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10.3: Age Related Dysfunctions of the Immune System - Biology

10.3: Age Related Dysfunctions of the Immune System - Biology


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General Decrease in Immune Responses

The interactions of the immune system are very complex. This means that the body’s ability to fight invading pathogens is decreasing, while it becomes more likely that the immune system will attack the body’s own healthy tissue.

Age Associated T-Lymphocyte Defects

The reduced activity of T lymphocytes and the reduction in cell-mediated immunity that results in considered to be a factor in the reactivation of lymphoma, tuberculosis, and shingles that occurs most often in older people.

Acquired Immune Deficiency Syndrome

The Worldwide AIDS Epidemic

(a) As of 2008, more than 15 percent of adults were infected with HIV in certain African countries. This grim picture had changed little by 2012. (b) In this scanning electron micrograph, HIV virions (green particles) are budding off the surface of a macrophage (pink structure). (credit b: C. Goldsmith)


In June 1981, the Centers for Disease Control and Prevention (CDC), in Atlanta, Georgia, published a report of an unusual cluster of five patients in Los Angeles, California. All five were diagnosed with a rare pneumonia caused by a fungus called Pneumocystis jirovecii (formerly known as Pneumocystis carinii).

Why was this unusual? Although commonly found in the lungs of healthy individuals, this fungus is an opportunistic pathogen that causes disease in individuals with suppressed or underdeveloped immune systems. The very young, whose immune systems have yet to mature, and the elderly, whose immune systems have declined with age, are particularly susceptible. The five patients from LA, though, were between 29 and 36 years of age and should have been in the prime of their lives, immunologically speaking. What could be going on?

A few days later, a cluster of eight cases was reported in New York City, also involving young patients, this time exhibiting a rare form of skin cancer known as Kaposi’s sarcoma. This cancer of the cells that line the blood and lymphatic vessels was previously observed as a relatively innocuous disease of the elderly. The disease that doctors saw in 1981 was frighteningly more severe, with multiple, fast-growing lesions that spread to all parts of the body, including the trunk and face. Could the immune systems of these young patients have been compromised in some way? Indeed, when they were tested, they exhibited extremely low numbers of a specific type of white blood cell in their bloodstreams, indicating that they had somehow lost a major part of the immune system.

Acquired immune deficiency syndrome, or AIDS, turned out to be a new disease caused by the previously unknown human immunodeficiency virus (HIV). Although nearly 100 percent fatal in those with active HIV infections in the early years, the development of anti-HIV drugs has transformed HIV infection into a chronic, manageable disease and not the certain death sentence it once was. One positive outcome resulting from the emergence of HIV disease was that the public’s attention became focused as never before on the importance of having a functional and healthy immune system.

Although many viruses cause suppression of the immune system, only one wipes it out completely, and that is HIV. It is worth discussing the biology of this virus, which can lead to the well-known AIDS, so that its full effects on the immune system can be understood. The virus is transmitted through semen, vaginal fluids, and blood, and can be caught by risky sexual behaviors and the sharing of needles by intravenous drug users. There are sometimes, but not always, flu-like symptoms in the first 1 to 2 weeks after infection. This is later followed by seroconversion. The anti-HIV antibodies formed during seroconversion are the basis for most initial HIV screening done in the United States. Because seroconversion takes different lengths of time in different individuals, multiple AIDS tests are given months apart to confirm or eliminate the possibility of infection.

After seroconversion, the amount of virus circulating in the blood drops and stays at a low level for several years. During this time, the levels of CD4+ cells, especially helper T cells, decline steadily, until at some point, the immune response is so weak that opportunistic disease and eventually death result. CD4 is the receptor that HIV uses to get inside T cells and reproduce. Given that CD4+ helper T cells play an important role in other in T cell immune responses and antibody responses, it should be no surprise that both types of immune responses are eventually seriously compromised.

