Chemokine Receptor Gene

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The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression

The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression

Chemokine receptor expression profile is altered follow- ing the engagement of the TCR to the major histocompat- ibility complex (MHC) on antigen presenting cells. For example, receptors for constitutively expressed chemok- ines such as CXCR4 and CCR7 are down-regulated as naïve T cells are activated and differentiated into effector cells [22]. This in turn allows the CD8+ T cells to migrate to peripheral tissues to perform their effector function. Others have reported that specific T cell dysfunctions in aging can also be rescued by co-activating the TCR and T cell co-stimulation pathways [23-25]. We therefore deter- mined the combined effect of T cell receptor (CD3)/cos- timulatory molecule (CD28) stimulation on young and old CD8+ T cell chemokine receptor expression profile (Figure 2). The results show that the CD8+ T cells CCR1, 2, 3, 5 and CXCR2, 4, 5 gene expression decreases after the CD3/CD28 activation. CCR4 is the only chemokine receptor that showed increased expression following anti- CD3/anti-CD28 mAb treatments, similar to what has been seen in CD4+ T cells [21]. Despite the age difference in basal chemokine receptor gene expression level, old CD8+ T cells exhibit similar robust CC and CXC chemok- ine receptor response to TCR/co-stimulatory activation as young CD8+ T cells.
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Human Cytomegalovirus Chemokine Receptor Gene US28 Is Transcribed in Latently Infected THP-1 Monocytes

Human Cytomegalovirus Chemokine Receptor Gene US28 Is Transcribed in Latently Infected THP-1 Monocytes

PCR signals for UL54 could not be observed in cDNA samples from PAA-treated cells, whereas the undiluted sample of un- treated HCMV-infected cells was RT-PCR positive (Fig. 5, lanes 1 to 12, middle panel). Although PAA treatment affects HCMV DNA polymerase activity, we did not expect UL54 transcript levels to be lower in PAA-treated cells than in un- treated cells. This might indicate that UL54 transcription is propelled by a late-phase positive feedback mechanism. We did not investigate this possibility further. Nevertheless, we have shown that (i) US28 is transcribed in HCMV-infected THP-1 cells at least until day 15 p.i., (ii) the amount of US28-tran- scribing THP-1 cells is approximately 10-fold that of UL54- FIG. 5. Quantitative comparison of US28 and HCMV DNA polymerase gene transcription in HCMV-infected THP-1 cells at day 7 p.i. RT-PCR samples are visualized on agarose gels as described in Fig. 2. The primer sets that correspond to each of the panels are indicated on the right of each panel. Black arrowheads denote the relevant PCR products. (A) Sensitivity of RT-PCR for the detection of US28 and HCMV DNA polymerase cDNA. The amount of target cDNA molecules that was included in each RT-PCR sample is indicated at the top. (B) Quantification of HCMV-infected THP-1 cells transcribing either US28 or the HCMV DNA polymerase gene at day 7 p.i. The quantities on top correspond to the amount of cells that were taken from the original HCMV-infected THP-1 culture and mixed with uninfected THP-1 cells to a total of 2 ⫻ 10 5
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Association of chemokine receptor gene (CCR2 CCR5) haplotypes with acquisition and control of HIV 1 infection in Zambians

Association of chemokine receptor gene (CCR2 CCR5) haplotypes with acquisition and control of HIV 1 infection in Zambians

In summary, our analysis of CCR2-CCR5 haplotypes consisting of common combinations of SNP alleles spanning those two genes has confirmed a previously reported association of haplotype HHF*2 with favorable response to HIV-1 infection; and our longitudinal analy- sis of seroconversion in HESN African heterosexual partners has detected probable contributions by the HHD/HHE diplotype to acquisition of infection [11,17,39]. Further insight into these relationships will be gained from studies of correlation between gene var- iation and gene function, as well as investigation of other representative and informative populations of infected and uninfected Africans.
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Frequency of CCR5?32 Variant in North-West of Iran

