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Background: Neuromyelitis optica spectrum disorder (NMOSD) associated with cognitive impairment (CI) is acknowledged. However, the underlying pathogenesis and involvement of the immune system remain unclear., Objectives: This study aimed to investigate the alterations in immune cells, cytokines, and GABA + levels in NMOSD patients with cognitive deficits., Methods: Thirty-eight NMOSD patients and 38 healthy controls (HCs) were included. NMOSD patients were stratified as NMOSD-CI and NMOSD-CP groups. The difference in cognitive functions, Tfh and cytokines, and GABA + levels were assessed, and their correlations were calculated., Results: NMOSD-CI patients showed worse performance on all cognitive tests, and the percentage of circulating follicular helper T cells (cTfh) was significantly elevated. The frequency of cTfh was positively and negatively correlated with Stroop-A and AVLT long-delayed scores, respectively. IL-21 was remarkably higher in NMOSD-CI and NMOSD-CP. The level of GABA + in medial prefrontal cortex (mPFC) was significantly decreased in NMOSD-CI and was proved positively and negatively correlated with Symbol Digit Modalities Test and the frequency of circulating Tfh cells, respectively., Conclusion: In NMOSD-CI patients, all cognitive domains were impacted, , while GABA + levels in mPFC were decreased. GABA + levels in NMOSD-CI were negatively correlated with the frequency of cTfh, suggesting the underlying coupling mechanism between immune responses and neurotransmitter metabolism in CI in NMOSD patients., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Introduction: Follicular helper T-cell lymphomas (TFHL) have an aggressive course with a poor outcome. European and US guidelines recommend anthracycline-based chemotherapy as a first-line treatment, but the 5-year overall survival rate is still approximately 30%. We describe here the features of a cohort of TFHL patients who experienced prolonged survival despite the absence of specific treatment or the initiation of steroid-based therapy., Patients and Methods: In our study, we describe 15 adult patients who suffered from TFHL and had not received intensive chemotherapy at diagnosis for any reason. Biopsies of these cases were centrally reviewed, and the mutational pattern was determined using next-generation sequencing., Results: These 15 patients had the classic clinical, biological and pathological features of TFHL, angioimmunoblastic-type. TET2 mutations were found in 83% of patients; RHOA G17V, IDH2 R172 and DNMT3A mutations were found in 67%, 42% and 33% of the patients, respectively. Among the 15 patients, 8 did not receive any treatment, and 7 received steroid-based treatment. Ten patients had progression (5 in each group). Four patients died (3 of them from the progression of their lymphoma). The median follow-up in our cohort was 53 months. The 5-year OS was 66%, 100% for untreated patients and 29% for the others. In those 2 groups, the median time to treatment initiation was 22 months from diagnosis., Conclusion: We described a series of 15 well-characterized TFHL patients with an indolent outcome, suggesting that a watch-and-wait approach can be proposed in selected patients. Identifying factors predicting such evolution is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

With the emergence and success of checkpoint blockade immunotherapy, immuno-oncology has primarily focused on CD8 T cells, whose cytotoxic programs directly target tumor cells. However, the limited response rate of current immunotherapy regimens has prompted investigation into other types of tumor-infiltrating immune cells, such as CD4 T cells and B cells, and how they interact with CD8 T cells in a coordinated network. Recent studies have demonstrated the potential therapeutic benefits of CD4 T follicular helper (TFH) cells and B cells in cancer, highlighting the important role of their crosstalk and interactions with other immune cell components in the tumor microenvironment. These interactions also occur in tumor-associated tertiary lymphoid structures (TLS), which resemble secondary lymphoid organs (SLOs) with orchestrated vascular, chemokine, and cellular infrastructures that support the developmental pathways of functional immune cells. In this review, we discuss recent breakthroughs on TFH biology and T cell-B cell interactions in tumor immunology, and their potential as novel therapeutic targets to advance cancer treatment., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aims: Nodal T follicular helper (TFH) cell lymphoma (nTFHL) is a rare type of clinically aggressive T cell lymphoma. With this lymphoma type, Epstein-Barr virus (EBV) infection is frequently detected in non-neoplastic B lymphocytes, but not yet identified in neoplastic T cells. We report two cases of nTFHL showing a classic morphology and immunoprofile, with EBV-encoded small RNAs (EBER) in-situ hybridisation positivity in neoplastic TFH cells., Methods and Results: Clonal T cell receptor (TR) gene rearrangement was detected in both cases. Whole exome sequencing identified TET2, RHOA p. G17V, as well as gene mutations unique to each case. Microdissection analysis showed EBER positivity in tumour cells and in background non-neoplastic T lymphocytes., Conclusion: These two immunocompetent cases of nTFHL with EBV-positive tumour cells exhibit the featured gene mutation profile and poor prognosis of this disease. This novel finding of EBV positivity in our cases expands the currently recognised spectrum of EBV-positive nodal T cell lymphomas to include rare cases of nTFHL., (© 2023 John Wiley & Sons Ltd.)

