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1.
Arthritis Res Ther ; 26(1): 159, 2024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39261963

RESUMEN

BACKGROUND: Systemic lupus erythematosus (SLE) is the quintessential autoimmune disease, as it is characterized by hyperactivity of CD4+ T cells and subsequently drives lupus pathology. Follicular helper T (TFH) cells play an important role in B cell maturation and antibody production. However, which specific subset of cTFH cells drives B cell function and contributes to the development of anti-dsDNA antibodies and SLE pathogenesis remains unclear. METHODS: Peripheral blood mononuclear cells from SLE patients with inactive (n = 11) and active (n = 21) were used to determine and detect frequencies and phenotypes of circulating TFH cells (cTFH), memory cTFH, and B cell subsets. The correlations among cTFH cell subsets and phenotypes, B cell subsets, anti-dsDNA autoantibodies, and clinical parameters were analyzed. RESULTS: In subjects with active SLE, cTFH1 and cTFH17 cells were significantly expanded and activated. These expanded cTFH cells expressed memory phenotypes; cTFH1 cells were predominantly central memory (CM) type, while cTFH17 cells were largely effector memory (EM) type. Phenotyping B cell subsets in these patients showed increased frequencies of aNAV and DN2 B cells. Clinically, ICOS+ cTFH1, ICOS+ cTFH17 cells, and SLEDAI-2k scores were found to be correlated. Analysis of cTFH-B cell relationship revealed positive correlations among ICOS+ cTFH1 cells, aNAV B cells, and anti-dsDNA antibodies. Activation of ICOS+ cTFH17 cells was significantly related to the expansion of aNAV and DN2 B cells. The presence of CM cells in cTFH1 and cTFH17 subsets was correlated with aNAV and DN2 B cell frequencies. CONCLUSION: SLE cTFH cells were found to be polarized toward cTFH1 and cTFH17 cells; activation of these cTFH subsets was significantly associated with disease activity score, aNAV, DN2 B cell expansion, and anti-dsDNA antibody level. Thus, the interactions among cTFH1, cTFH17, and B cells likely contribute to the development of autoantibodies and the pathogenesis in SLE.


Asunto(s)
Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/sangre , Femenino , Adulto , Masculino , Persona de Mediana Edad , Linfocitos B/inmunología , Activación de Linfocitos/inmunología , Células T Auxiliares Foliculares/inmunología , Células Th17/inmunología , Adulto Joven , Anticuerpos Antinucleares/inmunología , Anticuerpos Antinucleares/sangre
2.
Heliyon ; 10(14): e34364, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39108902

RESUMEN

Patients with thymoma (THYM)-associated myasthenia gravis (MG) typically have a poor prognosis and recurring illness. This study aimed to discover important biomarkers associated with immune cell infiltration and THYM-associated MG (THYM-MG) development. Gene expression microarray data were downloaded from The Cancer Genome Atlas website (TCGA) and Gene Expression Omnibus (GEO). A total of 102 differentially expressed genes were investigated. According to the immune infiltration data, the distribution of Tfh cells, B cells, and CD4 T cells differed significantly between the THYM-MG and THYM-NMG groups. WGCNA derived 25 coexpression modules; one hub module (the blue module) strongly correlated with Tfh cells. Combining differential genes revealed 21 intersecting genes. LASSO analysis subsequently revealed 16 hub genes as potential THYM-MG biomarkers. ROC curve analysis of the predictive model revealed moderate diagnostic value. The association between the 16 hub genes and infiltrating immune cells was further evaluated in TIMER2.0 and the validation dataset. Draggability analysis identified the therapeutic target genes PTGS2 and ALB, along with significant drugs including Firocoxib, Alclofenac, Pyridostigmine, and Stavudine. This was validated through MD simulation, PCA, and MM-GBSA analyses. The interaction between numerous activated B cells and follicular helper T cells is closely associated with THYM-MG pathogenesis from a bioinformatics perspective. Hub genes (including SP6, SCUBE3, B3GNT7, and MAGEL2) may be downregulated in immune cells in THYM-MG and associated with progression.