Frequency of CCR5?32 Variant in North-West of Iran

Table 3. Frequencies of homozygous and heterozygous genotypes for mutated and normal form of CCR5 chemokine receptor gene from 25 different populations were extracted and compared with present study (Ref. 22-25). The results of comparisons imply that significant differences were found among our study and others especially in north of Europe and Asia and the distribution of this allele is similar in different parts of Iran. Interestingly the distribution of mutant allele in Asia is about zero

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Interleukin 10 producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis

Interleukin 10 producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis

We have previously identified murine CD4 + CD25 − LAG3 + regulatory T cells that produce high amounts of IL-10 and interferon (IFN)-γ, lack Foxp3 expression, and suppress B-cell antibody production [21, 23]. They are regulated by early growth response gene 2 (Egr2), which is important for the maintenance of T-cell anergy by negatively regulating T-cell activation [24]. We therefore hypothesized that human CD4 + CD25 − LAG3 + T cells might have the same functions as those in mice and that they might be associated with human autoimmune dis- eases. We aimed to characterize CD4 + CD25 − LAG3 + T cells in healthy and autoimmune states and to determine the impact of abatacept treatment that targets T-cell responses.
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Complementary action of granulocyte macrophage colony stimulating factor and interleukin 17A induces interleukin 23, receptor activator of nuclear factor κB ligand, and matrix metalloproteinases and drives bone and cartilage pathology in experimental arth

Complementary action of granulocyte macrophage colony stimulating factor and interleukin 17A induces interleukin 23, receptor activator of nuclear factor κB ligand, and matrix metalloproteinases and drives bone and cartilage pathology in experimental arthritis: rationale for combination therapy in rheumatoid arthritis

Local production of cytokines and chemokines was mea- sured in joint washouts. The major cytokines produced by arthritic synoviocytes were IL-6, chemokine (C-X-C motif ) ligand 1 (CXCL1), CC chemokine ligand 2 (CCL2) and CCL3 (Fig. 2a). The production of IL-6 was not af- fected in mice treated with anti-IL-17 or anti-GM-CSF alone; however, combination treatment led to a significant increase in this cytokine compared with the other treat- ment groups (Fig. 2a). This is most likely due to the re- duced influx of IL-6 receptor-expressing naive CD4 + T cells and the absence of inflammatory cells and osteoclasts in the joints of these mice, resulting in reduced consump- tion of IL-6 [4, 28]. Production of CXCL1, CCL2 and CCL3 was not affected by antibody treatment. In agree- ment with earlier studies, tumour necrosis factor (TNF) was not detected in the joint washouts [29, 30] (data not shown). Synovial cells were also analysed by flow cytome- try to detect infiltrating CD4 + T cells. Anti-GM-CSF treat- ment and combination treatment resulted in a slight reduction of infiltrating CD4 + T cells. This effect was not observed in the mice treated with anti-IL-17 (Fig. 2b, c).
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CXCR-4 expression by circulating endothelial progenitor cells and SDF-1 serum levels are elevated in septic patients

CXCR-4 expression by circulating endothelial progenitor cells and SDF-1 serum levels are elevated in septic patients

SDF-1α /CXCR-4 axis is furthermore involved in EPC recruitment to the spleen [24] and CXCR-4 influences EPC homing through cellular polarization [11]. The receptor for advanced glycation endproducts RAGE is expressed by several cells of the innate immune system and activates NF-κ-B signaling [25]. RAGE signaling is also involved in integrin dependent homing of EPC [26]. The proto-oncogene c-Kit seems to play a crucial role in EPC recruitment to inflamed endothelium: EPC adhesion to tumor necrosis factor (TNF)-α treated endothelial cells mediated via c-Kit involves the intra- cellular Akt-pathway (Proteinkinase B, Akt) and can be prevented, when pretreating EPC with the c-Kit inhibi- tor imatinib [31]. Thus, the upregulation of CXCR-4, c-Kit and RAGE by EPC shown in our study indicates, that these factors could be important mediators of EPC
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Molecular Imaging of Chemokine Receptor CXCR4

Molecular Imaging of Chemokine Receptor CXCR4

CXCR4 was found to be expressed by many different types of human cancers and its ex- pression has been correlated with tumor aggressiveness, poor prognosis and resistance to chemotherapy. CXCR4 was also shown to contribute to metastatic seeding of organs that express its ligand CXCL12 and support the survival of these cells. These findings suggest that CXCR4 is a potentially attractive therapeutic target, and several antagonists and antibodies for this receptor were developed and are under clinical evaluation. Quantifying CXCR4 ex- pression non-invasively might aid in prognostication as a mean for personalized therapy and post treatment monitoring. Multiple attempts were done over the recent years to develop imaging agents for CXCR4 using different technologies including PET, SPECT, fluorescent and bioluminescence, and will be reviewed in this paper.
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Pulsed high dose dexamethasone modulates Th1 /Th2 chemokine imbalance in immune thrombocytopenia

Pulsed high dose dexamethasone modulates Th1 /Th2 chemokine imbalance in immune thrombocytopenia

pulmonary sarcoidosis, a Th1-associated disease [27]. Of the three ligands, CXCL11 has the highest receptor bind- ing affinity for CXCR3 through chemotactic migration and transient mobilization of intercellular calcium [28]. Here, we detected the status of CXCL11 and its receptor CXCR3 in ITP. We found that plasma CXCL11 levels in active ITP patients were higher than in controls, suggest- ing that CXCL11 may be an important chemoattractant for effector T cells involved in ITP. Moreover, CXCL11 acts as an antagonist for CCR3 but an agonist for CXCR3 [29]. In patients who responded well to pulsed HD- DXM (responders), plasma CXCL11 and mRNA levels of CXCL11 in PBMCs were decreased. Therefore, CXCL11 may be a potential therapeutic target for ITP, since the analogue is that Tizina et al. [30] successively modelled the structural determinants of these interactions of CXCL9/CXCR3, CXCL10/CXCR3 and CXCL11/CXCR3 complexes and their physico-chemical features in order to be used for drug design.
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Plasma VCAM1 levels correlate with disease severity in Parkinson’s disease

Plasma VCAM1 levels correlate with disease severity in Parkinson’s disease

Clinical and demographic characteristics of PD patients are provided in Table 1. The frequencies of T, B, NK, and NK-T cells and monocytes did not significantly differ be- tween PD patients and HDs (Fig. 1b). A significant down- regulation in the surface expression of the integrin “ very late antigen 4 ” (VLA4) on T cells ( p = 0.024), NK cells ( p = 0.026), and NK-T cells (p = 0.017) was observed in PD patients (Fig. 1c, d). No alteration in TLR4, CCR2, CCR5, CXCR3, CXCR4, CD11b, and IFN-gamma-receptor ex- pression was observed in PD patients relative to HDs (data not shown). Lymphocytes from PD patients showed di- minished directed motility towards an SDF-1 α gradient in a chemotaxis assay (Fig. 1e).
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Original Article Association between CXCL12 and CXCR4 polymorphisms and inflammatory bowel disease risk in a Guangxi Zhuang population

Original Article Association between CXCL12 and CXCR4 polymorphisms and inflammatory bowel disease risk in a Guangxi Zhuang population

Abstract: Objective: To explore the association of the CXCL12 gene polymorphism rs1801157 and the CXCR4 gene polymorphism rs2228014 and susceptibility to inflammatory bowel disease (IBD) in a Zhuang population from Guangxi, China. Methods: A case control study was performed, which included intestinal tissue samples of 245 Zhuang patients with IBD in the experimental group and 202 healthy Zhuang subjects in the control group from January 2013 to February 2016. All patients and healthy subjects were from the Guangxi Zhuang Autonomous Region of China. Genomic DNA was extracted from intestinal tissue by the centrifugal column method. CXCL12 rs1801157 and CXCR4 rs2228014 polymorphisms were amplified by polymerase chain reaction (PCR), and then genotyped by restriction fragment length polymorphism (RFLP) analysis and sequencing. Results: The allele and genotype distributions of CXCL12 rs1801157 and CXCR4 rs2228014 were all in Hardy-Weinberg equilibrium for the IBD group and the control group. The genotypes of CXCL12 rs1801157 and CXCR4 rs2228014, including the homozygous mutant, heterozygous mutant and wild-type genotype, were found in both IBD patients and healthy controls. No significant differences were noted in genotype and allele frequencies of CXCL12 rs1801157 among UC/CD and control groups (P > 0.05). Differences in allele frequency between UC/CD patients and control group for CXCR4 rs2228014 were statistically significant (χ 2 = 11.589, P = 0.001; χ 2 = 14.365, P < 0.001). Conclusion:
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X4 viruses are frequently archived in patients with long term HIV infection but do not seem to influence the “inflamm aging” process