A 76-year-old man presented with skin plaque and splenic nodules, and diffuse large B-cell lymphoma (DLBCL) with infiltration of T-cells was suspected based on the skin lesions. The disease showed indolent clinical behavior for three months, when systemic lymphadenopathy rapidly evolved. An inguinal lymph node biopsy revealed DLBCL with abundant infiltration of T follicular helper (TFH) cells. A polymerase chain reaction-based analysis of immunoglobulin variable heavy chain showed that the skin, splenic nodules, and inguinal lymph node shared the same clone. This case indicates that the dysregulated infiltration of TFH cells in the tumor microenvironment accelerates the lymphomagenesis and progression of DLBCL.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a high level of autoantibody production. T follicular helper (Tfh) cells and B cells participate in the development of SLE. Several studies have shown that CXCR3 + cells are increased in SLE patients. However, the mechanism through which CXCR3 influences lupus development remains unclear. In this study, we established lupus models to determine the role of CXCR3 in lupus pathogenesis. The concentration of autoantibodies was detected using the enzyme-linked immunosorbent assay (ELISA), and the percentages of Tfh cells and B cells were measured using flow cytometry. RNA sequencing (RNA-seq) was performed to detect the differentially expressed genes in CD4 + T cells from wild-type (WT) and CXCR3 knock-out (KO) lupus mice. Migration of CD4 + T cells in spleen section was assessed using immunofluorescence. CD4 + T cell function in helping B cells produce antibodies was determined using a co-culture experiment and supernatant IgG ELISA. Lupus mice were treated with a CXCR3 antagonist to confirm the therapeutic effects. We found that the expression of CXCR3 was increased in CD4 + T cells from lupus mice. CXCR3 deficiency reduced autoantibody production with decreased proportions of Tfh cells, germinal center (GC) B cells, and plasma cells. Expression of Tfh-related genes was downregulated in CD4 + T cells from CXCR3 KO lupus mice. Migration to B cell follicles and T-helper function of CD4 + T cells were reduced in CXCR3 KO lupus mice. CXCR3 antagonist AMG487 decreased the level of serum anti-dsDNA IgG in lupus mice. We clarify that CXCR3 may play an important role in autoantibody production by increasing the percentages of aberrant activated Tfh cells and B cells and promoting the migration and T-helper function of CD4 + T cells in lupus mice. Thus, CXCR3 may be a potential target for lupus therapy., Competing Interests: Conflict of interest The authors have declared that no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The study was designed to review the demographic, clinical, and pathologic characteristics of follicular helper T cells (TFH)-derived nodal PTCL in India including angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma (PTCL) with follicular helper T cell phenotype (P-TFH), and follicular T-cell lymphoma with additional immunohistochemistry (IHC) and RHOAG17V mutational analysis, as well as their impact on survival. This retrospective study included 88 cases of PTCL that were reclassified using IHC for TFH markers (PD1, ICOS, BCL6, and CD10) and dendritic-meshwork markers (CD21, CD23). Cases of TFH cell origin were evaluated for RHOAG17V mutation using Sanger sequencing and amplification-refractory mutation system-polymerase chain reaction (PCR) (validated using cloning and quantitative PCR) with detailed clinicopathologic correlation. Extensive re-evaluation with added IHC panel resulted in a total of 19 cases being reclassified, and the final subtypes were AITL (37 cases, 42%), PTCL-not otherwise specified (44, 50%), P-TFH (6, 7%), and follicular T-cell lymphoma (1, 1%). The presence of at least 2 TFH markers (>20% immunopositivity) determined the TFH origin. AITL patients tended to be male and showed increased presence of B-symptoms and hepatosplenomegaly. Histomorphology revealed that 92% of AITL cases had pattern 3 involvement. Sanger sequencing with conventional PCR did not yield any mutation, while RHOAG17V was detected by amplification-refractory mutation system-PCR in AITL (51%, P =0.027) and P-TFH (17%), which was validated with cloning followed by sequencing. Cases of RHOAG17V-mutant AITL had a worse Eastern Cooperative Oncology Group performance status initially but fared better in terms of overall outcome ( P =0.029). Although not specific for AITL, RHOAG17V mutation shows an association with diagnosis and requires sensitive methods for detection due to low-tumor burden. The mutant status of AITL could have prognostic implications and translational relevance., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T cell lymphoma that originates from T follicular helper (Tfh) cells and exhibits a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL, but their contribution to tumorigenesis is poorly understood. We developed an AITL mouse model that is driven by Idh2 and Tet2 mutations. Malignant Tfh cells display aberrant transcriptomic and epigenetic programs that impair TCR signaling. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered cross-talk with germinal center B cells that promotes B cell clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. The plasma cell count and angiogenesis are also increased in the Idh2-mutated tumors, implying a major relationship between Idh2 mutation and the characteristic AITL TME. Our mouse model recapitulates several features of human IDH2-mutated AITL and provides a rationale for exploring therapeutic targeting of Tfh-TME cross-talk for AITL patients., Competing Interests: Declaration of interests A.M. has consulted for Epizyme, Constellation, Daiichi Sankyo, AstraZeneca, BMS, Janssen, and ExoTherapeutics; has research funding from Epizyme, Janssen, Daiichi Sankyo, and AstraZeneca; and is on the advisory board of KDAC. C.E.M. is a cofounder and board member for Biotia and Onegevity Health as well as an advisor or grantee for Abbvie, ArcBio, Daiichi Sankyo, DNA Genotek, Tempus Labs, and Whole Biome. T.W.M. holds equity in Treadwell Therapeutics Inc. and Agios Pharmaceuticals and is a consultant for AstraZeneca and Tessa Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Whether naive CD4+ T cells are dysregulated and associated with the overactivation of CD4+ T cells in primary SS (pSS) remains unclear. We aimed to explore the role and underlying mechanism of naive CD4+ T cells in pSS., Methods: We examined the activation, proliferation and differentiation of naive CD4+ T cells from pSS patients and healthy controls. Differentially expressed genes were identified using RNA sequencing, and were overexpressed or silenced to determine the gene regulating follicular helper T (Tfh) cells. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) with chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) was performed to explore the epigenetic mechanism. Naive CD4+ T cells were treated with pSS-related cytokines to explore the upstream signalling pathway., Results: pSS naive CD4+ T cells had higher potentials of activation, proliferation and differentiation towards Tfh cells. Thymocyte selection-associated high mobility group box protein (TOX) was upregulated in pSS naive CD4+ T cells and promoted T cell activation and Tfh cell polarization. TOX silencing in pSS naive CD4+ T cells downregulated B cell lymphoma 6 (BCL6) expression and altered levels of multiple Tfh-associated genes. ChIP-seq analysis implied that TOX bound to the BCL6 locus, where there were accessible regions found by ATAC-seq. IFN-α induced TOX overexpression, which was attenuated by Janus kinase (JAK) and signal transducer and activator of transcription 1 (STAT1) inhibitors., Conclusion: Our data suggest that TOX in pSS naive CD4+ T cells is upregulated, which facilitates Tfh cell differentiation. Mechanistically, IFN-α induces TOX overexpression in naive CD4+ T cells through JAK-STAT1 signalling and TOX regulates BCL6 expression. Therefore, IFN-α-JAK-STAT1 signalling and TOX might be potential therapeutic targets in pSS., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that plays an essential role in immune system development and autoimmune diseases. This study aimed to characterize the role of EZH2 in the pathogenesis of primary Sjögren's syndrome (pSS)., Methods: We analyzed EZH2 expression in two transcriptomic datasets of peripheral blood mononuclear cells (PBMCs) from pSS patients and healthy controls. We measured EZH2 expression in CD4 + T cells, CD8 + T cells, and CD19 + B cells from pSS patients and healthy controls and correlated EZH2 expression with clinical parameters. We also examined the activation, proliferation, and T-cell differentiation of CD4 + T cells using the EZH2 inhibitor GSK126, EZH2 siRNA, and EZH2-expressing vector. We further examined the STAT3 signaling pathway after EZH2 inhibition and detected Tfh differentiation in EZH2-overexpressed CD4 + T cells with STAT3 knocked down., Results: EZH2 was upregulated in GSE164885 and GSE48378. EZH2 expression was higher in pSS CD4 + and CD8+ T cells, and EZH2 expression in circulating pSS CD4 + T cells was positively correlated with IgG, IgA, ESR, RF, and the circulating Tfh population. EZH2 inhibition and silencing EZH2 suppressed activation, proliferation, and Tfh differentiation. Furthermore, overexpressing EZH2 promoted activation, proliferation, and Tfh differentiation in CD4 + T cells. EZH2 inhibition attenuated STAT3 phosphorylation in CD4 + T cells. STAT3 knockdown abrogated EZH2-promoted Tfh differentiation., Conclusions: EZH2 expression was abnormally elevated in pSS CD4 + T cells, which facilitated Tfh differentiation of CD4 + T cells by enhancing STAT3 phosphorylation. EZH2 promotes Tfh differentiation and might be implicated in pSS pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 He, Yang, Chen, Liu, Lyu, Zeng, Wang, Li, Wang, Chen and Zhang.)

