CD33
Myeloid cell surface antigen CD33 precursor (Sialic acid-binding Ig-like lectin 3) (Siglec-3) (gp67) (CD33 antigen) [SIGLEC3]
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Microglia are brain macrophages that mediate neuroinflammation and contribute to and protect against neurodegeneration. The terminal sugar residue of all glycoproteins and glycolipids on the surface of mammalian cells is normally sialic acid, and addition of this negatively charged residue is known as "sialylation," whereas removal by sialidases is known as "desialylation." High sialylation of the neuronal cell surface inhibits microglial phagocytosis of such neurons, via: (i) activating sialic acid receptors (Siglecs) on microglia that inhibit phagocytosis and (ii) inhibiting binding of opsonins C1q, C3, and galectin-3. Microglial sialylation inhibits inflammatory activation of microglia via: (i) activating Siglec receptors CD22 and CD33 on microglia that inhibit phagocytosis and (ii) inhibiting Toll-like receptor 4 (TLR4), complement receptor 3 (CR3), and other microglial receptors. When activated, microglia release a sialidase activity that desialylates both microglia and neurons, activating the microglia and rendering the neurons susceptible to phagocytosis. Activated microglia also release galectin-3 (Gal-3), which: (i) further activates microglia via binding to TLR4 and TREM2, (ii) binds to desialylated neurons opsonizing them for phagocytosis via Mer tyrosine kinase, and (iii) promotes Aβ aggregation and toxicity [i]in vivo[/i]. Gal-3 and desialylation may increase in a variety of brain pathologies. Thus, Gal-3 and sialidases are potential treatment targets to prevent neuroinflammation and neurodegeneration.
Keywords
- aging
- desialylation
- galectin-3
- microglia
- neurodegeneration
- phagocytosis
- sialic acid
Neuroinflammatory responses mediated by microglia, the resident immune cells of the central nervous system, have long been a subject of study in the field of Alzheimer's disease (AD). Microglia express a wide range of receptors that act as molecular sensors, through which they can fulfill their various functions. In this review, we first analyzed the changes in the expression levels of microglial membrane receptors SR-A, TREM2, CD36, CD33, and CR3 in aging and AD and described the different roles of these receptors in amyloid-beta clearance and inflammatory responses. Two classical hallmarks of AD are extracellular amyloid-beta deposits and intracellular aggregated phosphorylated tau. In AD, microglia reaction was initially thought to be triggered by amyloid deposits. New evidence showed it also associated with increased phosphorylation of tau. However, which first appeared and induced activated microglia is not clear. Then we summarized diverse opinions on it. Besides, as AD is tightly linked to aging, and microglia changes dramatically on aging, yet the relative impacts of both aging and microglia are less frequently considered, so at last, we discussed the roles of aging microglia in AD. We hope to provide a reference for subsequent research.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Animals
- Brain
- CD36 Antigens
- Gene Expression
- Humans
- Inflammation
- Macrophage-1 Antigen
- Membrane Glycoproteins
- Microglia
- Phosphorylation
- Receptors, Immunologic
- Scavenger Receptors, Class A
- Sialic Acid Binding Ig-like Lectin 3
- tau Proteins
Keywords
- Aging
- Alzheimer's disease
- Immune response
- Microglia
- Microglial membrane receptors
Humans and orcas are among the very rare species that have a prolonged post-reproductive lifespan (PRLS), during which the aging process continues. Reactive oxygen species (ROS) derived from mitochondria and from the NADPH oxidase (NOX) enzymes of innate immune cells are known to contribute to aging, with the former thought to be dominant. CD33-related-Siglecs are immune receptors that recognize self-associated-molecular-patterns and modulate NOX-derived-ROS. We herewith demonstrate a strong correlation of lifespan with CD33rSIGLEC gene number in 26 species, independent of body weight or phylogeny. The correlation is stronger when considering total CD33rSIGLEC gene number rather than those encoding inhibitory and activating subsets, suggesting that lifetime balancing of ROS is important. Combining independent lines of evidence including the short half-life and spontaneous activation of neutrophils, we calculate that even without inter-current inflammation, a major source of lifetime ROS exposure may actually be neutrophil NOX-derived. However, genomes of human supercentenarians (>110 years) do not harbor a significantly higher number of functional CD33rSIGLEC genes. Instead, lifespan correlation with CD33rSIGLEC gene number was markedly strengthened by excluding the post-reproductive lifespan of humans and orcas (R = 0.83; P < .0001). Thus, CD33rSIGLEC modulation of ROS likely contributes to maximum reproductive lifespan, but other unknown mechanisms could be important to PRLS.