X4 viruses are frequently archived in patients with long term HIV infection but do not seem to influence the “inflamm aging” process

Even if several successive regimens might have masked the actual impact of therapy on CRT, according to other publi- cations [35], the duration and type of antiretroviral therapy did not seem to influence CRT in our series. This finding also confirms our previous observation that, in patients treated by HAART and sequentially tested for CRT, the co-receptor shift is independent of virological success [15]. None of the baseline demographic and clinical characteristics, apart from CD4 and viral load trends over time, seem to influence the predominant strain archived in proviral DNA. In particular, even if the risk factor for HIV acquisition might be a determinant for CRT selection at time of transmission [38], it seems to lose its importance over time. A lower proportion of X4 strains has been observed among some non-B-subtypes, in particular subtype C [39], suggesting a possible association with an improved virological outcome for non-B patients when excluding racial and social variables, as recently described by some authors [40,41]; in the present study, however, non B-subtypes were rare and no definite conclusion can be drawn concerning the relationship between CRT and viral subtype. Moreover, the co-infection with other viruses, in particular with HBV and HCV, failed to demonstrate any association with CRT. In HIV-HCV co-infection, the env gp120 of HIV was supposed to interact with HCV E2 in triggering the apoptosis mechanisms [42] to modulate the biology of human hepatic stellate cells which play a key role in the fibrosis pathogenesis [43], and to enhance the replication of HCV through the engagement of extracellular coreceptors on hepatocytes [44]. In this study, a slightly higher proportion of R5 patients was observed among the HCV-positive patients when compared to negatives, but without statis- tical significance. If R5 and X4 strains can be differentially Table 2 Lack of association of CRT with inflammatory
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Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma

Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma

IL-6 secreted by TAMs is an important factor involved in the occurrence and development of tumors [29, 30]. It is relatively clear that IL-6 mediates EMT mainly via the IL-6/STAT3 pathway. In this process, IL-6 binds to its receptor IL-6R, which consists of two polypeptide chains; a ligand-binding chain (GP80) and a signal con- duction chain (GP130). The latter is phosphorylated following interaction with Janus kinase resulting in acti- vation of STAT3 to form two homologous polymers that enter the nucleus to regulate transcription and promote EMT, a process that is observed in liver cancer [31]. Studies in both human samples and human HCC cell lines in vitro have shown that the IL-6/STAT3 axis com- prises a variety of “circuits”, including microRNAs such as miR-24, miR-629, and miR-124, and hepatocyte nu- clear factor 4α (HNF4α). In this circuit, IL-6/STAT3 ac- tivates the transcription of miRNAs, such as miR-24 and miR-629, which inhibit the activity of HNF4 α . HNF4 α is an important factor in the maintenance of the growth and normal biological functions of hepatocytes. When its activity is inhibited, hepatocytes enter the inflamma- tory state, which is exacerbated via a positive feedback mechanism resulting in a severe inflammatory micro- environment that promotes tumor invasion and metasta- sis (Fig. 2). That is quite similar to the “ snowball effect ” , with miR-124 representing the key factor in this circuit. In HepG2 and SNU-449 cells, it has been shown that miR-124 suppresses STAT3 activation, restores the function of HNF4 α and terminates the further develop- ment of the inflammatory environment. Furthermore, miR-124 was shown to inhibit the tumor invasion and me- tastasis in a mouse model [32]. The effectiveness of this approach has also been confirmed in studies of lung adenocarcinoma, breast cancer and head and neck tumors [33]. In addition to activating the JAK/STAT3 pathway via phosphorylation of STAT3, the IL-6/IL-6R interaction leads to low E-cadherin expression and high vimentin expression as well as upregulated expression of Snail, ZEB1, ZEB2, Twist and other transcription factors that promote tumor metastasis [34 – 36].
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Novel regulatory therapies for prevention of Graft-versus-host disease

