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Purpose To investigate the expression of Che-mokine(C-X-C Motif)receptor 5(CXCR5)and its clinico-pathological significance in classic Hodgkin lymphoma(CHL).Methods The expression of CXCR5 was assessed in 33 pa-tients by immunohistochemistry(IHC),and retrospectively ana-lyzed the expression and clinical significance of CXCR5 in the four subtypes of CHL.Meanwhile,10 cases of ALK-positive an-aplastic large cell lymphoma(ALCL)and 10 cases of ALK-neg-ative ALCL were collected as the control group.ResultsThere were 31 cases with CXCR5-positive in all 33 cases(93.94%),including 15/16(93.75%)in nodular sclerosis CHL,12/13(92.31%)in mixed cellularity CHL,2/2 in lymphocyte-rich CHL,and 2/2 in lymphocyte-depleted CHL.The positive ex-pressions of CXCR5 in different immunophenotypes of CHL were as follow,31/33(93.94%)in CD30 positive and PAX5 weakly positive CHL.12/14(85.71%)in CD15 negative CHL,24/26(92.31%)in CD20 negative CHL,10/11(90.91%)in EBER-negative CHL and 5/6 in LMP1-negative CHL.CXCR5 were not expressed in all 20 cases of ALCL.Conclusion The positive expression rate of CXCR5 in CHL is high.When the tumor cells are negative for CD15,LMP1 and CD20 or EBER,CXCR5 also has a high positive expression rate,which is helpful for the diagnosis of CHL.CXCR5 can be used to differentiate CHL from ALCL,especially the cases lacking typical morpholo-gy and immunohistochemistry.
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Epilepsy is a common, chronic neurological disorder that has been associated with impaired neurodevelopment and immunity. The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism. Here, we first determined the expression pattern and distribution of the CXCR5 gene in the mouse brain during different stages of development and the brain tissue of patients with epilepsy. Subsequently, we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylenetetrazol- and kainic acid-induced seizures, whereas CXCR5 overexpression had the opposite effect. CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons. Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model, we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment. Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability, resulting in an increased number of seizures. Finally, our results suggested that CXCR5 deficiency triggers seizure-related electrical activity through a previously unknown mechanism, namely, the disruption of neuronal polarity.
Subject(s)
Animals , Humans , Mice , Actin Cytoskeleton/metabolism , Actins/metabolism , Epilepsy/metabolism , Neurons/metabolism , Receptors, CXCR5/metabolism , Seizures/metabolismABSTRACT
Objective @#To investigate the expression of programmed death 1 (PD1) on CXCR5 -CD4 + T cells from the patients with rheumatoid arthritis (RA) and to analyze the clinical relevance to disease severity.@*Methods @#The expression of PD1 on CXCR5 -CD4 + T cells were examined from 82 RA patients and 46 healthy controls (HC) by the technique of flow cytometry.The expression of PD1 including mean fluorescence intensity (MFI) on CXCR5 - CD4 + T cells and percentage of PD1 + CXCR5 -CD4 + T cells were compared between RA patients and HC.Moreo- ver,its correlation with laboratory inspection was analyzed. @*Results @#① The percentage of PD1 + CXCR5 -CD4 + T cells and the MFI of PD1 on CXCR5 -CD4 + T cells from RA patients were significantly elevated compared with HC (P<0. 000 1,U = 1 082 ; P <0. 000 1 ,U = 917. 5) . ② The percentage of PD1 + CXCR5 - CD4 + T cells in RA patients were positively associated with rheumatoid factors (RF) (rs = 0. 267 9,P = 0. 022 9) ,increased RF (rs = 0. 419,P = 0. 001 1) ,increased anti-cyclic citrullinated peptide (anti-CCP) (rs = 0. 260 7,P = 0. 040 7) ,the percentage of plasmablasts (rs = 0. 302 4,P = 0. 029 3) ,DAS28-ESR (rs = 0. 244 7,P = 0. 042 7) . ③ The MFI of PD1 on CXCR5 -CD4 + T cells in RA patients were negatively with lymphocytes number (rs = -0. 338 7,P = 0. 002 0 ) ,lymphocytes percentage ( rs = -0. 347 9 ,P = 0. 001 4 ) ,lymphocyte-to-monocyte ratio ( rs = - 0. 263 7,P = 0. 017 4) .The MFI of PD1 on CXCR5 - CD4 + T cells in RA patients were positively associated with neutrophil percentage ( rs = 0. 304 7 ,P = 0. 005 4 ) ,neutrophilto-lymphocyte ratio ( rs = 0. 341 1 ,P = 0. 001 8) ,platelet-to-lymphocyte ratio (rs = 0. 232 1,P = 0. 037 1) ,systemic immune inflammation index (rs = 0. 288 0,P = 0. 009 1) ,derived Neutrophil to lymphocyte ratio ( rs = 0. 320 3,P = 0. 003 6) ,erythrocyte sedi- mentation rate (rs = 0. 259 5,P = 0. 019 3) ,patient visual analogue scale (rs = 0. 241 6,P = 0. 043 9) .The MFI of PD1 on CXCR5 - CD4 + T cells from high active RA patients was significantly elevated compared with non-high active group (P = 0. 040 7,U = 406. 0) .@*Conclusion @#The abnormal expression of PD1 on CXCR5 -CD4 + T cells are observed in patients with RA.Increased expression of PD1 on CXCR5 - CD4 + T cells are associated with the production of antibody,the percentage of plasmablasts,inflammation,and also disease activity.
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Pain consists of sensory-discriminative and emotional-affective components. The anterior cingulate cortex (ACC) is a critical brain area in mediating the affective pain. However, the molecular mechanisms involved remain largely unknown. Our recent study indicated that C-X-C motif chemokine 13 (CXCL13) and its sole receptor CXCR5 are involved in sensory sensitization in the spinal cord after spinal nerve ligation (SNL). Whether CXCL13/CXCR5 signaling in the ACC contributes to the pathogenesis of pain-related aversion remains unknown. Here, we showed that SNL increased the CXCL13 level and CXCR5 expression in the ACC after SNL. Knockdown of CXCR5 by microinjection of Cxcr5 shRNA into the ACC did not affect SNL-induced mechanical allodynia but effectively alleviated neuropathic pain-related place avoidance behavior. Furthermore, electrophysiological recording from layer II-III neurons in the ACC showed that SNL increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), decreased the EPSC paired-pulse ratio, and increased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio, indicating enhanced glutamatergic synaptic transmission. Finally, superfusion of CXCL13 onto ACC slices increased the frequency and amplitude of spontaneous EPSCs. Pre-injection of Cxcr5 shRNA into the ACC reduced the increase in glutamatergic synaptic transmission induced by SNL. Collectively, these results suggest that CXCL13/CXCR5 signaling in the ACC is involved in neuropathic pain-related aversion via synaptic potentiation.
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CXCR5⁺ T follicular helper (Tfh) cells are associated with aberrant autoantibody production in patients with antibody-mediated autoimmune diseases including lupus. Follicular regulatory T (Tfr) cells expressing CXCR5 and Bcl6 have been recently identified as a specialized subset of Foxp3+ regulatory T (Treg) cells that control germinal center reactions. In this study, we show that retroviral transduction of CXCR5 gene in Foxp3⁺ Treg cells induced a stable expression of functional CXCR5 on their surface. The Cxcr5-transduced Treg cells maintained the expression of Treg cell signature genes and the suppressive activity. The expression of CXCR5 as well as Foxp3 in the transduced Treg cells appeared to be stable in vivo in an adoptive transfer experiment. Moreover, Cxcr5-transduced Treg cells preferentially migrated toward the CXCL13 gradient, leading to an effective suppression of antibody production from B cells stimulated with Tfh cells. Therefore, our results demonstrate that enforced expression of CXCR5 onto Treg cells efficiently induces Tfr cell-like properties, which might be a promising cellular therapeutic approach for the treatment of antibody-mediated autoimmune diseases.