3.
Zhongguo Fei Ai Za Zhi ; 27(7): 550-558, 2024 Jul 20.
Artículo en Chino | MEDLINE | ID: mdl-39147710

RESUMEN

Non-small cell lung cancer (NSCLC) is a prevalent and aggressive global malignancy. Conventional surgical treatments, radiotherapy, chemotherapy, and targeted therapies often fall short in halting disease progression due to inherent limitations, resulting in suboptimal prognosis. Despite the advent of immunotherapy drugs offering new hope for NSCLC treatment, current efficacy remains insufficient to meet all patient needs. Therefore, actively exploring novel immunotherapeutic approaches to further reduce mortality rates in NSCLC patients has become a crucial focus of NSCLC research. This article aims to systematically review the anti-tumor effects of interleukin-21 and follicular helper T cells in NSCLC immunotherapy by summarizing and analyzing relevant literatures from both domestic and international sources, as well as exploring the potential for enhancing NSCLC treatment prospects through immune checkpoint regulation via immunotherapeutic means.
.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Interleucinas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Interleucinas/inmunología , Interleucinas/uso terapéutico , Inmunoterapia/métodos , Animales
5.
Biochim Biophys Acta Mol Basis Dis ; 1870(7): 167346, 2024 10.
Artículo en Inglés | MEDLINE | ID: mdl-38986820

RESUMEN

PDAC is a typical "cold tumor" characterized by low immune cell infiltration and a suppressive immune microenvironment. We previously observed the existence of a rare group of follicular helper T cells (Tfh) that could enhance antitumor immune responses by recruiting other immune cells in PDAC. In this study, we ectopically expressed BCL6 in CD4+ T cells, and successfully induced Tfh-like transdifferentiation in vitro. This strategy provided abundant Tfh-like cells (iTfhs) that can recruit CD8+ T cells like endogenous Tfhs. Subsequently, Chimeric Antigen Receptors (CARs) against both MSL (Mesothelin) and EPHA2 (Ephrin receptor A2) were used to modify iTfh cells, and the CAR-iTfh cells significantly improved infiltration and antitumor cytotoxicity of co-cultured CD8+ T cells. After that, combinatory administration of CAR-iTfh & CAR-CD8 T cell therapy displayed a better effect in repressing the PDAC tumors in xenograft mouse models, compared to conventional CAR-CD4 & CAR-CD8 combinations, and the models received the CAR-iTfh & CAR-CD8 T cells displayed a significantly improved survival rate. Our study revealed the plasticity of Thelper differentiation, expanded the source of Tfh-like cells for cell therapy, and demonstrated a novel and potentially more efficient cellular composition for CAR-T therapy.


Asunto(s)
Transdiferenciación Celular , Inmunoterapia Adoptiva , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas c-bcl-6 , Receptores Quiméricos de Antígenos , Animales , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Ratones , Inmunoterapia Adoptiva/métodos , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Transdiferenciación Celular/inmunología , Linfocitos T CD4-Positivos/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Microambiente Tumoral/inmunología , Receptor EphA2/inmunología , Receptor EphA2/genética , Linfocitos T Colaboradores-Inductores/inmunología , Femenino
6.
Arch Pharm Res ; 47(7): 632-644, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38977652

