Immunosenescence, inflammation and Alzheimer’s disease
© Martorana et al.; licensee BioMed Central Ltd. 2012
Received: 7 June 2012
Accepted: 9 July 2012
Published: 1 November 2012
Ageing impacts negatively on the development of the immune system and its ability to fight pathogens. Progressive changes in the T-cell and B-cell systems over the lifespan of individuals have a major impact on the capacity to respond to immune challenges. The cumulative age-associated changes in immune competence are termed immunosenescence that is characterized by changes where adaptive immunity deteriorates, while innate immunity is largely conserved or even upregulated with age. On the other hand, ageing is also characterized by “inflamm-ageing”, a term coined to explain the inflammation commonly present in many age-associated diseases. It is believed that immune inflammatory processes are relevant in Alzheimer’s disease, the most common cause of dementia in older people. In the present paper we review data focusing on changes of some immunoinflammatory parameters observed in patients affected by Alzheimer’s disease.
KeywordsImmunosenescence Alzheimer’s disease Inflammation Cytokine Chemokine Lymphocyte Ageing
Ageing and the immune system
During the past century, humans have gained more years of average life expectancy than in the last 10,000 years. Currently, people are living much longer than they used to; and the longer they live, the longer their bodies are exposed to environmental factors that increase the risk of age-associated diseases. The reduction of the response to environmental stimuli is associated with an increased inclination towards illness and death. In western countries, the mortality rate increases in people over 65 years old, if compared with younger individuals, by 100-fold for stroke or chronic lung disease, by 92-fold for heart disease, by 89-fold for influenza and correlated pneumonia infections, and by 43-fold for cancer . Ageing is the consequence of the collapse of self-organizing systems and reduced ability to adapt to the environment, and it has been suggested that normal human ageing is associated with a loss of complexity in a variety of anatomic structures and physiological processes . These losses lead to physical inability, impaired mental functional capacity and organ and apparatus deregulation , with the consequence of increased susceptibility to diseases and death. On the contrary, healthy ageing seems directly correlated with a good functioning of the immune system, suggesting that it is related to both environmental factors and genetic background. Indeed, many studies have focused on genetic determinants of longevity in genes regulating the immune-inflammatory response [4–7].
Ageing impacts negatively on the development of the immune system and its ability to function. Progressive changes in the T-cell and B-cell systems over the lifespan of individuals have a major impact on the capacity to respond to immune challenges. These cumulative age-associated changes in immune competence are termed immunosenescence. According to the remodeling theory of ageing proposed several years ago , the current data on human immunosenescence describe a complex scenario where adaptive immunity deteriorates, while innate immunity is largely conserved or even up-regulated with age. Under an evolutionary perspective, antigens are the cause of a persistent lifelong antigenic stress, responsible for the accumulation of effector CD8+/CD28- T cells, the decrease of naïve T lymphocytes (CD45RA+CD62L+) and the marked shrinkage of the T-cell repertoire with age [9–14]. The humoral compartment is also affected in the aged [15–20]; indeed, B-cell numbers are decreased and the B-cell repertoire is influenced by ageing through the quality of antibody response [21–25], and this decreased B-cell diversity is associated with poor health status [26–28]. Immunosenescence is thus not a random deteriorative phenomenon, as was hypothesized in 1989 in “the network theory of aging”, but could be envisaged as the result of the continuous challenge of the unavoidable exposure to a variety of potential antigens such as viruses and bacteria, but also food and self-molecules among others [12, 13, 29–31].
Modifications of T-cell and B-cell systems in older humans
T cells and B cells or B-cell products
CD3+, CD3+CD4+, CD3+CD8+
Total T cells, T helper cells,
(percentage and absolute number)
cytotoxic T lymphocytes
Naïve T cells
Effector T cells
Total B cells
(percentage and absolute number)
(percentage and absolute number)
Naïve B cells
Double Negative B cells
(after specific immunization)
Ageing is accompanied by a chronic low-grade inflammatory state demonstrated by the increased serum levels of inflammatory mediators such as cytokines and acute phase proteins in the aged [39, 40]. The most important role in this basal pro-inflammatory status in the older person seems to be played by chronic antigenic stress, which, interacting with the genetic background, potentially triggers the onset of age-related inflammatory diseases [6, 7, 41]. The inflammatory process is a physiological phenomenon that is necessary for the elimination of pathogenic viruses or bacteria, but the prolonged period to which aged people are exposed may lead to chronic inflammation that inevitably damages several organs. Chronic inflammation appears to be involved in the pathogenesis of all age-related diseases such as AD, atherosclerosis, diabetes, sarcopenia and cancer [4, 42–47].
Inflammation, Alzheimer’s disease and immune response
AD is the most common cause of dementia in older people and it is estimated that 27 million people are affected worldwide [48, 49]. As the life expectancy of the population increases, the number of affected individuals is predicted to triple by 2050 [49, 50]. Age is therefore the main risk factor in AD, although early-onset disease can occur before age 60. AD may not be an inevitable occurrence of the aging process, but it is a disease with significant genetic roots. Indeed, genetics is important not only in predicting susceptibility but also the age of disease onset in the older person . Other important risk factors are environmental events in early life as well as childhood IQ  and gender. In most studies, women were found to be at greater risk for AD. However, it is not clear whether this effect is due to genetic or hormonal differences between males and females or whether it is a surrogate marker of other still unmeasured socioeconomic factors .
