Immunological Functions Research Articles

A novel case of Takenouchi-Kosaki syndrome: Focus on hearing and language rehabilitation

Abstract Takenouchi-Kosaki syndrome (TKS) is a rare congenital condition, caused by a mutation in the cell division cycle 42 gene. This gene typo impacts various physiological processes, including hearing, hematopoiesis, immunologic functioning, and neurodevelopment. Despite the high prevalence of hearing impairment in TKS, existing literature has concentrated primarily on pharmacological treatments for hematoimmunologic diseases. This case report presents a novel case of TKS, highlighting the importance of audiological assessment and rehabilitating interventions in children with TKS. We discuss the case of a prematurely born boy who was diagnosed with TKS and who presented with profound bilateral sensorineural hearing loss and associated developmental delays. Following comprehensive audiological evaluation and intervention – including hearing aids, sign language, and alternative augmentative communication systems – a multidisciplinary approach was adopted to enhance his communicative abilities. From this study, it emerges the increasing need for tailored rehabilitation strategies for TKS patients to improve communication skills and overall quality of life. Further researches are needed to develop standardized protocols for assessment and treatment in patients with TKS.

Core needle biopsy changes the expression of TGFβ1 and TGFβRII at protein level, and the distribution of CD4 and CD8 positive T cells in primary breast cancer

Core needle biopsy (CNB) has become a paradigm in preoperative breast cancer (BC) diagnosis. Although considered safe, it is an invasive procedure, which changes the tumor microenvironment. It facilitates a tumor supportive immune response, induces epithelial-mesenchymal transition (EMT), and enables the release of circulating tumor cells. The cytokine Transforming Growth Factor β (TGFβ) with its pleiotropic immunologic functions has an important role in this process. The aim of this study was to clarify the specific impact of CNB on the activity of the TGFβ pathway in early BC. We compared formalin fixed paraffin embedded samples from CNBs to the corresponding surgical resection specimens (SRSs) of 49 patients with BC. We found that the expression of TGFβ1 at protein level was significantly higher in both tumor epithelial and benign stromal cells in the SRSs (p=0.001), whereas the expression of TGFβRII in tumor cells was lower (p=0.001). The frequency of intra tumoral CD8 and CD4 positive T lymphocytes was lower in SRSs (p=0081 and p=0001, respectively), while in the peripheral stroma their prevalence was increased (p=0001 and p=0012, respectively). Our results show that CNB changes the hallmarks of the TGFβ path way in early BC. These CNB-induced changes in the tumor and in its microenvironment suggest that the procedure may change the immunological anti-tumor response of the host.

Bioinformatics design of a peptide vaccine containing sarcoma antigen NY-SAR-35 epitopes against breast cancer and evaluation of its immunological function in BALB/c mouse model.

The development of a cancer vaccine has become an essential focus in the field of medical biotechnology and immunology. In our study, the NY-SAR-35 cancer/testis antigen was targeted to design a novel peptide vaccine using bioinformatics tools, and BALB/c mice were used to evaluate the vaccine's immunological function. This evaluation involved assessing peptide-specific IgG levels in the serum via ELISA and measuring the levels of IFN-γ, IL-4, and granzyme B in the supernatant of cultured splenocytes. The final vaccine construct consisted of two T lymphocyte epitopes linked by the AAY linker. This construct displayed high antigenicity, non-allergenicity, non-toxicity, stability, and ability to induce IFN-γ and IL-4. It showed stable dynamics with both human MHC-I and II molecules, as well as mouse MHC-II molecules, and revealed strong Van der Waals and electrostatic energies. Emulsifying our peptide vaccine in incomplete Freund's adjuvant resulted in a remarkable increase in the levels of IgG. The splenocytes of mice that received the combination of peptide and adjuvant displayed a noteworthy increase in IFN-γ, IL-4, and granzyme B secretion. Additionally, their lymphocytes exhibited higher proliferation rates compared to the control group. Our data demonstrated that our vaccine could stimulate a robust immune response, making it a promising candidate for cancer prevention. However, clinical trials are necessary to assess its efficacy in humans.

