IMMUNOLOGY, HUMAN

The immune system is an intricate network of cells and tissues that resists invasion from infectious agents (pathogens) and combats environmental stresses that induce allergic reactions, viral infections, infectious diseases, autoimmune syndromes, and cancer. The body eradicates foreign substances using innate (natural or nonspecific) and adaptive (acquired or specific) immune responses. Innate immunity refers to the body's initial nonspecific response to the invading substance using natural defensive barriers (skin, mucous membranes, temperature, and chemical mediators) and cells (macrophages, neutrophils, and natural killer [NK] cells) to limit or clear the foreign substance.

During an adaptive immune response, the body engages immune cells (T and B lymphocytes) that specifically recognize and selectively eliminate foreign substances. Adaptive immunity has four major characteristics: 1) antigen specificity, 2) diversity, 3) immunologic memory, and 4) ability to differentiate self from nonself. Antigen specificity is mediated by receptors on immune cells that recognize defined peptides called antigens. Receptor development is a spontaneous and random process that begins during fetal development so that the repertoire of receptors is present on lymphocyte membranes at birth. This large array of receptors, each having its own specificity for a particular antigen, is the basis for the diversity of the adaptive immune response. When a lymphocyte binds a peptide specific for its receptor, it becomes activated. Activation is multifaceted and induces proliferation and subsequent expansion of cells with that particular receptor. This clonal expansion of antigen-specific lymphocytes is the basis for immunologic memory. Immunologic memory enables immune cells to "remember" a previous encounter with a pathogen so that a more rapid response of higher magnitude can be produced after re-exposure to that same peptide. An absolutely critical feature of adaptive immunity is that immune cells must distinguish self from nonself. This recognition phase not only ensures that a specific immune response against only the invading pathogen is produced, but also prevents nonspecific responses against cells of the body that would result in autoimmunity.

Adaptive immunity consists of humoral and cell-mediated immune responses. The primary cells in adaptive immunity are B and T lymphocytes. B lymphocytes, which are principal mediators of humoral responses, originate in bone marrow and mature in the liver during fetal development, and subsequently in gut-associated mucosal lymphoid tissue. The antigen receptor on the B cell membrane is the immunoglobulin (Ig) molecule, which confers both specificity and diversity to humoral responses. During a humoral immune response, B cells differentiate into plasma cells, which secrete antibodies specific for the invading pathogen. T lymphocytes are responsible for the cell-mediated response. T cells originate in bone marrow and mature in the thymus. Upon exiting from the thymus, T cells will have differentiated into two subpopulations: helper (CD4+) T cells and cytotoxic (CD8+) T cells. These two populations facilitate cell-mediated immunity in two ways: CD4+ T cells produce cytokines (they are soluble factors that are released from cells after contact with specific antigens), enhance innate immunity, and induce antibody responses, while CD8+ T cells directly kill tumors or virus-infected cells.

Despite the presence of B and T cells at birth, neonates cannot produce a maximal adaptive immune response because their immune system has not yet fully matured. Maturational changes in the immune system continue after birth and are fairly complete by two years of age. However, subtle changes do occur until about puberty, at which point the immune response is fully developed.

Age-related changes in immunity

The incidence of infectious diseases, autoimmune syndromes, and cancers is increased in older adults and may be related to environmental and genetic factors. However, strong evidence also indicates that an overall dysregulation of the immune system may at least partially account for the increased incidence of these disorders in older adults.

Innate immunity. Changes in the innate immune response of older adults have received relatively little attention, and data thus far are inconclusive. Currently, the consensus is that NK activity does not dramatically change in older adults. However, lymphokine-activated killer-cell activity is decreased, at least to a limited extent, in older adults. Assessment of phagocytosis (process by which foreign substances (e.g., cells, bacteria, cell debris) are engulfed and destroyed) and cytokine production by cells of the innate response system has yielded inconsistent results, making it difficult to assess their role in the age-related decline in immune function. Clearly, additional controlled studies are necessary to define changes in innate immunity of older humans.

Adaptive immunity. Age-related changes in adaptive immunity have been studied extensively. Decreased antibody production after immunization or infection, reduced affinity of antibodies, and increased production of autoantibodies have been reported. However, these changes in B cell function cannot be explained by alterations in B cell numbers. The mechanism of age-related changes in B cell function has not yet been elucidated. Most evidence suggests that decreased B cell function probably reflects a decrease in help (i.e. cytokine production) from helper T cells, although some intrinsic changes in B cells have been identified.

There is a plethora of information regarding age-related changes in human T cell function. One of the earliest changes occurs in the thymus, the site of T cell maturation, which begins to involute at puberty. Involute refers to the atrophy of the thymus, resulting in a loss of collularity and a decrease in thymic function. However, the contribution of this change to decreased immune function of older adults is debatable, as involution occurs decades before decreased T cell responses are apparent. One of the most consistent findings is that proliferative responses of T cells to both nonspecific (mitogenic) and antigenic stimuli are decreased in elderly adults. A similar decrease is observed in both delayed-type hypersensitivity reactions and cytotoxic T cell activity.