Treatment for the disease consists of drugs that target virally encoded proteins that are necessary for viral replication but are absent from normal human cells. By targeting the virus itself and sparing the cells, this approach has been successful in significantly prolonging the lives of HIV-positive individuals. On the other hand, an HIV vaccine has been 30 years in development and is still years away. Because the virus mutates rapidly to evade the immune system, scientists have been looking for parts of the virus that do not change and thus would be good targets for a vaccine candidate.

Lymphomas

Lymphomas are malignancies of the lymph nodes. Typical symptoms include swollen lymph nodes, persistent fever, night sweat sweats, and weight loss. Lymphomas are classifies as either Hodgkin’s disease or non-Hodgkin’s lymphoma bases on different patterns of spread, clinical behavior, and cells or origin. Hodgkin’s disease shows a bimodal age distribution, with one peak occurring between 15 and 35 years of age and another peak between ages 50 and 80. The incidence of non-Hodgkin’s lymphoma increases progressively with age.


Frontiers in Immunology

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    Age and Immune Function

    Of the many different ways to assess aspects of immune function, most if not all suggest that immune function declines with age. Aging is associated with a well-documented reduced efficiency (“immunosenescence”) of both the innate immune system (which provides an immediate response to foreign invaders such as bacteria and certain viruses) and the adaptive immune system (a response which takes several days to engage but which is more efficient and effective once activated) (Gomez et al., 2005 Lord et al., 2001). Beginning soon after birth, there is a steady decrease in the ability of thymus gland to produce new (“naïve”) white blood cells (T-lymphocytes, or “T cells”), with a substantial reduction by age 50 and almost complete incapacity by age 60 (Parham, 2005). One result is that older individuals have a greater percentage of memory T cells, which have been trained to respond to a particular pathogen, than naïve T cells, which can respond to a novel invader. As a result of these and other changes, cells of older individuals become less able to respond to both novel and previously encountered infectious agents (Lord et al., 2001 Miller, 1996). As evidence of this, T cells from elderly individuals show a decreased ability to respond when 𠇌hallenged” with a substance to which they would normally respond, with large differences seen at age 60 and increasingly thereafter (Murasko et al., 1987). Studies like this are performed by observing white blood cells in an artificial medium outside the body (in vitro).

    Although adaptive immunity is most notably affected, measures of innate immunity also show immunosenescence (Gomez et al., 2005). For example, there is a decline in the functionality of natural killer (NK) cells with aging, although observable effects of this change are minimized by an increase in the number of NK cells in older individuals (Castle, 2000 Miller, 1996). An important component of the innate immune system, natural killer cells provide an early defense against viral infections and also have important implications for cancer progression and development (Heffner et al., 2003 Keller et al., 2000 Rabin, 1999). The most conclusive evidence of a decline in NK cell activity with aging comes from animals: Natural killer cells from the spleen and lymph nodes of older animals show in vitro decreases in their functionality compared to those from younger rats (Castle, 2000 Miller, 1996). Another change seemingly inherent in normal aging is that B-lymphocytes from elderly individuals show impaired functionality, with a corresponding decrease in the antibody production essential to both innate and adaptive immunity (Castle, 2000).

    The age-related immune changes described above put older adults at much greater risk of impairment and death from infection, such as from influenza or pneumonia (Castle, 2000 Yoshikawa, 1983). Relatedly, older adults do not respond as well to vaccines (Burns and Goodwin, 1997). Vaccine studies represent another technique for assessing immune function as they provide a window into how individuals typically respond to infection. Moreover, individuals who do not show an adequate response to a given vaccine may not be able to mount an effective immune defense if they encounter the virus: This is particularly true for individuals older than 65 years (Harper et al., 2005).

