CCR5
C-C chemokine receptor type 5 (C-C CKR-5) (CC-CKR-5) (CCR-5) (CCR5) (CHEMR13) (HIV-1 fusion coreceptor) (CD195 antigen) [CMKBR5]
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The aging process is a physiological phenomenon associated with progressive changes in metabolism, genes expression, and cellular resistance to stress. In neurons, one of the hallmarks of senescence is a disturbance of calcium homeostasis that may have far-reaching detrimental consequences on neuronal physiology and function. Among several proteins involved in calcium handling, plasma membrane Ca -ATPase (PMCA) is the most sensitive calcium detector controlling calcium homeostasis. PMCA exists in four main isoforms and PMCA2 and PMCA3 are highly expressed in the brain. The overall effects of impaired calcium extrusion due to age-dependent decline of PMCA function seem to accumulate with age, increasing the susceptibility to neurotoxic insults. To analyze the PMCA role in neuronal cells, we have developed stable transfected differentiated PC12 lines with down-regulated PMCA2 or PMCA3 isoforms to mimic age-related changes. The resting Ca increased in both PMCA-deficient lines affecting the expression of several Ca -associated proteins, i.e., sarco/endoplasmic Ca -ATPase (SERCA), calmodulin, calcineurin, GAP43, CCR5, IP Rs, and certain types of voltage-gated Ca channels (VGCCs). Functional studies also demonstrated profound changes in intracellular pH regulation and mitochondrial metabolism. Moreover, modification of PMCAs membrane composition triggered some adaptive processes to counterbalance calcium overload, but the reduction of PMCA2 appeared to be more detrimental to the cells than PMCA3.
MeSH Terms
- Aging
- Animals
- Humans
- Isoenzymes
- Mitochondria
- Models, Biological
- Neurons
- Plasma Membrane Calcium-Transporting ATPases
Keywords
- Ca2 signaling
- PC12 cells
- aging
- bioenergetics
- isoforms
- plasma membrane Ca2 -ATPase
Inactivation of the CCR5 gene by CRISPR editing in human embryos, as recently attempted in China, was touted as a positive change for the babies involved since it was expected to impart resistance to HIV infection. However, it turns out that the absence of CCR5 is not neutral but actually decreases fitness, as shown by survival analysis of population data in the UK biobank. This underlines the pitfalls of genetic enhancement, and emphasizes that any germline modification must be preceded by in-depth studies to exclude unforeseen negative effects. ‡.
MeSH Terms
- Adult
- Aged
- CRISPR-Cas Systems
- China
- Embryo Research
- Gene Editing
- Gene Silencing
- Genetic Enhancement
- Genome-Wide Association Study
- HIV Infections
- HIV-1
- Humans
- Longevity
- Middle Aged
- Receptors, CCR5
We use the genotyping and death register information of 409,693 individuals of British ancestry to investigate fitness effects of the CCR5-∆32 mutation. We estimate a 21% increase in the all-cause mortality rate in individuals who are homozygous for the ∆32 allele. A deleterious effect of the ∆32/∆32 mutation is also independently supported by a significant deviation from the Hardy-Weinberg equilibrium (HWE) due to a deficiency of ∆32/∆32 individuals at the time of recruitment.
MeSH Terms
- Adult
- Aged
- Databases, Genetic
- Female
- Genetic Fitness
- HIV Infections
- Homozygote
- Humans
- Life Expectancy
- Male
- Middle Aged
- Mortality
- Mutation
- Receptors, CCR5
- Registries
- Survival Rate
- United Kingdom
CC chemokine receptor type 5 (CCR5) is a chemokine receptor that influences the immune response to infectious and parasitic diseases. This study aimed to determine whether the CCR5Δ32 and CCR5 59029 A/G polymorphisms are associated with the development of ocular toxoplasmosis in humans. Patients with positive serology for Toxoplasma gondii were analyzed and grouped as 'with ocular toxoplasmosis' (G1: n=160) or 'without ocular toxoplasmosis' (G2: n=160). A control group (G3) consisted of 160 individuals with negative serology. The characterization of the CCR5Δ32 and CCR5 59029 A/G polymorphisms was by PCR and by PCR-RFLP, respectively. The difference between the groups with respect to the mean age (G1: mean age: 47.3, SD±19.3, median: 46 [range: 18-95]; G2: mean age: 61.3, SD±13.7, median: 61 [range: 21-87]; G3: mean age: 38.8, SD±17.9, median: 34 [range: 18-80]) was statistically significant (G1 vs.G2: p-value <0.0001; t=7.21; DF=318; G1 vs.G3: p-value <0.0001; t=4.32; DF=318; G2 vs. G3: p-value <0.0001; t=9.62; DF=318). The Nagelkerke r value was 0.040. There were statistically significant differences for the CCR5/CCR5 (p-value=0.008; OR=0.261), AA (p-value=0.007; OR=2.974) and AG genotypes (p-value=0.018; OR=2.447) between G1 and G2. Individuals with the CCR5/CCR5 genotype and simultaneously the CCR5-59029 AA or AG genotypes have a greater risk of developing ocular toxoplasmosis (4% greater), which may be associated with a strong and persistent inflammatory response in ocular tissue.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Case-Control Studies
- Female
- Genetic Predisposition to Disease
- Genotype
- Humans
- Male
- Middle Aged
- Polymerase Chain Reaction
- Polymorphism, Genetic
- Polymorphism, Restriction Fragment Length
- Receptors, CCR5
- Risk Factors