Aims: Angioimmunoblastic T-cell lymphoma (AITL) is genetically characterized by TET2 and DNMT3A mutations occurring in haematopoietic progenitor cells, and late events (e.g. the RHOA-G17V mutation) associated with malignant transformation. As TET2/DNMT3A-mutated progenitor cells can differentiate into multilineage progenies and give rise to both AITL and myeloid neoplasms, they may also have the potential to lead to other metachronous/synchronous neoplasms. We report two cases showing parallel evolution of two distinct potentially neoplastic lymphoid proliferations from a common mutated haematopoietic progenitor cell population., Methods and Results: Both cases presented with generalized lymphadenopathy. In case 1 (a 67-year-old female), an initial lymph node (LN) biopsy was dismissed as reactive, but a repeat biopsy showed a nodal marginal zone lymphoma (NMZL)-like proliferation with an increase in the number of T-follicular helper (TFH) cells. Immunohistochemistry, and clonality and mutational analyses by targeted sequencing of both whole tissue sections and microdissected NMZL-like lesions, demonstrated a clonal B-cell proliferation that harboured the BRAF-G469R mutation and shared TET2 and DNMT3A mutations with an underlying RHOA-G17V-mutant TFH proliferation. Review of the original LN biopsy showed histological and immunophenotypic features of AITL. In case 2 (a 66-year-old male), cytotoxic T-cell lymphoma with an increase in the number of Epstein-Barr virus-positive large B cells was diagnosed on initial biopsy. On review together with the relapsed biopsy, we identified an additional occult neoplastic TFH proliferation/smouldering AITL. Both T-cell proliferations shared TET2 and DNMT3A mutations while RHOA-G17V was confined to the smouldering AITL., Conclusions: In addition to demonstrating diagnostic challenges, these cases expand the potential of clonal haematopoiesis in the development of different lineage neoplastic proliferations., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Although many germinal centers (GCs) have been reported in immunoglobulin (Ig) G4-related disease, the significance of GCs in IgG4-related disease has not received attention. Both T follicular regulatory cells (Tfr), which are regulatory T cells (Treg) in GCs, and T follicular helper cells (Tfh) produce the cytokine interleukin (IL)-10 and regulate GC development. In whole-slide image analysis in surgical specimens using immunohistochemistry, IgG4-related sclerosing sialadenitis (IgG4-SS, n = 17) was characterized by markedly numerous, large, and irregular-shaped GCs with increased IL-10 + cells and Tfr and Tfh in the total area of the salivary gland compared with controls, including patients with chronic sialadenitis (n = 17) and Sjögren syndrome (n = 15). In particular, the central area of GC in IgG4-SS showed a higher Tfr number and Tfr/Tfh ratio than controls. The number of Tfr in the central area was significantly correlated with the number of IgG4 + plasmacytes and the number, size, and irregularity of GCs. In the mantle area, which surrounds GCs, IgG4-SS showed a higher Treg number and Treg/T helper cells (Th) ratio than controls. In IgG4-SS, the Treg/Th ratio was highest in the mantle area outside GCs and the Tfr/Tfh ratio was highest in the central area inside GCs. However, in controls, the Treg/Th ratio gradually decreased from outside to inside GCs. Our findings reveal that the morphological abnormality of GCs and the characteristic localization and altered balance of Treg and Th in the different compartments of inside and outside GCs would be the novel hallmarks of IgG4-SS., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Thymoma is the most common primary mass in anterior mediastinum. Although associated with low malignancy, it is often accompanied by myasthenia gravis resulting in poor prognosis. Due to the dual factors of tumor immune tolerance and autoimmune reaction, it is urgent to understand the immune status of MG with thymoma. In this study, RNA sequencing data were obtained from the TCGA and GEO cohorts to identify differentially expressed messenger RNAs and infiltrated immune cells. A total of 121 samples in TCGA and 43 samples in GEO were screened out. The infiltrated immune cells were identified by CIBERSORT, in which Tfh cells and activated DC cells were abnormal in thymoma patients. The differently expressed genes were performed by package LIMMA. The functional characteristics of differently expression genes were analyzed by GO and KEGG; one GO and seven KEGG pathways were both found in both TCGA and GEO cohorts. Meanwhile, 27 common differently expressed genes were obtained and were displayed by a Venn diagram. The TRRUST was used to screen the hub genes for the common 27 different genes and 6 genes were found. Then, PPI networks were constructed. Subsequently, the relationship between SCNAs of common genes and related immune cells tested by TIMER. Kaplan-Meier plots, ROC curve and Cox's expression model for immune infiltration and hub genes were also tested. In conclusion, we found that two types of immune infiltrated cells and six hub genes can predict the occurrence of myasthenia gravis in thymoma patients.