MeSH Terms
- Animals
- Gene Dosage
- Humans
- Longevity
- NADPH Oxidases
- Neutrophils
- Reactive Oxygen Species
- Sialic Acid Binding Ig-like Lectin 3
- Whale, Killer
Keywords
CD33rSIGLEC
- NADPH-oxidase
- prolonged post-reproductive lifespan
- reactive oxygen species
Late-onset Alzheimer's disease (LOAD) or sporadic AD is the most common form of AD. The precise pathogenetic changes that trigger the development of AD remain largely unknown. Large-scale genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in multiple genes which are associated with AD; most notably, these are ABCA7, bridging integrator 1 (B1N1), triggering receptor expressed on myeloid cells 2 (TREM2), CD33, clusterin (CLU), complement receptor 1 (CRI), ephrin type-A receptor 1 (EPHA1), membrane-spanning 4-domains, subfamily A (MS4A) and phosphatidylinositol binding clathrin assembly protein (PICALM) genes. The proteins coded by the candidate genes participate in a variety of cellular processes such as oxidative balance, protein metabolism, cholesterol metabolism and synaptic function. This review summarizes the major gene loci affecting LOAD identified by large GWASs. Tentative mechanisms have also been elaborated in various studies by which the proteins coded by these genes may exert a role in AD pathogenesis have also been elaborated. The review suggests that these may together affect LOAD pathogenesis in a complementary fashion.
MeSH Terms
- ATP-Binding Cassette Transporters
- Age of Onset
- Alzheimer Disease
- Clusterin
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Membrane Glycoproteins
- Polymorphism, Single Nucleotide
- Receptors, Immunologic
- Risk Factors
- Sialic Acid Binding Ig-like Lectin 3
Keywords
- Alzheimer's disease
- Heart and Aging Research in Genomic Epidemiology
- LOAD
- Translational Genomics Research Institute
- genome-wide association study
- single nucleotide polymorphism
With underrepresentation of elderly patients with lung adenocarcinoma (LADC) in anti-PD-1/PD-L1 clinical trials, better understanding of the interplay of PD-L1 and tumor-associated immune cells (TAICs) could assist clinicians in stratifying these patients for immunotherapy. One hundred and one patients with LADCs, stratified by age, were included for analysis of PD-L1 expression and density of TAICs expressing CD4, CD8, and CD33, by using multiplex chromogenic immunohistochemistry (IHC) assays and automated digital quantification. The CD4⁺/CD8⁺ ratio was significantly higher in elderly patients. In patients <75 years, the density of CD4⁺, CD8⁺, and PD-L1 in TAICs showed a positive significant correlation with PD-L1 expression in tumor cells (TCs), while a lower correlation was observed in the elderly population. In the latter, a high CD4⁺/CD8⁺ ratio, and combined PD-L1 expression ≥1% TCs with a low CD8⁺ density, low CD33⁺ density, and a high CD4⁺ density correlated to worse overall survival. We identified differences according to age in the CD4⁺/CD8⁺ ratio and in correlation between PD-L1 expression and the density of TAICs in LADC patients. Distinct groups of tumor microenvironments had an impact on the OS of elderly patients with LADC.