AD is a progressive brain disorder affecting regions of the brain that control memory and cognitive functions. The two major neuropathologic hallmarks of AD are extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles. The production of Aβ, a decisive event in AD, is the result of the cleavage of amyloid precursor protein (APP), whose levels are high in AD.
APP has important developmental functions in cell differentiation and in the organization of synapses . According to the Aβ hypothesis, AD begins with the abnormal processing of APP. Proteolysis of extracellular domains by sequential β-secretases and γ-secretases results in a family of peptides that form the β-amyloids (Aβ). Among these Aβ peptides, the more insoluble (Aβ42) has a propensity for self-aggregation into fibrils that form the senile plaques characteristic of AD pathology. Neurofibrillary tangles are composed of the tau-protein and in healthy neurons are integral components of microtubules, while in AD tau-protein becomes hyperphosphorylated and this phenomenon leads to the tangles binding to each other and forming tangled threads .
Brain inflammation is a pathological hallmark of AD, and we know that inflammation is a response to eliminate both the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult. If tissue health is not restored, inflammation becomes a chronic condition that continuously erodes the surrounding tissues . Inflammation clearly occurs in pathologically susceptible regions in brain AD, with increased expression of acute-phase proteins and pro-inflammatory cytokines [6, 7, 49, 56–58]. The cells responsible for the inflammatory reaction are microglia, astrocytes, and neurons. These activated cells produce high levels of inflammatory mediators such as pro-inflammatory cytokines and chemokines, prostaglandins, leukotrienes, thromboxanes, coagulation factors, free radicals as reactive oxygen species and nitric oxide, complement factors, proteases and protease inhibitors, and C-reactive protein [49, 58]. The hypothesis is that Aβ plaques and tangles stimulate a chronic inflammatory reaction . Inflammatory mediators, in turn, enhance APP production and the amyloidogenic processing of APP to induce Aβ42 peptide production. These circumstances also inhibit the generation of a soluble APP fraction that has a neuroprotective effect [60, 61]. On the contrary, Aβ induces the expression of pro-inflammatory cytokines in glial cells in a vicious cycle [62, 63].
To date, the timing with which neuroinflammation is believed to influence AD is unknown. In particular, clinical and experimental evidence from different transgenic models has suggested that a pro-inflammatory process might precede plaque deposition . A recent paper correlates the increased levels of C-reactive protein with the formation of senile plaques . C-reactive protein has been shown to exist in two forms: the monomeric form, which has pro-inflammatory properties [66, 67]; and the circulating pentamer form . Authors have recently shown that the aggregated forms of Aβ plaques lead to the formation of the pro-inflammatory monomeric form of C-reactive protein, which exacerbates local inflammation .
There is currently much evidence suggesting the involvement of a systemic immune response in AD. Indeed, numerous investigations suggest that in addition to the central nervous system (CNS) cells, blood-derived cells can also be blamed for the inflammatory response and seem to accumulate in the AD brain [69–71]. Other studies have shown changes in the distribution and reactivity of immune cells in the blood [63, 72–75]. Britschgi and Wyss-Coray have shown that there is communication between CNS and cells and factors involved in the systemic immune response . In particular, neuroinflammation induces the efflux of proteins, such as Aβ, or inflammatory mediators from CNS across the blood–brain-barrier (BBB); this may cause systemic immune reaction and recruitment of myeloid or lymphocytic cells into the CNS.
Indeed, it is known that BBB has a “monitoring role” between the immune system and AD to protect the brain from the entry of macromolecules, like immunoglobulins, and cells, including immunocompetent cells. A recent assumption supposes that microvascular diseases, often associated with AD, microtraumas and inflammation could cause the abnormal permeability of the BBB. The consequence of this impairment is the anomalous presence of serum proteins in the cerebrospinal fluid and in the brain, including Aβ. In the brain Aβ can bind astrocytes, starting a degenerative and inflammatory process. Finally, autoantibodies bound to neurons can induce Aβ42 internalization and deposition, increasing brain damage [74, 76].
Under physiological conditions T lymphocytes are few in the brain, although they are able to cross the BBB. The T-lymphocyte number increases in AD patients, especially in the hippocampus and temporal cortex. Herein, activated microglia increase the expression of MHC I and II, which allows the migration of T cells .
Communication between the CNS and the immune system in AD could thus influence both the lymphocyte distribution in the blood and the production of immune mediators . Therefore, despite T cells being able to enter the brain tissue, it is also possible that T cells exert their effects without entering the CNS. Indeed, peripheral blood mononuclear cells (PBMCs) from AD patients produce higher levels of pro-inflammatory cytokines, such as IL-1β and IL-6, compared with PBMCs from control subjects [6, 7, 77]. Other studies have shown that Aβ stimulates macrophage inflammatory protein (MIP)-1α overexpression by peripheral T cells and its receptor CCR5 expression on brain endothelial cells necessary for T cells crossing the BBB . Moreover, other altered immune parameters were documented, such as decreased percentages of naive T cells and an increase of memory T cells, an increased number of CD4+ T lymphocytes that lack the co-stimulatory molecule CD28, and a reduction of CD4+CD25high regulatory T cells .