Objectives: Follicular helper T cell (TFH) markers are expressed in angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma of the TFH phenotype (PTCL-TFH). However, differential expression and coexpression of these markers in benign and other malignant lymphoid proliferations have not been well studied., Methods: We performed programmed death-1 (PD-1), C-X-C motif chemokine ligand 13 (CXCL13), inducible costimulator (ICOS), CD10, and B-cell lymphoma 6 protein (BCL-6) immunohistochemistry on AITL, PTCL not otherwise specified (PTCL-NOS), PTCL-TFH, T-cell or histiocyte-rich large B-cell lymphoma (THRLBCL), classic Hodgkin lymphoma (CHL), atypical paracortical hyperplasia (PCH), progressive transformation of germinal centers (PTGC), and reactive follicular hyperplasia (RFH)., Results: CXCL13 and ICOS were more sensitive but less specific for AITL than PD-1, CD10, and BCL-6. Moreover, 74% of AITL (none of PTCL-NOS or PTCL-TFH) coexpressed more than 2 TFH markers. In background T cells of THRLBCL, 70% of cases coexpressed more than 1 marker. The background T cells of CHL expressed all TFH markers except CD10 in all cases. In addition, 13% of PCH cases coexpressed more than 1 marker. In RFH and PTGC, all markers were expressed mainly in germinal centers with rare extrafollicular staining., Conclusions: AITL, PTCL-NOS, and PTCL-TFH show differential expression of TFH markers. AITL frequently coexpresses more than 2 TFH markers. TFH markers can be expressed in PCH and in background T cells of THRLBCL and CHL. Consequently, caution should be used before a diagnosis of AITL is established, particularly with limited samples., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Follicular helper T-cell-derived peripheral T-cell lymphoma (TFH-derived PTCL) initially present in the Waldeyer's ring is a rare condition with a challenging diagnosis. This study aimed to evaluate the clinicopathological characteristics and diagnosis of Waldeyer's ring TFH-derived PTCL and raise awareness of this type of lymphoma. A series of 13 cases of Waldeyer's ring TFH-derived PTCL were retrospectively analyzed. Clinically, most patients presented with localized manifestations, such as painless cervical lymphadenopathy (7/13), pharyngalgia (6/13), and nasal obstruction (3/13), and systemic symptoms were uncommon. Macroscopically, plump mass (9/13) and nodular lesions (3/13) covered with intact and tense mucosa were the main findings on fiberoptic laryngoscopy examination. Pathologically, diffuse infiltration with atypical lymphocytes in the lamina propria (10/13) was the most common growth pattern. Clear cells (9/13) and vascular proliferation (11/13) within a polymorphic inflammatory background (11/13) were frequently observed. All cases expressed at least two TFH markers: PD-1 in 92.3% (12/13), BCL6 in 69.2% (9/13), CXCL13 in 53.8% (7/13), and CD10 in 46% (6/13). Targeted next-generation sequencing analysis identified frequent mutations, including TET2 (10/11), RHOA (6/11), DNMT3A (3/11), and IDH2 (2/11). The overall survival rate at 2 years was 35.5%, and survival analysis revealed that patients with localized disease showed better overall survival (P = 0.022). In conclusion, careful morphological observation combined with immunohistochemistry and molecular analysis would help in diagnosis of TFH-derived PTCL involving the Waldeyer's ring, which is a rare condition that frequently presents with atypical clinical manifestations., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

During pregnancy, humoural immunity is essential for protection against many extracellular pathogens; however, autoimmune diseases may be induced or aggravated. T follicular helper (Tfh) cells contribute to humoural immunity. The aim of this study was to test whether Tfh cell function can be manipulated via hormones. Seventy-four women who underwent in vitro fertilization were recruited and divided into four groups: menstrual period (MP), controlled ovarian hyperstimulation (COH), embryo transfer (ET) and pregnant after embryo transfer (P). A flow cytometry analysis was performed to identify Tfh cells in peripheral blood mononuclear cells (PBMCs). Bioinformatics analysis revealed a possible pathway between Tfh and B cells. Enzyme-linked immunosorbent assays were used to detect interleukin (IL)-21 and IL-6. The quantitative polymerase chain reaction was performed to quantify BCL-6, BACH2, XBP-1, IRF-4 and G protein-coupled (GP)ER-1 mRNA expression. Compared with the MP group, the COH, ET and P groups showed more Tfh and B cells, as well as higher IL-21, IL-6, BCL-6 and BACH2 expression. Furthermore, Tfh cell frequency in PBMCs, as well as serum IL-21 and IL-6 levels, were all positively correlated with serum estradiol (E 2 ) levels; the B cell percentage also correlated positively with Tfh cells in PBMCs. Combined with the bioinformatics analysis, XBP-1, IRF-4 and GPER-1 expression was related to E 2 levels, both in vivo