Keywords
- brightfield
- elderly
- immunosenescence
- lung adenocarcinoma
- multiplex immunohistochemistry
Alzheimer's disease (AD) is one of the most common neurodegenerative disorders mainly affecting elderly people. It is characterized by progressive loss of memory and cognitive function. More than 95% of AD cases are related to sporadic or late-onset AD (LOAD). The etiology of LOAD is still unclear. It has been reported that environmental factors and epigenetic alterations play a significant role in AD pathogenesis. Furthermore, recently, genome-wide association studies (GWAS) identified 10 novel risk genes: ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, MS4A6A, MS4A4E, and PICALM, which play an important role for LOAD. In this review, the therapeutic approaches of AD by epigenetic modifications have been discussed. Nowadays, HDAC inhibitors have clinically proven its activity for epigenetic modifications. Furthermore, we try to establish the relationship between HDAC inhibitors and above mentioned LOAD risk genes. Finally, we are hoping that this review may open new area of research for AD treatment.
MeSH Terms
- Aging
- Alzheimer Disease
- Animals
- Cognition Disorders
- Epigenesis, Genetic
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Histone Deacetylase Inhibitors
- Histone Deacetylases
- Humans
Keywords
- Alzheimer’s disease
- GWAS
- HDAC inhibitors
- LOAD
- epigenetic modification
Genome-wide association studies and meta-analyses implicated that increased risk of developing Alzheimer's diseases (AD) has been associated with the ABCA7, APOE, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB1, HLA-DRB4, INPP5D, MEF2C, MS4A4A, MS4A4E, MS4A6E, NME8, PICALM, PLD3, PTK2B, RIN3, SLC24A4, SORL1, and ZCWPW1 genes. In this study, we assessed whether single nucleotide polymorphisms (SNPs) within these 27 AD-associatedgenes are linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. We also analyzed the interactions between lifestyle and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examination (MMSE) scores were performed for all subjects to evaluate cognitive functions. Out of the 588 SNPs tested in this study, only the association between CASS4-rs911159 and cognitive aging persisted significantly (P = 2.2 x 10-5) after Bonferroni correction. Our data also showed a nominal association of cognitive aging with the SNPs in six more key AD-associated genes, including EPHA1-rs10952552, FERMT2-rs4901317, MEF2C-rs9293506, PLD3-rs11672825, RIN3-rs1885747, and SLC24A4-rs67063100 (P = 0.0018~0.0097). Additionally, we found the interactions among CASS4-rs911159, EPHA-rs10952552, FERMT2-rs4901317, MEF2C-rs9293506, or SLC24A4-rs67063100 on cognitive aging (P = 0.004~0.035). Moreover, our analysis suggested the interactions of SLC24A4-rs67063100 or MEF2C-rs9293506 with lifestyle such as alcohol consumption, smoking status, physical activity, or social support on cognitive aging (P = 0.008~0.041). Our study indicates that the AD-associated genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-lifestyle interactions.
MeSH Terms
- Age Factors
- Aged
- Alleles
- Alzheimer Disease
- Cognitive Aging
- Epistasis, Genetic
- Female
- Gene-Environment Interaction
- Genetic Association Studies
- Genetic Predisposition to Disease
- Humans
- Life Style
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Risk Factors
- Taiwan
Keywords
- Alzheimer’s diseases
- Gerotarget
- Mini-Mental State Examination
- cognitive aging
- gene-gene and gene-lifestyle interactions
- single nucleotide polymorphisms
Single nucleotide polymorphisms (SNPs) in and near ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, complement receptor 1 (CR1), EPHA1, EXOC3L2, FERMT2, HLA cluster (DRB5-DQA), INPP5D, MEF2C, MS4A cluster (MS4A3-MS4A6E), NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1 have been associated with Alzheimer's disease (AD) in large meta-analyses. We aimed to determine whether established AD-associated genes are associated with longitudinal cognitive decline by examining aggregate variation across these gene regions. In two single-sex cohorts of older, community-dwelling adults, we examined the association between SNPs in previously implicated gene regions and cognitive decline (age-adjusted person-specific cognitive slopes) using a Sequence Kernel Association Test (SKAT). In regions which showed aggregate significance, we examined the univariate association between individual SNPs in the region and cognitive decline. Only two of the original AD-associated SNPs were significantly associated with cognitive decline in our cohorts. We identified significant aggregate-level associations between cognitive decline and the gene regions BIN1, CD33, CELF1, CR1, HLA cluster, and MEF2C in the all-female cohort and significant associations with ABCA7, HLA cluster, MS4A6E, PICALM, PTK2B, SLC24A4, and SORL1 in the all-male cohort. We also identified a block of eight correlated SNPs in CD33 and several blocks of correlated SNPs in CELF1 that were significantly associated with cognitive decline in univariate analysis in the all-female cohort.
MeSH Terms
- Aged
- Aging
- Alzheimer Disease
- Cognition Disorders
- DNA
- Female
- Genetic Association Studies
- Genetic Predisposition to Disease
- Humans
- Male
- Polymorphism, Single Nucleotide
Keywords
- Candidate AD genes
- Cognitive decline
- SNP associations
The cluster of differentiation 33 (CD33) has been proved as a susceptibility locus associated with late-onset Alzheimer's disease (LOAD) based on recent genetic studies. Numerous studies have shown that multiple neuroimaging measures are potent predictors of AD risk and progression, and these measures are also affected by genetic variations in AD. Figuring out the association between CD33 genetic variations and AD-related brain atrophy may shed light on the underlying mechanisms of CD33-related AD pathogenesis. Thus, we investigated the influence of CD33 genotypes on AD-related brain atrophy to clarify the possible means by which CD33 impacts AD. A total of 48 individuals with probable AD, 483 mild cognitive impairment, and 281 cognitively normal controls were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We investigated the influence of CD33 SNPs on hippocampal volume, parahippocampal gyrus volume, posterior cingulate volume, middle temporal volume, hippocampus CA1 subregion volume, and entorhinal cortex thickness. We found that brain regions significantly affected by CD33 genetic variations were restricted to hippocampal and parahippocampal gyrus in hybrid population, which were further validated in subpopulation (MCI and NC) analysis. These findings reaffirm the importance of the hippocampal and parahippocampal gyrus in AD pathogenesis, and present evidences for the CD33 variations influence on the atrophy of specific AD-related brain structures. Our findings raise the possibility that CD33 polymorphisms contribute to the AD risk by altering the neuronal degeneration of hippocampal and parahippocampal gyrus.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Atrophy
- Cognitive Dysfunction
- Databases, Genetic
- Disease Progression
- Female
- Genetic Variation
- Hippocampus
- Humans
- Male
- Parahippocampal Gyrus
- Sialic Acid Binding Ig-like Lectin 3
Keywords
- Alzheimer’s disease
- Atrophy
- CD33
- Genetics
- Hippocampal
- Parahippocampal gyrus
The individuals of most vertebrate species die when they can no longer reproduce. Humans are a rare exception, having evolved a prolonged postreproductive lifespan. Elders contribute to cooperative offspring care, assist in foraging, and communicate important ecological and cultural knowledge, increasing the survival of younger individuals. Age-related deterioration of cognitive capacity in humans compromises these benefits and also burdens the group with socially costly members. We investigated the contribution of the immunoregulatory receptor CD33 to a uniquely human postreproductive disease, Alzheimer's dementia. Surprisingly, even though selection at advanced age is expected to be weak, a CD33 allele protective against Alzheimer's disease is derived and unique to humans and favors a functional molecular state of CD33 resembling that of the chimpanzee. Thus, derived alleles may be compensatory and restore interactions altered as a consequence of human-specific brain evolution. We found several other examples of derived alleles at other human loci that protect against age-related cognitive deterioration arising from neurodegenerative disease or cerebrovascular insufficiency. Selection by inclusive fitness may be strong enough to favor alleles protecting specifically against cognitive decline in postreproductive humans. Such selection would operate by maximizing the contributions of postreproductive individuals to the fitness of younger kin.
