Functional crosstalk between dendritic cells and Foxp3+ regulatory T cells in the maintenance of immune tolerance

Peripheral immune tolerance requires a controlled balance between the maintenance of self-tolerance and the capacity to engage protective immune responses against pathogens. Dendritic cells (DCs) serve as sentinels of the immune system by sensing environmental and inflammatory signals, and play an essential role in the maintenance of immune tolerance. To achieve this, DC play a key role in dictating the outcome of immune responses by influencing the balance between inflammatory or Foxp3+ regulatory T (Treg) cell responses. At the heart of this immunological balance is a finely regulated DC and Treg cell crosstalk whereby Treg cells modulate DC phenotype and function, and DC drive the differentiation of Foxp3+ Treg cells in order to control immune responses. This review will focus on recent advances, which highlight the importance of this bidirectional DC and Treg cell crosstalk during the induction of tolerance and organ-specific autoimmunity. More specifically, we will discuss how Treg cells modulate DC function for the suppression of inflammatory responses and how DC subsets employ diverse mechanisms to drive differentiation of Treg cells. Finally, we will discuss the therapeutic potential of tolerogenic DCs for the induction of tolerance in autoimmune diseases

Complicated clinical course of acute pelvic inflammatory disease

The absence of both the classic risk factors for pelvic inflammatory disease (PID) and the triad of cervical motion, uterine or adnexal tenderness does not preclude the diagnosis of PID and tubo-ovarian abscess. The clinical case demonstration presents the perimenopausal woman with complicated clinical course of acute PID

IL-2 as a therapeutic target for the restoration of Foxp3+ regulatory T cell function in organ-specific autoimmunity: implications in pathophysiology and translation to human disease

Peripheral immune tolerance requires a finely controlled balance between tolerance to self-antigens and protective immunity against enteric and invading pathogens. Self-reactive T cells sometimes escape thymic clonal deletion, and can subsequently provoke autoimmune diseases such as type 1 diabetes (T1D) unless they are controlled by a network of tolerance mechanisms in the periphery, including CD4+ regulatory T cells (Treg) cells. CD4+ Treg cells are characterized by the constitutive expression of the IL-2Rα chain (CD25) and preferentially express the forkhead winged helix transcriptional regulator Foxp3. These cells have been shown to possess immunosuppressive properties towards various immune cell subsets and their defects are thought to contribute to many autoimmune disorders. Strong evidence shows that IL-2 is one of the important stimulatory signals for the development, function and fitness of Treg cells. The non-obese diabetic (NOD) mouse model, a prototypic model of spontaneous autoimmunity, mimics many features of human T1 D. Using this model, the contribution of the IL-2-IL-2R pathway to the development of T1 D and other autoimmune disorders has been extensively studied. In the past years, strong genetic and molecular evidence has indicated an essential role for the IL-2/IL-2R pathway in autoimmune disorders. Thus, the major role of IL-2 is to maintain immune tolerance by promoting Treg cell development, functional fitness and stability. Here we first summarize the genetic and experimental evidence demonstrating a role for IL-2 in autoimmunity, mainly through the study of the NOD mouse model, and analyze the cellular and molecular mechanisms of its action on Treg cells. We then move on to describe how this data can be translated to applications for human autoimmune diseases by using IL-2 as a therapeutic agent to restore Treg cell fitness, numbers and functions

Correlation between placental pathology and neonatal morbidity: a case-control study