and in vitro. We speculate that E 2 augments Tfh cells and favours humoural immunity. This study indicates that Tfh cell regulation may be a novel target in maintaining the maternal-foetal immune balance., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Studies have recently shown that RHOA mutations play a crucial role in angioimmunoblastic T-cell lymphoma (AITL) pathogenesis. We aimed to pool data from these studies to provide a comparison of clinicopathological features between the RHOA mutant and RHOA wild-type groups in the AITL population., Methods: We searched PubMed and Web of Science for the keywords "RHOA AND lymphoma" and selected only studies reporting the clinical significance of RHOA mutations in AITL. We calculated the odds ratios (OR) or the mean difference with 95% CI using a random effect model., Results: Our pooled results showed a significant association between RHOA mutations and a T-follicular helper cell (TFH) phenotype, especially CD10 (OR, 5.16; 95% CI, 2.32-11.46), IDH2 mutations (OR, 10.70; 95% CI, 4.22-27.15), and TET2 mutations (OR, 7.03; 95% CI, 2.14-23.12). Although DNMT3A together with TET2 and IDH2 mutations are epigenetic gene alterations, we found an insignificant association between RHOA and DNMT3A mutations (OR, 1.72; 95% CI, 0.73-4.05). No significant associations of RHOA mutations with other clinicopathological features and overall survival were found., Conclusions: RHOA mutations are strongly correlated with a T-follicular helper cell phenotype and epigenetic mutations such as TET2 and IDH2. Further studies with large AITL samples should be conducted to validate the relationship of TET2, DNMT3A, and RHOA co-mutations., (Copyright © 2021. Published by Elsevier Inc.)

Objective: SSc is a connective tissue disease with multisystem disorder induced by the inflammation and fibrosis following T and B cell abnormalities. Follicular helper CD4+ T (TFH) cells play a crucial role in the formation of germinal centres and specialize in interacting to aid B cell differentiation. We aimed to investigate TFH cells and their subsets to evaluate their involvement with B cell alteration in SSc., Method: Circulating TFH cells (cTFH), B cells and their subsets were assessed by flow cytometry. The concentration of serum cytokines was measured by cytokine array assay. Immunohistochemistry and IF were performed to evaluate the migration of TFH cells in SSc skin lesions., Results: The proportion of cTFH cells did not differ from controls, but their subsets were imbalanced in SSc patients. The frequency of TFH 1 was increased and correlated with ACA titre, serum IgM or CRP levels of patients, and cytokine concentrations of IL-21 and IL-6 that induce B cell differentiation in SSc. cTFH cells from SSc showed activated phenotype with expressing higher cytokine levels compared with controls. The frequency of TFH 17 was also increased, but was not correlated with a high level of Th17 cytokines in patients' sera. Furthermore, infiltration of TFH cells was found in skin lesion of SSc patients., Conclusion: We here describe an imbalance of cTFH toward TFH 1 that may induce B cell alteration through IL-21 and IL-6 pathways and promote inflammation, contributing to the pathogenesis of SSc disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Transcription factor B cell lymphoma 6 (BCL6) is a master regulator of T follicular helper (Tfh) cells, which play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanisms by which BCL6 expression is regulated are poorly understood. Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important epigenetic factor that regulates DNA methylation and histone modifications. In the present study, we assessed whether UHRF1 can regulate BCL6 expression and influence the differentiation and proliferation of Tfh cells., Results: Compared to healthy controls, the mean fluorescence intensity of UHRF1 (UHRF1-MFI) in Tfh cells from SLE patients was significantly downregulated, whereas that of BCL6 (BCL6-MFI) was significantly upregulated. In vitro, UHRF1 knockdown led to BCL6 overexpression and promoted Tfh cell differentiation. In contrast, UHRF1 overexpression led to BCL6 downregulation and decreased Tfh cell differentiation. In vivo, conditional UHRF1 gene knockout (UHRF1-cKO) in mouse T cells revealed that UHRF1 depletion can enhance the proportion of Tfh cells and induce an augmented GC reaction in mice treated with NP-keyhole limpet hemocyanin (NP-KLH). Mechanistically, UHRF1 downregulation can decrease DNA methylation and H3K27 trimethylation (H3K27me3) levels in the BCL6 promoter region of Tfh cells., Conclusions: Our results demonstrated that UHRF1 downregulation leads to increased BCL6 expression by decreasing DNA methylation and H3K27me3 levels, promoting Tfh cell differentiation in vitro and in vivo. This finding reveals the role of UHRF1 in regulating Tfh cell differentiation and provides a potential target for SLE therapy.

