Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

• MeSH
• autofagie * genetika   MeSH
• běloši genetika   MeSH
• duktální karcinom slinivky břišní * genetika   patologie   MeSH
• forkhead transkripční faktory MeSH
• genetická predispozice k nemoci * MeSH
• hepatocytární jaderný faktor 3-alfa genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé MeSH
• nádorové biomarkery * genetika   MeSH
• nádorové supresorové proteiny * genetika   MeSH
• nádory slinivky břišní * genetika   patologie   MeSH
• studie případů a kontrol MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

BACKGROUND: Accumulating evidence suggests that spontaneous preterm labor is a syndrome caused by multiple pathological processes. The breakdown of maternal-fetal tolerance has been proposed as a key mechanism of idiopathic spontaneous preterm labor, often viewed as a chronic inflammatory process resulting from the maternal immune system's impaired tolerance of the fetus from early pregnancy. Regulatory T cells are crucial for maintaining maternal-fetal tolerance. Even a partial reduction in their levels can disrupt this tolerance, leading to adverse pregnancy outcomes such as preterm labor. Given the complexity of the T lymphocyte-mediated immune response, identifying candidate signaling pathways involved in maternal-fetal tolerance is challenging. However, current literature highlights the importance of the functional and developmental markers FoxP3, CD45RA, Helios, and CD39 due to their immunosuppressive abilities essential for maintaining pregnancy. OBJECTIVE: This study aimed to determine whether changes in numbers of selected regulatory T cell subpopulations in the first trimester are associated with subsequent spontaneous preterm labor. STUDY DESIGN: This prospective study enrolled 43 women with early singleton pregnancies, excluding those with autoimmune diseases, diabetes mellitus (type 1, type 2), primary hypertension, or who had been treated with vaginal progesterone prior to sample collection. We analyzed regulatory T cell subpopulations in maternal circulation using the DURAClone IM T cell kit, focusing on the following subsets: CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-. RESULTS: Among the participants, 7 experienced spontaneous preterm labor between the 23rd and 33rd weeks of gestation, while 36 delivered at term. The preterm group showed a significant reduction in numbers of all analyzed regulatory T cell subpopulations: CD4+CD25+FoxP3+ (median 0.0410×10ˆ9/L vs median 0.0550×10ˆ9/L, P=.0217), CD4+CD25+FoxP3+CD45RA- (median 0.0310×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0216), CD4+CD25+FoxP3+Helios+ (median 0.0270×10ˆ9/L vs median 0.0370×10ˆ9/L, P=.0260), CD4+CD25+FoxP3+CD39- (median 0.0300×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0427). CONCLUSION: Early first trimester alterations in specific regulatory T cell subpopulations, including diminished levels of CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA-, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-, are associated with idiopathic spontaneous preterm labor. These findings suggest that early changes in these lymphocyte subpopulations may be linked to spontaneous preterm birth. This highlights the need for further research to understand the mechanisms underlying regulatory T-cell dynamics and their impact on pregnancy outcomes.

• MeSH
• antigeny CD45 metabolismus   MeSH
• apyrasa imunologie   MeSH
• CD antigeny imunologie   MeSH
• dospělí MeSH
• forkhead transkripční faktory * metabolismus   MeSH
• lidé MeSH
• mladý dospělý MeSH
• předčasná porodní činnost * imunologie   MeSH
• prospektivní studie MeSH
• první trimestr těhotenství imunologie   MeSH
• regulační T-lymfocyty * imunologie   MeSH
• těhotenství MeSH
• transkripční faktor Ikaros MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