Potent Immunomodulators Developed from an Unstable Bacterial Metabolite of Vitamin B2 Biosynthesis

AbstractBacterial synthesis of vitamin B2 generates a by‐product, 5‐(2‐oxopropylideneamino)‐d‐ribityl‐aminouracil (5‐OP‐RU), with potent immunological properties in mammals, but it is rapidly degraded in water. This natural product covalently bonds to the key immunological protein MR1 in the endoplasmic reticulum of antigen presenting cells (APCs), enabling MR1 refolding and trafficking to the cell surface, where it interacts with T cell receptors (TCRs) on mucosal associated invariant T lymphocytes (MAIT cells), activating their immunological and antimicrobial properties. Here, we strategically modify this natural product to understand the molecular basis of its recognition by MR1. This culminated in the discovery of new water‐stable compounds with extremely powerful and distinctive immunological functions. We report their capacity to bind MR1 inside APCs, triggering its expression on the cell surface (EC50 17 nM), and their potent activation (EC50 56 pM) or inhibition (IC50 80 nM) of interacting MAIT cells. We further derivatize compounds with diazirine‐alkyne, biotin, or fluorophore (Cy5 or AF647) labels for detecting, monitoring, and studying cellular MR1. Computer modeling casts new light on the molecular mechanism of activation, revealing that potent activators are first captured in a tyrosine‐ and serine‐lined cleft in MR1 via specific pi‐interactions and H‐bonds, before more tightly attaching via a covalent bond to Lys43 in MR1. This chemical study advances our molecular understanding of how bacterial metabolites are captured by MR1, influence cell surface expression of MR1, interact with T cells to induce immunity, and offers novel clues for developing new vaccine adjuvants, immunotherapeutics, and anticancer drugs.

Potent Immunomodulators Developed from an Unstable Bacterial Metabolite of Vitamin B2 Biosynthesis.

Bacterial synthesis of vitamin B2 generates a by-product, 5-(2-oxopropylideneamino)-d-ribityl-aminouracil (5-OP-RU), with potent immunological properties in mammals, but it is rapidly degraded in water. This natural product covalently bonds to the key immunological protein MR1 in the endoplasmic reticulum of antigen presenting cells (APCs), enabling MR1 refolding and trafficking to the cell surface, where it interacts with T cell receptors (TCRs) on mucosal associated invariant T lymphocytes (MAIT cells), activating their immunological and antimicrobial properties. Here, we strategically modify this natural product to understand the molecular basis of its recognition by MR1. This culminated in the discovery of new water-stable compounds with extremely powerful and distinctive immunological functions. We report their capacity to bind MR1 inside APCs, triggering its expression on the cell surface (EC50 17 nM), and their potent activation (EC50 56 pM) or inhibition (IC50 80 nM) of interacting MAIT cells. We further derivatize compounds with diazirine-alkyne, biotin, or fluorophore (Cy5 or AF647) labels for detecting, monitoring, and studying cellular MR1. Computer modeling casts new light on the molecular mechanism of activation, revealing that potent activators are first captured in a tyrosine- and serine-lined cleft in MR1 via specific pi-interactions and H-bonds, before more tightly attaching via a covalent bond to Lys43 in MR1. This chemical study advances our molecular understanding of how bacterial metabolites are captured by MR1, influence cell surface expression of MR1, interact with T cells to induce immunity, and offers novel clues for developing new vaccine adjuvants, immunotherapeutics, and anticancer drugs.

Coordinated inflammation and immune response transcriptional regulation in breast cancer molecular subtypes.

Breast cancer, characterized by its complexity and diversity, presents significant challenges in understanding its underlying biology. In this study, we employed gene co-expression network analysis to investigate the gene composition and functional patterns in breast cancer subtypes and normal breast tissue. Our objective was to elucidate the detailed immunological features distinguishing these tumors at the transcriptional level and to explore their implications for diagnosis and treatment. The analysis identified nine distinct gene module clusters, each representing unique transcriptional signatures within breast cancer subtypes and normal tissue. Interestingly, while some clusters exhibited high similarity in gene composition between normal tissue and certain subtypes, others showed lower similarity and shared traits. These clusters provided insights into the immune responses within breast cancer subtypes, revealing diverse immunological functions, including innate and adaptive immune responses. Our findings contribute to a deeper understanding of the molecular mechanisms underlying breast cancer subtypes and highlight their unique characteristics. The immunological signatures identified in this study hold potential implications for diagnostic and therapeutic strategies. Additionally, the network-based approach introduced herein presents a valuable framework for understanding the complexities of other diseases and elucidating their underlying biology.