Adenosine deaminase 2 deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function of ADA2 gene, coding for a protein known to regulate the catabolism of extracellular adenosine. We therefore investigated immune phenotype and B- and T-cell responses in 14 DADA2 patients to address if ADA2 mutation affects B- and T-cell function. Here, we show a significant decrease in memory B cells, in particular class switch memory, and an expansion of CD21 low B cells in DADA2 patients. In vitro stimulated B lymphocytes were able to secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect resulting in an impairment of B-cell proliferation and differentiation. Moreover, CD4 + and CD8 + T cells were diminished; however, the frequency of circulating T follicular helper cells was significantly increased but they had an impairment in IL-21 production possibly contributing to an impaired B cell help. Our findings suggest that ADA2 mutation could lead to a B-cell intrinsic defect but also to a defective Tfh cell function, which could contribute to the immunodeficient phenotype reported in DADA2 patients., (© 2020 Wiley-VCH GmbH.)

T follicular helper (TFH) cells are recognized as a subtype of T cells that are involved in the germinal center formation and B cell development. When dysregulated, TFH cells may represent an important mechanism that contributes to a heightened humoral response and autoantibody production in autoimmune liver diseases (AILDs). TFH cells participate in the immune response associated with AILDs by expressing surface receptors such as programmed cell death protein-1, C-X-C motif chemokine receptor 5, and inducible T cell costimulators, as well as cytokines such as interleukin-21. TFH cells also downregulate chemokine (C-C motif) receptor 7 and promote the dysregulation of the T follicular regulatory/TFH axis. This review highlights the importance of TFH cells in AILDs., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Lin Li et al.)

Background: Peri-implantitis is an inflammation that occurs around the implant, resulting in varying degrees of inflammatory damage to the soft and hard tissues. The characteristic criterion is the loss of the supporting bone in an inflammatory environment. However, the specific mechanisms and biomarkers involved in peri-implantitis remain to be further studied. Recently, competing endogenous RNAs (ceRNA) and immune microenvironment have been found to play a more important role in the inflammatory process. In our study, we analyzed the expression of immune related microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and message RNAs (mRNAs) in peri-implantitis by analyzing GSE33774 and GSE57631., Methods: In this study, we explored the expression profile data of immune-related lncRNAs, miRNAs and mRNAs, and constructed immune-related ceRNA network involved in the pathogenesis of peri-implantitis. In addition, the CIBERSORT was used to evaluate the content of immune cells in normal tissues and peri-implantitis to detect the immune microenvironment of peri-implantitis., Results: In the analysis, 14 DElncRNAs, 16 DEmiRNAs, and 18 DEmRNAs were used to establish an immune related ceRNA network and the immune infiltration patterns associated with peri-implantitis was discovered. Through the mutual verification of the two datasets, we found that GSK3B and miR-1297 may have important significance in the immune microenvironment and pathogenesis of peri-implantitis and GSK3B was closely related to four types of immune cells, especially with the highest correlation with resting mast cells (P = 0.0003)., Conclusions: Through immune-related ceRNA network, immune-related genes (IRGs) and immune cell infiltration can further comprehensively understand the pathogenesis of peri-implantitis, which built up an immunogenomic landscape with clinical significance for peri-implantitis.

Lymphomatoid papulosis (LyP) is a benign skin condition that typically presents with grouped or scattered lesions on the body that self-resolve within weeks or months of onset. LyP belongs to the group of CD30-positive lymphoproliferative disorders. Several histological variants of LyP exist, and the histological features of LyP can overlap with other lymphoproliferative disorders; therefore, both histological and clinical correlations are needed for a proper diagnosis of LyP. We report an unusual case of LyP displaying a T follicular helper cell-like phenotype and histopathologically resembling the primary cutaneous CD4-positive small-sized to medium-sized T-cell lymphoproliferative disorder.

