M. De Martinis

The immune system in the elderly : I. Specific humoral immunity

Profound and complex changes in the immune response occur during the aging process. Immunosenescence is reflected by a sum of disregulations of the immune system and its interaction with other systems. Many of the changes would appear to implicate age-related deficiencies of the immune responses. The term immunosenescence designates therefore a sort of deterioration of the immune function which is believed to manifest itself in the increased susceptibility to cancer, autoimmune disease, and infectious disease. Evidence has been accumulating from several studies which suggest an association between immune function and individual longevity. However, there are observations, especially in very old healthy people, that several immune functions are unexpectedly well preserved and substantially comparable to those observed in young subjects. These findings raise the question of whether the alterations that can be observed in the immune parameters of the elderly are a cause or a result of underlying disease processes. Moreover, studies on centenarians revealed a remodeling of the immune system rather than a deterioration, suggesting that the changes observed during immunosenescence do not correspond to immunodeficiency. The underlying mechanisms of these events are however still unclear. The purpose of the present review is to assess the status of research on the immunobiology of aging. In this first section, we focus attention on the B cell biology of aging. In clinical practice, the changes in humoral immune responsiveness and antibody-mediated defense mechanisms could greatly influence the incidence and outcome of bacterial infections and autoimmune diseases as well as the response to vaccines.Profound and complex changes in the immune response occur during the aging process. Immunosenescence is reflected by a sum of disregulations of the immune system and its interaction with other systems. Many of the changes would appear to implicate age-related deficiencies of the immune responses. The term immunosenescence designates therefore a sort of deterioration of the immune function which is believed to manifest itself in the increased susceptibility to cancer, autoimmune disease, and infectious disease. Evidence has been accumulating from several studies which suggest an association between immune function and individual longevity. However, there are observations, expecially in very old healthy people, that several immune functions are unexpectedly well preserved and substantially comparable to those observed in young subjects. These findings raise the question of whether the alterations that can be observed in the immune parameters of the elderly are a cause or a result of underlying disease processes. Moreover, studies on centenarians revealed a remodeling of the immune system rather than a deterioration, suggesting that the changes observed during immunosenescence do not correspond to immunodeficiency. The underlying mechanisms of these events are however still unclear. The purpose of the present review is to assess the status of research on the immunobiology of aging. In this first section, we focus attention on the B cell biology of aging. In clinical practice, the changes in humoral immune responsiveness and antibody-mediated defense mechanisms could greatly influence the incidence and outcome of bacterial infections and autoimmune diseases as well as the response to vaccines.

Age-dependent modifications of Type 1 and Type 2 cytokines within virgin and memory CD4+ T cells in humans

Several alterations in immune function and a concomitant progressive increase in pro-inflammatory status are the major characteristics of ageing process. Cytokines play a key role during ageing acting both in regulatory communication among cells and in effector activity during an immune response. The impact of age on intracellular Type 1 (IFN-gamma and TNF-alpha) and Type 2 (IL-4) cytokines, after stimulation with PMA/ionomycin, was determined in three CD4+ T subsets, i.e. CD95- CD28+ (virgin), CD95+ CD28+ (activated/memory), and CD95+ CD28- (effector/memory) from 47 subjects aged between 21 and 99 years. The percentage of IFN-gamma positive cells significantly decreased in virgin CD4+ subset both in old and nonagenarian subjects, as well as in activated/memory T cells from old in comparison with young subjects. The percentage of TNF-alpha positive cells significantly decreased in activated/memory CD4+ subset from old people. Regarding Type 2 cytokines, IL-4 positive cells significantly increased in activated/memory CD4+ subset from nonagenarians. On the whole our data indicate that: (1) different Type 1 and Type 2 cytokine-positive CD4+ T subsets are differently affected by ageing process; (2) activated/memory T cells appear to be the most affected subset; (3) a shift towards an increased role of Type 2 cytokines and a diminished role of Type 1 cytokines emerges with ageing.

Immunological changes in the elderly

Immunosenescence is a complex remodelling of the immune system which may contribute significantly to morbidity and mortality in the elderly. Much evidence suggests an association between immune function and longevity. It was advanced that individuals who have survived in good health to the maximum life span are equipped with optimal cell defense mechanisms. Despite the great number of studies on the immune system in the elderly, little is known of the biological basis of immunosenescence in humans. This is partly due to the contrasting results often obtained by the various investigators. One source of discrepancy is that diseases are frequent in aging, and the alterations observed in the immune parameters of the elderly could be a cause or alternatively a consequence of the underlying pathological processes. Undoubtedly some diseases to which aged people are particularly susceptible, such as infectious, autoimmune and neoplastic pathologies, include dysregulation of several immune functions in their pathogenesis. On the other hand, recent studies in healthy centenarians suggest that the immunological changes observed during aging are consistent with a reshaping, rather than a generalized deterioration, of the main immune functions. Considering that the number of old people is dramatically increasing, and that geriatric pathology is becoming an important aspect of clinical practice, it seems particularly interesting to review the peculiar findings in the immune system of the elderly so as to better understand their susceptibility to certain diseases, and the links between health and longevity.