Systemic immune profile in Alzheimer’s disease
At present a correct diagnosis of AD, characterized by pathological changes in the AD brain (that include neurological loss, extracellular amyloid plaques and intracellular neurofibrillar tangles), can be only evaluated by post-mortem autopsy, although a recent study  emphasized the role of soluble Aβ oligomers as a key factor responsible for the early pre-plaque formation. Activation of microglia occurs in the early stages of the disease, even before plaque formation, and is correlated with early cognitive deficits. As a consequence of the microglial activation and the deregulation of nerve grow factor metabolism, these authors have indicated matrix metalloproteinase-9 as a possible biomarker for signaling the early stages of ongoing CNS inflammation . Another study has put in evidence the use of imaging techniques for early detection of glial activation prior to plaque deposition .
The evaluation of some modified parameters obtainable from the blood of patients could therefore be a goal for the research on AD.
The knowledge of the aforementioned systemic inflammation in AD patients has suggested a new research area that focuses on leukocyte modifications, as it would be desirable to have methods available that allow the use of peripheral blood from patients to identify “prognostic” or disease markers.
Main modifications of lymphocytes subpopulations between Alzheimer’s disease patients and age-matched controls
Changesin Alzheimer disease
Total B cells
Total B cells
Total T cells
Cytotoxic T lymphocytes
Naïve CD4+ T
Naïve CD4+ T
CD4+ T cells
Terminal effector memory RA cells
CD4+ T cells
Activated CD4+ T
Regulatory T cells
Senescent CD4+ T cells
More recently, the use of larger numbers of surface markers confirmed the significant reduction of naïve CD4+ T cells, identified as CD4+CD28+CD27+CD45RA+CD45RO- in AD patients, compared with age-matched controls and a contemporary increase of CD4+CD28–CD27-CD45RA+CD45RO+ late differentiated memory T cells . The further evaluation of CD57 and KLRG-1, commonly considered senescence markers on these cells, has demonstrated a significant increase of late differentiated KLRG-1+CD4+ T cells in AD patients compared with age-matched healthy controls. No differences have been reported concerning CD57 expression on CD4+ T cells when comparing AD patients and their controls . Moreover, the deep characterization of regulatory T cells as CD4+CD25+FoxP3+CD127low has demonstrated no differences between the two groups studied, thereby revealing that the previously reported data  are referred to activated T cells (CD4+CD25+) instead of regulatory cells. Table 2 describes the reported data.
Regarding CD8+ T cells, no modifications are reported in AD patients when compared with their age-matched controls. Indeed, this might be due to the well-known role of CD8+ T cells in age-related changes strictly correlated with chronic cytomegalovirus infection, which is a feature common to almost all older people (as well as AD patients) [35–37].
Aβ42 and in vitroperipheral blood mononuclear cell activation
A recent hypothesis suggests that persistent stimulation of the immune system by Aβ peptides leads to B-cell and T-cell responses, as well as to the release of inflammatory mediators.
Although the Aβ aggregates are mainly found in the brain amyloid plaques, the soluble forms, monomers and oligomers, predominate in the plasma where they may interact with the cells of the immune system .
Cytokines, growth factors, chemokines and chemokine receptors on Alzheimer’s disease patients after in vitro stimulation
Stimulated vs. unstimulated AD patients
CCR2 and CCR5 on T cells
CR5on B cells
The role of Aβ42 in the generation of an “inflammatory milieu” is also suggested by the observation that in vitro stimulation of PBMCs by rAβ42 induces the production of different chemokines and cytokines, rendering these cells active players in the inflammatory response in AD patients . In fact, after an in vitro stimulation of PBMCs, AD patients have shown a significantly high production of the inflammatory cytokines IL-1β, IL-6, TNF-α and IFN-γ. We have also reported an increase of the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist, so we hypothesized that this situation might balance the overproduction of the above-described pro-inflammatory cytokines. As previously stated, however, there is an efflux of amyloid from CNS that can prime lymphocytes. Some authors have demonstrated a reduction of both pro-inflammatory and anti-inflammatory cytokines, hence assuming a general impairment of immune functions in AD patients, whereas others have demonstrated a decrease of IL-10, an increase of MIP1-α and an increase of IFN-γ, respectively [74, 78, 82, 88]. Methodological differences (mitogen or Aβ stimulation) among the different studies, including inclusion criteria for both AD patients and healthy controls, might explain the great variability of data (Table 3).
Since monocytes are the main source of IL-6 and TNF-α and they possibly efficiently bind Aβ42 via CD36, the pattern of cytokine production observed by us is the one to be expected. Besides, we have previously demonstrated an increased expression of the scavenger receptor CD36 on monocytes from AD subjects in unstimulated and stimulated cultures that could be related to their efficient role to bind plasmatic Aβ which in turn causes the production of cytokines, chemokines, and reactive oxygen species, hence activating the signaling cascade necessary for cellular migration, adhesion, and phagocytosis .
In addition, the engagement of monocytes might render these cells more efficient in T-cell activation . Some studies have suggested receptors for advanced glycosylation end products as possible candidates for the role of soluble Aβ receptors. These receptors have been found on CD4+ T-cell surfaces and are known to bind various molecules including Aβ; ligation of receptors for advanced glycosylation end products results in cell activation and inflammatory response . Another possible receptor might be Toll-like receptor-4 [92, 93], expressed on CD4+ T cells, for which the potentially modulatory effect upon ligation by Aβ may even be direct.