Background: Preterm births occur in approximately 12% of pregnancies worldwide and in 5.6% of pregnancies in Latvia, and the incidence has increased. Prematurity poses the major challenge in perinatology and pediatrics, accounting for 75% of perinatal mortalities and 50% of long-term complication. The placenta is a unique organ in explaining the incomprehensible pathogenesis of prematurity.Methods: The retrospective case-control study was conducted to determine placental histological and microbiological findings associated with gestational age and neonatal morbidity.Results: Histological chorioamnionitis was the most prevalent lesion in extremely preterm and very preterm birth groups compared with moderate to late preterm and term birth groups (P=0.027). A higher rate of funisitis was detected among extremely preterm and very preterm birth cases (P=0.001). Microbiological examination of placentas in preterm birth cases most commonly revealed Streptococcus agalactiae, Staphylococcus epidermidis, Staphylococcus haemolyticus. Umbilical cord vessels thrombosis and placental thrombotic vasculopathy were found mostly in moderate to late preterm birth category (P=0.032; P=0.008, respectively). Intrauterine growth restriction was linked to chorionic villous edema (P=0.007) and chorionic villous fibrinoid necrosis (P=0.014). Chorion-decidual hemorrhage and deciduitis were significantly associated with respiratory distress syndrome (P=0.036; P=0.022, respectively). Chorion-decidual hemorrhage was the main predisposing factor for hypoxic-ischemic encephalopathy (P=0.058).Conclusions: Comprehension of the pathogenic mechanisms of prematurity of the placenta and preterm births, and the impact of placental prematurity on neonatal morbidity may lead to improved prenatal diagnostic and enhanced preventive care for both the mother and the child

Pregnancy and lactation associated osteoporosis: unrecognized cause of musculoskeletal pain syndrome during the peri-pregnancy period

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare disorder, usually occurring in late pregnancy and the early post-partum period. The prevalence, etiology, pathogenesis and therapy remains unclear. Three clinical cases of PLO present patients with multiple severe osteoporotic fractures during the peri-pregnancy period and different treatment strategies

Analysis of invasive cervical cancer cases in Latvia

Background: The aim of the study is to evaluate the cervical cancer screening programme in Latvia and to determine how early cervical cancer diagnostics can be improved and the burden of the disease can be reduced.Methods: All cervical cancer cases diagnosed in 2014 and treated in Oncology Centre of Latvia were included in the retrospective cross-sectional study. Cervical cancer cases were classified according to the cytological sampling interval: a “short” (5 years) interval.Results: There were 189 patients identified during the study period. Information was obtained from 130 (68.7%) patients. 49.2% (n=64) of all patients had had a cytological examination within the last three years. For 11.6% (n=15) women, the screening interval was regular, while 21.5% (n=28) had had their last cytological examination more than five years before. 17.7% (n=23) had never had cytological examination. A tendency for more frequent early stage cervical cancer detection in the group of cytological sampling interval less than three years compared to a 3–5 years interval (71.9% vs. 53.3%, p=0.003) was observed.Conclusions: In Latvia, cervical cancer is an unresolved healthcare issue for women. Despite the fact that lack of a quality management system, diagnostic imperfections and non-attendance in the organized, cytology-based screening programme remain the main barrier of cervical cancer control, introduction of a more sensitive test, such as primary testing for oncogenic human papilloma virus types, could significantly reduce the burden of the disease

Re-education of macrophages as a therapeutic strategy in cancer.

Tumor-associated macrophages (TAMs) can be educated within the tumor microenvironment to promote cancer development and progression. While TAM-targeted agents have largely focused on macrophage depletion as an anticancer strategy, it is becoming increasingly evident that TAM re-education may represent a more effective approach. In this perspective, we discuss different means to achieve TAM re-education, and review the beneficial effects of these strategies, particularly when combined with immune checkpoint inhibitors

Graves’ disease as a manifestation of immune reconstitution inflammatory syndrome in an HIV-1-infected adolescent patient : A case report

Funding Information: Paediatric Endocrinology Department staff, Children's Clinical University Hospital; Outpatient Department of the Latvian Centre of Infectious Diseases; Rare Diseases Centre, Children's Clinical University Hospital. Publisher Copyright: © 2022 The AuthorsIntroduction: Although Graves' disease (GD) is the most common cause of hyperthyroidism in adolescents, it is very rare for it to result from the production of thyroid-stimulating hormone (TSH) receptor autoantibodies due to Graves' immune reconstitution inflammatory syndrome (IRIS). Especially for paediatric patients, very little is known about the aetiology and complete pathogenesis of Graves’ IRIS. Furthermore, details of a valid treatment plan are severely lacking. The case report presented here is only the third for paediatric patients worldwide. Case presentation: We report on a Caucasian female adolescent who initially presented with non-specific complaints about discomfort and tightness in the anterior part of the neck and thyroid enlargement. Based on clinical, laboratory and thyroid ultrasound findings, she was diagnosed with GD. However, after several months of outpatient treatment, the patient's GD could still not be fully managed with conservative therapy alone. Only when the patient was hospitalized for the third time was it discovered that she had previously been diagnosed with human immunodeficiency virus infection and had received highly active antiretroviral therapy (HAART) for the previous 29 months. Consequently, the production of autoantibodies to TSH receptors and abnormal changes in thyroid hormones had led to the development of GD and her final diagnosis was established as Graves' IRIS. Ultimately, a total thyroidectomy was performed. Discussion/conclusion: This case report demonstrates how fundamentally important it is to have full access to a patient's complete anamnesis and results of all previous investigations. Clinicians should be made aware of the potential existence of thyroid dysfunction and other autoimmune or infectious processes in paediatric patients initiating or reinitiating HAART. Further research is needed to optimize the treatment for such paediatric patients.publishersversionPeer reviewe