    Although direct causal relationships between age-related immune changes and the occurrence or severity of specific diseases are not always clear (Castle, 2000), immunosenescence plays a significant role in the increased incidence of shingles (herpes zoster) in late life, and is also relevant to the onset of other diseases such as tuberculosis, diabetes mellitus, and certain cancers (Kiecolt-Glaser and Glaser, 2001 Yoshikawa, 1983). In addition, wound infections increase with age and the elderly are at greater risk for surgical complications, including death from postsurgical infection (Kiecolt-Glaser et al., 1998 Yoshikawa, 1983).

    Dysregulation of inflammatory processes may further explain declines in physical function with age (Cesari et al., 2004). Inflammatory processes are intimately intertwined with immune function: Under conditions of acute infection or tissue damage, elements of the immune system trigger inflammatory processes that play an adaptive role in wound healing and sickness response in the short-term even while they may cause temporary discomfort, such as swelling and fever. Proinflammatory cytokines, proteins that enable communication between cells, play a key role in this process. In fact, one likely mechanism underlying impaired wound healing in the elderly may be a diminished ability of macrophages (other key cells in the innate immune response) to produce proinflammatory cytokines in the local environment (Gomez et al., 2005).

    In contrast, chronic inflammation represents a dangerous disruption of homeostasis and confers an increased risk for development and severity of a range of diseases, including atherosclerosis and cardiovascular disease, certain cancers, osteoporosis, and rheumatoid arthritis (Harris et al., 1999 Pradhan, 2001 Ridker et al., 2000). As compared to young adults, middle aged and particularly elderly adults typically have higher levels of cytokines with proinflammatory functions circulating in their blood, such as interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) (Ershler, 1993 Krabbe et al., 2004). Peripheral blood mononuclear lymphocyte cells from aged people also produce more IL-6 than those from younger subjects when stimulated in vitro (Krabbe et al., 2004 Roubenoff et al., 1998). Another marker of inflammation is C-reactive protein (CRP), which is produced in the liver largely in response to elevations in IL-6. This general marker of inflammation is also elevated in older adults relative to young ones (Ballou et al., 1996). All of these specific changes put older individuals at an increased risk for the diseases mentioned above, including but not limited to cardiovascular disease. Although pre-existing conditions or sub-acute illness may contribute to the presence of greater inflammation in older adults, IL-6 and CRP (in women) increase with age in samples with a wide age range even after controlling for cardiovascular risk factors and symptomotology (Ferrucci et al., 2005).

    There are also other immune-related changes common to aging, which are reviewed in detail elsewhere (e.g., Burns and Goodwin, 1997 Solomon and Morley, 2001). For example, aging is associated with endocrine, autoimmune, and cognitive changes, all of which are related to immune and inflammatory responses.


    IMMUNOSENESCENCE

    Aging is associated with a decline in multiple areas of immune function ( Burns and Goodwin 1997 BURNS EA AND GOODWIN JS. 1997. Immunodeficiency of Aging. Drugs & Aging 11(5): 374-397. ). Aging is associated with a sort of paradox: a state of increased autoimmunity and inflammation coexistent with a state of immunodeficiency ( Sardi et al. 2011 SARDI F, FASSINA L, VENTURINI L, INGUSCIO M, GUERRIERO F, ROLFO E AND RICEVUTI G. 2011. Alzheimer's disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev 11(2): 149-153. ). Immunosenescence is a new concept that reflects the immunological changes associated with age. ( Boraschi and Italiani 2014 BORASCHI D AND ITALIANI P. 2014. Immunosenescence and vaccine failure in the elderly: strategies for improving response. Immunol Lett 162(1): 346-353. , Fulop et al. 2014 FULOP T, LE PAGE A, FORTIN C, WITKOWSKI JM, DUPUIS G AND LARBI A. 2014. Cellular signaling in the aging immune system. Curr Opin Immunol 29(1): 105-111. , Poland et al. 2014 POLAND GA, OVSYANNIKOVA IG, KENNEDY RB, LAMBERT ND ANDKIRKLAND JL . 2014. A systems biology approach to the effect of aging, immunosenescence and vaccine response. Curr Opin Immunol 29(1): 62-68. ). There are three theories that explain the phenomenon of immunosenescence:


    Electronic supplementary material is available online at https://dx.doi.org/10.6084/m9.figshare.c.4318640.