Many modifications of immune and inflammatory systems have been reported in patients affected by AD. These changes might be the consequence of the overproduction of Aβ that can activate the blood cells, rendering them active producers of inflammatory mediators. On the contrary, the role of the genetic background namely the polymorphisms of genes involved in the immune-inflammation must be considered to fully elucidate the complex mechanisms that play a role in the generation of AD. Moreover, as a high proportion of women are affected by AD, especially at a very advanced age, it is important to consider the role played both by hormones and levels of education regarding the different propensity of males and females to develop disease. Fascinatingly, other important risk factors that could be related to the typical pro-inflammatory status of older people are environmental events in early life as well as childhood IQ.
amyloid precursor protein
chemokine receptor type
central nervous system
immunological risk phenotype
killer cell lectin-like receptor subfamily G member 1
major histocompatibility complex
macrophage inflammatory protein
peripheral blood mononuclear cell
recombinant amyloid-beta 42
regulated upon activation, normal T-cell expressed, and secreted
tumor necrosis factor.
AM is a PhD student of the Pathobiology PhD course (directed by CC) at Palermo University and this work is submitted in partial fulfillment of the requirement for her PhD degree.
- Troen BR: The biology of ageing. Mt Sinai J Med. 2003, 70: 3-22.PubMedGoogle Scholar
- Goldberger AL, Peng CK, Lipsitz LA: What is physiologic complexity and how does it change with aging and disease?. Neurobiol Aging. 2002, 23: 23-26. 10.1016/S0197-4580(01)00266-4.View ArticlePubMedGoogle Scholar
- Wick G, Berger P, Jansen-Dürr P, Grubeck-Loebenstein BA: Darwinian-evolutionary concept of age-related diseases. Exp Gerontol. 2003, 38: 13-25. 10.1016/S0531-5565(02)00161-4.View ArticlePubMedGoogle Scholar
- Candore G, Colonna-Romano G, Balistreri CR, Di Carlo D, Grimaldi MP, Listì F, Nuzzo D, Vasto S, Lio D, Caruso C: Biology of longevity: role of the innate immune system. Rejuvenation Res. 2006, 9: 143-148. 10.1089/rej.2006.9.143.View ArticlePubMedGoogle Scholar
- Franceschi C, Motta L, Motta M, Malaguarnera M, Capri M, Vasto S, Candore G, Caruso C: The extreme longevity: the state of the art in Italy. Exp Gerontol. 2008, 43: 45-52. 10.1016/j.exger.2007.06.006.View ArticlePubMedGoogle Scholar
- Di Bona D, Plaia A, Vasto S, Cavallone L, Lescai F, Franceschi C, Licastro F, Colonna-Romano G, Lio D, Candore G, Caruso C: Association between the interleukin-1β polymorphisms and Alzheimer’s disease: a systematic review and meta-analysis. Brain Res Rev. 2008, 59: 155-163. 10.1016/j.brainresrev.2008.07.003.View ArticlePubMedGoogle Scholar
- Di Bona D, Vasto S, Capurso C, Christiansen L, Deiana L, Franceschi C, Hurme M, Mocchegiani E, Rea M, Lio D, Candore G, Caruso C: Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis. Ageing Res Rev. 2009, 8: 36-42. 10.1016/j.arr.2008.09.001.View ArticlePubMedGoogle Scholar
- Franceschi C, Cossarizza A: Introduction: the reshaping of the immune system with age. Int Rev Immunol. 1995, 12: 1-4s. 10.3109/08830189509056697.View ArticlePubMedGoogle Scholar
- Cossarizza A, Ortolani C, Paganelli R, Barbieri D, Monti D, Sansoni P, Fagiolo U, Castellani G, Bersani F, Londei M, Franceschi C: CD45 isoforms expression on CD4+ and CD8+ T cells throughout life, from newborns to centenarians: implications for T cell memory. Mech Ageing Dev. 1996, 86: 173-195. 10.1016/0047-6374(95)01691-0.View ArticlePubMedGoogle Scholar
- Vasto S, Colonna-Romano G, Larbi A, Wikby A, Caruso C, Pawelec G: Role of persistent CMV infection in configuring T cell immunity in the elderly. Immun Ageing. 2007, 4: 2-10.1186/1742-4933-4-2.PubMed CentralView ArticlePubMedGoogle Scholar
- Pawelec G, Larbi A: Immunity and ageing in man: annual review 2006/2007. Exp Gerontol. 2008, 43: 34-38.PubMedGoogle Scholar
- Sauce D, Appay V: Altered thymic activity in early life: how does it affect the immune system in young adults?. Curr Opin Immunol. 2011, 23: 543-548. 10.1016/j.coi.2011.05.001.View ArticlePubMedGoogle Scholar
- Appay V, Fastenackels S, Katlama C, Ait-Mohand H, Schneider L, Guihot A, Keller M, Grubeck-Loebenstein B, Simon A, Lambotte O, Hunt PW, Deeks SG, Costagliola D, Autran B, Sauce D: Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS. 2011, 25: 1813-1822. 10.1097/QAD.0b013e32834640e6.View ArticlePubMedGoogle Scholar
- Pawelec G, McElhaney JE, Aiello AE, Derhovanessian E: The impact of CMV infection on survival in older humans. Curr Opin Immunol. 2012, 24: 1-5. 10.1016/j.coi.2012.01.004.View ArticleGoogle Scholar
- Colonna-Romano G, Cossarizza A, Aquino A, Scialabba G, Bulati M, Lio D, Candore G, Di Lorenzo G, Fradà G, Caruso C: Age- and gender-related values of lymphocyte subsets in subjects from Northern and Southern Italy. Arch Gerontol Geriatr Suppl. 2002, 8: 99-107.View ArticlePubMedGoogle Scholar
- Colonna-Romano G, Bulati M, Aquino A, Scialabba G, Candore G, Lio D, Motta M, Malaguarnera M, Caruso C: B cells in the aged: CD27, CD5, and CD40 expression. Mech Ageing Dev. 2003, 124: 389-393. 10.1016/S0047-6374(03)00013-7.View ArticlePubMedGoogle Scholar
- Shi Y, Yamazaki T, Okubo Y, Uehara Y, Sugane K, Agematsu K: Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell. J Immunol. 2005, 175: 3262-3267.View ArticlePubMedGoogle Scholar
- Veneri D, Ortolani R, Franchini M, Tridente G, Pizzolo G, Vella A: Expression of CD27 and CD23 on peripheral blood B lymphocytes in humans of different ages. Blood Transfus. 2009, 7: 29-34.PubMed CentralPubMedGoogle Scholar
- Colonna-Romano G, Bulati M, Aquino A, Pellicanò M, Vitello S, Lio D, Candore G, Caruso C: A double-negative (IgD–CD27–) B cell population is increased in the peripheral blood of elderly people. Mech Ageing Dev. 2009, 130: 681-690. 10.1016/j.mad.2009.08.003.View ArticlePubMedGoogle Scholar
- Buffa S, Bulati M, Pellicanò M, Dunn-Walters DK, Wu YC, Candore G, Vitello S, Caruso C, Colonna-Romano G: B cell immunosenescence: different features of naive and memory B cells in elderly. Biogerontology. 2011, 12: 473-483. 10.1007/s10522-011-9353-4.View ArticlePubMedGoogle Scholar
- Listì F, Candore G, Modica MA, Russo M, Di Lorenzo G, Esposito-Pellitteri M, Colonna-Romano G, Aquino A, Bulati M, Lio D, Franceschi C, Caruso C: A study of serum immunoglobulin levels in elderly persons that provides new insights into B cell immunosenescence. Ann N Y Acad Sci. 2006, 1089: 487-495. 10.1196/annals.1386.013.View ArticlePubMedGoogle Scholar
- Chong Y, Ikematsu H, Yamaji K, Nishimura M, Nabeshima S, Kashiwagi S, Hayashi J: CD27(+) (memory) B cell decrease and apoptosis-resistant CD27(−) (naive) B cell increase in aged humans: implications for age-related peripheral B cell developmental disturbances. Int Immunol. 2005, 17: 383-390. 10.1093/intimm/dxh218.View ArticlePubMedGoogle Scholar
- Frasca D, Riley RL, Blomberg BB: Humoral immune response and B-cell functions including immunoglobulin class switch are downregulated in aged mice and humans. Semin Immunol. 2005, 17: 378-384. 10.1016/j.smim.2005.05.005.View ArticlePubMedGoogle Scholar
- Bulati M, Buffa S, Candore G, Caruso C, Dunn-Walters DK, Pellicanò M, Wu YC, Colonna Romano G: B cells and immunosenescence: a focus on IgG+IgD–CD27– (DN) B cells in aged humans. Ageing Res Rev. 2011, 10: 274-284. 10.1016/j.arr.2010.12.002.View ArticlePubMedGoogle Scholar
- Frasca D, Diaz A, Romero M, Phillips M, Mendez NV, Landin AM, Blomberg BB: Unique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine. Int Immunol. 2012, 24: 175-182. 10.1093/intimm/dxr123.PubMed CentralView ArticlePubMedGoogle Scholar
- Candore G, Di Lorenzo G, Mansueto P, Melluso M, Fradà G, Li Vecchi M, Esposito Pellitteri M, Drago A, Di Salvo A, Caruso C: Prevalence of organ-specific and non organ-specific autoantibodies in healthy centenarians. Mech Ageing Dev. 1997, 94: 183-190. 10.1016/S0047-6374(96)01845-3.View ArticlePubMedGoogle Scholar
- Weksler ME, Szabo P: The effect of age on the B-cell repertoire. J Clin Immunol. 2000, 20: 240-249. 10.1023/A:1006659401385.View ArticlePubMedGoogle Scholar
- Gibson KL, Wu YC, Barnett Y, Duggan O, Vaughan R, Kondeatis E, Nilsson BO, Wikby A, Kipling D, Dunn-Walters DK: B-cell diversity decreases in old age and is correlated with poor health status. Ageing Cell. 2009, 8: 18-25. 10.1111/j.1474-9726.2008.00443.x.View ArticleGoogle Scholar
- Akbar AN, Henson SM: Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?. Nat Rev Immunol. 2011, 11: 289-295. 10.1038/nri2959.View ArticlePubMedGoogle Scholar
- Henson SM, Riddell NE, Akbar AN: Properties of end-stage human T cells defined by CD45RA re-expression. Curr Opin Immunol. 2012, 24: 1-6. 10.1016/j.coi.2012.01.004.View ArticleGoogle Scholar
- Macaulay R, Akbar AN, Henson SM: The role of the T cell in age-related inflammation. Age (Dordr). 2012, 10.1007/s11357-012-9381-2.Google Scholar
- Blomberg BB, Frasca D: Quantity, not quality, of antibody response decreased in the elderly. J Clin Invest. 2011, 121: 2981-2983. 10.1172/JCI58406.PubMed CentralView ArticlePubMedGoogle Scholar