RESUMEN

Systemic lupus erythematosus (SLE) is a common autoimmune disease, and its pathogenesis mainly involves the aberrant activation of B cells through follicular helper T (Tfh) cells to produce pathogenic antibodies, which requires more effective and safe treatment methods. Dihydroartemisinin (DHA) is the main active ingredient of artemisinin and has immunosuppressive effects. In this study, in vitro experiments confirmed that DHA inhibited Tfh cell induction and weakened its auxiliary function in B cell differentiation; furthermore, DHA directly inhibited B cell activation, differentiation, and antibody production. Furthermore, a mouse model of SLE was established, and we confirmed that DHA significantly reduced the symptoms of SLE and lupus nephritis, and decreased serum immunoglobulin (Ig)G, IgM, IgA, and anti-dsDNA levels. Moreover, DHA reduced the frequencies of total Tfh cells, activated Tfh cells, and B cell lymphoma 6, and interleukin (IL)-21 levels in Tfh cells from the spleen and lymph nodes, as well as the levels of B cells, germinal center B cells, and plasma cells in the spleen, lymph nodes, and kidneys. Additionally, DHA inhibited Tfh cells by blocking IL-2-inducible T cell kinase (ITK) signaling and its downstream nuclear factor (NF)-κB, nuclear factor of activated T cell, and activating protein-1 pathways, and directly inhibited B cells by blocking Bruton's tyrosine kinase (BTK) signaling and the downstream NF-κB and Myc pathways. Overall, our results demonstrated that DHA inhibited Tfh cells by blocking ITK signaling and also directly inhibited B cells by blocking BTK signaling. Therefore, reducing the production of pathogenic antibodies might effectively treat SLE.


Asunto(s)
Artemisininas , Linfocitos B , Lupus Eritematoso Sistémico , Artemisininas/farmacología , Animales , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Ratones , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Femenino , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/efectos de los fármacos , Células T Auxiliares Foliculares/metabolismo , Modelos Animales de Enfermedad , Diferenciación Celular/efectos de los fármacos
7.
Dermatopathology (Basel) ; 11(3): 218-229, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39051325

RESUMEN

IgG4-RD is a multisystem fibroinflammatory disease characterized by the infiltration of tissues by IgG4 plasma cells. Combined skin and biliary tract involvement in IgG4-RD has not been described. We present perhaps the most comprehensive analysis of lymphocyte subsets in the first case of IgG4-related generalized skin rash and first case of combined skin and biliary tract manifestations. A 55-year-old male presented with painful jaundice and generalized macular pigmented pruritic eruptions, and CT abdomen revealed biliary obstruction. Ampulla and skin biopsies were subjected to histology and immunostaining. Naïve, central memory (TCM), effector memory (TEM), terminally differentiated effector memory (TEMRA) subsets of CD4+ and CD8+ T cells, T follicular helper subsets, naïve, transitional, marginal zone (MZ), germinal center (GC), IgM memory, and class-switched memory (CSM) B cells, and T follicular regulatory, regulatory B cells, CD4 Treg, and CD8 Treg were analyzed. Serum IgG4 was elevated at 448 mg/dL. Ampula biopsy showed lamina propria fibrosis and increased IgG4-positive plasma cells. Skin punch biopsy showed lymphoplasmacytic infiltrates with a 67% ratio of IgG4+:IgG+ plasma cells. CD4+TN and CD4+TCM decreased, whereas CD4+TEM increased. Naïve B cells increased; transitional, MZ, CSM, GC B cells, and plasmablasts decreased compared to control. CD4 Treg increased, whereas CD8 Treg and Breg decreased. In conclusion, IgG-RD may present with combined biliary tract and generalized dermatological manifestations. Changes in regulatory lymphocytes suggest their role in the pathogenesis of IgG4-RD.

8.
medRxiv ; 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-39006439

RESUMEN

Leveraging endogenous tumor-resident T-cells for immunotherapy using bispecific antibodies (BsAb) targeting CD20 and CD3 has emerged as a promising therapeutic strategy for patients with B-cell non-Hodgkin lymphomas. However, features associated with treatment response or resistance are unknown. To this end, we analyzed data from patients treated with epcoritamab-containing regimens in the EPCORE NHL-2 trial (NCT04663347). We observed downregulation of CD20 expression on B-cells following treatment initiation both in progressing patients and in patients achieving durable complete responses (CR), suggesting that CD20 downregulation does not universally predict resistance to BsAb-based therapy. Single-cell immune profiling of tumor biopsies obtained following one cycle of therapy revealed substantial clonal expansion of cytotoxic CD4+ and CD8+ T-cells in patients achieving CR, and an expansion of follicular helper and regulatory CD4+ T-cells in patients whose disease progressed. These results identify distinct tumor-resident T-cell profiles associated with response or resistance to BsAb therapy.