Subject(s)
Humans , Adoptive Transfer , Antibody Formation , Autoimmune Diseases , B-Lymphocytes , Germinal Center , T-Lymphocytes , T-Lymphocytes, Regulatory , ZidovudineABSTRACT
Objective To detect levels of C?X?C chemokine receptor type 5 (CXCR5) and inducible costimulator(ICOS)in blister fluid of patients with bullous pemphigoid(BP), and to explore their significance in the pathogenesis of BP. Methods Blister fluid samples were collected from 15 patients with BP(experimental group)and 15 patients with second?degree burns(control group). Enzyme?linked immunosorbent assay(ELISA)was performed to detect the levels of CXCR5 and ICOS in the 2 groups. Results The level of CXCR5 was significantly higher in the experimental group than in the control group(219 ± 145.31 vs. 147 ± 23.83 ng/L, t=4.577, P 0.05). Conclusion The expression of CXCR5 may be associated with the occurrence of BP, but further researches are needed to determine the relationship between ICOS and the occurrence of BP.
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Objective To explore the expression and significance of CXCL13 in gastric mucosa of children with nodular gastritis. Methods A total of 216 pediatric patients with clinically diagnosed gastritis under gastroscopy were randomly divided into nodular group and non-nodular group according to whether there were nodular changes under endoscopy. The pathological characteristics of gastric mucosa and the expression of CXCL13/CXCR5 in gastric mucosa of all patients were evaluated. Results The infection rates of Helicobacter pylori(HP)in gastric mucosa in nodule group(n=102)and non-nodular group(n=114)were 70.59% and 42.11%, respectively; the rate of severe mononuclear cell infiltration were 74.51% and 22.81%, respectively; the proportion of neutrophil infiltration were 62.75% and 33.33%, respectively; lymph follicles occurred in 64.71% and 20.18%, respectively; and there were statistical differences between the two groups (P<0.001). Positive staining of CXCL13 and CXCR5 were found in the gastric mucosa of all HP infected patients. The percentages of positive cells of CXCL13 and CXCR5 in the gastric mucosa of the nodules group were (71.33±7.14)% and (73.54 ± 7.92)%, which were higher than those in the non-nodule group (45.88 ± 5.92)% and (50.42 ± 5.98)%, respectively, and there were statistical differences (P<0.001). Conclusions Nodular gastritis in children is mainly associated with Hp infection. The expression of CXCL13/CXCR5 is increased in gastric mucosa in children with Hp infection, especially in nodular gastritis, it may be involved in the formation of lymphoid tissue in gastric mucosa.
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Objective To investigate the changes of follicular helper T cells (Tfh cells) and Tfh cells associated molecules in the peripheral blood (PB) of patients with malignant lymphoid diseases (MLD) dynamically, and explore their roles on pathogenesis of the diseases. Methods Fifty-five patients with MLD were enrolled in this study,including 9 patients with acute lymphocyte leukemia (ALL), 30 patients with non-Hodgkin lymophoma (NHL) and 16 patients with multiple myeloma (MM), and 10 healthy controls (NC) of similar age were also enrolled. The percentage of CD4+CXCR5+cells (Tfh cells) and expression of ICOS+, PD1+among the T cells were detected by flow cytometry (FCM), while the levels of interleukin 21 (IL-21) in plasma were detected by ELISA tests. Results The percentage of Tfh cells and expression of ICOS and/or PD-1 in PB of all untreated patients were significantly higher than those of NC (all P 0.05), and apparently lower than those who achieved PR (P 0.05), and much higher than NC (P< 0.01). The concentration of IL-21 in patients were much higher than that in NC [(326.56±32.44) pg/ml] (P<0.01), and MM group
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How follicular T-helper (Tfh) cells develop is incompletely understood. We find that, upon antigen exposure in vivo, both naïve and antigen-experienced T cells sequentially upregulate CXCR5 and Bcl6 within the first 24 h, relocate to the T-B border, and give rise to phenotypic Bcl6(+)CXCR5(+) Tfh cells before the first cell division. CXCR5 upregulation is more dependent on ICOS costimulation than that of Bcl6, and early Bcl6 induction requires T-cell expression of CXCR5 and, presumably, relocation toward the follicle. This early and rapid upregulation of CXCR5 and Bcl6 depends on IL-6 produced by radiation-resistant cells. These results suggest that a Bcl6(hi)CXCR5(hi) phenotype does not automatically define a Tfh lineage but might reflect a state of antigen exposure and non-commitment to terminal effector fates and that niches in the T-B border and/or the follicle are important for optimal Bcl6 induction and maintenance.