- Wolf J, Weinberger B, Grubeck-Loebenstein B: The immunoregulatory effects of CMV-infection in human fibroblasts and the impact on cellular senescence. Immun Ageing. 2012, 9: 1-6. 10.1186/1742-4933-9-1.PubMed CentralView ArticlePubMedGoogle Scholar
- Herndler-Brandstetter D, Landgraf K, Tzankov A, Jenewein B, Brunauer R, Laschober GT, Parson W, Kloss F, Gassner R, Lepperdinger G, Grubeck-Loebenstein B: The impact of aging on memory T cell phenotype and function in the human bone marrow. J Leukoc Biol. 2012, 91: 197-205. 10.1189/jlb.0611299.View ArticlePubMedGoogle Scholar
- Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Löfgren S, Nilsson BO, Ernerudh J, Pawelec G, Johansson B: An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci. 2005, 60: 556-565. 10.1093/gerona/60.5.556.View ArticlePubMedGoogle Scholar
- Strindhall J, Nilsson BO, Löfgren S, Ernerudh J, Pawelec G, Johansson B, Wikby A: No immune risk profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study. Exp Gerontol. 2007, 42: 753-761. 10.1016/j.exger.2007.05.001.View ArticlePubMedGoogle Scholar
- Wikby A, Månsson IA, Johansson B, Strindhall J, Nilsson SE: The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20–100 years of age. Biogerontology. 2008, 9: 299-308. 10.1007/s10522-008-9138-6.View ArticlePubMedGoogle Scholar
- Vasto S, Caruso C: Immunity & Ageing: a new journal looking at ageing from an immunological point of view. Immun Ageing. 2004, 1: 1-4. 10.1186/1742-4933-1-1.PubMed CentralView ArticlePubMedGoogle Scholar
- Krabbe KS, Pedersen M, Bruunsgaard H: Inflammatory mediators in the elderly. Exp Gerontol. 2004, 39: 687-699. 10.1016/j.exger.2004.01.009.View ArticlePubMedGoogle Scholar
- Bruunsgaard H: The clinical impact of systemic low-level inflammation in elderly populations. With special reference to cardiovascular disease, dementia and mortality. Dan MedBull. 2006, 53: 285-309.Google Scholar
- De Martinis M, Franceschi C, Monti D, Ginaldi L: Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett. 2005, 579: 2035-2039. 10.1016/j.febslet.2005.02.055.View ArticlePubMedGoogle Scholar
- Spirig R, Tsui J, Shaw S: The emerging role of TLR and innate immunity in cardiovascular disease. Cardiol Res Pract. 2012, 2012: 181394-PubMed CentralPubMedGoogle Scholar
- Gui T, Shimokado A, Sun Y, Akasaka T, Muragaki Y: Diverse roles of macrophages in atherosclerosis: from inflammatory biology to biomarker discovery. Mediators Inflamm. 2012, 2012: 693083-PubMed CentralView ArticlePubMedGoogle Scholar
- Coussens LM, Werb Z: Inflammation and cancer. Nature. 2002, 420: 860-867. 10.1038/nature01322.PubMed CentralView ArticlePubMedGoogle Scholar
- Shacter E, Weitzman SA: Chronic inflammation and cancer. Oncology. 2002, 16: 217-226.PubMedGoogle Scholar
- Rubin DC, Shaker A, Levin MS: Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Front Immunol. 2012, 3: 107-10.3389/fimmu.2012.00107.PubMed CentralView ArticlePubMedGoogle Scholar
- Yamauchi H, Woodward WA, Valero V, Alvarez RH, Lucci A, Buchholz TA, Iwamoto T, Krishnamurthy S, Yang W, Reuben JM, Hortobagyi GN, Ueno NT: Inflammatory breast cancer: what we know and what we need to learn. Oncologist. 2012, 17: 891-899. 10.1634/theoncologist.2012-0039.PubMed CentralView ArticlePubMedGoogle Scholar
- Wimo A, Jonsson L, Winblad B: An estimate of the worldwide prevalence and direct costs of dementia in 2003. Dement Geriatr Cogn Disord. 2006, 21: 175-181. 10.1159/000090733.View ArticlePubMedGoogle Scholar
- Rubio-Perez JM, Morillas-Ruiz JM: A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal. 2012, 2012: 756357-PubMed CentralView ArticlePubMedGoogle Scholar
- Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA: Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003, 60: 1119-1122. 10.1001/archneur.60.8.1119.View ArticlePubMedGoogle Scholar
- Candore G, Balistreri CR, Colonna-Romano G, Lio D, Listì F, Vasto S, Caruso C: Gender-related immune-inflammatory factors, age-related diseases, and longevity. Rejuvenation Res. 2010, 13: 292-297. 10.1089/rej.2009.0942.View ArticlePubMedGoogle Scholar
- Luciano M, Marioni RE, Gow AJ, Starr JM, Deary IJ: Reverse causation in the association between C reactive protein and fibrinogen levels and cognitive abilities in an aging sample. Psychosom Med. 2009, 71: 404-409. 10.1097/PSY.0b013e3181a24fb9.View ArticlePubMedGoogle Scholar
- Henderson VW: Estrogen-containing hormone therapy and Alzheimer’s disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience. 2006, 138: 1031-1039. 10.1016/j.neuroscience.2005.06.017.View ArticlePubMedGoogle Scholar