- Toxoplasma
- Toxoplasmosis, Ocular
- Young Adult
Keywords
- CCR5 receptor
- Chemokines
- Genetic polymorphism
- Ocular toxoplasmosis
- Toxoplasma gondii
Mucosal-associated invariant T (MAIT) cells play an important role in innate host defence. MAIT cells appear to undergo exhaustion and are functionally weakened in chronic viral infections. However, their role in chronic hepatitis C virus (HCV) infection remains unclear. We investigated the frequency of CD8( ) CD161( ) TCR Vα7.2( ) MAIT cells in a cross-sectional cohort of chronic HCV-infected patients (n = 25) and healthy controls (n = 25). Peripheral blood mononuclear cells were investigated for circulating MAIT cell frequency, liver-homing (CCR5 and CD103), biomarkers of immune exhaustion (PD-1, TIM-3 and CTLA-4), chronic immune activation (CD38 and HLA-DR), and immunosenescence (CD57) by flow cytometry. The frequency of MAIT cells was significantly decreased, and increased signs of immune exhaustion and chronic immune activation were clearly evident on MAIT cells of HCV-infected patients. Decrease of CCR5 on circulating MAIT cells is suggestive of their peripheral loss in chronic HCV-infected patients. MAIT cells also showed significantly increased levels of HLA-DR, CD38, PD-1, TIM-3 and CTLA-4, besides CD57 in chronic HCV disease. Immune exhaustion and senescence of CD8( ) CD161( ) TCR Vα7.2( ) MAIT cells could contribute to diminished innate defence attributes likely facilitating viral persistence and HCV disease progression.
MeSH Terms
- ADP-ribosyl Cyclase 1
- Adult
- Antigens, CD
- Biomarkers
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- CTLA-4 Antigen
- Case-Control Studies
- Cohort Studies
- Cross-Sectional Studies
- Female
- Flow Cytometry
- HLA-DR Antigens
- Hepatitis A Virus Cellular Receptor 2
- Hepatitis C, Chronic
- Humans
- Immunity, Innate
- Immunosenescence
- Integrin alpha Chains
- Lymphocyte Count
- Male
- Membrane Proteins
- Middle Aged
- NK Cell Lectin-Like Receptor Subfamily B
- Programmed Cell Death 1 Receptor
- Receptors, Antigen, T-Cell, alpha-beta
- Receptors, CCR5
- Viral Load
- Young Adult
Keywords
- CD38
- HCV infection
- MAIT cells
- PD-1
- TCRVα7.2
- exhaustion
Elderly HIV-1 infected individuals progress to AIDS more frequently and rapidly than people becoming infected at a young age. To identify possible reasons for these differences in clinical progression, we performed comprehensive phenotypic analyses of CD4 T cells from uninfected young and elderly individuals, and examined their susceptibility to HIV-1 infection and programmed death. Peripheral blood mononuclear cells (PBMCs) from older people contain an increased percentage of central memory and Th17 CD4 T cells that are main target cells of HIV-1 and strongly reduced proportions of naïve T cells that are poorly susceptible to HIV-1. Unstimulated T cells from elderly individuals expressed higher levels of activation markers, death receptors, and the viral CXCR4 co-receptor than those from young individuals but responded poorly to stimulation. CD4 T cells from older individuals were highly susceptible to CXCR4- and CCR5-tropic HIV-1 infection but produced significantly lower quantities of infectious virus than cells from young individuals because they were highly prone to apoptosis and thus presumably had a very short life span. The increased susceptibility of T cells from the elderly to HIV-1 infection correlated directly with CXCR4 and inversely with CD4 expression. The levels of apoptosis correlated with the cell surface expression of FAS but not with the expression of programmed death receptor 1 (PD1) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Increased levels of activated and highly susceptible HIV-1 target cells, reduced CD4 and enhanced CXCR4 cell surface expression, together with the high susceptibility to FAS-induced programmed cell death may contribute to the rapid CD4 T cell depletion and accelerated clinical course of infection in elderly HIV-1-infected individuals.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Apoptosis
- CD4 Antigens
- CD4-Positive T-Lymphocytes
- Female
- HIV Infections
- HIV-1
- Humans
- Immunologic Memory
- Leukocytes, Mononuclear
- Male
- Membrane Glycoproteins
- Middle Aged
- Programmed Cell Death 1 Receptor
- Receptors, CXCR4
- Signal Transduction
- Young Adult
- fas Receptor
During organismal aging, human T-cells shift towards less functional phenotypes, often called senescent cells. As these cells have not been well characterized, we aimed to relate surface markers of human T-cell senescence with characteristics of in vitro cellular aging and to further characterize these cells. We identified, by flow cytometry, subpopulations of CD8 T-cells based on CD57 and CD28 expression, and tested them for some markers of cellular senescence, apoptosis, differentiation and homing. Elderly persons presented significantly higher proportions not only of CD28-CD57 , but also of CD28 CD57 cells. CD28 CD57 cells had the highest expression of p16, p21, Bcl-2, CD95, CD45RO, CCR5 and PD-1, thereby arguing in favor of a senescent phenotype. Among CD8 T-lymphocytes, CD28 CD57 cells represent a subset with some senescent features that are distinct from the CD28-CD57 cells.