WW domain binding protein 1-like (WBP1L), also known as outcome predictor of acute leukemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which was shown to correlate with ETV6-RUNX1 translocation and favorable prognosis in childhood leukemia. It has a broad expression pattern in hematopoietic and non-hematopoietic cells. Our previous work described WBP1L as a regulator of CXCR4 signaling and hematopoiesis. Here, we show that hematopoiesis in the mice with Wbp1l germline deletion is dysregulated, already at the level of hematopoietic stem cells and early progenitors. We further demonstrate that thymi of WBP1L-deficient mice are significantly enlarged and contain increased numbers of thymocytes of all subsets. This can potentially be explained by increased generation of multipotent progenitors 4 (MPP4) in the bone marrow, from which the thymus-seeding progenitors are derived. We also observed increases in multiple cell types in the blood. In addition, we show that WBP1L regulates hematopoietic stem cell functionality and leukocyte progenitor proliferation and gene expression during hematopoietic stem and progenitor cell transplantation, which contribute to more efficient engraftment of WBP1L-deficient cells. WBP1L thus emerges as a regulator of hematopoietic stem and progenitor cell function, which controls leukocyte numbers at the steady state and after bone marrow transplantation.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• buněčná diferenciace MeSH
• hematopoetické kmenové buňky * metabolismus   cytologie   MeSH
• hematopoéza * genetika   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované * MeSH
• myši MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The use of biomaterials and implants for joint replacement, fracture fixation, spinal stabilization and other orthopedic indications has revolutionized patient care by reliably decreasing pain and improving function. These surgical procedures always invoke an acute inflammatory reaction initially, that in most cases, readily subsides. Occasionally, chronic inflammation around the implant develops and persists; this results in unremitting pain and compromises function. The etiology of chronic inflammation may be specific, such as with infection, or be unknown. The histological hallmarks of chronic inflammation include activated macrophages, fibroblasts, T cell subsets, and other cells of the innate immune system. The presence of cells of the adaptive immune system usually indicates allergic reactions to metallic haptens. A foreign body reaction is composed of activated macrophages, giant cells, fibroblasts, and other cells often distributed in a characteristic histological arrangement; this reaction is usually due to particulate debris and other byproducts from the biomaterials used in the implant. Both chronic inflammation and the foreign body response have adverse biological effects on the integration of the implant with the surrounding tissues. Strategies to mitigate chronic inflammation and the foreign body response will enhance the initial incorporation and longevity of the implant, and thereby, improve long-term pain relief and overall function for the patient. The seminal research performed in the laboratory of Dr. James Anderson and co-workers has provided an inspirational and driving force for our laboratory's work on the interactions and crosstalk among cells of the mesenchymal, immune, and vascular lineages, and orthopedic biomaterials. Dr. Anderson's delineation of the fundamental biologic processes and mechanisms underlying acute and chronic inflammation, the foreign body response, resolution, and eventual functional integration of implants in different organ systems has provided researchers with a strategic approach to the use of biomaterials to improve health in numerous clinical scenarios.

• MeSH
• biokompatibilní materiály * chemie   MeSH
• lidé MeSH
• ortopedie metody   MeSH
• protézy a implantáty škodlivé účinky   MeSH
• reakce na cizí těleso * patologie   MeSH
• zánět * patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Plasmacytoid dendritic cells (pDCs) are a minority subset of dendritic cells that despite their tiny quantity play an important role in the immune system, especially in antiviral immunity. They are known mostly as the major producers of type I IFN, which they secrete upon stimulation of endosomal Toll-like receptors 7 and 9 with viral RNA and DNA. However, the functionality of pDCs is more complex, as they were shown to be also involved in autoimmunity, inflammation, and cancer. In the context of the tumor microenvironment, pDCs mostly show substantial functional defects and thus contribute to establishing immunosuppressive micromilieu. Indeed, tumor-infiltrating pDCs were shown to be predominantly pro-tumorigenic, with reduced ability to produce IFNα and capacity to prime regulatory T cells via the ICOS/ICOS-L pathway. Here we describe in detail a method to assess the functional capacity of pDCs upon exposure to tumor-derived cell culture supernatants. The same technique can be implemented with minimal variations to test any soluble factor's impact on pDC phenotype and function.