- Müller UC, Zheng H: Physiological functions of APP family proteins. Cold Spring Harb Perspect Med. 2012, 2: a006288-PubMed CentralView ArticlePubMedGoogle Scholar
- Braak H, Del Tredici K: The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 2011, 121: 171-181. 10.1007/s00401-010-0789-4.View ArticlePubMedGoogle Scholar
- Griffin WS, Mrak RE: Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease. J Leukoc Biol. 2002, 72: 233-238.PubMed CentralPubMedGoogle Scholar
- Cacquevel M, Lebeurrier N, Cheenne S, Vivien D: Cytokines in neuroinflammation and Alzheimer’s disease. Curr Drug Targets. 2004, 5: 529-534. 10.2174/1389450043345308.View ArticlePubMedGoogle Scholar
- Finch CE, Morgan TE: Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper. Curr Alzheimer Res. 2007, 4: 185-189. 10.2174/156720507780362254.View ArticlePubMedGoogle Scholar
- Town T, Nikolic V, Tan J: The microglial ‘activation’ continuum: from innate to adaptive responses. J Neuroinflammation. 2005, 2: 24-33. 10.1186/1742-2094-2-24.PubMed CentralView ArticlePubMedGoogle Scholar
- Friedlander RM: Apoptosis and caspases in neurodegenerative diseases. N Engl J Med. 2003, 348: 1365-1375. 10.1056/NEJMra022366.View ArticlePubMedGoogle Scholar
- Atwood CS, Obrenovich ME, Liu T: Amyloid-β: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-β. Brain Res Rev. 2003, 43: 1-16. 10.1016/S0165-0173(03)00174-7.View ArticlePubMedGoogle Scholar
- Lindberg C, Hjorth E, Post C, Winblad B, Schultzberg M: Cytokine production by a human microglial cell line: effects ofβ-amyloid andα-melanocyte-stimulating hormone. Neurotox Res. 2005, 8: 267-276. 10.1007/BF03033980.View ArticlePubMedGoogle Scholar
- Pellicanò M, Bulati M, Buffa S, Barbagallo M, Di Prima A, Misiano G, Picone P, Di Carlo M, Nuzzo D, Candore G, Vasto S, Lio D, Caruso C, Colonna-Romano G: Systemic immune responses in Alzheimer’s disease: in vitro mononuclear cell activation and cytokine production. J Alzheimers Dis. 2010, 21: 181-192.PubMedGoogle Scholar
- Ferretti MT, Cuello AC: Does a pro-inflammatory process precede Alzheimer’s disease and mild cognitive impairment?. Curr Alzheimer Res. 2011, 8: 164-174.View ArticlePubMedGoogle Scholar
- Strang F, Scheichl A, Chen YC, Wang X, Htun NM, Bassler N, Eisenhardt S, Habersberger J, Peter K: Amyloid plaques dissociate pentameric to monomeric C-Reactive-Protein: a novel pathomechanism driving cortical inflammation in Alzheimer’s disease?. Brain Pathol. 2012, 22: 337-346. 10.1111/j.1750-3639.2011.00539.x.View ArticlePubMedGoogle Scholar
- Ji SR, Wu Y, Zhu L, Potempa LA, Sheng FL, Lu W, Zhao J: Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m). FASEB J. 2007, 21: 284-294.View ArticlePubMedGoogle Scholar
- Eisenhardt SU, Habersberger J, Murphy A, Chen YC, Woollard KJ, Bassler N, et al: Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. Circ Res. 2009, 105: 128-137. 10.1161/CIRCRESAHA.108.190611.View ArticlePubMedGoogle Scholar
- Pepys MB, Hirschfield GM: C-reactive protein: a critical update. J Clin Invest. 2003, 111: 1805-1812.PubMed CentralView ArticlePubMedGoogle Scholar
- Bonotis K, Krikki E, Holeva V, Aggouridaki C, Costa V: Systemic immune aberrations in Alzheimer’s disease patients. J Neuroimmunol. 2008, 193: 183-187. 10.1016/j.jneuroim.2007.10.020.View ArticlePubMedGoogle Scholar
- Miscia S, Ciccocioppo F, Lanuti P, Velluto L, Bascelli A: Aβ(1–42) stimulated T cells express P-PKC-delta and P-PKC-zeta in Alzheimer disease. Neurobiol Aging. 2009, 30: 394-406. 10.1016/j.neurobiolaging.2007.07.011.View ArticlePubMedGoogle Scholar
- Liu YJ, Guo DW, Tian L, Shang DS, Zhao WD: Peripheral T cells derived from Alzheimer’s disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-α-dependent. Neurobiol Aging. 2010, 31: 175-188. 10.1016/j.neurobiolaging.2008.03.024.View ArticlePubMedGoogle Scholar
- Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL: Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer’s disease. J Clin Invest. 2003, 112: 415-422.PubMed CentralView ArticlePubMedGoogle Scholar
- Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC, Gustavson A, Sayre J, Sofroni E, Suarez T, Chiappelli F, Bernard G: Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J Alzheimers Dis. 2005, 7: 221-232.PubMedGoogle Scholar
- Britschgi M, Wyss-Coray T: Systemic and acquired immune responses in Alzheimer’s disease. Int Rev Neurobiol. 2007, 82: 205-233.View ArticlePubMedGoogle Scholar