MeSH Terms
- Aged
- Aging
- Biomarkers
- CD28 Antigens
- CD57 Antigens
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p21
- Flow Cytometry
- Humans
- Immunophenotyping
- Phenotype
Keywords
- CD28
- CD57
- CXCR2
- Cellular aging
- p16
- p21
The number of memory phenotype CD8 T cells increases dramatically with aging in both humans and mice. However, the mechanism for this is unknown. The prevailing hypothesis is that memory T cells accumulate with aging as a result of lifelong antigenic stimulation. However, data supporting this supposition are lacking. In this study, we demonstrate that central memory CD8 T cells, which represent a large majority of memory CD8 T cells in aged mice, are not memory cells that develop in response to antigenic stimulation but are virtual memory cells that develop without antigenic stimulation. In addition to phenotypic evidence, we show that accumulation of central memory CD8 T cells is independent of CD4 T cells, CCR5, and CXCR3, all of which are known to be essential for Ag-driven development of central memory CD8 T cells. Thus, this study reveals a novel mechanism for aging-related changes in CD8 T cells.
MeSH Terms
- Aging
- Animals
- Antigens
- CD4 Antigens
- CD8-Positive T-Lymphocytes
- Female
- Hyaluronan Receptors
- Immunologic Memory
- Interleukin-15
- L-Selectin
- Lymphocyte Count
- Lymphopoiesis
- Male
- Mice
- Mice, Congenic
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Immunological
- Radiation Chimera
- Receptors, CCR5
- Receptors, CXCR3
- T-Lymphocyte Subsets
In order to estimate the distribution of some polymorphisms for the CCR5, CCR2, apoE, p53, ITGB3, and HFE genes in Russian long-livers from Western Siberia, a sample of 271 individuals (range 90-105 years) was examined. It was demonstrated that carriage of the delta32 polymorphism for the CCR5 gene, V64/polymorphism for the CCR2 gene, e2/e3/e4 for the apoE gene, L33P for the ITGB3 gene, as well as H63D and S65C polymorphisms for the HFE gene does not influence on predisposition to the longevity; carriage of the 282 Y allele for the HFE gene negatively influences on the longevity; carriage of the heterozygous genotype for the R72P polymorphism for the p53 gene correlates with the longevity of elderly people.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Alleles
- Apolipoproteins E
- DNA
- Gene Frequency
- Genes, p53
- Genotype
- Hemochromatosis Protein
- Histocompatibility Antigens Class I
- Humans
- Integrin beta3
- Longevity
- Male
- Membrane Proteins
- Middle Aged
- Polymerase Chain Reaction
- Polymorphism, Genetic
- Receptors, CCR5
- Siberia
Lymph nodes (LNs) are among the first sites of tumor metastasis. The expression of chemokines and chemokine receptors in LNs are involved in cancer prognosis and are considered to be good predictors of tumor progression. The main aim of this study was to assess the expression of important, tumor-promoting chemokines and chemokine receptors in LNs of breast cancer patients. LNs were isolated from eighteen women diagnosed with breast cancer. Data were compared between positive and negative LNs. Expression of chemokines and chemokine receptors were determined by quantitative real-time PCR (qRT-PCR) and flow cytometry. Results of qRT-PCR showed that all chemokines, in particular MCP-1, IL-8, SDF-1 and CXCL13, and chemokine receptors CXCR3, CXCR4 and CCR5 showed greater mRNA expression in LN( ) compared to LN(-) samples. However, these differences were not statistically significant. IL-8 and CXCR5 gene transcripts had significantly higher expression in LN( )patients with stage III compared to those with stage II tumors (P value = 0.04). Results of flow cytometry analysis showed a higher, significant presence of CD69( ), CCR5( ) and CD3( )CCR5( ) cells in LN of LN( ) compared to LN(- )breast cancer patients (P value<0.05). Expression of MCP-1 was higher in LN( ) patients, which was near significance (P value = 0.07). Our findings provide additional information on the expression of essential chemokines and chemokine receptors in LN and on their relationships to important prognostic factors in breast cancer. These findings have important implications for immunotherapeutic interventions in the treatment of breast cancer.
MeSH Terms
- Aging
- Breast Neoplasms
- Chemokines
- Female
- Flow Cytometry
- Gene Expression Regulation, Neoplastic
- Humans
- Lymph Nodes
- Lymphatic Metastasis
- Middle Aged
- RNA, Messenger
- Receptors, Chemokine
The chemokine receptor CCR5 is pivotal in determining an individual's susceptibility to HIV-1 infection and rate of disease progression. To establish whether population-based differences exist in cell surface expression of CCR5 we evaluated the extent of CCR5 expression across all peripheral blood cell types in individuals from two populations, South African Africans (SAA) and South African Caucasians (SAC). Significant differences in CCR5 expression, both in number of CCR5 molecules per cell (density) and the percentage of CCR5-expressing cells, were observed between the two study groups, within all cell subsets. Most notably, the percentage of all CCR5( ) cell subsets was significantly lower in SAC compared with SAA individuals (P < 0·01) among natural killer (NK) -cell subsets (CD56( ) , CD16( ) CD56( ) and CD56(dim) ) whereas CCR5 density was significantly higher in SAC compared with SAA individuals in CCR5( ) CD8( ) T-cell subsets and CCR5( ) NK-cell subsets (CD56( ) , CD16( ) CD56( ) and CD56(dim) ) (all P < 0·05). These relationships were maintained after exclusion of CCR5Δ32 heterozygous individuals (n = 7) from the SAC dataset. The SAA individuals exhibited significantly higher cell activation levels, as measured by HLA-DR expression, than SAC individuals in CD4( ) T-cell subsets (P = 0·002) and CD56( ) NK-cell subsets (P < 0·001). This study serves to demonstrate that ethnically divergent populations show marked differences in both cell activation and CCR5 expression, which are likely to impact on both susceptibility to HIV-1 infection and the rate of HIV-1 disease progression.
MeSH Terms
- Adult
- African Continental Ancestry Group
- Aged
- Aging
- CD4-Positive T-Lymphocytes
- CD56 Antigen
- CD8-Positive T-Lymphocytes
- Disease Progression
- European Continental Ancestry Group
- Female
- HIV Infections
- HIV-1
- Humans
- Killer Cells, Natural
- Lymphocyte Activation
- Male
- Middle Aged
- Receptors, CCR5
- Receptors, IgG
- South Africa
- Young Adult
Although persistent inflammation has been related to unsuccessful aging, a pro-inflammatory status is the common phenotype in older people. To assess for a genetic component in the inflammatory status of the oldest we studied the distribution of two polymorphic chemokine pathway genes, RANTES and CCR5, in elderly. RANTES -403G/A and RANTES Int1.1T/C polymorphisms and CCR5Δ32 polymorphism were genotyped in 104 elderly and 110 controls. RANTES -403A and RANTES Int1.1C alleles have been associated with pro-inflammatory and anti-inflammatory status, respectively. CCR5Δ32 abrogates functional receptor expression of the pro-inflammatory CCR5-mediated action. Prevalence of RANTES -403G allele, associated in other studies with high RANTES production, was reduced in elderly males, compared with controls. In addition, RANTES pro-inflammatory haplotype -403A-Int1.1T was overrepresented in elderly males, while RANTES anti-inflammatory haplotype -403G-Int1.1C was overrepresented in elderly females. Our results suggest a sex-specific RANTES inflammatory genetic determinant that could contribute to the known sex-related differences in aging.
MeSH Terms
- Adolescent
- Adult
- Aged, 80 and over
- Chemokine CCL5
- Female
- Humans
- Inflammation
- Longevity
- Male
- Polymorphism, Genetic
- Receptors, CCR5
The ageing process is very complex. Human longevity is a multifactorial trait which is determined by genetic and environmental factors. Twin and family studies imply that up to 25% of human lifespan is heritable. The longevity gene candidates have generally fallen into the following categories: inflammatory and immune-related factors, stress response elements, mediators of glucose and lipid metabolism, components of DNA repair and cellular proliferation and mitochondrial DNA haplogroups. Because of the central role of HLA molecules in the development of protective immunity and the extraordinary degree of polymorphism of HLA genes, many studies have addressed the possible impact of these genes on human longevity. Most of the data available so far demonstrated a possible role of HLA class II specificities in human longevity but definitive evidence has remained elusive. Although the data are limited and controversial, it has been hypothesized that longevity could be associated with cytokine gene polymorphisms correlating with different levels of cytokine production, thereby modulating immune responses in health and disease. Because of the essential role of cytokines in immune responses, the regulation of cytokine gene expression and their polymorphic nature, the genetic variations of these loci with functional significance could be appropriate immunogenetic candidate markers implicated in the mechanism of successful ageing and longevity. In addition, several other genes such as Toll-like receptor genes, Cycloxygenases (COX)/Lipoxygenases (LOX), CCR5, NK receptor genes and MBL2 have been assessed as a possible biomarkers associated with ageing. This review will summarize the data on the role of these immune genes in human longevity.