• MeSH
• dendritické buňky * imunologie   metabolismus   MeSH
• lidé MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory * imunologie   patologie   metabolismus   MeSH
• průtoková cytometrie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Antigen-presenting cells (APCs) are master regulators of the immune response by directly interacting with T cells to orchestrate distinct functional outcomes. Several types of professional APC exist, including conventional dendritic cells, B cells and macrophages, and numerous other cell types have non-classical roles in antigen presentation, such as thymic epithelial cells, endothelial cells and granulocytes. Accumulating evidence indicates the presence of a new family of APCs marked by the lineage-specifying transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and demonstrates that these APCs have key roles in shaping immunity, inflammation and tolerance, particularly in the context of host-microorganism interactions. These RORγt+ APCs include subsets of group 3 innate lymphoid cells, extrathymic autoimmune regulator-expressing cells and, potentially, other emerging populations. Here, we summarize the major findings that led to the discovery of these RORγt+ APCs and their associated functions. We discuss discordance in recent reports and identify gaps in our knowledge in this burgeoning field, which has tremendous potential to advance our understanding of fundamental immune concepts.

• MeSH
• antigen prezentující buňky metabolismus   MeSH
• endoteliální buňky MeSH
• jaderné receptory - podrodina 1, skupina F, člen 3 * metabolismus   MeSH
• lidé MeSH
• lymfocyty * MeSH
• přirozená imunita MeSH
• transportní proteiny metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Suppressive function of regulatory T cells (Treg) is dependent on signaling of their antigen receptors triggered by cognate self, dietary, or microbial peptides presented on MHC II. However, it remains largely unknown whether distinct or shared repertoires of Treg TCRs are mobilized in response to different challenges in the same tissue or the same challenge in different tissues. Here we use a fixed TCRβ chain FoxP3-GFP mouse model to analyze conventional (eCD4) and regulatory (eTreg) effector TCRα repertoires in response to six distinct antigenic challenges to the lung and skin. This model shows highly 'digital' repertoire behavior with easy-to-track challenge-specific TCRα CDR3 clusters. For both eCD4 and eTreg subsets, we observe challenge-specific clonal expansions yielding homologous TCRα clusters within and across animals and exposure sites, which are also reflected in the draining lymph nodes but not systemically. Some CDR3 clusters are shared across cancer challenges, suggesting a response to common tumor-associated antigens. For most challenges, eCD4 and eTreg clonal response does not overlap. Such overlap is exclusively observed at the sites of certain tumor challenges, and not systematically, suggesting transient and local tumor-induced eCD4=>eTreg plasticity. This transition includes a dominant tumor-responding eCD4 CDR3 motif, as well as characteristic iNKT TCRα CDR3. In addition, we examine the homeostatic tissue residency of clonal eTreg populations by excluding the site of challenge from our analysis. We demonstrate that distinct CDR3 motifs are characteristic of eTreg cells residing in particular lymphatic tissues, regardless of the challenge. This observation reveals the tissue-resident, antigen-specific clonal Treg populations.

• MeSH
• buněčné klony MeSH
• CD4-pozitivní T-lymfocyty * MeSH
• myši MeSH
• peptidy MeSH
• receptory antigenů T-buněk genetika   MeSH
• regulační T-lymfocyty * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Understanding the immune response to Leishmania infection and identifying biomarkers that correlate with protection are crucial for developing effective vaccines. One intriguing aspect of Leishmania infection is the persistence of parasites, even after apparent lesion healing. Various host cells, including dendritic cells, fibroblasts, and Langerhans cells, may serve as safe sites for latent infection. Memory T cells, especially tissue-resident memory T cells (TRM), play a crucial role in concomitant immunity against cutaneous Leishmania infections. These TRM cells are long-lasting and can protect against reinfection in the absence of persistent parasites. CD4+ TRM cells, in particular, have been implicated in protection against Leishmania infections. These cells are characterized by their ability to reside in the skin and rapidly respond to secondary infections by producing cytokines such as IFN-γ, which activates macrophages to kill parasites. The induction of CD4+ TRM cells has shown promise in experimental immunization, leading to protection against Leishmania challenge infections. Identifying biomarkers of protection is a critical step in vaccine development and CD4+ TRM cells hold potential as biomarkers, as their presence and functions may correlate with protection. While recent studies have shown that Leishmania-specific memory CD4+ T-cell subsets are present in individuals with a history of cutaneous leishmaniasis, further studies are needed to characterize CD4+ TRM cell populations. Overall, this review highlights the importance of memory T cells, particularly skin-resident CD4+ TRM cells, as promising targets for developing effective vaccines against leishmaniasis and as biomarkers of immune protection to assess the efficacy of candidate vaccines against human leishmaniasis.

