CCL19
C-C motif chemokine 19 precursor (Beta-chemokine exodus-3) (CK beta-11) (Epstein-Barr virus-induced molecule 1 ligand chemokine) (EBI1 ligand chemokine) (ELC) (Macrophage inflammatory protein 3 beta) (MIP-3-beta) (Small-inducible cytokine A19) [ELC] [MIP3B] [SCYA19]
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How lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated cell-adhesion molecules, which increased LCs in the brain but was insufficient to induce CNSL. Astrocyte-derived CCL19 was required for gliosis-induced CNSL. Deleting CCL19 in mice or CCR7 from LCs abrogated CNSL development. Two-photon microscopy revealed LCs transiently entering normal brain parenchyma. Astrocytic CCL19 enhanced parenchymal CNS retention of LCs, thereby promoting CNSL formation. Aged, gliotic wild-type mice were more susceptible to forming CNSL than young wild-type mice, and astrocytic CCL19 was observed in both human gliosis and CNSL. Therefore, CCL19-CCR7 interactions may underlie an increased age-related risk for CNSL.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Animals
- Astrocytes
- Blood-Brain Barrier
- Cell Line, Tumor
- Central Nervous System Neoplasms
- Chemokine CCL19
- Chemokine CXCL12
- Disease Models, Animal
- Female
- Gliosis
- Humans
- Intravital Microscopy
- Lymphoma
- Male
- Mice
- Mice, Transgenic
- Microscopy, Fluorescence, Multiphoton
- Middle Aged
- NF-kappa B
- Receptors, CCR7
- Time-Lapse Imaging
- Young Adult
Keywords
- CCL19
- CNSL
- CXCL12
- DLBCL
- PCNSL
- SCNSL
- gliosis
- lymphoma
- metastasis
- neuroinflammation
The concept of age-dependent host control of cancer development raises the natural question of how these effects manifest across the host tissue/organ types with which a tumor interacts, one important component of which is the aging immune system. To investigate this, changes in the spleen, an immune nexus in the mouse, was examined for its age-dependent interactive influence on the carcinogenesis process. The model is the C57BL/6 male mice (adolescent, young adult, middle-aged, and old or 68, 143, 551 and 736 days old respectively) with and without a syngeneic murine tumor implant. Through global transcriptome analysis, immune-related functions were found to be key regulators in the spleen associated with tumor progression as a function of age with CD2, CD3ε, CCL19, and CCL5 being the key molecules involved. Surprisingly, other than CCL5, all key factors and immune-related functions were not active in spleens from non-tumor bearing old mice. Our findings of age-dependent tumor-spleen signaling interaction suggest the existence of a global role of the aging host in carcinogenesis. Suggested is a new avenue for therapeutic improvement that capitalizes on the pervasive role of host aging in dictating the course of this disease.
MeSH Terms
- Age Factors
- Animals
- Cell Proliferation
- Disease Progression
- Humans
- Mice
- Neoplasms
- Signal Transduction
- Spleen
- Tumor Microenvironment
Keywords
- CD2
- CD3e
- Gerotarget
- aging and cancer
- tumor microenvironment
- tumor progression
Recent evidence has determined a phenotypic and functional heterogeneity for macrophage populations. This plasticity of macrophage function has been related to specific properties of subsets (M1 and M2) of these cells in inflammation, adaptive immune responses and resolution of tissue destructive processes. This investigation hypothesized that targeted alterations in the distribution of macrophage phenotypes in aged individuals, and with periodontitis would be skewed towards M1 inflammatory macrophages in gingival tissues. The study used a non-human primate model to evaluate gene expression profiles as footprints of macrophage variation in healthy and periodontitis gingival tissues from animals 3-23 years of age and in periodontitis tissues in adult and aged animals. Significant increases in multiple genes reflecting overall increases in macrophage activities were observed in healthy aged tissues, and were significantly increased in periodontitis tissues from both adults and aged animals. Generally, gene expression patterns for M2 macrophages were similar in healthy young, adolescent and adult tissues. However, modest increases were noted in healthy aged tissues, similar to those seen in periodontitis tissues from both age groups. M1 macrophage gene transcription patterns increased significantly over the age range in healthy tissues, with multiple genes (e.g. CCL13, CCL19, CCR7 and TLR4) significantly increased in aged animals. Additionally, gene expression patterns for M1 macrophages were significantly increased in adult health versus periodontitis and aged healthy versus periodontitis. The findings supported a significant increase in macrophages with aging and in periodontitis. The primary increases in both healthy aged tissues and, particularly periodontitis tissues appeared in the M1 phenotype.