Inducible co-stimulator-positive (ICOS) and programmed cell death 1-positive (PD-1) are important markers for follicular helper T cells (Tfh); however, their roles and clinical values in ulcerative colitis (UC) remain unknown. In this study, we recruited 68 UC patients and 34 healthy controls. Circulating ICOS + , PD-1 + and ICOS + PD-1 + Tfh subsets were analyzed by flow cytometry. Twelve active UC patients achieving remission after treatment with 5-aminosalicylic acid were followed-up and Tfh subset changes were analyzed. Serum immunoglobulin (Ig)G, C-reactive protein (CRP), interleukin (IL)-4 and IL-21 levels and B cell subsets were analyzed and Mayo scores were calculated. Correlation analyses were performed between Tfh subsets and the clinical indicators. Receiver operating characteristic (ROC) curves were generated to evaluate the efficiency of Tfh subsets for disease monitoring. We found that levels of ICOS + , PD-1 + and ICOS + PD-1 + Tfh cells were significantly increased in active UC and significantly decreased when achieving clinical remission. Activated ICOS + PD-1 + Tfh cells were positively correlated with serum CRP and Mayo scores. Furthermore, ICOS + PD-1 + Tfh cells were significantly correlated with circulating new memory B cells and plasmablasts, as well as serum IgG, IL-4 and IL-21. ROC analyses showed that when ICOS + PD-1 + Tfh cells were used in combination with PD-1 + Tfh cells, the diagnostic efficacy in distinguishing active UC from stable remission patients was higher than that of any one used alone, with area under curve (AUC) value 0·931. Our findings suggest that increased ICOS + PD-1 + Tfh cells are associated with the activation of B cells in the pathogenesis of UC, and may be a potential biomarker for UC disease monitoring., (© 2020 British Society for Immunology.)

T follicular helper (Tfh) cell migration into germinal centers (GCs) is essential for the generation of GC B cells and antibody responses to T cell-dependent (TD) antigens. This process requires interactions between lymphocyte function-associated antigen 1 (LFA-1) on Tfh cells and ICAMs on B cells. The mechanisms underlying defective antibody responses to TD antigens in DOCK8 deficiency are incompletely understood. We show that mice selectively lacking DOCK8 in T cells had impaired IgG antibody responses to TD antigens, decreased GC size, and reduced numbers of GC B cells. However, they developed normal numbers of Tfh cells with intact capacity for driving B cell differentiation into a GC phenotype in vitro. Notably, migration of DOCK8-deficient T cells into GCs was defective. Following T cell receptor (TCR)/CD3 ligation, DOCK8-deficient T cells had impaired LFA-1 activation and reduced binding to ICAM-1. Our results therefore indicate that DOCK8 is important for LFA-1-dependent positioning of Tfh cells in GCs, and thereby the generation of GC B cells and IgG antibody responses to TD antigen.

Myocarditis is an inflammatory disease of the myocardium that is associated with immune dysfunction. Earlier studies have suggested that T helper 1/2 cell imbalance plays an important role in the development of myocarditis, but the role of T follicular helper (Tfh) cells in the development of autoimmune myocarditis has not previously been reported. Here, we investigated this involvement by using a rat model of experimental autoimmune myocarditis (EAM). Inflammatory cell infiltration, myocardial structure destruction and tissue necrosis were observed in EAM myocardial tissues, and the percentages of CD4 + CXCR5 + Tfh cells and CD19 + B cells were both significantly higher in spleen and myocardial tissues of the EAM model as compared with the control group. Furthermore, the expression levels of interleukin-21, CXCL13 and myosin antibody were significantly higher in the serum of rats with EAM compared with the control group on days 14 and 35 after immunization. Fourteen or 35 days after immunization, the expression levels of interleukin-21 and CXCL13 were both significantly higher in myocardial tissues of rats with EAM as compared with the control group. Our findings suggest that Tfh cell balance is disrupted during the pathological process of autoimmune myocarditis., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

A growing body of evidence has indicated that behaviors of cancers are defined by not only intrinsic activities of tumor cells but also tumor-infiltrating immune cells (TIICs) in the tumor microenvironment. However, it still lacks a well-structured and comprehensive analysis of TIICs and its therapeutic value in esophageal cancer (EC). The proportions of 22 TIICs were evaluated between 150 normal tissues and 141 tumor tissues of EC by the CIBERSORT algorithm. Besides, correlation analyses between proportions of TIICs and clinicopathological characters, including age, gender, histologic grade, tumor location, histologic type, LRP1B mutation, TP53 mutation, tumor stage, lymph node stage, and TNM stage, were conducted. We constructed a risk score model to improve prognostic capacity with 5 TIICs by least absolute shrinkage and selection operator (lasso) regression analysis. The risk score = -1.86∗plasma + 2.56∗T cell follicular helper - 1.37∗monocytes - 3.64∗activated dendritic cells - 2.24∗resting mast cells (immune cells in the risk model mean the proportions of immune cell infiltration in EC). Patients in the high-risk group had significantly worse overall survival than these in the low-risk group (HR: 2.146, 95% CI: 1.243-3.705, p = 0.0061). Finally, we identified Semustine and Sirolimus as two candidate compounds for the treatment of EC based on CMap analysis. In conclusion, the proportions of TIICs may be important to the progression, prognosis, and treatment of EC., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Guangrong Lu et al.)