• MeSH
• biologické markery MeSH
• CD4-pozitivní T-lymfocyty MeSH
• leishmanióza kožní * MeSH
• lidé MeSH
• paměťové T-buňky MeSH
• účinnost vakcíny MeSH
• vakcíny * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Our current understanding of whether B cell involvement in the tumor microenvironment benefits the patient or the tumor - in distinct cancers, subcohorts and individual patients - is quite limited. Both statements are probably true in most cases: certain clonal B cell populations contribute to the antitumor response, while others steer the immune response away from the desired mechanics. To step up to a new level of understanding and managing B cell behaviors in the tumor microenvironment, we need to rationally discern these roles, which are cumulatively defined by B cell clonal functional programs, specificities of their B cell receptors, specificities and isotypes of the antibodies they produce, and their spatial interactions within the tumor environment. Comprehensive analysis of these characteristics of clonal B cell populations is now becoming feasible with the development of a whole arsenal of advanced technical approaches, which include (1) methods of single-cell and spatial transcriptomics, genomics, and proteomics; (2) methods of massive identification of B cell specificities; (3) methods of deep error-free profiling of B cell receptor repertoires. Here we overview existing techniques, summarize their current application for B cells studies and propose promising future directions in advancing B cells exploration.

• MeSH
• B-lymfocyty MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory * MeSH
• podskupiny B-lymfocytů * MeSH
• receptory antigenů B-buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVE: The aim of the study is to analyze the absolute count of leukocytes, neutrophils, monocytes, eosinophils, T cells, natural killer cells, B cells and to evaluate the expression of functionally important CD23 and CD200 molecules on B cells in patients suffering from atopic dermatitis (AD), (with and without dupilumab therapy). MATERIALS AND METHODS: We examined 45 patients suffering from AD - 32 patients without dupilumab treatment (10 men, 22 women, average age 35.0 years), 13 patients with dupilumab treatment (7 men, 6 women, average age 43.4 years) and 30 healthy control (10 men, 20 women, average age 44.7 years). Immunophenotype was examined by flow cytometry (Navios Flow Cytometer - Beckman Coulter). The blood count was examined with a Sysmex XN 3000, Sysmex SP10, microscope DI60 for digital morphology evaluating cell division and microscope Olympus BX40. We compared the absolute count of leukocytes and their subsets, T cells (CD4, CD8), natural killers cells, absolute and relative count of B lymphocytes and expression of surface molecules CD23 and CD200 on B cells in AD patients and in control group. Non-parametric Kruskal-Wallis one-factor analysis of variance with post-hoc (follow-up multiple comparison) and Dunn's test with Bonferroni modification of significance level were used for statistical analysis. RESULTS: We confirmed the significantly higher number of neutrophils, monocytes and eosinophils and higher expression of CD23 and CD200 on B cells in peripheral blood of AD patients (either with or without dupilumab) therapy. We demonstrated the lower number of CD8+ T cells. CONCLUSION: We demonstrated the difference in the count of white blood cells populations in patients suffering from AD compared with healthy control. There were a differences in the expression of immunoregulatory molecules CD23 and CD200 on B cells in AD patients (either with or without dupilumab therapy) in comparison to healthy controls.

• MeSH
• atopická dermatitida * farmakoterapie   MeSH
• B-lymfocyty MeSH
• dospělí MeSH
• humanizované monoklonální protilátky farmakologie   terapeutické užití   MeSH
• lidé MeSH
• monocyty MeSH
• stupeň závažnosti nemoci MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH