CCR6
C-C chemokine receptor type 6 (C-C CKR-6) (CC-CKR-6) (CCR-6) (Chemokine receptor-like 3) (CKR-L3) (DRY6) (G-protein coupled receptor 29) (GPR-CY4) (GPRCY4) (LARC receptor) (CD196 antigen) [CKRL3] [CMKBR6] [GPR29] [STRL22]
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Aging is a significant risk factor for dry eye. Here we used a murine aging model to investigate the effects of aging on antigen presenting cells (APCs) and generation of pathogenic T helper (Th)-1 cells. Our results showed that APCs from aged mice accumulate at the conjunctiva, have higher levels of co-activation marker CD86 and lower aldehyde dehydrogenase activity. Using topical ovalbumin peptide as a surrogate antigen, we observed an increased number of antigen-loaded APCs in the draining cervical lymph nodes in the aged group and loss of tight junction protein occludin in the conjunctiva. Aged cervical lymph nodes APCs showed a greater generation of Th1 cells than young APCs in antigen-presentation assays in vitro. Aged lacrimal glands, and draining nodes showed an accumulation of IFN-γ producing CD4 T cells, while Th-17 cells were present only in aged draining nodes. There was also an age-related increase in CD4 CXCR3 IFN-γ cells in the conjunctiva, nodes, and lacrimal glands while CD4 CCR6 IL-17A cells increased in the draining nodes of aged mice. Adoptive transfer of aged CD4 CXCR3 cells into young, naive immunodeficient recipients caused greater goblet cell loss than young CD4 CXCR3 donor cells. Our results demonstrate that age-associated changes in APCs are critical for the pathogenesis of age-related dry eye.
MeSH Terms
- Adoptive Transfer
- Aging
- Animals
- Antigen-Presenting Cells
- Biomarkers
- Cellular Senescence
- Cytokines
- Disease Models, Animal
- Dry Eye Syndromes
- Female
- Lymphocyte Activation
- Mice
- Mice, Knockout
- Th1 Cells
Human lifespan is determined by genetic and environmental factors. Potential longevity genes are neither specific nor reproducible, and longevity-related genes are constantly confused with age-related genes. To distinguish specific age- and longevity-related genes, we analyzed a Gene Expression Omnibus (GEO) dataset established by the Leiden Longevity Study. The individuals were classified into longevity (mean age, 93.4 ± 3.0 years), longevity offspring (60.8 ± 6.1) and control (61.9 ± 6.9) groups. The series matrix files were downloaded, and average expression values were calculated. Differentially expressed genes (DEGs) between longevity and control groups and those between longevity and their offspring were identified by GEO2R online. A total of 507 longevity- and 755 age-related DEGs were visualized using a Venn diagram. Weighted gene co-expression network analysis (WGCNA) was performed on the longevity- and age-related DEGs. Age-related color modules and genes were identified. However, no longevity-related modules or genes were found. The green module, with 46 age-related DEGs, was the most biologically significant to age and aging. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction pathway analyses were conducted on these 46 DEGs, which are mainly enriched in B cell activation and receptor signaling pathways. CR2, VPREB3, MS4A1 and CCR6 were considered the most crucial candidate genes for aging.
