Analysis of clinicopathological and molecular abnormalities of angioimmunoblastic T-cell lymphoma / 北京大学学报(医学版)

OBJECTIVE@#To analyze the clinicopathological features, molecular changes and prognostic factors in angioimmunoblastic T-cell lymphoma (AITL).@*METHODS@#Sixty-one cases AITL diagnosed by Department of Pathology of Peking University Cancer Hospital were collected with their clinical data. Morphologically, they were classified as typeⅠ[lymphoid tissue reactive hyperplasia (LRH) like]; typeⅡ[marginal zone lymphoma(MZL)like] and type Ⅲ [peripheral T-cell lymphoma, not specified (PTCL-NOS) like]. Immunohistochemical staining was used to evaluate the presence of follicular helper T-cell (TFH) phenotype, proliferation of extra germinal center (GC) follicular dendritic cells (FDCs), presence of Hodgkin and Reed-Sternberg (HRS)-like cells and large B transformation. The density of Epstein-Barr virus (EBV) + cells was counted with slides stained by Epstein-Barr virus encoded RNA (EBER) in situ hybridization on high power field (HPF). T-cell receptor / immunoglobulin gene (TCR/IG) clonality and targeted exome sequencing (TES) test were performed when necessary. SPSS 22.0 software was used for statistical analysis.@*RESULTS@#Morphological subtype (%): 11.4% (7/61) cases were classified as type Ⅰ; 50.8% (31/61) as type Ⅱ; 37.8% (23/61) as type Ⅲ. 83.6% (51/61) cases showed classical TFH immunophenotype. With variable extra-GC FDC meshwork proliferation (median 20.0%); 23.0% (14/61) had HRS-like cells; 11.5% (7/61) with large B transformation. 42.6% (26/61) of cases with high counts of EBV. 57.9% (11/19) TCR+/IG-, 26.3% (5/19) TCR+/IG+, 10.5% (2/19) were TCR－/IG－, and 5.3% (1/19) TCR－/IG+. Mutation frequencies by TES were 66.7% (20/30) for RHOA, 23.3% (7/30) for IDH2 mutation, 80.0% (24/30) for TET2 mutation, and 33.3% (10/30) DNMT3A mutation. Integrated analysis divided into four groups: (1) IDH2 and RHOA co-mutation group (7 cases): 6 cases were type Ⅱ, 1 case was type Ⅲ; all with typical TFH phenotype; HRS-like cells and large B transformation were not found; (2) RHOA single mutation group (13 cases): 1 case was type Ⅰ, 6 cases were type Ⅱ, 6 cases were type Ⅲ; 5 cases without typical TFH phenotype; 6 cases had HRS-like cells, and 2 cases with large B transformation. Atypically, 1 case showed TCR－/IG－, 1 case with TCR－/IG+, and 1 case with TCR+/IG+; (3) TET2 and/or DNMT3A mutation alone group (7 cases): 3 cases were type Ⅱ, 4 cases were type Ⅲ, all cases were found with typical TFH phenotype; 2 cases had HRS-like cells, 2 cases with large B transformation, and atypically; (4) non-mutation group (3 cases), all were type Ⅱ, with typical TFH phenotype, with significant extra-GC FDC proliferation, without HRS-like cells and large B transformation. Atypically, 1 case was TCR－/IG－. Univariate analysis confirmed that higher density of EBV positive cell was independent adverse prognostic factors for both overall survival (OS) and progression free survival(PFS), (P=0.017 and P=0.046).@*CONCLUSION@#Pathological diagnoses of ALTL cases with HRS-like cells, large B transformation or type Ⅰ are difficult. Although TCR/IG gene rearrangement test is helpful but still with limitation. TES involving RHOA, IDH2, TET2, DNMT3A can robustly assist in the differential diagnosis of those difficult cases. Higher density of EBV positive cells counts in tumor tissue might be an indicator for poor survival.

First report of expansion of CD4+/CD28 null T-helper lymphocytes in adult patients with idiopathic autoimmune hemolytic anemia

ABSTRACT CD28 null T helper (Th) cells are rare in healthy individuals, but they are increased in various inflammatory and immune-mediated diseases. In this study, we determined the size of the CD4+/CD28 null T lymphocyte compartment in the peripheral blood of 40 autoimmune hemolytic anemia (AIHA) patients (idiopathic and secondary) and 20 healthy control subjects, using tri-color flow cytometry. The frequency and absolute count of CD4+/CD28 null T helper (Th) cells was significantly higher in idiopathic AIHA patients, compared to healthy controls (p = 0.001 and 0.001, respectively) and to patients with secondary AIHA (p = 0.04 and 0.01, respectively). The percentage of CD4+/CD28 null Th cells was also negatively correlated to the hemoglobin (Hb) level (p = 0.03). These findings demonstrate, for the first time, the expansion of this phenotypically-defined population of T lymphocytes in patients with idiopathic AIHA and indicate that it likely plays an etiological role in the development of this disease. However, establishing the use of this marker for diagnosis or monitoring treatment of such patients needs further studies.

