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The Failing Immune System and Its Role in Pulmonary Disease

In the paper quoted below, researchers review the links between immune system dysfunction in aging and pulmonary diseases - diseases of the lungs, ranging from infections to fibrosis. This is just one of many classes of medical condition that are much more serious and frequent in the elderly.

We all know that the immune system fails in its duties with aging. The elderly are frail in large part because they have little resistance to infection, their healing is impaired, and other functions depending on components of the immune system are similarly diminished. This is partially the result of high levels of various forms of cell and tissue damage, and partially the result of the immune system having evolved into a form that cannot continue to adapt to new threats indefinitely. To oversimplify somewhat, parts of it run out of space, too many cells devoted to memory of pathogens and too few to devoted to the destruction of those pathogens and potentially harmful cells.

The immune system is an enormously complex array of specialized cell populations, and so its progressive failure is similarly complicated. Beyond the disarray within the immune system, we must also consider that immune cells have intricate parts to play in the proper function of many different organs and tissue types, all of which are impacted as the immune system as a whole runs down. Wound healing, for example, falters in the old in part because of dysregulation in the macrophage population. One of the consequences of immune aging is a rising level of chronic inflammation, and it is known that inflammation contributes meaningfully to the development of many age-related conditions. Inflammation grows troublesome in lung tissues for example, the result of changing behavior on the part of immune cells.

The good news is that there are numerous potential ways to adjust the old immune system for more youthful performance, some of which could be realized quite soon, even though none are as yet comprehensive. Any engineering effort that results in more active, useful immune cells in circulation should be beneficial, however. This could be achieved through, for example, restoration of thymic function, or by destroying the clutter of memory cells or other unwanted sections of an experienced immune cell population, or even by using the techniques of stem cell medicine to grow a supply of immune cells and infuse large numbers of them on a regular basis.

The Impact of Immunosenescence on Pulmonary Disease

The shift in global demographics as a consequence of increased life expectancies has given greater clinical and research focus to the physiological process of aging and its impact on chronic disease. Morbidity and mortality from pulmonary illness have interestingly increased while those from other prevalent diseases such as cardiovascular or neurological have remained stable or in some cases decreased. This has led to recognition of the importance of age-related changes to the development and progression of lung disease.

While a multitude of cellular and molecular changes occur with age, their specific impact on the respiratory system, pulmonary physiology, and disease susceptibility remains undetermined. Age-related declines in immune function, termed "immunosenescence," likely play a critical role in the manifestation of age-related pulmonary diseases. Influencing both innate and adaptive components of the immune system, immunosenescence shapes the clinical phenotype observed in many chronic respiratory diseases including asthma and pulmonary fibrosis. This importantly differs from the same disease observed in younger cohorts. Age-related change in immunity additionally predisposes the elderly to pulmonary infection such as influenza and pneumococcus while a poorer vaccine response contributes to poorer outcomes.

Immunosenescence causes age-related declines in immune function at both cellular and serologic levels. Specific responses to foreign and self-antigens ensue promoting an increased susceptibility of the elderly to diseases including infection, cancer, autoimmune, and other chronic processes in addition to a poorer vaccine response. Both innate and adaptive arms of immune function are affected. Autoimmunity, immunodeficiency, and immune-dysregulation are some of the theories put forward to account for this physiological phenomenon; however it is likely that a combination of these takes place in vivo. Aging is associated with a chronic low grade inflammatory state. As such, proinflammatory cytokines including TNF-α, IL-1, and IL-6 are systemically elevated. Such "inflamm-aging" may be part of the aging process itself; however it has been proposed in the pathogenesis of several age-related inflammatory diseases including atherosclerosis, diabetes, and Alzheimer's.

Asthma and Allergy

While the asthmatic phenotype in children is well defined, "late-onset" asthma has lagged behind. This is largely explained by the heterogeneous nature of disease despite the similar treatment approaches. Until recently, phenotypes of "late-onset asthma" were based on aetiology, for instance, aspirin sensitivity, toxic exposures, or occupational influence or alternatively clinical disease characteristics such as mild, moderate, or severe. Consequently, mechanisms associated with late-onset asthma are incompletely understood. Suggestions are that it may occur as a consequence to viral infection that promotes persistent inflammatory change when coupled to the effects of immunosenescence.

Pulmonary Infection

Respiratory infections remain a leading cause of morbidity and mortality worldwide especially in older adults. The increased risk of community-acquired pneumonia in elderly patients ranges from 15 to 30% independent of socioeconomic status or comorbidities. Despite advances in molecular based detection techniques, there is limited evidence addressing specific mechanisms by which immunosenescence predisposes to pneumococcal associated disease. It is very likely that immunosenescence plays a role in increasing susceptibility to respiratory infection in the elderly population. This is likely facilitated by an impaired mucosal barrier, reduced mucociliary clearance, and blunted airway immune and inflammatory responses on exposure to potentially pathogenic microorganisms.

Pulmonary Fibrosis

Several of the affected cellular and molecular mechanisms associated with the aging process are implicated in idiopathic pulmonary fibrosis (IPF). Patients with IPF also demonstrate increased markers of oxidative stress both within the airway and systemically. Abnormal cellular senescence is demonstrated in patients with IPF, particularly from bone marrow derived stem cells such as fibrocytes. Fibrocytes have been shown to traffic into the lungs and to contribute to IPF pathogenesis. Additionally, high levels of circulating fibrocytes have been shown to herald a poor prognosis in IPF. A chronic background inflammatory state occurs in IPF that compares with immunosenescence associated "inflamm-aging."

Autoimmune Disease, Vasculitis, and Other Respiratory Diseases

The elderly have a higher rate of autoimmunity but lower prevalence of autoimmune disease. The explanation for this is uncertain; however, it is postulated to be due to the increased expansion of peripheral regulatory T-cells. Autoimmunity may increase the affinity of T-cells to self-antigens or latent viruses promoting an autoimmune process. Older adults have been shown to possess increased amounts of circulating autoantibodies due to the increased amount of tissue and cell damage coupled with apoptosis. Importantly however higher levels of autoimmunity do not equate with increased autoimmune disease. Thymic T-regulatory cells (Tregs) increase autoimmunity and reduce the CD4 and CD8 response which in turn increases susceptibility to infection and cancers. Recurrent bacterial and viral infections stimulate the release of proinflammatory cytokines which in turn are further expanded by activation of Tregs. Treg expansion is associated with T-helper 17 (Th17) cells and the persistence of chronic inflammation, a phenomenon that occurs during the physiological aging process.

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