9.
Arthritis Res Ther ; 26(1): 117, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38845046

RESUMEN

BACKGROUND: The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF­06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18-70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03-6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3-10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant. RESULTS: In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4-121.4 h (SAD cohorts) and 162.0-234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3-99.3%/62.4-98.7% [SAD] and 91.1-99.6%/89.5-98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375. CONCLUSIONS: These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03334851.


Asunto(s)
Artritis Reumatoide , Lupus Eritematoso Sistémico , Receptores CXCR5 , Humanos , Persona de Mediana Edad , Adulto , Método Doble Ciego , Femenino , Masculino , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Anciano , Adulto Joven , Relación Dosis-Respuesta a Droga , Adolescente , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/farmacocinética , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos
10.
Front Immunol ; 15: 1395684, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38868776

RESUMEN

Circulating follicular helper T cells (cTfh) can show phenotypic alterations in disease settings, including in the context of tissue-damaging autoimmune or anti-viral responses. Using severe COVID-19 as a paradigm of immune dysregulation, we have explored how cTfh phenotype relates to the titre and quality of antibody responses. Severe disease was associated with higher titres of neutralising S1 IgG and evidence of increased T cell activation. ICOS, CD38 and HLA-DR expressing cTfh correlated with serum S1 IgG titres and neutralising strength, and interestingly expression of TIGIT by cTfh showed a negative correlation. TIGIT+cTfh expressed increased IFNγ and decreased IL-17 compared to their TIGIT-cTfh counterparts, and showed reduced capacity to help B cells in vitro. Additionally, TIGIT+cTfh expressed lower levels of CD40L than TIGIT-cTfh, providing a potential explanation for their poor B-helper function. These data identify phenotypic changes in polyclonal cTfh that correlate with specific antibody responses and reveal TIGIT as a marker of cTfh with altered function.


Asunto(s)
Anticuerpos Antivirales , Linfocitos B , COVID-19 , Receptores Inmunológicos , SARS-CoV-2 , Células T Auxiliares Foliculares , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , COVID-19/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Activación de Linfocitos/inmunología , Receptores Inmunológicos/inmunología , SARS-CoV-2/inmunología , Células T Auxiliares Foliculares/inmunología , Anciano de 80 o más Años
11.
Methods Mol Biol ; 2813: 281-293, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38888784

RESUMEN

The development of an effective humoral response to pathogens and immunogens is a multiphase biological process, which is mediated by the coordinated function of specialized immune cell types in secondary lymphoid organs and particularly in T cell and follicular areas. More specifically, within the follicular/germinal center area, the orchestrated interplay between B cells, follicular helper CD4 T cells (Tfh), and stromal cells triggers a cascade of immune reactions leading to the development of memory B cells and plasma cells able to generate effective, antigen-specific antibodies. The role of Tfh cells in this process is critical. Given the need for vaccines capable to induce antibodies of high affinity, neutralizing activity, and durability, understanding the cellular and molecular mechanisms regulating Tfh cell development is of great importance. Here, we describe novel approaches for the comprehensive understanding of these cells and possible implications for future studies in vaccine development and the understanding of the pathogenesis of relevant diseases.


Asunto(s)
Células T Auxiliares Foliculares , Humanos , Células T Auxiliares Foliculares/inmunología , Centro Germinal/inmunología , Centro Germinal/citología , Linfocitos B/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Diferenciación Celular/inmunología
12.
Front Immunol ; 15: 1413860, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38911857

RESUMEN

IgG4-related disease (IgG4-RD) is a recently described autoimmune disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4+ plasma cells in multiple organ systems. Recent advancements have significantly enhanced our understanding of the pathological mechanism underlying this immune-mediated disease. T cell immunity plays a crucial role in the pathogenesis of IgG4-RD, and follicular helper T cells (Tfh) are particularly important in germinal center (GC) formation, plasmablast differentiation, and IgG4 class-switching. Apart from serum IgG4 concentrations, the expansion of circulating Tfh2 cells and plasmablasts may also serve as novel biomarkers for disease diagnosis and activity monitoring in IgG4-RD. Further exploration into the pathogenic roles of Tfh in IgG4-RD could potentially lead to identifying new therapeutic targets that offer more effective alternatives for treating this condition. In this review, we will focus on the current knowledge regarding the pathogenic roles Tfh cells play in IgG4-RD and outline potential therapeutic targets for future clinical intervention.