Human follicular helper T lymphocytes critical players in antibody responses / Linfócitos T auxiliares foliculares humanos: células essenciais para a resposta de anticorpos

ABSTRACT Follicular helper T lymphocytes are a subpopulation of CD4+ T lymphocytes initially identified in germinal centers of follicles found in secondary lymphoid organs. The primary function of follicular helper T lymphocytes is to help B lymphocytes' antibody production. Changing of antibody class and affinity, B cell differentiation and memory generation depend on cooperation between follicular helper T lymphocytes and B cells. In blood, follicular helper T lymphocytes are called circulating follicular helper T lymphocytes. They are considered to have specificities similar to those developed in the secondary lymphoid organs. The phenotype of human follicular helper T lymphocytes is given by simultaneous expression of the markers CXCR5, Bcl-6, CD40L, PD-1, and ICOS. In germinal centers, follicular helper T lymphocytes synthesize interleukin 21 as predominant cytokine. In blood, subpopulations of circulating follicular helper T lymphocytes can be recognized, with different expressions of the classical follicular helper T lymphocytes markers and, in addition, can express other markers such as CXCR3 and CCR6. Presently, there is great interest in follicular helper T lymphocytes and circulating follicular helper T lymphocytes in vaccination studies as indicators of immunization efficacy. In addition, follicular helper T lymphocytes are investigated as possible markers of activity in many diseases and potential therapeutic intervention. This short review describes aspects of immunobiology and quantification of follicular helper T lymphocytes and circulating follicular helper T lymphocytes, and presents a few examples of related findings in systemic lupus erythematosus, rheumatoid arthritis, HIV infection and vaccination.

RESUMO Linfócitos T auxiliares foliculares são uma subpopulação de linfócitos T CD4+ identificada inicialmente nos centros germinativos dos folículos dos órgãos linfoides secundários. Sua função primordial é auxiliar os linfócitos B na produção de anticorpos. A mudança de classe e de afinidade dos anticorpos, a diferenciação das células B e a geração de memória dependem da cooperação entre os linfócitos T auxiliares foliculares e as células B. No sangue, recebem o nome de linfócitos T auxiliares circulantes. Considera-se que possuem especificidades semelhantes às desenvolvidas nos órgãos linfoides secundários. O fenótipo dos linfócitos T auxiliares humanos é dado pela expressão conjunta dos marcadores CXCR5, Bcl-6, CD40L, PD-1 e ICOS. Nos folículos, linfócitos T auxiliares sintetizam a interleucina 21 como citocina predominante. No sangue, são descritas várias subpopulações de linfócitos T auxiliares circulantes com expressões variadas dos marcadores clássicos de linfócitos T auxiliares, além de poderem agregar outros, como CXCR3 e CCR6. Existe um enorme interesse no estudo de linfócitos T auxiliares e linfócitos T auxiliares circulantes, para a avaliação de eficácia de vacinação. São também investigados como possíveis marcadores de atividade em muitas doenças e potenciais intervenções terapêuticas. Esta breve revisão descreve aspectos da imunobiologia e da quantificação de linfócitos T auxiliares humanos e linfócitos T auxiliares circulantes, além de apresentar alguns achados relacionados em lúpus eritematoso sistêmico, artrite reumatoide, infecção por HIV e vacinação.