MeSH Terms
- Aging
- Cytokines
- Histocompatibility Antigens Class II
- Humans
- Immunogenetic Phenomena
- Inflammation
- Toll-Like Receptors
Generalized vitiligo is thought to have an autoimmune etiology and has been correlated with the presence of CD8 T cells specific for melanocyte differentiation Ag. However, limited animal models for the disease have hampered its understanding. Thus, we generated TCR transgenic mice that recognize an epitope of the melanocyte protein, tyrosinase. These animals develop vitiligo with strikingly similar characteristics to the human disease. Vitiligo develops temporally and spatially, with juvenile lesions forming bilaterally in head and facial areas, and only arising later in the body of adult animals. Vitiligo is entirely dependent on CD8 T cells, whereas CD4 T cells exert a negative regulatory effect. Importantly, CD8 T cells can be pervasively present in the skin in the steady state without inducing vitiligo in most areas. This points to developmental differences in melanocyte susceptibility and/or immunological effector mechanisms over time, or in different body locations. Disease is strongly dependent on both IFN-gamma and CXCR3, whereas dependence on CCR5 is more limited, and both CCR4 and perforin are dispensable. Genetic ablation of CXCR3 or IFN-gamma also resulted in scarce CD8 T cell infiltration into the skin. Our results identify unexpected complexity in vitiligo development and point toward possible therapeutic interventions.
MeSH Terms
- Aging
- Animals
- Antigen Presentation
- Autoimmune Diseases
- CD8-Positive T-Lymphocytes
- Disease Models, Animal
- HLA-A Antigens
- HLA-A2 Antigen
- Humans
- Hypopigmentation
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Monophenol Monooxygenase
- Receptors, Antigen, T-Cell
- Self Tolerance
- Vitiligo
Age-associated thymic involution is characterized by decreased thymopoiesis, adipocyte deposition and changes in the expression of various thymic microenvironmental factors. In this work, we characterized the distribution of fat-storing cells within the aging thymus. We found an increase of unilocular adipocytes, ERTR7( ) and CCR5( )fat-storing multilocular cells in the thymic septa and parenchymal regions, thus suggesting that mesenchymal cells could be immigrating and differentiating in the aging thymus. We verified that the expression of CCR5 and its ligands, CCL3, CCL4 and CCL5, were increased in the thymus with age. Hypothesizing that the increased expression of chemokines and the CCR5 receptor may play a role in adipocyte recruitment and/or differentiation within the aging thymus, we examined the potential role for CCR5 signaling on adipocyte physiology using 3T3-L1 pre-adipocyte cell line. Increased expression of the adipocyte differentiation markers, PPARgamma2 and aP2 in 3T3-L1 cells was observed under treatment with CCR5 ligands. Moreover, 3T3-L1 cells demonstrated an ability to migrate in vitro in response to CCR5 ligands. We believe that the increased presence of fat-storing cells expressing CCR5 within the aging thymus strongly suggests that these cells may be an active component of the thymic stromal cell compartment in the physiology of thymic aging. Moreover, we found that adipocyte differentiation appear to be influenced by the proinflammatory chemokines, CCL3, CCL4 and CCL5.
MeSH Terms
- 3T3-L1 Cells
- Adipocytes
- Aging
- Animals
- Blotting, Western
- Cell Differentiation
- Cell Movement
- Chemokine CCL3
- Chemokine CCL4
- Chemokine CCL5
- Immunohistochemistry
- Mice
- Mice, Inbred BALB C
- Oligonucleotide Array Sequence Analysis
- Receptors, CCR5
- Reverse Transcriptase Polymerase Chain Reaction
- Thymus Gland
Keywords
- adipocyte
- adipokines
- aging
- chemokines
- chemotaxis
- differentiation
- involution
- thymus
Elderly subjects suffer from increased levels of activated T cells and a TH1/TH2 imbalance. Zinc deficiency of the aged is correlated with decreased cell-mediated immune responses. The association of age and zinc adjustment with the amounts of TH1 (CCR5 ) and TH2 (CCR4 ) cell populations in healthy aged old donors enrolled in the European ZINCAGE project was examined. Old and nonagenarian individuals revealed increased TH1, TH2 cell numbers and a decreased TH2/TH1 ratio in comparison to young individuals. The differences between TH2/TH1 ratios of young and old/nonagenarians arose from young females. Adjusted zinc status led to enhanced TH2 and TH1 amounts in fresh whole blood and thawed cells of aged donors whereas increased HLA-DR expression and a generally lower CCR5 expression was observed on thawed PBMC. In conclusion, aging is associated with an increase in T helper cell polarization, and changes in TH2/TH1 subsets are more obvious in women than in men. Advanced healthy aging is accompanied by TH cell polarization, too. Moderate zinc supplementation in vivo alters TH proportions. Longer zinc treatment will give more insight into the beneficial effect of zinc on T helper cell modulation.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Dietary Supplements
- Female
- Humans
- Lymphocyte Activation
- Male
- Receptors, CCR4
- Receptors, CCR6
- T-Lymphocyte Subsets
- Th1 Cells
- Th2 Cells
- Trace Elements
- Zinc
The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family. CCR5 has the characteristic structure of a seven transmembrane G protein-coupled receptor (GPCR), which regulates trafficking and effector functions of memory/effector Th1 cells, macrophages, NK cells, and immature dendritic cells. CCR5 and its ligands are important molecules in viral pathogenesis. CCR5 represents the co-receptor for macrophage (M) and dual (T cell and M)-tropic immunodeficiency viruses. Recent evidence has also demonstrated the role of CCR5 in a variety of human diseases, ranging from infectious and inflammatory diseases to cancer. In this article, we describe the involvement of CCR5 in two age-related diseases, atherosclerosis and Alzheimer's disease, suggesting a possible role of chemokine system on these diseases' pathophysiology. Finally, we review the data on the probable association between CCR5Delta32 deletion and cardiovascular diseases and Alzheimer's disease.
MeSH Terms
- Aging
- Alzheimer Disease
- Atherosclerosis
- Cardiovascular Diseases
- Dendritic Cells
- Gene Deletion
- Genome
- Humans
- Inflammation
- Killer Cells, Natural
- Ligands
- Macrophages
- Microglia
- Models, Biological
- Receptors, CCR5
We previously reported that interleukin (IL)-4 treatment of nonobese diabetic (NOD) mice elevates intrapancreatic CCL4 expression and protects from type 1 diabetes. Here, we show that antibody neutralization of CCL4 abrogates the ability of T-cells from IL-4-treated NOD mice to transfer protection against type 1 diabetes. Intradermal delivery of CCL4 via a plasmid vector stabilized by incorporation of the Epstein-Barr virus EBNA1/oriP episomal maintenance replicon (pHERO8100-CCL4) to NOD mice beginning at later stages of disease progression protects against type 1 diabetes. This protection was associated with a Th2-like response in the spleen and pancreas; decreased recruitment of activated CD8( ) T-cells to islets, accompanied by diminished CCR5 expression on CD8( ) T-cells; and regulatory T-cell activity in the draining pancreatic lymph nodes. Thus, inflammatory responses that target islet beta-cells are suppressed by CCL4, which implicates the use of CCL4 therapeutically to prevent type 1 diabetes.
MeSH Terms
- Aging
- Animals
- Chemokine CCL4
- Chemokines, CC
- Diabetes Mellitus, Type 1
- Genetic Therapy
- Inflammation
- Insulin-Secreting Cells
- Interleukin-4
- Islets of Langerhans Transplantation
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Mice, Transgenic
- Spleen
- T-Lymphocytes
The number of older adults with HIV-1 disease is increasing but little is known about how age influences behavioral deficits associated with HIV-1 infection. The purpose of this study was to determine in a murine model if aging influenced sickness behavior following central injection of HIV-1 gp120. In initial studies, behavioral deficits induced by acute and repeated intracerebroventricular (ICV) injection of gp120 were greater in aged mice than in adults. Furthermore, repeated ICV injection of gp120 increased hippocampal levels of IL-1 beta and IL-6 mRNA in aged mice but not in adults. To determine if IL-6, which is elevated in aged brain, affects expression of the gp120-binding target, CCR5, microglia (BV-2 cell line) were incubated with increasing concentrations of IL-6. Cell surface expression of CCR5 was increased by IL-6 in a dose-dependent manner. Additionally, IL-6 increased gp120-dependent chemotaxis. These results suggest that aging increases the sensitivity of mice to behavioral deficits caused by ICV gp120, perhaps by increasing expression of CCR5 and augmenting production of cytokines.
MeSH Terms
- Aging
- Animals
- Brain
- Cell Line
- Cells, Cultured
- HIV Envelope Protein gp120
- Injections, Intraventricular
- Male
- Mice
- Mice, Inbred BALB C
- Motor Activity
- Social Behavior
Accumulation of CD28(null)CD8 T cells and the defects of these cells in response to antigenic stimulation are the hallmarks of age-associated decline of T cell function. However, the mechanism of these age-associated changes is not fully understood. In this study, we report an analysis of the growth of human CD28(null) and CD28 CD8 memory T cells in response to homeostatic cytokine IL-15 in vitro. We showed that 1) there was no proliferative defect of CD28(null)CD8 memory T cells in response to IL-15 compared with their CD28 counterparts; 2) stable loss of CD28 expression occurred in those actively dividing CD28 CD8 memory T cells responding to IL-15; 3) the loss of CD28 was in part mediated by TNF-alpha that was induced by IL-15; and 4) CCL4 (MIP-1beta), also induced by IL-15, had a significant inhibitory effect on the growth of CD28(null) cells, which in turn down-regulated their expression of CCL4 receptor CCR5. Together, these findings demonstrate that CD28(null)CD8 memory T cells proliferate normally in response to IL-15 and that IL-15 and its induced cytokines regulate the generation and growth of CD28(null)CD8 T cells, suggesting a possible role of IL-15 in the increase in CD28(null)CD8 T cells that occurs with aging.
MeSH Terms
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cell Proliferation
- Cytokines
- Humans
- Immunologic Memory
- Interleukin-15
- Reverse Transcriptase Polymerase Chain Reaction
Mild zinc deficiency is a common condition in healthy elderly individuals leading to impaired cell-mediated immune response. Here we report the effect of improved zinc status on TH1/TH2 balance and on the activation status of T helper cells in 19 healthy elderly subjects aged 69.8 /- 5.1 years. Our investigations revealed a mild zinc deficiency which was adjusted by oral zinc supplementation for seven weeks. Improved serum zinc levels significantly reduced levels of activated T helper cells whereas changes in TH1/TH2 ratio (determined by CCR4 and CCR5 expression) were not observed. These findings suggest that elderly individuals may benefit from moderate zinc supplementation due to improved immune response leading to reduced incidences of autoimmune diseases and infections.
MeSH Terms
- Administration, Oral
- Aged
- Aged, 80 and over
- Aging
- CD4 Antigens
- Dietary Supplements
- Female
- Humans
- Interleukin-2 Receptor alpha Subunit
- Lymphocyte Activation
- Lymphocyte Count
- Male
- Receptors, CCR4
- Receptors, CCR5
- Receptors, Chemokine
- Reference Values
- Th1 Cells
- Th2 Cells
- Zinc
- Zinc Compounds
The major trait characterizing offspring in centenarians is a reduction in the prevalence of cardiovascular disease. Because a pro-inflammatory genotype seems to contribute significantly to the risk of coronary heart disease, alleles associated with disease susceptibility would not be included in the genetic background favoring longevity, as suggested by our previous studies on inflammatory cytokines. To confirm whether genotypes of inflammatory molecules play an opposite role in atherosclerosis and longevity, we are studying the role of other proinflammatory alleles, such as pyrin and CCR5, in acute myocardial infarction and longevity. The results support the hypothesis that the genetic background favoring cardiovascular diseases is detrimental to longevity. In addition, they suggest that the centenarian genetic background may be useful for investigating genetic key components of age-associated diseases that are characterized by a multifactorial etiology.
MeSH Terms
- Acute Disease
- Aged, 80 and over
- Alleles
- Cytoskeletal Proteins
- Genetic Predisposition to Disease
- Humans
- Inflammation
- Longevity
- Myocardial Infarction
- Pyrin
- Receptors, CCR5
- Sicily
Chemokine and chemokine receptor expression in gingival tissues plays a central role in periodontal disease during aging. In the present study, we explored the modulation of chemokines and chemokine receptors expression in aging rat gingival tissues. In the 24-month-old (Old) rat gingival tissues, RANTES and CCR5 mRNA and protein levels were 2-4 fold increased over those of the 6-month-old (Young) rats. The Old rats had considerable enhancement of all three of the studied MAPK activities: extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. These results suggest that age-related increases in RANTES and CCR5 expression are associated with increased IkappaBalpha, nuclear NF-kappaB, and MAPK activity in gingival tissues.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Blotting, Western
- Chemokine CCL5
- Electrophoretic Mobility Shift Assay
- Gingiva
- Male
- Mitogen-Activated Protein Kinases
- NF-kappa B
- Proteins
- RNA, Messenger
- Rats
- Rats, Sprague-Dawley
- Receptors, CCR5
- Reverse Transcriptase Polymerase Chain Reaction
The P53 protein is a key regulator of modified-cell apoptosis. The functional oligonucleotide polymorphism of the p53 gene causes the substitution of arginine (Arg) for praline (Pro) in the codon 72. A reduced apoptotic activity of p53 and, as a consequence, development of oncology pathology is associated with the above polymorphism. CCR5 is a compound transmembrane receptor-protein, which apart from chemokines, binds with some molecules and is a coreceptor for HIV-1. 32 bp deletion within the CCR5 encoding region results in the loss of the protein's receptor function. It has been demonstrated that the transmission of the "external" (in respect to cell) stimulus, via the CCR5 system, induces expression of the p53 gene and initiates apoptosis. Allele variants and p53 and CCR5 genotypes (separately and in combinations) were investigated, within the present case study, for 131 long-livers from Novosibirsk and Tyumen Regions. A trend was detected towards accumulation of the p53 Pro alleles in association with the CCR5del32 allele in the study group, which, as the authors believe, can enhance the genome resistance to variable factors that cut the life span.
MeSH Terms
- Aged
- Aged, 80 and over
- Alleles
- Genes, p53
- Humans
- Longevity
- Polymorphism, Genetic
- Receptors, CCR5
- Siberia
HIV-1 infection alters expression of CCR5 and CXCR4 on CD4 T cells in adults, although an effect by virus on expression of coreceptor genes in pediatric subjects is unknown. We designed an exploratory study to evaluate surface expression of CXCR4 and CCR5 on CD45RA and CD45RO subsets of CD4 T lymphocytes from 17 HIV-1-infected infants and adolescents and 16 healthy age-matched individuals. While age in the absence of HIV-1 infection was unrelated to coreceptor expression, infection affected coreceptor expression differentially in infants and adolescents. Among infected adolescents, CCR5 and CXCR4 expression was significantly increased on CD4 CD45RO T cells, while CXCR4 was diminished in the CD4 CD45RA subset. Although HIV-1 infection in infants was also associated with increased CXCR4 expression on the CD4 CD45RO subset, in contrast to adolescents, infection in infants had no impact on coreceptor expression within the CD45RA CD4 subset. The proportion of CD4 T cells coexpressing CD45RA and CD45RO was increased by infection in both infants and adolescents. The CD45RA CD45RO subset in culture expressed high levels of CD4, CXCR4, and CD69, an early activation marker, and was highly susceptible to HIV-1 infection and replication. Infection of transitional CD4 T cells coexpressing CD45RA and CD45RO could contribute in part to provirus in either CD45RA or CD45RO subsets. Deleterious effects by HIV-1 infection on CD4 T cell homeostasis were greater in infants then adolescents, indicating that adolescence may be an optimal age group for assessing vaccines to prevent or treat HIV-1 infection.