    Published by the Royal Society. All rights reserved.

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    The Worldwide AIDS Epidemic

    (a) As of 2008, more than 15 percent of adults were infected with HIV in certain African countries. This grim picture had changed little by 2012. (b) In this scanning electron micrograph, HIV virions (green particles) are budding off the surface of a macrophage (pink structure). (credit b: C. Goldsmith)

    In June 1981, the Centers for Disease Control and Prevention (CDC), in Atlanta, Georgia, published a report of an unusual cluster of five patients in Los Angeles, California. All five were diagnosed with a rare pneumonia caused by a fungus called Pneumocystis jirovecii (formerly known as Pneumocystis carinii).

    Why was this unusual? Although commonly found in the lungs of healthy individuals, this fungus is an opportunistic pathogen that causes disease in individuals with suppressed or underdeveloped immune systems. The very young, whose immune systems have yet to mature, and the elderly, whose immune systems have declined with age, are particularly susceptible. The five patients from LA, though, were between 29 and 36 years of age and should have been in the prime of their lives, immunologically speaking. What could be going on?

    A few days later, a cluster of eight cases was reported in New York City, also involving young patients, this time exhibiting a rare form of skin cancer known as Kaposi’s sarcoma. This cancer of the cells that line the blood and lymphatic vessels was previously observed as a relatively innocuous disease of the elderly. The disease that doctors saw in 1981 was frighteningly more severe, with multiple, fast-growing lesions that spread to all parts of the body, including the trunk and face. Could the immune systems of these young patients have been compromised in some way? Indeed, when they were tested, they exhibited extremely low numbers of a specific type of white blood cell in their bloodstreams, indicating that they had somehow lost a major part of the immune system.

    Acquired immune deficiency syndrome, or AIDS, turned out to be a new disease caused by the previously unknown human immunodeficiency virus (HIV). Although nearly 100 percent fatal in those with active HIV infections in the early years, the development of anti-HIV drugs has transformed HIV infection into a chronic, manageable disease and not the certain death sentence it once was. One positive outcome resulting from the emergence of HIV disease was that the public’s attention became focused as never before on the importance of having a functional and healthy immune system.

    Although many viruses cause suppression of the immune system, only one wipes it out completely, and that is HIV. It is worth discussing the biology of this virus, which can lead to the well-known AIDS, so that its full effects on the immune system can be understood. The virus is transmitted through semen, vaginal fluids, and blood, and can be caught by risky sexual behaviors and the sharing of needles by intravenous drug users. There are sometimes, but not always, flu-like symptoms in the first 1 to 2 weeks after infection. This is later followed by seroconversion. The anti-HIV antibodies formed during seroconversion are the basis for most initial HIV screening done in the United States. Because seroconversion takes different lengths of time in different individuals, multiple AIDS tests are given months apart to confirm or eliminate the possibility of infection.

    After seroconversion, the amount of virus circulating in the blood drops and stays at a low level for several years. During this time, the levels of CD4 + cells, especially helper T cells, decline steadily, until at some point, the immune response is so weak that opportunistic disease and eventually death result. CD4 is the receptor that HIV uses to get inside T cells and reproduce. Given that CD4 + helper T cells play an important role in other in T cell immune responses and antibody responses, it should be no surprise that both types of immune responses are eventually seriously compromised.

    Treatment for the disease consists of drugs that target virally encoded proteins that are necessary for viral replication but are absent from normal human cells. By targeting the virus itself and sparing the cells, this approach has been successful in significantly prolonging the lives of HIV-positive individuals. On the other hand, an HIV vaccine has been 30 years in development and is still years away. Because the virus mutates rapidly to evade the immune system, scientists have been looking for parts of the virus that do not change and thus would be good targets for a vaccine candidate.