Clinical Significance of Tfh/Tfr Cell Imbalance in Patients with B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To explore the role of follicular helper T cell (Tfh)/ follicular regulatory T cell (Tfr) imbalance in B-cell lymphoma (BCL).@*METHODS@#Sixteen BCL patients who were admitted to the Department of Hematology of The First People's Hospital of Yichang and 20 healthy people from December 2019 to November 2020 were enrolled and respectively divided into observation group and control group. The levels of Tfh and Tfr in peripheral blood were detected by flow cytometry. The changes of Tfh, Tfr, and Tfh/Tfr ratio were compared and the relationship between Tfh/Tfr ratio and efficacy, prognosis was analyzed.@*RESULTS@#Compared with the healthy controls, Tfh and Tfh/Tfr ratio in peripheral blood of the BCL patients increased (P<0.05, P<0.01), while levels of Tfr was decreased (P<0.01). After chemotherapy, Tfh and Tfh/Tfr ratio in peripheral blood of the BCL patients decreased significantly than before chemotherapy (P<0.01), but Tfr was no significant difference. Multivariate analysis showed that Tfh and Tfh/Tfr ratio were positively correlated with international prognostic index (IPI) score and Ann Arbor stage (r=0.626, 0.564, 0.573, 0.608, respectively), while Tfr negatively (r=－0.504, －0.542, respectively). According to the average value of Tfh/Tfr ratio at initial diagnosis, BCL patients were divided into Tfh/Tfr high ratio group and low ratio group. It was found that the complete remission (CR) rate, overall response rate (ORR), and survival time in the high ratio group were significantly lower than the low ratio group (P<0.01).@*CONCLUSION@#There is an imbalance of Tfh/Tfr ratio in peripheral blood of the BCL patients, and those with a high Tfh/Tfr ratio have lower CR, ORR and shorter survival time.

Effect of fasudil on experimental autoimmune neuritis and its mechanisms of action

This study aimed to investigate the therapeutic effect of fasudil on treating experimental autoimmune neuritis (EAN). Twenty-four EAN mice were randomly assigned to fasudil treatment (Fasudil group) or saline treatment (EAN model group) for 28 days. Clinical symptom score was evaluated every other day; inflammatory cell infiltration, demyelination, anti-myelin basic protein (MBP), inflammatory cytokines, inducible nitric oxide synthase (iNOS), and arginase-1 were detected in sciatic nerves at day 28. Th1, Th2, Th17, and Tregs proportions in splenocytes were detected at day 28. Clinical symptom score was found to be attenuated in the Fasudil group compared to the EAN model group from day 12 to day 28. Sciatic nerve inflammatory cell counts by HE staining and demyelination by luxol fast blue staining were both reduced, while MBP was increased in the Fasudil group compared to the EAN model group at day 28. Interferon γ (IFN-γ) and interleukin (IL)-17 were reduced, while IL-4 and IL-10 were elevated in the Fasudil group at day 28. Sciatic nerve M1 macrophages marker iNOS was decreased while M2 macrophages marker arginase-1 was increased in the Fasudil group at day 28. CD4+IFN-γ+ (Th1) and CD4+IL-17+ (Th17) cell proportions were both decreased, CD4+IL-4+ (Th2) cell proportion was similar, while CD25+FOXP3+ (Treg) cell proportion in splenocytes was increased in the Fasudil group. In summary, fasudil presented a good therapeutic effect for treating EAN by attenuating Th1/Th17 cells and promoting Tregs activation as well as M2 macrophages polarization.

Role of IL-17A in Chronic Rhinosinusitis With Nasal Polyp

PURPOSE: Th17-associated inflammation is increased in chronic rhinosinusitis with nasal polyp (CRSwNP), and is associated with disease severity and steroid resistance. Overexpressed interleukin (IL)-17A affects CRSwNP by tissue remodeling, eosinophilic accumulation, and neutrophilic infiltration. We aimed to identify the role of IL-17A in CRSwNP and to evaluate the effects of anti-IL-17A blocking antibody on nasal polyp (NP) formation using a murine NP model. Moreover, we sought to investigate whether the inhibition of mechanistic target of the rapamycin (mTOR) signal pathway could suppress IL-17A expression and NP formation.METHODS: Human sinonasal tissues from control subjects and patients with chronic rhinosinusitis (CRS) were analyzed using immunohistochemistry (IHC) and immunofluorescence staining. The effects of IL-17A neutralizing antibody and rapamycin were evaluated in a murine NP model. Mouse samples were analyzed using IHC, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay.RESULTS: IL-17A+ inflammatory cells were significantly increased in number in NP from patients with CRSwNP compared to that in uncinate process tissues from control subjects and patients with CRS without NP or CRSwNP. CD68+ M1 macrophages dominantly expressed IL-17A, followed by neutrophils and T helper cells, in NP tissues. Neutralization of IL-17A effectively reduced the number of NPs, inflammatory cytokines, and IL-17A-producing cells, including M1 macrophages. Inhibition of IL-17A via the mTOR pathway using rapamycin also attenuated NP formation and inflammation in the murine NP model.CONCLUSIONS: IL-17A possibly plays a role in the pathogenesis of CRSwNP, the major cellular source being M1 macrophage in NP tissues. Targeting IL-17A directly or indirectly may be an effective therapeutic strategy for CRSwNP.