Management of Pregnancy with Cervical Shortening: Real-Life Clinical Challenges

Funding Information: The study was funded by the Fundamental and Applied Research Projects grant of The Latvian Council of Science (Project No. 2020/1-0042 to DR). The funders had no role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2023 by the authors.Background and Objectives: Preterm birth is the leading cause of neonatal mortality worldwide and may be responsible for lifelong morbidities in the survivors. Cervical shortening is one of the common pathways to preterm birth associated with its own diagnostic and management challenges. The preventive modalities that have been tested include progesterone supplementation and cervical cerclage and pessaries. The study aimed to assess the management strategies and outcomes in a group of patients with a short cervix during pregnancy or cervical insufficiency. Materials and Methods: Seventy patients from the Riga Maternity Hospital in Riga, Latvia, were included in the prospective longitudinal cohort study between 2017 and 2021. Patients were treated with progesterone, cerclage, and/or pessaries. The signs of intra-amniotic infection/inflammation were assessed, and antibacterial therapy was given when the signs were positive. Results: The rates of PTB were 43.6% (n = 17), 45.5% (n = 5), 61.1% (n = 11), and 50.0% (n = 1) in progesterone only, cerclage, pessary, and cerclage plus pesssary groups, respectively. The progesterone therapy was associated with a reduced preterm birth risk (x2(1) = 6.937, p = 0.008)), whereas positive signs of intra-amniotic infection/inflammation significantly predicted the risk of preterm birth (p = 0.005, OR = 3.82, 95% [CI 1.31–11.11]). Conclusions: A short cervix and bulging membranes, both indicators of intra-amniotic infection/inflammation, are the key risk factors in preterm birth risk predictions. Progesterone supplementation should remain at the forefront of preterm birth prevention. Among patients with a short cervix and especially complex anamnesis, the preterm rates remain high. The successful management of patients with cervical shortening lies between the consensus-based approach for screening, follow-up, and treatment on the one side and personalising medical therapy on the other.publishersversionPeer reviewe

TAF6δ orchestrates an apoptotic transcriptome profile and interacts functionally with p53

<p>Abstract</p> <p>Background</p> <p>TFIID is a multiprotein complex that plays a pivotal role in the regulation of RNA polymerase II (Pol II) transcription owing to its core promoter recognition and co-activator functions. TAF6 is a core TFIID subunit whose splice variants include the major TAF6α isoform that is ubiquitously expressed, and the inducible TAF6δ. In contrast to TAF6α, TAF6δ is a pro-apoptotic isoform with a 10 amino acid deletion in its histone fold domain that abolishes its interaction with TAF9. TAF6δ expression can dictate life versus death decisions of human cells.</p> <p>Results</p> <p>Here we define the impact of endogenous TAF6δ expression on the global transcriptome landscape. TAF6δ was found to orchestrate a transcription profile that included statistically significant enrichment of genes of apoptotic function. Interestingly, gene expression patterns controlled by TAF6δ share similarities with, but are not equivalent to, those reported to change following TAF9 and/or TAF9b depletion. Finally, because TAF6δ regulates certain p53 target genes, we tested and demonstrated a physical and functional interaction between TAF6δ and p53.</p> <p>Conclusion</p> <p>Together our data define a TAF6δ-driven apoptotic gene expression program and show crosstalk between the p53 and TAF6δ pathways.</p