MeSH Terms
- Alleles
- Alternative Splicing
- Alzheimer Disease
- Animals
- Apolipoproteins E
- Biological Evolution
- Brain
- Cerebrovascular Disorders
- Cognition Disorders
- Fertility
- Genetic Fitness
- Genetic Loci
- Humans
- Pan troglodytes
- Selection, Genetic
- Sialic Acid Binding Ig-like Lectin 3
Keywords
- Alzheimer’s disease
- CD33
- Siglec
- cognitive capacity
- postreproductive lifespan
Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.
MeSH Terms
- Animals
- Body Weight
- Homeostasis
- Immunomodulation
- Longevity
- Male
- Mammals
- Mice, Inbred C57BL
- Multigene Family
- Oxidative Stress
- Phenotype
- Phylogeny
- Reactive Oxygen Species
- Receptors, Cell Surface
- Sialic Acid Binding Immunoglobulin-like Lectins
Keywords
- Siglec
- aging
- evolutionary biology
- genomics
- immunology
- inflammation
- mouse
- reactive oxygen species
The treatment of cancer remains a formidable challenge owing to the difficulties in differentiating tumor cells from healthy cells to ameliorate the disease without causing intolerable toxicity to patients. In addition, the emergence of MDR1-Pgp mediated multi-drug resistance (MDR) it is a biological phenomenon that inhibits the curative potential of chemotherapeutic treatments. One way to improve the selectivity of therapeutic molecules in tumors would be to target them on the tumor site, thereby sparing normal tissues. In this overview, we will discuss the biological factors influencing the safety and efficacy of the humanized mAb hP67.6 linked to the potent cytotoxic drug calicheamicingamma1 (gemtuzumab ozogamicin) that target CD33 cell surface antigen expressed on AML cells. In addition, we highlight key aspects of MDR1-Pgp biology as a platform to understand its functional role in gemtuzumab ozogamicin immunotherapy which is tightly linked to an accurate assessment of the MDR status of AML cells. Several factors may affect the efficacy and safety of immunoconjugates. These include the common issues of chemical and antibody therapeutics such as specificity, heterogeneous target antigen expression and the complex pharmacokinetics profile of conveyed antibody. Further, the delivered drug may not be sufficient for providing therapeutic benefit, since the curative cytotoxic compound may be affected by intrinsic or acquired resistance of target cells. These and other potential problems, as well as the possible ways to overcome them will be discussed in this review by examining the biological factors involved in safety and efficacy of the first in class antibody drug conjugate (ADC) gentuzumab ozogamicin. Despite this set-back, the extensive recorded data and the lessons learned from gentuzumab ozogamicin recently withdrawn from the market for safety concerns helped to pave the way for next generations of clinically promising new ADCs which are currently investigated in clinical trials and two of them, Brentuximab vedotin, and Trastuzumab emtansine (T-DM1) have been recently approved for commercial distribution in US by Food and Drug Administration (FDA).
MeSH Terms
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- ATP-Binding Cassette Transporters
- Aging
- Aminoglycosides
- Animals
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Cell Line, Tumor
- Drug Design
- Gemtuzumab
- Humans
- Immunotherapy
- Immunotoxins
- Leukemia, Myeloid, Acute
- Prognosis
- Safety
Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.