MeSH Terms
- Aged
- Aged, 80 and over
- Blood Cells
- Female
- Gene Expression Profiling
- Gene Regulatory Networks
- Humans
- Longevity
- Male
- Middle Aged
- Transcriptome
Keywords
- WGCNA
- age
- aging
- differentially expressed genes
- longevity
The pathogenic role and frequency of T cell subtypes in early rheumatoid arthritis are still unclear. We therefore performed a comprehensive analysis of the circulating T cell subtype pattern in patients with untreated early rheumatoid arthritis compared to healthy control subjects. Peripheral blood mononuclear cells were obtained from 26 patients with untreated early rheumatoid arthritis and from with 18 age- and sex-matched healthy control subjects. T helper cell types Th0, Th1, Th2, Th17, and Th1/17 and nonclassic T helper subsets were defined by flow cytometry based on the expression of chemokine receptors CCR4, CCR6, and CXCR3. Regulatory T cells were defined by expression of CD25 CD127 and also FOXP3 CXCR5 cells among regulatory and nonregulatory T cells were defined as T follicular regulatory and T follicular helper cells, respectively. The phenotype of T cell subsets was confirmed by transcription factor and cytokine secretion analyses. Multivariate discriminant analysis showed that patients with untreated early rheumatoid arthritis were segregated from healthy control subjects based on the circulating T cell subset profile. Among the discriminator subsets, CCR4 CXCR3 (Th2 and Th17), CTLA4 and FOXP3 subsets were present in significantly higher frequencies, whereas CCR4 (Th1/Th17, CCR6 CCR4 CXCR3 , and Th1) subsets were present in lower frequencies in patients with untreated early rheumatoid arthritis compared with healthy control subjects. The proportions of Th2 and Th17 subsets associated positively with each other and negatively with the CXCR3 /interferon γ-secreting subsets (Th1 and Th1/Th17) in patients with untreated rheumatoid arthritis. The proportions of Th2 cells increased with age in patients with untreated early rheumatoid arthritis and healthy control subjects. The dominance of circulating CCR4 CXCR3 T helper subsets (Th2 and Th17) in untreated early rheumatoid arthritis point toward a pathogenic role of these cells in early stages of the disease.
MeSH Terms
- Adult
- Aged
- Aging
- Antigens, Differentiation, T-Lymphocyte
- Arthritis, Rheumatoid
- Case-Control Studies
- Cytokines
- Disease Progression
- Female
- Flow Cytometry
- Gene Expression Profiling
- Humans
- Immunophenotyping
- Lymphocyte Count
- Male
- Middle Aged
- Receptors, CXCR3
- T-Lymphocyte Subsets
- T-Lymphocytes, Helper-Inducer
- T-Lymphocytes, Regulatory
- Transcription Factors
Keywords
- T cell profile
- autoimmunity
- chemokine receptors
- multivariate discriminant analysis
Alzheimer's disease (AD) is a progressive, irreversible, and debilitating disease for which no effective preventive or disease modifying therapies or treatments have so far been detected. The crucial step in AD pathogenesis is the production of amyloid-β42 peptide, which causes chronic inflammation. Activated cells in the central nervous system (CNS) produce pro-inflammatory mediators that lead to the recruitment of myeloid or lymphocytic cells. As a consequence, the communication between the CNS and peripheral blood of AD subjects could influence the lymphocyte distribution and/or the expression of phenotypic markers. In the present paper, we show a significant decrease in total CD19 B lymphocytes and a remodeling of the B cell subpopulations in moderate-severe AD patients, compared with their coeval healthy controls and mild AD subjects. In particular, we report a significant reduction in naïve B cells (IgD CD27-) and a simultaneous increase in double negative (DN, IgD-CD27-) memory B lymphocytes. We have also evaluated the expression of the pro-inflammatory chemokine receptors CCR6 and CCR7 in total and naïve/memory B cells from mild and moderate-severe AD patients, with the aim to detect a possible relationship between the trafficking profile and the stage of the disease. Our results demonstrate that both the amount and the trafficking profile of B cells are related to the severity of AD. The results discussed in this paper suggest a well-selected antibody panel should be used as an additional test for the identification of early AD.
MeSH Terms
- Aged
- Aged, 80 and over
- Alzheimer Disease
- B-Lymphocyte Subsets
- Cohort Studies
- Female
- Flow Cytometry
- Humans
- Immunoglobulin D
- Immunoglobulin G
- Male
- Mental Status Schedule
- Phenotype
- Receptors, CCR6
- Receptors, CCR7
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Keywords
- Aging
- Alzheimer's disease
- B cells
- CCR6
- CCR7
- trafficking profile
The impairment of humoral immune response in elderly humans has been extensively demonstrated. We have reported the increase of memory B cells (IgG( )IgD(-)CD27(-), double negative, DN) population in the elderly, in which there is also a typical inflammatory micro-environment. In order to evaluate whether this pro-inflammatory status could influence the trafficking phenotype of naïve/memory B cells, we have assessed the expression of CCR7, CCR6, CXCR3, CXCR4, CXCR5 and CD62L on naïve/memory B cell subpopulations in young and elderly subjects. Moreover, the combination of pro-inflammatory interleukin-21 (IL-21) and B cell receptor (BCR) stimulation enables B cells to produce and secrete granzyme B (GrB), which plays a critical role in early anti-viral immune responses, in the regulation of autoimmune mechanisms and in cancer immunosurveillance. Our data demonstrate that in the elderly, naïve/memory B cell populations present a different expression of the studied receptors that could be discussed in terms of "inflamm-aging". In particular IgG( )IgD(-)CD27(-) DN B cells show a tissue trafficking phenotype and they can be stimulated to produce GrB.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- B-Lymphocyte Subsets
- Granzymes
- Humans
- Immunoglobulin D
- Immunoglobulin G
- Interleukins
- L-Selectin
- Phenotype
- Receptors, CXCR
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Keywords
- B lymphocytes
- Chemokine receptors
- Elderly
- Granzyme B
- IL-21
- Inflamm-aging
Aging has been reported to be associated with changes in immune function. Although frequent infection and the development of malignancy suggest the decline of immune function with aging, changes toward proinflammatory conditions also develop at the same time. Th17 cells are well known CD4( ) T cell subpopulation closely linked to chronic inflammation and autoimmunity. In this study, changes in the Th17 population were investigated to elucidate a possible mechanism for this response with aging. Splenocytes were isolated from 2-month-old (young) and 20-month-old (aged) mice. CD4( )CD44( ) memory T cells and CD4( )CD62L( ) naïve T cells were isolated and sorted using magnetic beads and flow cytometry. The frequency of IL-17-producing cells was measured using flow cytometry. The expression of IL-17 and Th17-related factors at the mRNA level was measured with RT-PCR. IL-17 and Il-1β expression in spleen tissues was additionally assessed using confocal microscopy. The proportion of IL-17-producing CD4( ) T cells was higher in the splenocytes among the old mice than those of the young mice. When splenocytes were cultured in Th17 polarizing conditions, the proportion of IL-17 producing CD4( ) T cells was higher in aged mice as well. This was consistently observed when naïve and memory cells were isolated and differentiated into Th17 respectively. In addition, the expression of retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) and other Th17-related factors (AhR, CCR6, and CCL20) increased in the splenocytes of aged mice compared to the young mice. The expression of IL-1β, showing to promote Th17 differentiation, was higher in the aged mice. Likewise, CD4( ) T cell expression of IL-1R was higher in the aged mice, suggesting that the CD4( ) T cells of the aged mice are readily prepared to differentiate into Th17 cells in response to IL-1β. Confocal microscopy showed that cells positive for IL-1R or IL-1β were more frequent in the spleens of the aged mice. When an anti-IL-2 antibody was applied, the proportion of IL-17-producing cells increased more prominently in the young mice. We observed that IL-2 production and IL-2R expression were reduced in the aged mice, respectively, explaining the blunted response to the anti-IL-2 antibody treatment and the consequent minimal change in the Th17 population. We demonstrated that the proportion of Th17 cells increased in the aged mice both in naïve and memory cell populations. Elevation of IL-1R and IL-1β expression and the reduction in IL-2 and IL-2R expression in aged mice seemed to promote Th17 differentiation. Our results suggest that enhanced Th17 differentiation in aging may have a pathogenic role in the development of Th17-mediated autoimmune diseases.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Cells, Cultured
- Coculture Techniques
- Interleukin-17
- Interleukin-1beta
- Interleukin-2
- Lymphocyte Count
- Male
- Mice
- Mice, Inbred C57BL
- Receptors, Interleukin-1
- Spleen
- Th17 Cells
- Up-Regulation
Keywords
- Aging
- IL-1
- IL-2
- Th17