Novel regulatory therapies for prevention of Graft-versus-host disease

APC: antigen-presenting cells; BMT: bone marrow transplantation; CCR5: C-C chemokine receptor; CXCR3: CXC chemokine receptor 3; DC: dendritic cells; FC: facilitating cells; FoxP3: forkhead/winged helix transcription factor; GVHD: graft-versus-host disease; GVL: graft-versus-leukemia; HLA: human leukocyte antigen; HSC: hematopoietic stem cell; IL-1: interleukin-1; MHC: major histocompatibility complex; NK: natural killer; p-preDC: plasmacytoid precursor dendritic cells; TCD: T cell depletion; Tcon: conventional donor- derived T cells; TCR: T cell receptor; TGF- β : transforming growth factor beta; T reg : regulatory T cell; TNF- α : tumor necrosis factors- α ; UCB: umbilical cord
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Bone marrow stem cells to destroy circulating HIV: a hypothetical therapeutic strategy

Bone marrow stem cells to destroy circulating HIV: a hypothetical therapeutic strategy

Soon after transfusion the riBFU-Es will find its way to the bone marrow by ‘stem-cell homing’ [57–60] and once in the specific niche the engineered stem cell will prolif- erate to yield numerous riRBCs naturally from the bone marrow (Fig. 3). Bone marrow derived riRBCs along with the transfused riRBCs in the peripheral blood will then engage in receptor mediated capturing of circulating HIV particles. The fascinating feature of this engineered riRBC is that a single riRBC can confine numerous HIV particles till its natural destruction after 120  days in patient’s body. Once circulating HIVs bind with the receptor and co-receptor associated complex on the riRBC membrane by its envelop glycoproteins gp 120 and gp 41, viral membrane will readily fuse with cell mem- brane leading to partial core shell uncoating and entry into riRBC cytoplasm [4, 6]. This event would immedi- ately facilitate reverse transcription of genomic HIV- RNA to yield pre-integration complex (PIC) [4, 6, 11, 61]. Up to this event HIV follows its normal path of infection but once PIC has been formed inside riRBC cytoplasm, due to the lack of nucleus it will be unable to complete its replication and life cycle and eventually will stall. Sin- gle riRBC will carry numerous of such PICs and eventu- ally be destroyed along with the riRBC by the action of
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Immunostimulatory RNA leads to functional reprogramming of myeloid-derived suppressor cells in pancreatic cancer

Immunostimulatory RNA leads to functional reprogramming of myeloid-derived suppressor cells in pancreatic cancer

p < 0.001, ≥ 2-fold change) in PMN-MDSC (spleen: 420; tumor: 180; shared: 100) and M-MDSC (spleen: 584; tumor: 210; shared: 113) (Additional file 1: Figure S3C). Functional annotation analysis using the Database for An- notation, Visualization and Integrated Discovery (DAVID) was done with differentially expressed genes from spleen. Genes were found to be significantly enriched in gene ontology biological process (GO:BP) clusters related to immune system processes, virus and IFN response-related pathways, and antigen presentation-related genes (Fig. 3c and Additional file 1: Figure S4). Most importantly, gene set enrichment analysis of splenic differentially expressed genes revealed an enrichment of neutrophil-associated gene signature for PMN-MDSC and enrichment of M1- associated genes for M-MDSC after poly(I:C) c therapy,
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Th17 and Th22 cells in psoriatic arthritis and psoriasis