- Pellicanò M, Larbi A, Goldeck D, Colonna-Romano G, Buffa S, Bulati M, Rubino G, Iemolo F, Candore G, Caruso C, Derhovanessian E, Pawelec G: Immune profiling of Alzheimer patients. J Neuroimmunol. 2012, 242: 52-59. 10.1016/j.jneuroim.2011.11.005.View ArticlePubMedGoogle Scholar
- Sardi F, Fassina L, Venturini L, Inguscio M, Guerriero F, Rolfo E, Ricevuti G: Alzheimer’s disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev. 2011, 11: 149-153. 10.1016/j.autrev.2011.09.005.View ArticlePubMedGoogle Scholar
- Reale M, Iarlori C, Gambi F, Lucci I, Salvatore M, Gambi D: Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1 beta and interleukin-6 release from lymphocytes of Alzheimer’s disease patients. Exp Gerontol. 2005, 40: 165-171. 10.1016/j.exger.2004.12.003.View ArticlePubMedGoogle Scholar
- Man SM, Ma YR, Shang DS, Zhao WD, Li B, Guo DW, Fang WG, Zhu L, Chen YH: Peripheral T cells overexpress MIP-1α to enhance its transendothelial migration in Alzheimer’s disease. Neurobiol Aging. 2007, 28: 485-496. 10.1016/j.neurobiolaging.2006.02.013.View ArticlePubMedGoogle Scholar
- Larbi A, Pawelec G, Witkowski JM, Schipper HM, Derhovanessian E, Goldeck D, Fulop T: Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer’s disease. J Alzheimers Dis. 2009, 17: 91-103.PubMedGoogle Scholar
- Sastre M, Richardson JC, Gentleman SM, Brooks DJ: Inflammatory risk factors and pathologies associated with Alzheimer's disease. Curr Alzheimer Res. 2011, 8: 132-141.View ArticlePubMedGoogle Scholar
- Richartz-Salzburger E, Batra A, Stransky E, Laske C, Köhler N, Bartels M, Buchkremer G, Schott K: Altered lymphocyte distribution in Alzheimer’s disease. J Psychiatr Res. 2007, 41: 174-178. 10.1016/j.jpsychires.2006.01.010.View ArticlePubMedGoogle Scholar
- Speciale L, Calabrese E, Saresella M, Tinelli C, Mariani C, Sanvito L, Longhi R, Ferrante P: Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients. Neurobiol Aging. 2007, 28: 1163-1169. 10.1016/j.neurobiolaging.2006.05.020.View ArticlePubMedGoogle Scholar
- Xue SR, Xu DH, Yang XX, Dong WL: Alterations in lymphocyte subset patterns and co-stimulatory molecules in patients with Alzheimer disease. Chin Med J (Engl). 2009, 122: 1469-1472.Google Scholar
- Jóźwik A, Landowski J, Bidzan L, Fülop T, Bryl E, Witkowski JM: Beta-amyloid peptides enhance the proliferative response of activated CD4CD28 lymphocytes from Alzheimer disease patients and from healthy elderly. PLoS One. 2012, 7: e33276-10.1371/journal.pone.0033276.PubMed CentralView ArticlePubMedGoogle Scholar
- Querfurth HW, LaFerla FM: Alzheimer’s disease. N Engl J Med. 2010, 362: 329-344. 10.1056/NEJMra0909142.View ArticlePubMedGoogle Scholar
- Teeling JL, Perry VH: Systemic infection and inflammation in acute CNS injury and chronic neurodegeneration: underlying mechanisms. Neuroscience. 2009, 158: 1062-1073. 10.1016/j.neuroscience.2008.07.031.View ArticlePubMedGoogle Scholar
- Li M, Shang DS, Zhao WD, Tian L, Li B, Fang WG, Zhu L, Man SM, Chen YH: Amyloid beta interaction with receptor for advanced glycation end products up-regulates brain endothelial CCR5 expression and promotes T cells crossing the blood–brain barrier. J Immunol. 2009, 182: 5778-5788. 10.4049/jimmunol.0803013.View ArticlePubMedGoogle Scholar
- Reale M, Iarlori C, Feliciani C, Gambi D: Peripheral chemokine receptors, their ligands, cytokines and Alzheimer’s disease. J Alzheimers Dis. 2008, 14: 147-159.PubMedGoogle Scholar
- Iarlori C, Gambi D, Gambi F, Lucci I, Feliciani C, Salvatore M, Reale M: Expression and production of two selected beta-chemokines in peripheral blood mononuclear cells from patients with Alzheimer’s disease. Exp Gerontol. 2005, 40: 605-611. 10.1016/j.exger.2005.04.007.View ArticlePubMedGoogle Scholar
- Stuart LM, Bell SA, Stewart CR, Silver JM, Richard J, Goss JL, Tseng AA, Zhang A, El Khoury JB, Moore KJ: CD36 signals to the actin cytoskeleton and regulates microglial migration via a p130Cas complex. J Biol Chem. 2007, 282: 27392-27401. 10.1074/jbc.M702887200.View ArticlePubMedGoogle Scholar
- Schmidt AM, Sahagan B, Nelson RB, Selmer J, Rothlein R, Bell JM: The role of RAGE in amyloid-beta peptide-mediated pathology in Alzheimer’s disease. Curr Opin Investig Drugs. 2009, 10: 672-680.PubMedGoogle Scholar
- Buchanan MM, Hutchinson M, Watkins LR, Yin H: Toll-like receptor 4 in CNS pathologies. J Neurochem. 2010, 114: 13-27.PubMed CentralPubMedGoogle Scholar
- González-Navajas JM, Fine S, Law J, Datta SK, Nguyen KP, Yu M, Corr M, Katakura K, Eckman L, Lee J, Raz E: TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice. J Clin Invest. 2010, 120: 570-581. 10.1172/JCI40055.PubMed CentralView ArticlePubMedGoogle Scholar
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