MeSH Terms
- Age Factors
- Aging
- Animals
- Disease Models, Animal
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Gingiva
- Macaca mulatta
- Macrophage Activation
- Macrophages
- Male
- Periodontitis
- Transcriptome
Keywords
- Aging
- gene expression
- gingival tissue
- macrophage polarization
- periodontitis
In addition to the secretion of Ag-specific Abs, B cells may play an important role in the generation of immune responses by efficiently presenting Ag to T cells. We and other investigators recently described a subpopulation of CD11c( ) B cells (Age/autoimmune-associated B cells [ABCs]) that appear with age, during virus infections, and at the onset of some autoimmune diseases and participate in autoimmune responses by secreting autoantibodies. In this study, we assessed the ability of these cells to present Ag and activate Ag-specific T cells. We demonstrated that ABCs present Ag to T cells, in vitro and in vivo, better than do follicular B cells (FO cells). Our data indicate that ABCs express higher levels of the chemokine receptor CCR7, have higher responsiveness to CCL21 and CCL19 than do FO cells, and are localized at the T/B cell border in spleen. Using multiphoton microscopy, we show that, in vivo, CD11c( ) B cells form significantly more stable interactions with T cells than do FO cells. Together, these data identify a previously undescribed role for ABCs as potent APCs and suggest another potential mechanism by which these cells can influence immune responses and/or the development of autoimmunity.
MeSH Terms
- Aging
- Animals
- Antigen-Presenting Cells
- Autoantibodies
- Autoimmunity
- B-Lymphocytes
- CD11c Antigen
- Chemokine CCL19
- Chemokine CCL21
- Female
- Gene Expression Regulation
- Mice
- Mice, Inbred C57BL
- Receptors, CCR7
- Signal Transduction
- Spleen
- T-Lymphocytes
With increasing age the immune system shows functional decline. In the skin this is associated with an increased incidence of epidermal malignancies and infections. Epidermal Langerhans cells (LCs) act as sentinels of the immune system, recognizing, processing and presenting antigen and inducing T-cell responses. Previous investigations have demonstrated a reduction in the number of epidermal LCs in elderly subjects. Moreover, the ability of LCs to migrate in response to tumour necrosis factor (TNF)-α, but not interleukin (IL)-1β, is significantly impaired in the elderly. To characterize further the changes in LC function that are associated with increasing chronological age, we have evaluated age-related changes in the response of monocyte-derived LCs (mLCs) to IL-1β and TNF-α. The phenotype and function of mLCs were compared in six young (≤ 30 years) and six aged (≥ 70 years) healthy individuals using a combination of flow cytometry, cytokine and chemokine array, and a Transwell migration assay. Monocytes from aged individuals were able to differentiate into LCs. There were no significant differences in expression of activation markers, or in baseline or inducible cytokine secretion, by mLCs derived from aged or young subjects. Furthermore, migration in response to a chemokine ligand, CCL19, was equivalent in both age groups. These data demonstrate that changes in LC function in the elderly are not associated with changes in systemic dendritic cell phenotype and function. Conditioning of LCs in situ by the epidermal microenvironment is likely to be more important.