MeSH Terms
- Age Distribution
- Aging
- Alzheimer Disease
- Chromosome Mapping
- Genetic Markers
- Genetic Predisposition to Disease
- Genetic Variation
- Genome-Wide Association Study
- Humans
- Polymorphism, Single Nucleotide
- Prevalence
To determine whether exercise increases endothelial progenitor cells (EPCs) in patients with peripheral vascular disease, we developed a multi-parameter flow cytometry assay to rigorously assess EPCs and mature endothelial cells (ECs) in control subjects and patients with peripheral artery disease (PAD) subjected to graded exercise. Blood was collected from young healthy subjects (n = 9, mean age 33 years), older healthy subjects (n = 13, mean age 66 years), and older subjects with PAD (n = 15, mean age 69 years) before and 10 minutes after exercise. White blood cells were isolated and stained with a five-color antibody panel: FITC-anti-CD31, PE-anti-CD146, PE-anti-CD133, PerCP-Cy5.5-anti-CD3,-CD19,-CD33, PE-Cy7-anti-CD34, and APC-anti-VEGF-R2. Viability was assessed by propidium iodide exclusion. Viable, low, side scatter singlets that were CD3-, 19-, and 33-negative were counted. While baseline levels of EPCs and ECs were similar among all subjects, young healthy subjects demonstrated significantly greater (p < 0.05) levels of progenitor cells (PCs) than older healthy and PAD subjects. Levels of EPCs and ECs tended to increase in all subjects after exercise; however, increases in PCs were only observed in young healthy and PAD subjects. Further, trends in the magnitude of change of subsets with exercise were most similar between young and PAD subjects. Our findings suggest that aging may reduce baseline circulating levels of PCs, but not EPCs or ECs, and that exercise-induced mobilization of subsets may differ depending on age and presence of PAD.
MeSH Terms
- Adult
- Aged
- Aging
- Antigens, CD
- Cell Differentiation
- Cell Lineage
- Cell Shape
- Cells, Cultured
- Colony-Forming Units Assay
- Endothelial Cells
- Exercise
- Flow Cytometry
- Humans
- Intermittent Claudication
- Lectins
- Lipoproteins, LDL
- Peripheral Vascular Diseases
- Stem Cells
- Vascular Endothelial Growth Factor Receptor-2
- von Willebrand Factor
Age and cardiovascular disease status appear to alter numbers and function of circulating endothelial progenitor cells (EPCs). Despite no universal phenotypic definition, numerous studies have implicated progenitors with apparent endothelial potential in local responses to vascular injury and with cardiovascular disease in general. To further define the role of this lineage in peripheral artery disease (PAD), we developed a multiparameter flow cytometry assay to analyze multiple phenotypic definitions of progenitor cells (PCs), EPCs, and mature endothelial cells (ECs) and evaluate effects of age and PAD on baseline levels of each subset. Blood was collected from young healthy subjects (N = 9, mean age 33 /- 8 years), older healthy subjects (N = 13, mean age 66 /- 8 years), and older subjects with PAD (N = 15, mean age 69 /- 8 years). After ammonium chloride lysis, cells were stained and analyzed on a Becton-Dickinson LSR II with a 5-color antibody panel: FITC-anti-CD31, PE-anti-CD146, PE-anti-CD133, PerCP-Cy5.5-anti-CD3,-CD19,-CD33 (lineage panel), PE-Cy7-anti-CD34, and APC-anti-VEGF-R2. Viability was assessed by propidium iodide exclusion, and only viable, low to medium side scatter lineage-negative singlets were analyzed. In some studies, cells were sorted for morphological studies. Subsets were defined as indicated later. Our results, using a comprehensive flow cytometric panel, indicate that CD133 , CD34 , and CD133 /CD34 PCs are elevated in younger healthy individuals compared to older individuals, both healthy and with PAD. However, the number of EPCs and mature ECs did not significantly differ among the three groups. Assessment of endothelial colony forming units and dual acLDL-lectin staining supported the flow cytometric findings. We describe a comprehensive flow cytometric method to detect circulating mature and progenitor endothelial populations confirmed by conventional morphological and functional assays. Our findings suggest that aging may influence circulating levels of PCs, but not EPCs or ECs; PAD had no effect on baseline levels of any populations investigated. This study provides the basis for evaluating the potential effects of acute stress and therapeutic intervention on circulating progenitor and endothelial populations as a biomarker for cardiovascular status.
