity decreases in aging as well as interferon-gamma (IFN-gamma) production by both activated cell types. Their innate and acquired immune responses are preserved in very old age. However, NKT cells bearing T-cell receptor (TCR) gammadelta also display an increased cytotoxicity and IFN-gamma production in very old age. This fact suggests that NKT cells bearing TCRgammadelta are more involved in maintaining innate and adaptive immune response in aging leading to successful aging. The role played by the neuroendocrine-immune network and by nutritional factors, such as zinc, in maintaining NK and NKT cell functions in aging is discussed.     

Complement and IL-12: yin and yang

Interleukin 12 (IL-12) is central to the orchestration of cell-mediated immune responses in the innate as well as the adaptive immune system. Recent studies of the pathogenesis of diseases as disparate as measles and asthma have suggested that the complement system, itself at the interface of innate and adaptive immunity, is a biologically relevant regulator of IL-12 production. These data are reviewed here.     

Cooperativity of adaptive and innate immunity: implications for cancer therapy

The dichotomy of immunology into innate and adaptive immunity has created conceptual barriers in appreciating the intrinsic two-way interaction between immune cells. An emerging body of evidence in various models of immune rejection, including cancer, indicates an indispensable regulation of innate effector functions by adaptive immune cells. This bidirectional cooperativity in innate and adaptive immune functions has broad implications for immune responses in general and for regulating the tumor-associated inflammation that overrides the protective antitumor immunity. Mechanistic understanding of this two-way immune cross-talk could provide insights into novel strategies for designing better immunotherapy approaches against cancer and other diseases that normally defy immune control.     

Innate immunity and adjuvants

Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection.     

Factors that may impact on immunosenescence: an appraisal

The increasing ratio of ageing population poses new challenges to healthcare systems. The elderly frequently suffer from severe infections. Vaccination could protect them against several infectious diseases, but it can be effective only if cells that are capable of responding are still present in the repertoire. Recent vaccination strategies in the elderly might achieve low effectiveness due to age-related immune impairment. Immunosenescence affects both the innate and adaptive immunity. Beside individual variations of genetic predisposition, epigenetic changes over the full course of human life exert immunomodulating effects. Disturbances in macrophage-derived cytokine release and reduction of the natural killer cell mediated cytotoxicity lead to increased frequency of infections. Ageing dampens the ability of B cells to produce antibodies against novel antigens. Exhausted memory B lymphocyte subsets replace naïve cells. Decline of cell-mediated immunity is the consequence of multiple changes, including thymic atrophy, reduced output of new T lymphocytes, accumulation of anergic memory cells, and deficiencies in cytokines production. Persistent viral and parasitic infections contribute to the loss of immunosurveillance and premature exhaustion of T cells. Reduced telomerase activity and Toll-like receptor expression can be improved by chemotherapy. Reversion of thymic atrophy could be achieved by thymus transplantation, depletion of accumulated dysfunctional naive T cells and herpesvirus-specific exhausted memory cells. Administration of interleukin (IL)-2, IL-7, IL-10, keratinocyte growth factor, thymic stromal lymphopoietin, as well as leptin and growth hormone boost thymopoiesis. In animals, several strategies have been explored to produce superior vaccines. Among them, virosomal vaccines containing polypeptide antigens or DNA plasmids as well as new adjuvanted vaccine formulations elicit higher dendritic cell activity and more effective serologic than conventional vaccines responses in the elderly. Hopefully, at least some of these approaches can be translated to human medicine in a not too far future.     

Giant cell arteritis: immune and vascular aging as disease risk factors

Susceptibility for giant cell arteritis increases with chronological age, in parallel with age-related restructuring of the immune system and age-induced remodeling of the vascular wall. Immunosenescence results in shrinkage of the naïve T-cell pool, contraction of T-cell diversity, and impairment of innate immunity. Aging of immunocompetent cells forces the host to take alternative routes for protective immunity and confers risk for pathogenic immunity that causes chronic inflammatory tissue damage. Dwindling immunocompetence is particularly relevant as the aging host is forced to cope with an ever growing infectious load. Immunosenescence coincides with vascular aging during which the arterial wall undergoes dramatic structural changes and medium and large arteries lose their pliability and elasticity. On the molecular level, elastic fibers deteriorate and matrix proteins accumulate biochemical modifications. Thus, the aging process impacts the two major biologic systems that liaise to promote giant cell arteritis; the immune system and the vessel wall niche.     

H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection

Persistent infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high gastric cancer risk, but has also been linked to protection from allergic, chronic inflammatory and autoimmune diseases. In the course of tens of thousands of years of co-existence with its human host, H. pylori has evolved elaborate adaptations that allow it to persist in the hostile environment of the stomach in the face of a vigorous innate and adaptive immune response. For this review, we have identified several key immune cell types and signaling pathways that appear to be preferentially targeted by the bacteria to establish and maintain persistent infection. We explore the mechanisms that allow the bacteria to avoid detection by innate immune cells via their pattern recognition receptors, to escape T-cell mediated adaptive immunity, and to reprogram the immune system towards tolerance rather than immunity. The implications of the immunomodulatory properties of the bacteria for the prevention of allergic and auto-immune diseases in chronically infected individuals are also discussed.     

Biological roles of host defense peptides: lessons from transgenic animals and bioengineered tissues

Host defense peptides (HDPs) have long been recognized as microbicidal agents, but their roles as modulators of innate and adaptive immunity have only more recently been appreciated. The study of transgenic animal and tissue models has provided platforms to improve our understanding of the immune modulatory functions of HDPs. Here, the characterization of transgenic animals or tissue models that over-express and/or are deficient for specific HDPs is reviewed. We also attempt to reconcile this data with evidence from human studies monitoring HDP expression at constitutive levels and/or in conjunction with inflammation, infection models, or disease states. We have excluded activities ascribed to HDPs derived exclusively from in vitro experiments. An appreciation of the way that HDPs promote innate immunity or influence the adaptive immune response is necessary in order to exploit their therapeutic or adjuvant potential and to open new perspectives in understanding the basis of immunity. The potential applications for HDPs are discussed.     

Immunological Control of Fish Diseases

All metazoans possess innate immune defence system whereas parameters of the adaptive immune system make their first appearance in the gnathostomata, the jawed vertebrates. Fish are therefore the first animal phyla to possess both an innate and adaptive immune system making them very interesting as regards developmental studies of the immune system. The massive increase in aquaculture in recent decades has also put greater emphasis on studies of the fish immune system and defence against diseases commonly associated with intensive fish rearing. Some of the main components of the innate and adaptive immune system of fish are described. The innate parameters are at the forefront of immune defence in fish and are a crucial factor in disease resistance. The adaptive response of fish is commonly delayed but is essential for lasting immunity and a key factor in successful vaccination. Some of the inherent and external factors that can manipulate the immune system of fish are discussed, the main fish diseases are listed and the pathogenicity and host defence discussed. The main prophylactic measures are covered, including vaccination, probiotics and immunostimulation. A key element in the immunological control of fish diseases is the great variation in disease susceptibility and immune defence of different fish species, a reflection of the extended time the present day teleosts have been separated in evolution. Future research will probably make use of molecular and proteomic tools both to study important elements in immune defence and prophylactic measures and to assist with breeding programmes for disease resistance.     

Infection History Determines Susceptibility to Unrelated Diseases

Epidemiological data suggest that previous infections can alter an individual's susceptibility to unrelated diseases. Nevertheless, the underlying mechanisms are not completely understood. Substantial research efforts have expanded the classical concept of immune memory to also include long‐lasting changes in innate immunity and antigen‐independent reactivation of adaptive immunity. Collectively, these processes provide possible explanations on how acute infections might induce long‐term changes that also affect immunity to unrelated diseases. Here, we review lasting changes the immune compartment undergoes upon infection and how infection experience alters the responsiveness of immune cells towards universal signals. This heightened state of alert enhances the ability of the immune system to combat even unrelated infections but may also increase susceptibility to autoimmunity. At the same time, infection‐induced changes in the regulatory compartment may dampen subsequent immune responses and promote pathogen persistence. The concepts presented here outline how infection‐induced changes in the immune system may affect human health.     

Immunosenescence in wild animals: meta‐analysis and outlook

Immunosenescence, the decline in immune defense with age, is an important mortality source in elderly humans but little is known of immunosenescence in wild animals. We systematically reviewed and meta‐analysed evidence for age‐related changes in immunity in captive and free‐living populations of wild species (321 effect sizes in 62 studies across 44 species of mammals, birds and reptiles). As in humans, senescence was more evident in adaptive (acquired) than innate immune functions. Declines were evident for cell function (antibody response), the relative abundance of naïve immune cells and an in vivo measure of overall immune responsiveness (local response to phytohaemagglutinin injection). Inflammatory markers increased with age, similar to chronic inflammation associated with human immunosenescence. Comparisons across taxa and captive vs free‐living animals were difficult due to lack of overlap in parameters and species measured. Most studies are cross‐sectional, which yields biased estimates of age‐effects when immune function co‐varies with survival. We therefore suggest longitudinal sampling approaches, and highlight techniques from human cohort studies that can be incorporated into ecological research. We also identify avenues to address predictions from evolutionary theory and the contribution of immunosenescence to age‐related increases in disease susceptibility and mortality.     

Are zinc-bound metallothionein isoforms (I+II and III) involved in impaired thymulin production and thymic involution during ageing?

In the elderly, many alterations of both innate and clonotypic immunity have been described. Alterations to the immune system in the elderly are generally viewed as a deterioration of immunity, leading to the use of the term immunosenescence. However, although many immunological parameters are often notably reduced in the elderly, retained function of both innate and clonotypic immunity in the elderly is tightly correlated to health status. Recognising the important role of the immune system in ageing, over the last few years, journals oriented towards gerontology and geriatric sciences have increasingly published articles dealing with the immunology of ageing, but a specialised journal in this area does not exist. Immunity & Ageing is a new Open Access, peer reviewed journal that aims to cover all the topics dealing with innate and clonotypic immunity which are relevant to ageing. The journal will provide an opportunity to focus on this topic, which is emerging as one of the critical mechanisms of ageing. Furthermore, as an online, Open Access journal, Immunity & Ageing will promote immediate accessibility to research, which is generally not possible for articles published in printed journals. We hope this forum, concentrating on the themes of ageing and immunology with a strong focus on human studies, will create a new perspective for viewing a world that is inevitably becoming older.     

Novel therapeutic strategies based on toll-like receptor signaling

The innate immune system is a critical first line of defense against many microbial, fungal and viral pathogens. Toll-like receptors play a central role in innate immunity, recognizing conserved pathogen-associated molecular patterns and generating signals leading to the initiation of an adaptive immune response. Because of their ability to modulate adaptive immunity, Toll-like receptors represent strategic therapeutic targets for diseases that involve inappropriate adaptive immune responses, such as sepsis, autoimmune disorders, cancer and allergy.     

Immunological and genetic bases of new primary immunodeficiencies

Since 1952, when congenital agammaglobulinaemia was described by Bruton, the characterization of genetically defined immunodeficiencies in humans has been crucial for a better understanding of the biology of the innate and adaptive immune responses. This Review focuses on the characterization of new primary immunodeficiencies and disease-related genes. A series of primary defects of innate immunity have recently been discovered and are discussed here. Moreover, new defects in pre-B-cell and B-cell differentiation and antibody maturation are summarized and recently discovered monogenic immunodeficiencies that disturb the homeostasis of both the innate and the adaptive immune systems are discussed.     

Regulation of dendritic cell differentiation and function by estrogen receptor ligands

Estrogen receptor (ER) ligands can modulate innate and adaptive immunity and hematopoiesis, which may explain the clear sex differences in immune responses during autoimmunity, infection or trauma. Dendritic cells (DC) are antigen presenting cells important for initiation of innate and adaptive immunity, as well as immune tolerance. DC progenitors and terminally differentiated DC express ER, indicating the ER ligands may regulate DC at multiple developmental and functional stages. Although there are profound differences in innate immunity between males and females or upon systemic imposition of sex hormones, studies are just beginning to link these differences to DC. Our and others studies demonstrate that estradiol and other ER ligands regulate the homeostasis of bone marrow myeloid and lymphoid progenitors of DC, as well as DC differentiation mediated by GM-CSF and Flt3 Ligand. Since DC have a brief lifespan, these data suggest that relatively short exposures to ER ligands in vivo will alter DC numbers and intrinsic functional capacity related to their developmental state. Studies in diverse experimental models also show that agonist and antagonist ER ligands modulate DC activation and production of inflammatory mediators. These findings have implications for human health and disease since they suggest that both DC development and functional capacity will be responsive to the physiological, pharmacological and environmental ER ligands to which an individual is exposed in vivo.     

Role of chemokines,innate and adaptive immunity

Polycystic Kidney Disease (PKD) triggers a robust immune system response including changes in both innate and adaptive immunity. These changes involve immune cells (e.g., macrophages and T cells) as well as cytokines and chemokines (e.g., MCP-1) that regulate the production, differentiation, homing, and various functions of these cells. This review is focused on the role of the immune system and its associated factors in the pathogenesis of PKDs as evidenced by data from cell-based systems, animal models, and PKD patients. It also highlights relevant pre-clinical and clinical studies that point to specific immune system components as promising candidates for the development of prognostic biomarkers and therapeutic strategies to improve PKD outcomes.     

Cytokines as critical co-stimulatory molecules in modulating the immune response of natural killer cells

Cytokines are involved in directing the activation of natural killer （NK） cells. NK cells are involved in the recognition of cells that have been altered; thus they do not recognize specific insults to the host, but when activated, are capable of destroying infected cells directly, as well as promoting the recruitment and response of the other components of the immune system by the release of cytokines and chemokines. It is these properties that have made NK cells a critical part of innate immunity and adaptive immunity, and they play a principal role linking innate and adaptive immunity by the recruitment of an adaptive immune response to an innate immune reaction.