Cell Proliferation and Apoptosis in the Immune System in the Elderly

Loss of the cell proliferative capability and involution of tissues and organs are among the most important phenomena that characterize the aging process. Some of the aged-linked immune dysfunctions could be partly due to a dysregulation of apoptotic processes and to a lower responsiveness of aged lymphoid cells to activation and proliferation signals. The main changes in proliferative activity and cell death during aging and their impact on the process of immunosenescence are discussed. In fact, a very important function that has been suggested to deteriorate with age and to play a major role in the aging process is the capability of cells from aged subjects to respond to mitogenic stimuli and, consequently, to undergo cell proliferation. However, the cellular activation processes are very complex and the proliferative responses can follow different interconnected signal transduction pathways, and only some of them appear to be modified during age. Moreover, cell growth, immunosenescence, and longevity are strictly interconnected and deeply related to programmed cell death or apoptosis. The cellular equilibrium between cell survival and proliferation, on the one hand, and programmed cell death, on the other hand, seems to be unbalanced with advancing age, although in each type of immune cell it could be differentially modulated, resulting in a variety of clincopathological consequences. Thus, cell proliferation and cell death are two physiologically active phenomena closely linked and regulated and a failure of these mechanisms determines profound dysregulations of cell homeostasis with major consequences in immune functioning and the onset of autoimmune diseases and cancer, whose incidence appears to be increased in the elderly.

Senile osteoporosis: is it an immune-mediated disease?

Abstract.Osteoporosis is a major cause of morbidity in older people. There are a large number of risk factors for the development of senile osteoporosis. Howeover, recent discoveries suggest that these risk factors could exert their effects through immunologically mediated modulation of bone remodelling. Inflamm-ageing itself plays a role in bone remodelling through pro-inflammatory cytokines, which are known to influence osteoclasts and osteoblasts, together with other more recently discovered immunological mediators and transcription factors. Senile osteoporosis is an example of the central role of immune-mediated inflammation in determining bone resorption. In this review, we will discuss the pathogenesis of osteoporosis in the context of immunosenescence.

Determination of meropenem in serum by high-performance liquid chromatography with column switching

A rapid, accurate and sensitive liquid chromatographic assay with on-line solid-phase extraction for determination of meropenem in serum is described. Sample was directly injected onto the extraction column for sample clean-up and extraction. Thereafter, using an on-line column-switching system the drug was quantitatively transferred and separated on a C18 analytical column. Ultraviolet absorption at 298 nm was used for detection. The assay was linear from 1 to 100 micrograms/ml. Recovery was 98.5%. Based on a 20-microliters sample volume (serum- water, 1:1, v/v), detection limit was 0.1 microgram/ml. An application of the method to study the pharmacokinetics of meropenem is given.

The effect of age on hemopoiesis

Although several workers have described numerous changes affecting the hemopoietic system during senescence, the existence of univocal “hematological disease” closely related to the elderly is controversial. Many of the hematological changes described, such as sideropenic or megaloblastic anemia, are frequently the consequence of the different pathological conditions which often affect elderly patients. This review will consider the most important alterations of hemopoiesis and coagulation in the elderly, the causes capable of influencing hematological changes in old people, and their pathogenesis. Some of the major diagnostic problems encountered in the management of elderly subjects with hematological changes are also addressed. In the presence of an elderly patient with hematological alterations, it is necessary to follow a precise diagnostic schedule, which should first of all exclude the presence of a primary hematological disorder, and consider the different extrahematological conditions which frequently occur in elderly subjects (malignancies, malnutrition, chronic infections from immunological abnormalities, hormonal changes, deficiencies of various organs and systems etc.) and are responsible for many different hematological changes. These must be tackled rationally so that treatment may not only be symptomatic, but may also directly intervene on the cause of the disorder.

Determination of Cefodizime in Human Plasma by High-Performance Liquid Chromatography with Column-Switching

Abstract A column-switching high-performance liquid chromatographic assay with ultraviolet detection, at 263 nm, was developed to determine cefodizime, a new parenteral cephalosporin, in human plasma. The method is based on pre-column extraction in a closed system allowing direct injection of plasma samples without any sample pretreatment. The method allows direct, rapid, precise, and simple determination of cefodizime in plasma over the range of 1–400 μg/ml using a 100 μ1 loop and 25 μ1 of plasma. The detection limit of the assay was 0.1 μg/ml. Recovery for spiked plasma samples was near 100% and relative retention time showed good repeteability. An application of the method to study the pharmacokinetics of cefodizime in immunodepressed patients is given.