MeSH Terms
- AC133 Antigen
- Adult
- Aged
- Aging
- Antigens, CD
- Antigens, CD34
- Biomarkers
- Cell Count
- Colony-Forming Units Assay
- Endothelial Cells
- Flow Cytometry
- Glycoproteins
- Humans
- Middle Aged
- Peptides
- Peripheral Vascular Diseases
- Phenotype
- Stem Cells
We observed three cases of acute leukemia with trisomy 10 ( 10) as the sole abnormality, two were adult patients with ANLL (subtype M0 and M1 respectively), and the third that of a child with ALL. The literature describes nine additional cases, four with ALL (all of whom were children) and five with ANLL (all of whom were adults). Cell marker studies on the ANLL cases showed a common positivity for CD7 and CD33 in our two cases, as well as in four of the previously reported cases, whereas in ALL the only two informative cases were classified as early pre-B ALL. There appears to be an age-related pattern in the specificity of the leukemic lineage. Trisomy 10 appears to be associated exclusively with ALL in children and with ANLL (usually M0-M1) in adults. The prognosis appears to be also divided between the two groups, being good in the pediatric group and moderate in the adult group.
MeSH Terms
- Aged
- Aging
- Bone Marrow
- Child, Preschool
- Chromosomes, Human, Pair 10
- Female
- Humans
- Leukemia, Myeloid, Acute
- Male
- Middle Aged
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Prognosis
- Trisomy
Bone marrow cells from 109 patients (median age 60) with newly diagnosed acute myeloid leukaemia (AML) were prospectively immunophenotyped (IP) and the prognostic value of monoclonal antibody (MAB) reactivities was analysed to detect differences in complete remission rates and survival, not only between groups of MAB and - bone marrow cells, but also in cases with or without prominent MAB reactivity as compared to normal BM reactivity of the respective MABs. This approach was based on the assumption that the qualitative expression of antigens is not an all or none phenomenon, but that different degrees of expression of antigens exist. Patients with significantly elevated CD13 (MY7 ) cells in bone marrows (CD13 greater than reference value one standard deviation) (S.D.) showed decreased probability of entering CR (p less than 0.05) and a significantly shorter survival (p less than 0.05). Superior CR rates (p less than 0.05) without difference in long-term survival were seen in patients with low CD33 (MY9) or low HLA-DR expression, while high CD14 (MY4) expression showed a trend towards an adverse factor (p = 0.12). No other antibody reactivities showed differences in CR rates (CD3, CD20, CDw65 (VIM-2) and NAT-9). The more prominent bone marrow expression of CD33 antigen than CD13 (CD33/CD13 greater than 1) correlated to a better chance of entering CR (p = 0.01) and to improved survival (p = 0.002), while the expression of high numbers of VIM-2 cells was a favourable prognostic factor regarding length of survival (p = 0.002). The importance of a high CD33/CD13 ratio as a positive prognostic factor was evaluated using stratified analysis according to age or leucocyte counts at presentation. In both cases, CD33/CD13 was associated with longer survival (age: p = 0.05, leucocyte counts: p = 0.03). A Cox multiparameter analysis revealed that the CD33/CD13 ratio was a favourable prognostic factor (p = 0.03) together with age (p = 0.001) and leucocyte counts in peripheral blood (p less than 0.01). We conclude that establishing the immunologic phenotype can be of prognostic value in cases of AML, especially with regard to the relationship between the CD33 and CD13 antigens.
MeSH Terms
- Acute Disease
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Analysis of Variance
- Antibodies, Monoclonal
- Antigens, Neoplasm
- Antineoplastic Combined Chemotherapy Protocols
- Female
- Humans
- Immunophenotyping
- Leukemia, Myeloid
- Leukocyte Count
- Male
- Middle Aged
- Multivariate Analysis
- Prognosis
- Prospective Studies