MeSH Terms
- Adult
- Aged
- Aging
- Cell Differentiation
- Cell Movement
- Cellular Senescence
- Cytokines
- Female
- Flow Cytometry
- Humans
- Interleukin-1beta
- Langerhans Cells
- Male
- Monocytes
- Tumor Necrosis Factor-alpha
- Young Adult
A pivotal role for tertiary lymphoid structures (TLSs) in promoting Ag-specific humoral responses during chronic inflammation is emerging in several autoimmune conditions, including rheumatoid arthritis, Sjogren's syndrome, and autoimmune thyroiditis. However, there is limited evidence on the cellular and molecular mechanisms underlying TLS formation and their contribution to autoimmunity in the pancreas during autoimmune insulitis. In this study, we performed a detailed and comprehensive assessment of the evolution of TLSs during autoimmune insulitis in 126 female NOD mice from 4 to 38 wk of age. We demonstrated that during progression from peri- to intrainsulitis in early diabetic mice, T and B cell infiltration follows a highly regulated process with the formation of lymphoid aggregates characterized by T/B cell segregation, follicular dendritic cell networks, and differentiation of germinal center B cells. This process is preceded by local upregulation of lymphotoxins alpha/beta and lymphoid chemokines CXCL13 and CCL19, and is associated with infiltration of B220( )/IgD( )/CD23( )/CD21(-) follicular B cells expressing CXCR5. Despite a similar incidence of insulitis, late diabetic mice displayed a significantly reduced incidence of fully organized TLSs and reduced levels of lymphotoxins/lymphoid chemokines. Upon development, TLSs were fully functional in supporting in situ autoreactive B cell differentiation, as demonstrated by the expression of activation-induced cytidine deaminase, the enzyme required for Ig affinity maturation and class switching, and the presence of CD138( ) plasma cells displaying anti-insulin reactivity. Overall, our work provides direct evidence that TLSs are of critical relevance in promoting autoimmunity and chronic inflammation during autoimmune insulitis and diabetes in NOD mice.
MeSH Terms
- Aging
- Animals
- Autoantibodies
- B-Lymphocyte Subsets
- Cell Differentiation
- Cell Movement
- Cytidine Deaminase
- Dendritic Cells, Follicular
- Diabetes Mellitus, Type 1
- Disease Progression
- Female
- Germinal Center
- Inflammation
- Insulin-Secreting Cells
- Lymphoid Tissue
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Rabbits
- Rats
- T-Lymphocyte Subsets
Progressive neurological dysfunction is a key aspect of human aging. Because of underlying differences in the aging of mice and humans, useful mouse models have been difficult to obtain and study. We have used gene-expression analysis and polymorphism screening to study molecular senescence of the retina and hippocampus in two rare inbred mouse models of accelerated neurological senescence (SAMP8 and SAMP10) that closely mimic human neurological aging, and in a related normal strain (SAMR1) and an unrelated normal strain (C57BL/6J). The majority of age-related gene expression changes were strain-specific, with only a few common pathways found for normal and accelerated neurological aging. Polymorphism screening led to the identification of mutations that could have a direct impact on important disease processes, including a mutation in a fibroblast growth factor gene, Fgf1, and a mutation in and ectopic expression of the gene for the chemokine CCL19, which is involved in the inflammatory response. We show that combining the study of inbred mouse strains with interesting traits and gene-expression profiling can lead to the discovery of genes important for complex phenotypes. Furthermore, full-genome polymorphism detection, sequencing and gene-expression profiling of inbred mouse strains with interesting phenotypic differences may provide unique insights into the molecular genetics of late-manifesting complex diseases.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Brain
- Chemokine CCL19
- Chemokines, CC
- Chromosomes, Mammalian
- Fibroblast Growth Factor 1
- Gene Expression Profiling
- Mice
- Mice, Inbred AKR
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Molecular Sequence Data
- Mutation
- Nervous System
- Phenotype
- RNA, Messenger
- Retina
- Species Specificity