Expression and significance of follicular helper T cells and galactose-deficient IgA1 in children with Henoch-Schönlein purpura / 中国当代儿科杂志

OBJECTIVE@#To study the role of follicular helper T (Tfh) cells and galactose-deficient IgA1 (Gd-IgA1) in the pathogenesis of childhood Henoch-Schönlein purpura (HSP) and the correlation between them.@*METHODS@#A total of 36 children with newly-diagnosed HSP were enrolled. They were divided into two groups: HSP nephritis (HSPN) group with 11 children and non-HSPN group with 25 children according to the presence or absence of HSPN. Another 15 children who underwent physical examination at the outpatient service were enrolled as the healthy control group. Flow cytometry was used to measure the proportion of Tfh cells (CD4CXCR5ICOS) in peripheral blood. ELISA was used to measure the levels of interleukin-21 (IL-21) and interleukin-6 (IL-6) in peripheral blood and the serum levels of IgA1 and Gd-IgA1. A Pearson correlation analysis was used to investigate the correlation of serum Gd-IgA1 concentration with Tfh cells and related factors expression in the children with HSP.@*RESULTS@#Both the HSPN and non-HSPN groups had significantly higher proportion of Tfh cells and expression levels of IL-21 and IL-6 in peripheral blood than the healthy control group (P<0.05). The HSPN group had significant increases in the above indices compared with the non-HSPN group (P<0.05). Both the HSPN and non-HSPN groups had significantly higher serum levels of IgA1 and Gd-IgA1 than the healthy control group (P<0.05). The HSPN group had significantly higher serum levels of IgA1 and Gd-IgA1 than the non-HSPN group (P<0.05). In the children with HSP, serum Gd-IgA1 level was positively correlated with Tfh cells proportion and IL-21 and IL-6 levels (P<0.05).@*CONCLUSIONS@#Tfh cells and related cytokines and serum Gd-IgA1 are involved in the development of HSP/HSPN. Tfh cells may mediate the increased production of Gd-IgA1.

Sodium Chloride Aggravates Arthritis via Th17 Polarization

PURPOSE: Sodium chloride (NaCl) has been proposed as a driving factor in autoimmune diseases through the induction of pathogenic CD4+ T helper cells that produce interleukin-17 (Th17 cells). This study investigated the effects of NaCl on inflammatory arthritis in mice and humans. MATERIALS AND METHODS: Collagen-induced arthritis (CIA) mice were fed a normal or high-salt diet ad libitum, and clinical and histologic features of arthritis were evaluated. The proportion of Th17 cells in the spleens of CIA mice fed a normal or high-salt diet was evaluated by flow cytometry, and the expression of IL-17 in joints and intestines was determined by immunohistochemical staining. We also analyzed the effect of NaCl on Th17 differentiation from peripheral blood monocytes of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and evaluated the contents of sodium and IL-17 in the synovial fluid of RA and OA patients. RESULTS: NaCl increased murine and human Th17 cell differentiation in a dose-dependent manner. Clinical and histological arthritis was more severe in the high-salt-fed CIA mice, compared to control CIA mice. The proportion of Th17 cells among splenocytes was higher in CIA mice fed a high-salt diet. Expression of synovial and intestinal IL-17 was also higher in high-salt-fed CIA mice. Comparison of synovial fluid between RA patients and OA patients revealed that Na+ and IL-17 were more abundant in RA synovial fluid. CONCLUSION: This study suggests that NaCl can aggravate arthritis by affecting Th17 differentiation. Accordingly, limiting salt intake may be helpful for treating inflammatory arthritis, such as RA.

Enhancement of T Follicular Helper Cell-Mediated Humoral Immunity Reponses During Development of Experimental Autoimmune Myasthenia Gravis / 神经科学通报·英文版

