Immunosenescence and age-related viral diseases

Immunosenescence is described as a decline in the normal functioning of the immune system associated with physiologic ageing.Immunosenescence contributes to reduced efficacy to vaccination and increased susceptibility to infectious diseases in the elderly.Extensive studies of laboratory animal models of ageing or donor lymphocyte analysis have identified changes in immunity caused by the ageing process.Most of these studies have identified phenotypic and functional changes in innate and adaptive immunity.However,it is unclear which of these defects are critical for impaired immune defense against infection.This review describes the changes that occur in innate and adaptive immunity with ageing and some age-related viral diseases where defects in a key component of immunity contribute to the high mortality rate in mouse models of ageing.     

Immunosenescence and Vaccination

The problems associated with the ageing immune system and vaccination were discussed recently at an international workshop at the Jenner Institute for Vaccine Research, Compton, UK, 6–7 October, 2005. This is a commentary on that session. The meeting included discussions on T and B cell differentiation and ageing, as well as dendritic cell and neutrophil data, with the emphasis on T cell immunosenescence, perceived as the most important hindrance to satisfactory responses to vaccines in the elderly. The main questions to be addressed in this context are the reasons for dysfunctionality of T cells in the elderly and what to do to improve T cell function. Several of the major reasons for poor T cell responses in the elderly were discussed; however, many important questions remain: The next meeting at the Jenner Institute may already be able to provide some of the answers to these questions, which have serious implications for public health issues in increasingly elderly populations.     

Immunosenescence and lymphomagenesis

One of the most important determinants of aging-related changes is a complex biological process emerged recently and called “immunosenescence”. Immunosenescence refers to the inability of an aging immune system to produce an appropriate and effective response to challenge. This immune dysregulation may manifest as increased susceptibility to infection, cancer, autoimmune disease, and vaccine failure. At present, the relationship between immunosenescence and lymphoma in elderly patients is not defined in a satisfactory way.This review presents a brief overview of the interplay between aging, cancer and lymphoma, and the key topic of immunosenescence is addressed in the context of two main lymphoma groups, namely Non Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL). Epstein Barr Virus (EBV) plays a central role in the onset of neoplastic lymphoproliferation associated with immunological changes in aging, although the pathophysiology varies vastly among different disease entities. The interaction between immune dysfunction, immunosenescence and Epstein Barr Virus (EBV) infection appears to differ between NHL and HL, as well as between NHL subtypes.     

Ficolins and infectious diseases

Ficolins are serum complement lectins, with a structure similar to mannose-binding lectin (MBL) and lung surfactant protein (SP)-A and SP-D. Ficolins activate the lectin complement system and play important roles in host innate immunity. Ficolins are members of the collectin family of proteins, which act as pattern recognition receptors (PRRs). They are soluble oligomeric defense proteins with lectin-like activity, and are able to recognize pathogen-associated molecular patterns (PAMPs), which are carbohydrate molecules on the surface of pathogens, and of apoptotic, necrotic, and malignant cells. Upon binding to their specific PAMPs, ficolins may trigger activation of the immune system either (1) by initiating activation of complement via the lectin pathway, (2) by a primitive type of opsonophagocytosis, or (3) by stimulating secretion of the inflammatory cytokines interferon (IFN)-Γ, interleukin (IL)-17, IL-6, and tumor necrosis factor (TNF)-α, and production of nitric oxide (NO) by macrophages, thus limiting the infection and concurrently orchestrating the subsequent adaptive immune response. Recently, a number of reports have shown that dysfunction or abnormal expression of ficolins may play crucial roles in viral and bacterial diseases and in inflammation. This review summarizes the reports on the roles of ficolins in the infectious diseases, and provides insight into ficolins as novel innate immune therapeutic options to treat these diseases.     

Transfusion-transmitted infectious diseases

A spectrum of blood-borne infectious agents is transmitted through transfusion of infected blood donated by apparently healthy and asymptomatic blood donors. The diversity of infectious agents includes hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency viruses (HIV-1/2), human T-cell lymphotropic viruses (HTLV-I/II), Cytomegalovirus (CMV), Parvovirus B19, West Nile Virus (WNV), Dengue virus, trypanosomiasis, malaria, and variant CJD. Several strategies are implemented to reduce the risk of transmitting these infectious agents by donor exclusion for clinical history of risk factors, screening for the serological markers of infections, and nucleic acid testing (NAT) by viral gene amplification for direct and sensitive detection of the known infectious agents. Consequently, transfusions are safer now than ever before and we have learnt how to mitigate risks of emerging infectious diseases such as West Nile, Chikungunya, and Dengue viruses.     