Asunto(s)
Centro Germinal , Enfermedad Relacionada con Inmunoglobulina G4 , Inmunoglobulina G , Células T Auxiliares Foliculares , Humanos , Enfermedad Relacionada con Inmunoglobulina G4/inmunología , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/terapia , Células T Auxiliares Foliculares/inmunología , Animales , Inmunoglobulina G/inmunología , Centro Germinal/inmunología , Células Plasmáticas/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Biomarcadores
13.
Front Immunol ; 15: 1391404, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38799444

RESUMEN

Introduction: Follicular Lymphoma (FL) results from the malignant transformation of germinal center (GC) B cells. FL B cells display recurrent and diverse genetic alterations, some of them favoring their direct interaction with their cell microenvironment, including follicular helper T cells (Tfh). Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the follicular regulatory T cell (Tfr) compartment, is still sparse. Methods: The aim of this study was to characterize FL-Tfr phenotype by cytometry, gene expression profile, FL-Tfr origin by transcriptomic analysis, and functionality by in vitro assays. Results: CD4+CXCR5+CD25hiICOS+ FL-Tfr displayed a regulatory program that is close to classical regulatory T cell (Treg) program, at the transcriptomic and methylome levels. Accordingly, Tfr imprinting stigmata were found on FL-Tfh and FL-B cells, compared to their physiological counterparts. In addition, FL-Tfr co-culture with autologous FL-Tfh or cytotoxic FL-CD8+ T cells inhibited their proliferation in vitro. Finally, although FL-Tfr shared many characteristics with Treg, TCR sequencing analyses demonstrated that part of them derived from precursors shared with FL-Tfh. Discussion: Altogether, these findings uncover the role and origin of a Tfr subset in FL niche and may be useful for lymphomagenesis knowledge and therapeutic management.


Asunto(s)
Linfoma Folicular , Linfocitos T Reguladores , Linfoma Folicular/inmunología , Linfoma Folicular/genética , Linfoma Folicular/patología , Humanos , Linfocitos T Reguladores/inmunología , Perfilación de la Expresión Génica , Transcriptoma , Microambiente Tumoral/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/metabolismo , Masculino , Femenino , Técnicas de Cocultivo , Centro Germinal/inmunología
14.
J Autoimmun ; 146: 103235, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38696926

RESUMEN

Soluble components secreted by Tfh cells are critical for the germinal center responses. In this study, we investigated whether Tfh cells could regulate the B-cell response by releasing small extracellular vesicles (sEVs). Our results showed that Tfh cells promote B-cell differentiation and antibody production through sEVs and that CD40L plays a crucial role in Tfh-sEVs function. In addition, increased Tfh-sEVs were found in mice with collagen-induced arthritis (CIA). Adoptive transfer of Tfh cells significantly exacerbated the severity of CIA; however, the effect of Tfh cells on exacerbating the CIA process was significantly diminished after inhibiting sEVs secretion. Moreover, the levels of plasma Tfh-like-sEVs and CD40L expression on Tfh-like-sEVs in RA patients were significantly higher than those in healthy subjects. In summary, Tfh cell-derived sEVs can enhance the B-cell response, and exacerbate the procession of autoimmune arthritis.