MeSH Terms
- Adolescent
- Adult
- Aging
- CD4-Positive T-Lymphocytes
- Cells, Cultured
- Child
- Child, Preschool
- Female
- HIV Infections
- HIV-1
- Humans
- Infant
- Leukocyte Common Antigens
- Male
- Protein Tyrosine Phosphatase, Non-Receptor Type 1
- Receptors, CCR5
- Receptors, CXCR4
- T-Lymphocyte Subsets
Older age is a strong predictor of accelerated human immunodeficiency virus (HIV) disease progression. We investigated the possible immunologic basis of this interaction by comparing older (>/=45 years) and younger (</=30 years) HIV-infected adults with simultaneously enrolled, aged-matched, healthy volunteers. Cross-sectional comparisons suggested age-associated reductions in naive CD8( ) cells and in the expression of CD28( ) on CD8( ) cells among both HIV-infected subjects and control subjects. Opposite patterns of CD4( ) and CD8( ) cell differences were apparent between these subject groups. HIV infection, but not age, was associated with impairments in delayed-type hypersensitivity responses, lymphoproliferation, and spontaneous apoptosis and with alterations in expression of chemokine receptors CCR5 and CXCR4. Reduced thymic volumes were associated with age and with HIV infection among younger, but not older, subjects. Because of their common association with age and HIV disease, naive CD8( ) cell depletion, diminished CD28 expression on CD8( ) cells, and reduced thymic volumes are possible correlates of the interaction of age with HIV disease.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- CD28 Antigens
- CD8-Positive T-Lymphocytes
- Cross-Sectional Studies
- Disease Progression
- Female
- Gene Expression Regulation
- HIV Infections
- HIV-1
- Humans
- Male
- Middle Aged
- Phenotype
- Thymus Gland
The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)-infected patients with hemophilia. One patient (0.6%) had the CCR5Delta32/CCR5Delta32 genotype (which occurs in approximately 2% of the Scandinavian population) and a rapid disease course. His HIV V3 region contained genotypic features attributable to X4 virus and resembled functionally verified X4 virus and virus from patients treated with a CD4 cell-stimulating drug, tucaresol. Age-related differences in disease progression rate and survival time were seen for CCR5/CCR5 patients. Surprisingly, no protective effect of the CCR5/CCR5Delta32 genotype on disease progression or survival was seen for children but was evident for adults. Age group-related immunologic differences might explain this variation, and transmission route and/or viral phenotype variation within donor virus may be related to the limited protection of the CCR5Delta32/CCR5Delta32 genotype. Sequence comparisons indicate that X4 virus can be selected in vivo due to either absence of CCR5 receptors or relative increase of CXCR4 receptors.
MeSH Terms
- Adolescent
- Adult
- Aging
- Amino Acid Sequence
- CD4 Lymphocyte Count
- Cohort Studies
- Cytomegalovirus Infections
- Disease Progression
- Female
- Genetic Predisposition to Disease
- Genotype
- HIV
- HIV Infections
- Hemophilia A
- Hemophilia B
- Humans
- Incidence
- Male
- Middle Aged
- Molecular Sequence Data
- Receptors, CCR5
- Risk Factors
- Survival Rate
While numerous previous studies have investigated age-related changes of cytokine production, little is known about chemokines, the importance of which in regulating immune response is becoming increasingly evident. In this study, a group of healthy subjects over 90 years old is compared to a group of young subjects, we evaluated the ability of monocytes, T lymphocytes and NK cells: (1) to produce RANTES and MIP-1alpha, either in basal conditions or after stimulation with, respectively, LPS, anti-CD3 MoAb and IL-2; (2) to express the corresponding chemokine receptors (CCR1, CCR3, CCR5). We demonstrate that: (a) monocytes, T lymphocytes and NK cells spontaneously produced detectable amounts of chemokines, both in young and old subjects; (b) monocyte-dependent RANTES and MIP-1alpha production induced by LPS was up-regulated in nonagenarian subjects as anti-CD3-induced secretion from T cells; (c) RANTES and MIP-1alpha production by IL-2 stimulated NK cells was reduced in elderly subjects; (d) CCR1, CCR3 and CCR5 were widely expressed on monocytes, but less expressed on T lymphocytes and NK cells. The diversity within PBMC might reflect their different states of activation and/or responsiveness, influencing the ability to develop rapid innate and long-lasting adaptive immune responses.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cells, Cultured
- Chemokine CCL3
- Chemokine CCL4
- Chemokine CCL5
- Female
- Humans
- Killer Cells, Natural
- Lipopolysaccharides
- Macrophage Inflammatory Proteins
- Male
- Monocytes
- Receptors, CCR1
- Receptors, CCR3
- Receptors, CCR5
- Receptors, Chemokine
- T-Lymphocytes