Myasthenia gravis (MG) is a prototypical antibody-mediated neurological autoimmune disease with the involvement of humoral immune responses in its pathogenesis. T follicular helper (Tfh) cells have been implicated in many autoimmune diseases. However, whether and how Tfh cells are involved in MG remain unclear. Here, we established and studied a widely-used and approved animal model of human MG, the rat model with acetylcholine receptor alpha (AChRα) subunit (R-AChR)-induced experimental autoimmune myasthenia gravis (EAMG). This model presented mild body-weight loss 10 days after the first immunization (representing the early stage of disease) and more obvious clinical manifestations and body-weight loss 7 days after the second immunization (representing the late stage of disease). AChR-specific pre-Tfh cells and mature Tfh cells were detected in these two stages, respectively. In co-cultures of Tfh cells and B cells, the number of IgG2b-secreting B cells and the level of anti-AChR antibodies in the supernatant were higher in the cultures containing EAMG-derived Tfh cells. In immunohistochemistry and immunofluorescence assays, a substantial number of CD4/Bcl-6 T cells and a greater number of larger germinal centers were observed in lymph node tissues resected from EAMG rats. Based on these results, we hypothesize that an AChR-specific Tfh cell-mediated humoral immune response contributes to the development of EAMG.

Role of Th9, Th17, Treg Cells levels and IL-9, IL-17 and TGF-β Expression in Peripheral Blood of Patients with ITP in Pathogenesis of ITP / 中国实验血液学杂志

OBJECTIVE@#To detect the levels of Treg, Th17, Th9 cells and expression of transforming growth factor-β (TGF-β), interleukin-17 (IL-17) and interleukin-9 (IL-9) in peripheral blood of patients with immune thrombocytopenia (ITP) and to explore its role in the pathogenesis of ITP.@*METHODS@#Fifty-four patients with ITP (ITP group) and 40 healthy volunteers (control group) were selected in our hospital. The of Treg, Th17 and Th9 cells in peripheral blood of 2 groups were measured by flow cytometry, and the expression of cytokines, such as TGF-β, IL-17 and IL-9 in the peripheral blood of 2 groups were detected by enzyme linked immunosorbent assay (ELISA).@*RESULTS@#The level of Treg cells in the peripheral blood of the ITP group was significantly decreased in comparison with the control group, while the levels of Th17 and Th9 cells significantly increased in comparison with the control group (all P<0.01). The expression of cytokine such as TGF-β in the peripheral blood of the case group significantly decreased in comparison with the control group, while the expression levels of IL-17 and IL-9 significantly increased in comparison with the control group (P<0.01). The results of Pearson correlation analysis showed that there was a positive correlation between the level of Treg cells and platelet count (PLT) in peripheral blood of the ITP group (r=0.35, P<0.05), and there were negative correlation between the level rate of Th17, Th9 cells and Plt count (r=-0.37, -0.43, P<0.05); there was a positive correlation between the expression of the TGF-β in the ITP group and Plt count (r=0.46, P<0.05), while the expression of IL-17 and IL-9 showed negative correlation with PLT (r=-0.48, -0.54, P<0.05).@*CONCLUSION@#The percentage of Treg, Th17 and Th9 cells in the peripheral blood of patients with ITP is abnormal, and the expression of TGF-β, IL-17 and IL-9 also is abnormal, which may play an important role in the pathogenesis of ITP.

Relation of Circulating Follicular Helper T Cell Changes with B Cell Dysfunction in MDS Patients / 中国实验血液学杂志

OBJECTIVE@#To explore the relation of circulating follicular helper T cell (c Tfh) changes with B cell dysfunction in MDS patients.@*METHODS@#20 patients diagnosed as MDS from Auguct 2015 to October 2017 were enrolled in MDS group, and 20 healthy valuntears matching in age and sex were enrolled in healthy control (HC) group. The perepheral blood in 2 groups were collected, the mononuclear cells (PBMC) from which were isolated by densily gradient contrifugation, at the same time, the serum left in isolation process was reserved for further study. The flow cytometry was used to detect the ratio of cTfh such as CD4CXCR5 T cells and its subset CD4CXCR5ICOS T cells, CD4CXCR5PD-1 T cells in PBMC, as well as the ratio of plasmablast CD19CD20CD38 B cells. The ELISA was used to detect the concentration of IgA, IgM and IgG. The differences in ratio of cTfh cells and plasmablast B cells, as well as the concentration of IgA, IgM and IgG between MDS and HC groups were compared, at the same time, the correlation of cTfh cell ratio with the plasmablast B cell ratio and the concentration of IgA, IgM and IgG in MDS patient was analyzed.@*RESULTS@#The ratio of CD4CXCR5T, CD4CXCR5ICOST cells and CD19CD20CD38B cells and the concentration of IgA, IgM and IgG decreased in MDS patients, while the ratio of CD4CXCR5PD-1T cells increased in MDS patients. The ratio of CD4CXCR5T cells, CD4CXCR5ICOST cells positively correlated with the ratio of CD19CD20CD38B cells, as well as with the concentration of IgA, IgM and IgG in MDS patients. However, the ratio of CD4CXCR5PD-1T cells negatively correlated with the ratio of CD19CD20CD38B cells, as well as with the concentration of IgA, IgM and IgG.@*CONCLUSION@#The ratio of circulating Tfh cells and their subsets showed significant changes, that correlate with B cell dysfunction in MDS patients.

Effects of Triptolide on Tc and Th Cell Excursion in Peripheral Blood of Nude Mice with Systemic Lupus Erythematosus BALB/c-un / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of triptolide on the excursion of Tc and Th cells in peripheral blood of systemic lupus erythematosus (SLE) BALB/c-un nude mice induced by pristane.@*METHODS@#Eighteen female BALB/c-un nude mice were randomly divided into blank, SLE and triptolide group, each with 6 mice by random table method. Group SLE and group triptolide were established by single intraperitoneal injection of pristane, and blank group was used as blank control group. SLE model was established by single intraperitoneal injection. Triptolide group was fed with triptolide at the dose of 5 mg/(kg·d), and the blank group and SLE group were fed normally. Blood samples were collected from the caudal vein before treatment and 1, 3 and 6 months after treatment respectively. Fluorescence labeled flow cytometry was used to delect Tc and Th lymphocyte subsets at different stages of treatment.@*RESULTS@#After treatment for 3 and 6 moths, the percentages of Tcl, Thl cells and CD8, Tcl/Tc2, Thl/Th2 and CD4/CD8 all decreased in the group of triptolide, and the percentage of CD4, Tc2 and Th2 cells increased (P＜0.05).@*CONCLUSION@#The mechanism of triptolide in the treatment of SLE may be related with the excursion of Tc and Th cells to Tcl and Tc2 to maintain the relative homeostasis of Tc and Th cells at different stage, thus affecting the immune response and the inflammatory reaction.

Effects of chemerin/chemR23 axis on Th9/Treg in patients with psoriasis / 中南大学学报(医学版)

To investigate the effects of chemerin on helper T cells 9 (Th9)/regulatory T cells (Treg) in patients with psoriasis and the potential molecular mechanisms.
 Methods: Twenty-five patients with psoriasis and twenty healthy volunteers were selected for this study. CD4+ T cells were isolated from peripheral blood of samples by magnetic bead separation. The levels of chemerin and its receptor chemR23 were detected by real-time RT-PCR and ELISA. CD4+ T cells isolated from the healthy volunteers were treated with different concentrations of chemerin (50, 100, 150, 200 ng/mL), then cell viability was detected by MTT assay. The expression of inflammatory molecules and Th9/Treg were detected by ELISA and flow cytometry, respectively.
 Results: The expressions of chemerin and chemR23 in peripheral blood from patients with psoriasis were higher than those in healthy control (both P<0.05). The Th9/Treg was higher in patients with psoriasis than that in healthy control (P<0.05). After treating CD4+ T cells with 150 ng/mL of chemerin, the levels of IL-6, IL-9 and IL-17 were increased significantly (all P<0.05). Additionally, Th9/Treg was increased (P<0.05) and the cell balance was disrupt. However, the effects of chemerin on CD4+ T cells were reversed by silencing of chemR23 (all P<0.05).
 Conclusion: Chemerin may regulate the immune balance for Th9/Treg in CD4+ T cells from patients of psoriasis.

Circulating CCR7(lo)PD-1(hi) Follicular Helper T Cells Indicate Disease Activity and Glandular Inflammation in Patients with Primary Sjögren's Syndrome

Since primary Sjögren's syndrome (pSS) is an autoummune disease of B cell hyperactivity and pathologic autoantibody response, follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are suggested to be key players in pSS. We examined subsets of Tfh and Tfr cells from the blood in pSS patients, and whether these subsets represent disease activity, glandular inflammation, or autoantibody responses in pSS. Circulating Tfh and Tfr cells, along with their specific subsets, were identified from the peripheral blood of 18 pSS patients and 14 age- and sex-matched healthy controls (HCs) using flow cytometry analysis. Blood Tfr and Tfh cell ratios were increased in pSS patients compared with HCs. The CCR7(lo)PD-1(hi) subset of circulating Tfh cells was increased in pSS patients with high degree of focal lymphocytic sialadenitis; whereas circulating Tfh cells did not differ between pSS patients and HCs. The frequency of CCR7(lo)PD-1(hi) Tfh cells was significantly correlated with disease activity scores and differentiated B cells. PD-1 expression on blood Tfh and Tfr cells showed positive correlations with IL-21 in pSS. Increasing trend of blood Tfr cells was observed in pSS patients, and blood Tfr cells (particularly Th1 and Th17 subsets) represented hypergammaglobulinemia in pSS. In summary, circulating CCR7(lo)PD-1(hi) Tfh cells indicated disease activity and glandular inflammation in pSS. Circulating Tfr cells, shifted toward Th1 and Th17 subsets, indicated ongoing IgG production in pSS. Subsets of circulating Tfh or Tfr cells could be biomarkers for disease monitoring and patient stratification in pSS.

Evaluation of Protective Immunity of Peptide Vaccines Composed of a 15-mer N-terminal Matrix Protein 2 and a Helper T-Cell Epitope Derived from Influenza A Virus

The matrix protein 2 of influenza A virus (IFAV) has a relatively conserved ectodomain (M2e) composed of 23 amino acids, and M2e-based vaccines have been suggested to induce broad protective immunity in mice. In this study, we investigated whether N-terminal sequence of M2e (nM2e)-based vaccines with more conserved nM2e could induce influenza viral neutralizing activity. We constructed linear peptide vaccines with an nM2e sequence for PR8 virus (nM2Pr) connected to a probable 17-mer IFAV-derived helper T-cell epitope (ThE: T1, T2, or T3) at its N- or C-terminus. The peptide vaccines induced significant production of nM2e Abs regardless of either type or location of the ThE-epitope in BALB/c mice, while only T3 was effective in C57BL/6 mice. The Abs against nM2Pr-T3 elicited broader binding affinities to the nM2e peptides derived from various IFAVs than those against T3-nM2Pr. In addition, the nM2e-based vaccines efficiently protected the immunized mice from the lethal challenge of PR8 virus. These results suggest that the more conserved nM2e without cysteine will be useful for development of universal peptide vaccines than M2e.

Expansion and Sub-Classification of T Cell-Dependent Antibody Responses to Encompass the Role of Innate-Like T Cells in Antibody Responses

In addition to T cell-dependent (TD) Ab responses, T cells can also regulate T cell-independent (TI) B cell responses in the absence of a specific major histocompatibility complex (MHC) class II and antigenic peptide-based interaction between T and B cells. The elucidation of T cells capable of supporting TI Ab responses is important for understanding the cellular mechanism of different types of TI Ab responses. Natural killer T (NKT) cells represent 1 type of helper T cells involved in TI Ab responses and more candidate helper T cells responsible for TI Ab responses may also include γδ T cells and recently reported B-1 helper CD4⁺ T cells. Marginal zone (MZ) B and B-1 cells, 2 major innate-like B cell subsets considered to function independently of T cells, interact with innate-like T cells. Whereas MZ B and NKT cells interact mutually for a rapid response to blood-borne infection, peritoneal memory phenotype CD49d(high)CD4⁺ T cells support natural Ab secretion by B-1 cells. Here the role of innate-like T cells in the so-called TI Ab response is discussed. To accommodate the involvement of T cells in the TI Ab responses, we suggest an expanded classification of TD Ab responses that incorporate cognate and non-cognate B cell help by innate-like T cells.

Changes in T helper lymphocytes and their subsets in children with tic disorders / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To explore the changes in T helper lymphocytes and their subsets in children with tic disorders (TD) and their clinical significance.</p><p><b>METHODS</b>Flow cytometry was used to measure the percentages of T helper lymphocytes and their subsets in the peripheral blood of children with TD and healthy children (controls).</p><p><b>RESULTS</b>The percentage of T helper lymphocytes was significantly lower in the TD group than in the control group (P<0.001). The abnormal rate of T helper lymphocytes in the TD group was significantly higher than that in the control group (68.7% vs 18.8%; P<0.001). The percentage of T helper lymphocytes was negatively correlated with Yale Global Tic Severity Scale score (r=-0.3945, P<0.001). As for the subsets of T helper lymphocytes, the TD group had a significantly higher percentage of Th1 cells and a significantly lower percentage of Th2 cells compared with the control group (P<0.001).</p><p><b>CONCLUSIONS</b>The abnormality of T helper lymphocytes and the imbalance of their subsets may be associated with the pathogenesis of TD in children. The percentage of T helper lymphocytes can be used as an indicator for assessing the severity of TD.</p>

MicroRNA-mediated Regulation of the Development and Functions of Follicular Helper T cells

The germinal center reaction is a key event of humoral immunity, providing long-lived immunological memory. Follicular helper T (T(FH)) cells are a specialized subset of CD4⁺ T cells located in the follicles, which help B cells and thus control the germinal center reaction. T(FH) cell development is achieved by multi-step processes of interactions with dendritic cells and B cells along with the coordination of various transcription factors. Since the T helper cell fate decision program is determined by subtle changes in regulatory molecules, fine tuning of these dynamic interactions is crucial for the generation functional T(FH) cells. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulatory molecules for gene expression, which consequently modulate diverse biological functions. In the last decade, the miRNA-mediated regulation network for the germinal center reaction has been extensively explored in T cells and B cells, resulting in the identification of several key miRNA species and their target genes. Here, we review the current knowledge of the miRNA-mediated control of the germinal center reaction, focusing on the aspect of T cell regulation in particular. In addition, we highlight the most important issues related to defining the functional target genes of the relevant miRNAs. We believe that the studies that uncover the miRNA-mediated regulatory axis of T(FH) cell generation and functions by defining their functional target genes might provide additional opportunities to understand germinal center reactions.

The Role of B Cells in Transplantation Rejection / 대한이식학회지

B cells play a role in graft rejection via several mechanisms. Specifically, B cells produce high-affinity antibodies to alloantigens including allogeneic major histocompatibility complex (MHC) with the help of follicular helper T cells. B cells also function as antigen-presenting cells for alloreactive T cells, resulting in the activation of alloreactive T cells. Conversely, the frequency of regulatory B cells increases under inflammatory conditions and suppresses the rejection process. Here, the differential roles of the major B cell subpopulations (B-1, follicular B, marginal zone B, and regulatory B cells) involved in transplantation rejection are discussed together with their interaction with T cells.

Distinct characteristics of nasal polyps with and without eosinophilia / Diferenças nas características de pólipos nasais com e sem eosinofilia

Abstract Introduction Eosinophilic and noneosinophilic Nasal polyps (NPs) are different subtypes of NPs and require different treatment methods. Objective To compare the histologic characteristics, mRNA and protein expression between Nasal Polyps with and without eosinophilia. Methods NPs tissues were obtained from eighty-six NPs patients during surgery. Eosinophilic and noneosinophilic NPs were distinguished according to immunochemical results of the specimen. The histological, mRNA and protein expression features were compared between the two groups. Results In eosinophilic NPs, we observed a significantly higher GATA-3, IL-5, IL-4, IL-13 mRNA and protein expression. In noneosinophilic NPs, IL-17, IL-23 and RORc mRNA and protein expression were increased. Immunohistochemistry tests showed, more mast cells and less neutrophils in eosinophilic NPs compared with noneosinophilic NPs. Eosinophilic NPs patient presented more severe symptom scores when compared to noneosinophilic NPs. Conclusion We demonstrate for the first time that Th2 is the predominant reaction in eosinophilic NPs while Th17 is the predominant reaction in noneosinophilic NPs. Our study may provide new treatment strategy for NPs.

Resumo Introdução Pólipos nasais (PNs) eosinofílicos e não eosinofílicos são diferentes subtipos de PNs e requerem diferentes métodos de tratamento. Objetivo Comparar as características histológicas e a expressão de mRNAs e proteínas entre PNs com e sem eosinofilia. Método Amostras de PNs foram obtidos de 86 pacientes durante a cirurgia. PNs eosinofílicos e não eosinofílicos foram diferenciados segundo os resultados imunoistoquímicos de cada amostra. As características histológicas e de expressão de mRNAs e de proteínas foram comparadas entre os dois grupos. Resultados Em PNs eosinofílicos, observamos uma expressão significativamente maior dos mRNAs e proteínas GATA-3, IL-5, IL-4 e IL-13. Nos PNs não eosinofílicos, aumentou a expressão dos mRNAs e das proteínas IL-17, IL-23 e RORc. Nos testes imunoistoquímicos, observamos maior número de mastócitos e menor número de neutrófilos nos PNs eosinofílicos, em comparação com PNs não eosinofílicos. Os pacientes com PNs eosinofílicos obtiveram escores de sintomas mais graves vs. PNs não eosinofílicos. Conclusão Demonstramos, pela primeira vez, uma reação Th2 predominante em PNs eosinofílicos e uma reação Th17 predominante em PNs não eosinofílicos. Nosso estudo pode proporcionar novas estratégias terapêuticas para a rinossinusite crônica.