    Etiology of age-related changes in the microbiome

    The precise etiologic explanation for these age-related changes remains incomplete. Across the age-spectrum, dramatic increases in the use of antibiotics and increasing pervasiveness of a high-saturated fat and high-sugar “western” diet are proposed to directly contribute to the depletion of important beneficial components of the microbiome [50, 77]. In turn, these changes contribute to chronic activation of the immune system and a dramatic rise in the prevalence of chronic inflammatory disorders. These two factors also represent key modifiable health factors which may contribute to exacerbated dysbiosis among older adults.

    In the United States of America, rates of antibiotic prescription actually dropped from 2000–2010 among children and young to middle-aged adults [78]. In contrast, prescription rates increased among older adults with the most dramatic increases seen among persons ≥80 years of age [78]. Additionally, rates of antibiotic prescription have risen substantially in recent years in residential care facilities [79]. These trends may at least partially explain age-related changes in the microbiome, particularly those observed in the ELDERMET cohort among residents of long-term care facilities.

    Similarly, age-related changes in nutrient intake may also contribute to late-life dysbiosis. It is well-recognized that diet is one of the primary contributors to gut health. Advanced age is associated with deterioration in various aspects of nutrient intake and absorption including dentition, salivary function, digestion, and intestinal transit time [73, 80]. Sensory changes, including taste and smell, may also alter the appetite making certain foods unappealing and thus altering eating habits [81]. It is possible that these changes contribute to dysbiosis though it may be more likely that altered immune responses to “inflammatory” foods among older adults may exacerbate microbial changes.

    Another prominent possibility is that chronic activation of the innate and adaptive immune systems due to immunosenescence contributes to an altered bacterial composition in the gut. Such an affect may manifest at least partially due to known increases in hypothalamus-pituitary-adrenal (HPA) axis activity in advanced age [82] as HPA-mediated inflammatory stress responses are known to induce to both immune dysregulation [83] and dysbiosis [84]. Conversely, however, it remains possible—given the known inflammatory effects of dysbiosis—that changes to the microbiome due to other factors (e.g., diet) exacerbate inflammation and altered immunity. Thus, it is presently difficult to decipher the temporal relationship between these changes. Furthermore, this known interplay suggests a tantalizing hypothesis that the processes of immunosenescence and dysbiosis may in fact be interdependent.

    Moreover, physical changes to the intestinal epithelial barrier may play a role in dysbiosis and age-related inflammation. Jakobsson et al. previously demonstrated that the composition of the gut microbiota is directly related to the leaky gut [85]. Recent evidence suggests now that intestinal permeability may increase with age. Man et al. [86] recently demonstrated that, compared to younger adults, ileal tissues from older adults demonstrated increased IL-6 concentrations that were accompanied by increased intestinal permeability as a result of elevated claudin-2. These data provide novel evidence from humans indicating the likelihood of a “leaky gut” during advanced age whereby the intestinal barrier preventing harmful substances from reaching the bloodstream is permeated. The leaky gut is well-associated with inflammatory bowel conditions but is now being proposed as a contributor to a wide variety of health conditions [87, 88]—with particular interest in a gut-brain axis which regulates the blood brain barrier [61, 62, 75, 76].

    Though somewhat speculative at present, it is possible that the leaky gut is a primary source of inflammation long-observed within the circulation. Studies in Drosophila have reported that age-related changes in the microbiome increase intestinal permeability [89] and drive chronic inflammation [90]. More recently, Thevaranjan et al. [91] were the first to our knowledge to publish work from mammals directly supporting this hypothesis. Using germ-free and conventionally raised mice, this group reported that the germ-free animals did not display an age-related increase in systemic pro-inflammatory cytokines. Moreover, co-housing germ-free with old—but not young—conventionally raised mice increased circulating pro-inflammatory cytokines [91]. Anti-TNF therapy also reversed age-related microbial changes. These data are the strongest to date suggesting the critical role of gut changes in driving age-related inflammation and provide a solid backdrop for continued investigation in this area.


    COVID-19 and your body’s mitochondria

    Researchers from the USC Leonard Davis School of Gerontology conducted a study that sought to more completely understand COVID-19’s suppression of the body’s immune response. Their research suggests mitochondria, the tiny “powerhouses” in each cell of the body, are one of the first lines of defense against COVID-19 and identifies important differences in how SARS-CoV-2 impacts mitochondria compared with other viruses.

    The USC study expands on recent findings that COVID-19 tamps down the body’s innate inflammatory response, finding it does so by diverting mitochondria from their normal function. To get to the bottom of the immune system’s failure to defend against COVID-19, lead author Brendan Miller says the researchers looked at how the virus specifically targets mitochondria, a crucial part of the body’s innate immune system and energy production.

    Looking at data from the early days of the COVID-19 outbreak, the team performed an analysis that compared how the mitochondria functioned when facing SARS-CoV-2, versus other viruses. They were able to identify three ways in which COVID-19, but not the other viruses, mutes the mitochondrial protective response…

    • Most importantly, they found that SARS-CoV-2 reduces mitochondrial proteins. This effect may lower the cell’s metabolic output and reactive oxygen species (ROS) generation that would normally produce a virus-killing inflammatory response. With that action sabotaged, the virus spreads.
    • Another finding is that SARS-CoV-2 doesn’t illicit the “messenger warning” which informs cells a viral attack has happened, giving the cell time to self-destruct so the virus cannot replicate. The other viruses used in the analysis were not able to block this warning system as the coronavirus did.
    • In addition, the researchers found certain mitochondria-encoded genes were not being turned on or off by SARS-CoV-2 at rates to be expected when confronted with a virus. This process is believed to produce energy that can help the cell evade a virus.

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    According to USC Leonard Davis School Dean Dr. Pinchas Cohen, senior author of the study, these differences could explain why older adults and people with metabolic disfunction, who in both cases are more likely to experience mitochondrial dysfunction, have more severe responses to COVID-19. They could also provide a starting point for more targeted approaches that could help identify therapeutics.

    “If you already have mitochondrial and metabolic dysfunction, then you may, as a result, have a poor first line of defense against COVID-19,” Dr. Cohen says. “Future work should consider mitochondrial biology as a primary intervention target for SARS-CoV-2 and other coronaviruses.”


    A Multi-Phenotype System to Discover Therapies for Age-Related Dysregulation of the Immune Response to Viral Infections

    Age-related immune dysregulation contributes to increased susceptibility to infection and disease in older adults. We combined high-throughput laboratory automation with machine learning to build a multi-phenotype aging profile that models the dysfunctional immune response to viral infection in older adults. From a single well, our multi-phenotype aging profile can capture changes in cell composition, physical cell-to-cell interaction, organelle structure, cytokines, and other hidden complexities contributing to age-related dysfunction. This system allows for rapid identification of new potential compounds to rejuvenate older adults’ immune response. We used our technology to screen thousands of compounds for their ability to make old immune cells respond to viral infection like young immune cells. We observed beneficial effects of multiple compounds, of which two of the most promising were disulfiram and triptonide. Our findings indicate that disulfiram could be considered as a treatment for severe coronavirus disease 2019 and other inflammatory infections.


    Affiliations

    Department of Anesthesiology, Medicine, and Surgery, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Hospices Civils de Lyon, Immunology Laboratory, Hôspital E, Herriot, 5, Place d'Arsonval, Lyon, 69003, France

    Department of Anesthesiology & Critical & Service Mobile d'Urgence Rapide (SMUR), Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris and Université Paris 7 Denis Diderot, 2 rue Ambroise Paré, Paris, 75010, France