Th17 and Th22 cells in psoriatic arthritis and psoriasis

Whereas recent evidence implicates interleukin 22 (IL- 22) in the pathogenesis of skin disease in Ps [6,7], PsA has been postulated to more likely involve IL-17 [8,9]. Both cy- tokines can be made by the T helper 17 (Th17) cell subset, but recent reports have described T cells that make IL-22 alone [10,11]. These T cells, subsequently termed Th22 cells, produce IL-22 without IL-17 or interferon γ (IFNγ) and are characterized by the expression of certain chemo- kine receptors, including chemokine receptor 4 (CCR4) and CCR6, which can influence homing to skin and joints [12]. Both Th17 and Th22 cells are influenced by the cyto- kine IL-23, which is required for their expansion and
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Aging, inflammation, stem cells, and bone healing

Aging, inflammation, stem cells, and bone healing

In addition to macrophages, MSCs are critical for bone regeneration. MSCs are multipotent and can differenti- ate into many cell types, including chondrocytes and osteoblasts for endochondral and intramembranous ossi- fication, respectively [14]. A key step in bone healing is the localization of MSCs to the site of injury. For ex- ample, in a parabiosis model, Shinoara et al. [15] demon- strated that the stromal cell-derived factor 1/CXCR4 (SDF-1/CXCR4) ligand-receptor axis is critical for the homing of progenitor cells that participate in fracture healing. Similarly, Kitaori et al. [16] used an exchanging- graft and autograft mouse model to show that SDF-1 +/− and CXCR4 +/− are important to the recruitment of MSCs during skeletal repair. Many other studies have confirmed the beneficial role of MSCs in bone regener- ation [17, 18]. Nevertheless, the origin of the MSCs that are directly involved in fracture healing is controversial. Colnot et al. [19] showed that periosteum and endos- teum are primary sources of MSCs for fracture repair. Similarly, using a parabiotic mouse model, Kumagai et al. [20] showed little to no contribution of circulating cells to direct repair of the injured bone. At a minimum, systemically migrated MSCs and osteoprogenitors are thought to play an important paracrine role, modulating both inflammation and subsequent bone repair.
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CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab secreting cells

CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab secreting cells

The dissemination of IgA-dependent immunity between mucosal sites has important implications for mucosal immunoprotection and vaccine development. Epithelial cells in diverse gastrointestinal and nonintestinal mucosal tissues express the chemokine MEC/CCL28. Here we demonstrate that CCR10, a receptor for MEC, is selectively expressed by IgA Ab-secreting cells (large s/cIgA + CD38 hi CD19 int/– CD20 – ), including circulating IgA + plasmablasts and almost all IgA + plasma cells in the salivary gland, small intestine, large intestine, appendix, and tonsils. Few T cells in any mucosal tissue examined express CCR10. Moreover, tonsil IgA plasmablasts migrate to MEC, consistent with the selectivity of CCR10 expression. In contrast, CCR9, whose ligand TECK/CCL25 is
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Increased CCL19 and CCL21 levels promote fibroblast ossification in ankylosing spondylitis hip ligament tissue

Increased CCL19 and CCL21 levels promote fibroblast ossification in ankylosing spondylitis hip ligament tissue

There are some limitations to our study. First, patho- logical studies demonstrated that multiple cell types, in- cluding fibroblasts, periosteal cells, endothelial cells and stem cells, are present in LT, so other cells that express CCR7 should also be considered. Second, all of the pa- tients in our study were admitted for joint replacement surgery and exhibited severely restricted hip activity and a poor BASFI score (average BASFI = 62.24, indicating severe functional limitations), and these patients do not represent the entire AS population. Third, there is a significant difference in the average age between the AS and OA groups, which may influence the results. Fourth, the precise concentrations of CCL19/CCL21 in AS LT (n = 10) and peripheral blood are similar to those of RA synovium and peripheral blood [16], but ossifica- tion is not observed in RA patients. Two reasons may account for these results: ossification is caused by changes in the gene expression level in AS, and CCL19/ CCL21 may accelerate this progress; and the concentra- tion of CCL19/CCL21 used in this study, 10 ng/ml, which is far more than the levels in LT, induced the acti- vation of ossification in cultured fibroblasts in vitro. In addition, the number of AS patients included in our study is small for correlation analysis. Further investiga- tion using larger sample sizes would provide more con- vincing results.
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