新发感染病

新发感染病(EID)是指在过去20年中发病率增加或在不久的将来可能增加的人类感染病。EID严重危害着公共卫生安全,是目前感染病研究的热门领域和核心内容。就EID的概念及出现原因作简要分析,并提出对于预防EID的意见。     

Immunosenescence and cancer vaccines

Experimental and clinical data demonstrate that ageing is associated with the gradual deterioration of the immune system, generally referred to as immunosenescence. Age-related immune dysfunction may have an impact not only on the incidence of cancer, but also on the preventive and therapeutic approaches, which are based on immune system activation. Over the last few years the use of immunological measures to prevent cancer in experimental mouse models involving preimmunisation with new vaccines against even a poor or apparently non-immunogenic tumour has yielded worse outcomes in older age than in young adults. Different mechanisms, which may be due to age-related numerical or functional dysfunction of immune cells and/or to tumour microenvironmental changes, could be responsible for this defect. This review summarises the impact of immunosenescence on the effectiveness of cancer vaccines, knowledge of cancer immunisation in old age and the potential mechanisms implicated in the poorer effectiveness of anticancer immune-based approaches in advanced age. Several approaches to, and possibilities of correcting the low effectiveness of immunisation procedures in old age are described.     

Climate change and emerging infectious diseases

The ranges of infectious diseases and vectors are changing in altitude, along with shifts in plant communities and the retreat of alpine glaciers. Additionally, extreme weather events create conditions conducive to clusters of insect-, rodent- and water-borne diseases. Accelerating climate change carries profound threats for public health and society.     

TGF-beta in infections and infectious diseases

Since it was first described as having the ability to inhibit macrophage activation, transforming growth factor-beta (TGF-beta) has been analyzed for its role in regulating immune responses to a variety of pathogens, including viruses, bacteria, yeast, and protozoa. Most of the studies have involved organisms that infect macrophages, and this discussion will attempt to highlight these findings. Perhaps the most work has been performed with protozoan pathogens, including Trypanosoma cruzi and a variety of Leishmania species, so the discussion will begin with these organisms. Other studies have focused on mycobacteria and viruses, including human immunodeficiency virus, so these areas will also be emphasized in the discussion. For the most part, investigators have reported that TGF-beta has, as expected, a negative influence on host responses and a beneficial effect on the survival and growth of intracellular pathogens. However, other studies have found that TGF-beta may have a positive or beneficial effect in some models of infection. This review will attempt to highlight studies and conclusions on the roles of TGF-beta in infection.     

Protein crystallography and infectious diseases.

The current rapid growth in the number of known 3-dimensional protein structures is producing a database of structures that is increasingly useful as a starting point for the development of new medically relevant molecules such as drugs, therapeutic proteins, and vaccines. This development is beautifully illustrated in the recent book, Protein structure: New approaches to disease and therapy (Perutz, 1992). There is a great and growing promise for the design of molecules for the treatment or prevention of a wide variety of diseases, an endeavor made possible by the insights derived from the structure and function of crucial proteins from pathogenic organisms and from man. We present here 2 illustrations of structure-based drug design. The first is the prospect of developing antitrypanosomal drugs based on crystallographic, ligand-binding, and molecular modeling studies of glycolytic glycosomal enzymes from Trypanosomatidae. These unicellular organisms are responsible for several tropical diseases, including African and American trypanosomiases, as well as various forms of leishmaniasis. Because the target enzymes are also present in the human host, this project is a pioneering study in selective design. The second illustrative case is the prospect of designing anti-cholera drugs based on detailed analysis of the structure of cholera toxin and the closely related Escherichia coli heat-labile enterotoxin. Such potential drugs can be targeted either at inhibiting the toxin's receptor binding site or at blocking the toxin's intracellular catalytic activity. Study of the Vibrio cholerae and E. coli toxins serves at the same time as an example of a general approach to structure-based vaccine design. These toxins exhibit a remarkable ability to stimulate the mucosal immune system, and early results have suggested that this property can be maintained by engineered fusion proteins based on the native toxin structure. The challenge is thus to incorporate selected epitopes from foreign pathogens into the native framework of the toxin such that crucial features of both the epitope and the toxin are maintained. That is, the modified toxin must continue to evoke a strong mucosal immune response, and this response must be directed against an epitope conformation characteristic of the original pathogen.     

The eradication of infectious diseases

edited by W.R. Dowdle and D.R. Hopkins, Wiley, 1998. pound60.00 (hbk) (xv +218 pages) ISBN 0 471 98089 7.