Asunto(s)
Artritis Experimental , Linfocitos B , Vesículas Extracelulares , Células T Auxiliares Foliculares , Animales , Artritis Experimental/inmunología , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Ratones , Linfocitos B/inmunología , Linfocitos B/metabolismo , Humanos , Células T Auxiliares Foliculares/inmunología , Masculino , Artritis Reumatoide/inmunología , Diferenciación Celular/inmunología , Activación de Linfocitos/inmunología , Traslado Adoptivo , Ligando de CD40/metabolismo , Ligando de CD40/inmunología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Índice de Severidad de la Enfermedad , Femenino
15.
Front Neurol ; 15: 1356300, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38751878

RESUMEN

Myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness and fatigue. It is caused by pathological autoantibodies against components expressed at neuromuscular junctions, such as acetylcholine receptor (AChR). Interleukin-6 (IL-6) has been suggested to play a role in the pathogenesis of MG, and IL-6 receptor (IL-6R) antibody treatment may provide a novel therapeutic option. In this study, we investigated the effects of IL-6R antibody treatment in an experimental autoimmune MG (EAMG) mouse model. We demonstrated that IL-6R antibody treatment improved muscle weakness, reduced IgG deposition at neuromuscular junctions, and the levels of AChR autoantibodies in serum. In addition, follicular helper T cells and Th17, plasma cells in lymph nodes were lower in IL-6R antibody treated mice. Our findings suggest that IL-6R blockade may be a novel and effective therapeutic strategy for the treatment of MG.

16.
Clin Immunol ; 264: 110217, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38621471

RESUMEN

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (TFH) play a central role in humoral immunity, we examined TFH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate TFH, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased TFH17 and increased TFH1 subsets; this was associated with increased transitional B cells and decreased IgG+ B and IgD-IgM-CD27+ memory B cells. ICOS expression on CVID CD4+ T cells was also decreased. However, ICOS activation of CD4+ T cells by vopratelimab significantly increased total CVID TFH, TFH2, cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG+ B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of TFH modulation in restoring TFH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency.


Asunto(s)
Linfocitos B , Inmunodeficiencia Variable Común , Proteína Coestimuladora de Linfocitos T Inducibles , Células T Auxiliares Foliculares , Humanos , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/tratamiento farmacológico , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Linfocitos B/inmunología , Linfocitos B/efectos de los fármacos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Inmunoglobulina G/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Anciano , Adulto Joven
17.
Front Immunol ; 15: 1340001, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38680492

RESUMEN

Germinal center (GC) responses are essential for establishing protective, long-lasting immunity through the differentiation of GC B cells (BGC) and plasma cells (BPC), along with the generation of antigen-specific antibodies. Among the various pathways influencing immune responses, the STING (Stimulator of Interferon Genes) pathway has emerged as significant, especially in innate immunity, and extends its influence to adaptive responses. In this study, we examined how the STING ligand cGAMP can modulate these key elements of the adaptive immune response, particularly in enhancing GC reactions and the differentiation of BGC, BPC, and follicular helper T cells (TFH). Employing in vivo models, we evaluated various antigens and the administration of cGAMP in Alum adjuvant, investigating the differentiation of BGC, BPC, and TFH cells, along with the production of antigen-specific antibodies. cGAMP enhances the differentiation of BGC and BPC, leading to increased antigen-specific antibody production. This effect is shown to be type I Interferon-dependent, with a substantial reduction in BPC frequency upon interferon (IFN)-ß blockade. Additionally, cGAMP's influence on TFH differentiation varies over time, which may be critical for refining vaccine strategies. The findings elucidate a complex, antigen-specific influence of cGAMP on T and B cell responses, providing insights that could optimize vaccine efficacy.


Asunto(s)
Diferenciación Celular , Centro Germinal , Proteínas de la Membrana , Nucleótidos Cíclicos , Transducción de Señal , Centro Germinal/inmunología , Centro Germinal/metabolismo , Animales , Nucleótidos Cíclicos/metabolismo , Nucleótidos Cíclicos/inmunología , Diferenciación Celular/inmunología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/inmunología , Ratones , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Ratones Endogámicos C57BL , Activación de Linfocitos/inmunología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo
18.
Heliyon ; 10(6): e27687, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38515720

RESUMEN

It is well established that increased peripheral helper T cells (TPH) and follicular helper T cells (TFH) was found in systemic lupus erythematosus (SLE) patients. However, the expression patterns and immunomodulatory roles of TIGIT and PD1 on TPH/TFH in SLE are poorly understood. The expression patterns of TIGIT and PD1 on TPH and TFH cells were examined using flow cytometry and their expression patterns in SLE patients were then further evaluated for their correlation with auto-antibodies, disease activity and severity, B cell differentiation. Logistic regression was used to analyze the risk factors. And the receiver operating characteristic curves and logistic regression model were created to evaluate the predicting role in SLE. TIGIT±PD1+TPH, TIGIT±PD1+TFH cells in the peripheral blood of SLE patients were upregulated, whereas TIGIT+PD1-TFH was downregulated. TIGIT ± PD1+TPH, TIGIT ± PD1+TFH cells positively correlated with auto-antibodies production, disease activity and severity, whereas TIGIT+PD1-TFH cells negatively correlated. TIGIT ± PD1+TPH, TIGIT-PD1+TFH were positively correlated with the frequency of plasmablasts. Furthermore, higher TIGIT+PD1+TPH and TIGIT+PD1+TFH were shown to be risk factors for SLE, whereas TIGIT+PD1-TFH was found to be a protective factor, according to logistic regression analysis. A further logistic regression model showed that combination of TPH/TFH and routine blood indicators may has potential predicting value for SLE, with AUC of 0.957. The increased TIGIT ± PD1+TPH, increased TIGIT ± PD1+TFH, decreased TIGIT+PD1-TFH correlates with disease severity and activity, may boost our comprehending of the role of TIGIT and PD1 on TPH/TFH in SLE, and a logistic regression model based on combination of TPH/TFH and routine blood indicators shows prominent value for predicting SLE.

19.
J Autoimmun ; 145: 103198, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38428341

RESUMEN

OBJECTIVES: Expansion of follicular helper T (Tfh) cells and abnormal glucose metabolism are present in patients with systemic lupus erythematosus (SLE). Pyruvate kinase M2 (PKM2) is one of the key glycolytic enzymes, and the underlying mechanism of PKM2-mediated Tfh cell glycolysis in SLE pathogenesis remains elusive. METHODS: We analyzed the percentage of Tfh cells and glycolysis in CD4+ T cells from SLE patients and healthy donors and performed RNA sequencing analysis of peripheral blood CD4+ T cells and differentiated Tfh cells from SLE patients. Following Tfh cell development in vitro and following treatment with PKM2 activator TEPP-46, PKM2 expression, glycolysis, and signaling pathway proteins were analyzed. Finally, diseased MRL/lpr mice were treated with TEPP-46 and assessed for treatment effects. RESULTS: We found that Tfh cell percentage and glycolysis levels were increased in SLE patients and MRL/lpr mice. TEPP-46 induced PKM2 tetramerization, thereby inhibiting Tfh cell glycolysis levels. On the one hand, TEPP-46 reduced the dimeric PKM2 entering the nucleus and reduced binding to the transcription factor BCL6. On the other hand, TEPP-46 inhibited the AKT/GSK-3ß pathway and glycolysis during Tfh cell differentiation. Finally, we confirmed that TEPP-46 effectively alleviated inflammatory damage in lupus-prone mice and reduced the expansion of Tfh cells in vivo. CONCLUSIONS: Our results demonstrate the involvement of PKM2-mediated glycolysis in Tfh cell differentiation and SLE pathogenesis, and PKM2 could be a key therapeutic target for the treatment of SLE.


Asunto(s)
Diferenciación Celular , Glucólisis , Inflamación , Lupus Eritematoso Sistémico , Ratones Endogámicos MRL lpr , Piruvato Quinasa , Células T Auxiliares Foliculares , Animales , Femenino , Humanos , Ratones , Modelos Animales de Enfermedad , Inflamación/inmunología , Inflamación/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Piruvato Quinasa/metabolismo , Transducción de Señal , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Proteínas de Unión a Hormona Tiroide , Hormonas Tiroideas/metabolismo
20.
J Ethnopharmacol ; 328: 118072, 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38508431

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Bushen Formula (BSF) is the effective traditional Chinese medicine (TCM) for chronic hepatitis B (CHB) according to our previous researches. However, the special effectiveness of BSF treating CHB patients in different stages and the immunoregulatory mechanisms remain to be explored. AIM OF THE STUDY: To compare the therapeutic effects of BSF in both treatment-naive patients and Peg-IFN-α-treated patients, and explore the potential mechanism of immunomodulation. MATERIALS AND METHODS: Ultra-high performance liquid chromatography-quadrupole electrostatic field-orbital trap high resolution mass spectrometry and the TCMSP database were used to determine the main components of BSF. Two hundred and sixty-six patients were enrolled in the retrospective study, and they were divided into the treatment group (T-Group, BSF plus Peg-IFN-α) and the control group (C-Group, Peg-IFN-α monotherapy). Within each group, patients were further grouped into subgroups, namely T1/C1 groups (treatment-naive patients, T1 = 34, C1 = 94) and T2/C2 groups (Peg-IFN-α-treated patients, T2 = 56, C2 = 82). Serum HBV markers, serum HBV DNA levels, serum ALT/AST and TCM symptoms were obtained from the record. Bioinformatics analysis was employed to obtain the potential immunoregulatory mechanisms of BSF treating CHB patients. Among patients in T2 and C2 group, peripheral mononuclear cells from 36 patients were used to analyze the characteristics of peripheral follicular helper T (Tfh) cells and B-cell subtypes by flow cytometry. Preparation of BSF-containing serum in rats. In vitro, the co-culture system of CXCR5+ cells and HepG2.2.15 cells was built to investigate the immunoregulatory effects of BSF. RESULTS: A total of 14 main active compounds were detected in BSF, which were deemed critical for the treatment of CHB. Our findings indicated that the T2-Group exhibited the higher percentage of HBsAg decline ≥ 1-log10 IU/ml and rate of HBeAg seroclearance compared to the C2-Group (35.7% vs. 15.9%, P = 0.033; 33.9% vs. 11.0%, P = 0.002). Additionally, the T2-Group demonstrated the higher percentage of HBsAg decline ≥ 1-log10 IU/ml and rate of HBeAg seroclearance compared to the T1-Group (35.7% vs. 14.7%, P = 0.031; 33.9% vs. 2.9%, P = 0.000). The total effective rate based on TCM clinical syndrome in T1-Group and T2-Group were significantly greater than those in C1-Group and C2-Group (85.3% vs. 61.7%, P = 0.012; 89.1% vs. 63.4%, P = 0.000). Bioinformatics analysis indicated that the immunoregulatory mechanisms of BSF treating CHB patients were mainly linked to the growth and stimulation of B-cell, T-cell differentiation, and the signaling pathway of the B-cell receptor. Furthermore, the frequencies of Tfh cells and its IL-21 level, and the IL-21R expressed by B-cell were all increased after BSF treatment. Additionally, in the co-culture system of CXCR5+ cells and HepG2.2.15 cells, HBsAg and HBeAg levels were decreased after BSF-containing serum treatment,as well as the up-regulating of Tfh cell frequencies and down-regulating of B-cell frequencies. CONCLUSIONS: BSF have the higher percentage of HBsAg decline and HBeAg seroclearance in Peg-IFN-α-treated patients compared with treatment-naive patients. The potential immunoregulatory mechanism may correlate with promoting the interaction between Tfh cells and B-cell through IL-21/IL-21R signaling pathway.


Asunto(s)
Subgrupos de Linfocitos B , Medicamentos Herbarios Chinos , Hepatitis B Crónica , Humanos , Ratas , Animales , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Células T Auxiliares Foliculares , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/diagnóstico , Antivirales/farmacología , Antivirales/uso terapéutico , Antígenos e de la Hepatitis B , Estudios Retrospectivos , Biomarcadores , ADN Viral , Resultado del Tratamiento , Polietilenglicoles/uso terapéutico
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