To elucidate possible mechanisms for these age-related changes in T cell function, total cell number, distribution among various subsets, and cytokine production have been evaluated. Most, but not all, reports concur that the circulating number or percentage of T cells is not dramatically affected by age. However, investigators generally agree that a shift from a naïve to a memory phenotype is seen with advancing age in both CD4+ and CD8+ T subpopulations. This shift in phenotype could explain the reduced ability of older adults to produce immune responses to antigens that they have not encountered previously. The effects of age on T cell cytokine production have been variable and dependent on the cytokine measured and the stimulus (i.e., mitogen (substance that induces proliferation (cell division) of T and B cells, regardless of antigen specificity) or antigen) used for induction. The most consistent observation among human studies is that mitogen-induced interleukin (IL-2) production is decreased in elderly individuals. In contrast, IL-4, IL-6, IL-10 and interferon-γlevels after stimulation with either mitogen or antigen have been observed to increase, decrease, or not change with age. Collectively, however, current data clearly indicate that aging preferentially and consistently affects T cell function. This suggests that maintenance and/or restoration of T cell function are critical for sustaining immune function in older adults.

Theories of aging

General theories of aging have been postulated to explain the decline in immune function of older adults. Among these many theories, the free radical (a free radical is an atom, molecule, or compound with one or more unpaired electrons in its outer orbit. When oxygen is utilized during oxidative metabolism, oxygen intermediates, such as superoxides, hydrogen peroxide, and hydroxyP radicals, are formed due to the partial reduction of oxygen. Although most of these oxygen intermediates will react with hydrogen to form water, some will remain as free radicals. These free radicals can cause damage to cell membranes by reacting with nearby molecules in the cell.) theory of aging is one of the most popular and well documented. This theory states that the production of free radicals increases with age, and that these molecules permanently modify the structure of lipids, proteins, DNA, and cells; and thus impairs their function. Although this theory seems plausible, there is little direct evidence that the accumulation of free radicals is causally related to decreased immune responsiveness in humans. Reduction of free radical levels has improved some, but not all, indices of immune function, and the effects seemed to be indirect.

A second general theory of aging is that age-related changes in physiologic and biologic processes are due to changes in the composition of cell membranes, rendering them dysfunctional. Proponents of the free radical theory of aging believe that these alterations in membrane composition result from increased free radicals, which attack membrane phospholipids, increase the cholesterol to phospholipid ratio, and increase cell membrane rigidity. Although limited in scope, studies have shown that lymphocyte membranes of aged donors are more rigid and less fluid. Reports have also shown that a more rigid membrane impairs receptor movement within the cell membrane, and therefore inhibits activation and proliferation of lymphocytes and other immune cells. In addition, these changes in the cell membrane could affect cognate interactions between immune cells, or between immune cells with target cells. It is likely that a combination of several interrelated but independent theories of aging will ultimately explain the age-related decline in the immune response of elderly humans.

Dietary supplementation

Dietary supplementation with antioxidant micronutrients—such as beta-carotene, vitamin E, zinc, and vitamin A—to offset the age-associated decline in immune function of older adults has received much attention in the media. The premise of these studies is that supplementation with antioxidants reduces the deleterious effects of increased free radical production and, thereby, minimizes the age-related decline in the immune response and decreases the incidence of infections and cancer. Several studies have supported this view by showing positive effects of micronutrient supplementation on cell-mediated and humoral immunity and a decrease in the duration of infection. However, equally well-controlled studies have indicated that micronutrient supplementation in older adults produced only transient positive effects, adverse effects, or no effect on indices of immune function and protection from infectious disease. Differences in study design (i.e., the micronutrient tested, the dose given, and the duration of supplementation) probably account for these discrepant results. Although most evidence suggests that supplementation with moderate doses of micronutrients is not harmful, studies must be conducted to determine whether long-term supplementation produces any deleterious effects on the immune response of older adults. Likewise, future studies must investigate whether or not positive effects of these micronutrients are mediated by their antioxidant properties or by acting to maintain or enhance immune function in older adults by other mechanisms. Such studies are necessary so that the lay public, particularly older adults, understands the implications, and possible consequences, of using micronutrient supplementation as a method to offset the age-related decline in immune function.

In summary, an age-related decrease in immune function is well established in humans and several other mammalian species. This decrease has been consistently observed in T cell proliferation and is associated with a shift to a memory T-cell phenotype. Alterations in cytokine production, antibody responses, and innate immunity have also been observed in some cases. However, the dependence of these changes on T cell alterations must be established to clearly elucidate possible mechanisms of age-related changes in the immune response of elderly humans.

Donna M. Murasko Elizabeth M. Gardner

See also Immune System; Immunology, Animal Models; Nutrition; Theories of Biological Aging.

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