Subject(s)
Animals , Mice , CD40 Ligand , Metabolism , Cell Differentiation , Physiology , DNA-Binding Proteins , Metabolism , Inducible T-Cell Co-Stimulator Protein , Metabolism , Interleukin-6 , Metabolism , Proto-Oncogene Proteins c-bcl-6 , Receptors, CXCR5 , Metabolism , T-Lymphocytes, Helper-Inducer , MetabolismABSTRACT
Objective To investigate the frequencies of CD4+CXCR5+T cells in the CD4+T cells of peripheral blood of patients with systemic lupus erythematosus (SLE) and the effect of glucocorticoid on it.Methods Frequencies of CD4+CXCR5+T cell were analyzed by flow cytometry in 45 active,20 inactive SLE patients and 20 healthy controls.Differences between groups and the effect of glucocorticoid were analyzed.Meanwhile, the expression of CXCR5 on CDI9+B cells was analyzed. Independent sample t test was used for statistical analysis between twogroups, ANOVA was applied for data analysis between 3 groups,,nonparameterical Spearman's analysis was used for correlation analysis and repeated measurement ANOVA were used to compare the parameters before and after treatment. Results The percentage of CD4+CXCR5+ in CD4+T cells was increased in patients with SLE compared with healthy controls[(16±7)% vs (12±3)%, P<0.01].It was increased in patients with active SLE [(18±7)%] compared with healthy controls (P<0.05) but there was no significant difference between inactive SLE[(11±4)%] and healthy controls(P>0.05). The percentage in patients with LN was higher than that in patients without LN, but without significant difference[(18±7)%vs (14±7)%, P=0.05 ]. The percentage of CD4+CXCR5+T cells was positively correlated with SLEDAI,the titer of ANA and level of ESR but negatively correlated with the level of C3 (P<0.05 for each).No correlation was found between duration and the levels of CRP and immunoglobulin.. The percentage in patients with high anti-dsDNA group was also higher than that of the low group, but no differences were found between anti-Sm antibody positive and negative groups neither between anti-SSA/SSB antibody positive and negative groups(P>0.05 for each).The expression level of CXCR5 on CD19+B cells in active SLE patients was lower than that of healthy controls[(85±11)% vs (94±3)%, P<0.05 ]. The percentages of CD4+CXCR5+T cells in 10 untreated active SLE patients were decreased at day 1,day 3 and day 7 after being treated with dexamethasone (20mg/d) when compared with those before the treatment (P<0.05 for each), but the percentages of CD19+CXCR5+B cells had no significant change (P>0.05 for each).Conclusion These results demonstrate that the abnormality of CD4+CXCR5+T cells may play an important role in the pathogenesis of SLE.
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BACKGROUND: In spite that several lines of evidence suggest that gastric MALT lymphoma arises from Helicobacter pylori (H. pylori)-associated acquired MALT(mucosa-associated lymphoid tissue), the exact underlying pathogenic mechanism has not yet been clearly exploited. The high expression of B cell attracting chemokine-1 (BCA-1) and modulation of cell death by apoptosis have been suggested as possible pathogenic determinants for whether the cases with H. pylori infection will develop MALToma or not. METHODS: We have studied the expression of BCA-1 and its receptor CXCR5 in gastric tissue samples obtained from patients suffering with H. pylori-positive gastritis, H. pylori-negative gastritis and H. pylori-positive low grade MALT lymphoma, respectively. TUNEL (Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling) staining for detecting apoptotic cells was also included. Furthermore, the changes of the BCA-1 and CXCR5 expressions before and after the complete remission of MALToma were compared. The in vitro influencing effect of H. pylori infection on the BCA-1 and CXCR5 expression was observed. RESULTS: Significantly higher levels of BCA-1 and its receptor CXCR5 expression were observed in H. pylori-positive MALToma specimens as compared with either the H. pylori-positive gastritis or H. pylori-negative gastritis specimens; its levels were significantly reduced after the remission of MALToma. In contrast to the increased apoptotic activity after H. pylori infection, a significant reduction of epithelial apoptosis was observed in the H. pylori-positive MALToma specimens. H. pylori infection directly induced the expression of BCA-1 in the cultured gastric epithelial cells. CONCLUSION: The up-regulated BCA-1 expression and the decreased apoptosis in H. pylori infected gastric epithelial cells might contribute to the development of MALT lymphoma.