Known pathogenic gene variants and new candidates detected in sudden unexpected infant death using whole genome sequencing.

The purpose of this study is to gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID). Whole Genome Sequencing (WGS) was performed on 144 infants that succumbed to SUID, and 573 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences. Variants of interest were identified in 88 genes, in 64.6% of our cohort. Seventy-three of these have been previously associated with SIDS/SUID/SUDP. Forty-three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders and in two genes associated with immunological function. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy-two infants met the triple risk hypothesis criteria. Our study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism have important mechanistic implications for the pathophysiology of SUID.

Comprehensive analysis of EphA2 in pan-cancer: A prognostic biomarker associated with cancer immunity.

Several studies have reported a significant relationship between Ephrin receptor A2 (EphA2) and malignant progression in numerous cancers. However, there is a lack of comprehensive pan-cancer analysis on the prognostic value, mutation status, methylation landscape, and potential immunological function of EphA2. Using The Cancer Genome Atlas, Genotype Tissue Expression Database and GEO data, we analysed the differences in EphA2 expression between normal and tumour tissues and the effects of EphA2 on the prognosis of different tumours. Furthermore, using GSCALite, cBioPortal, TISDB, ULCLAN and TIMER 2.0 databases or platforms, we comprehensively analysed the potential oncogenic mechanisms or manifestations of EphA2 in 33 different tumour types, including tumour mutation status, DNA methylation status and immune cell infiltration. The correlation of EphA2 with immune checkpoints, tumour mutational burden, DNA microsatellite instability and DNA repair genes was also calculated. Finally, the effects of EphA2 inhibitors on the proliferation of human glioma and lung cancer cells were verified in cellular experiments. EphA2 is differentially expressed in different tumours, and patients with overexpression have poorer overall survival. In addition, gene mutations, gene copy number variation and DNA/RNA methylation of EphA2 have been identified in various tumours. Moreover, EphA2 is positively associated with immune infiltration involving macrophages and CD8+ T cells. Further, EphA2 mRNA expression is significantly associated with immune checkpoint in various cancers, especially programmed death-ligand 1. Finally, the EphA2 inhibitor ALW-II-41-27 shows potent anti-tumour activity. Our first pan-cancer study of EphA2 provides insight into the prognostic and immunological roles of EphA2 in different tumours, suggesting that EphA2 might be a potential biomarker for poor prognosis and immune infiltration in cancer.

Identification of a New B-Cell Epitope on the Capsid Protein of Avian Leukosis Virus and Its Application.

Avian leukosis virus (ALV) is an avian oncogenic retrovirus that can impair immunological function, stunt growth and decrease egg production in avian flocks. The capsid protein (P27) is an attractive candidate for ALV diagnostics. In the present study, a new hybridoma cell (1F8) stably secreting an anti-P27 monoclonal antibody (mAb) was developed. The mAb exhibited a high affinity constant (Ka) of 8.65 × 106.0 L/mol, and it could be used for the detection of ALV-A/B/J/K strains. Moreover, a total of eight truncated recombinant proteins and five synthetic polypeptides were utilized for the identification of the B-cell epitopes present on P27. The results revealed that 218IIKYVLDRQK227 was the minimal epitope recognized by 1F8, which had never been reported before. Additionally, the epitopes could strongly react with different ALV subgroup's specific positive serum and had a complete homology among all the ALV subgroups strains. Finally, a new sandwich ELISA method was created for the detection of ALV antigens, demonstrating increased sensitivity compared to a commercially available ELISA kit. These results offer essential knowledge for further characterizing the antigenic composition of ALV P27 and will facilitate the development of diagnostic reagents for ALV.

An Integrative Network Pharmacology and Bioinformatics Approach for Deciphering the Multi-target Effect of Nyctanthes arbortristis L. against COVID-19.

The COVID-19 pandemic represents a significant challenge across scientific, medical, and societal dimensions. The unpredictability of the disease progression, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), underscores the urgent need for identifying compounds that target multiple aspects of the virus to ensure swift and effective treatment. Nyctanthes arbortristis L., a delicate, perennial, deciduous shrub found across various Asian regions, has been recognized for its wide range of pharmacological benefits, including hepatoprotective, antimalarial, antibacterial, anti-inflammatory, antioxidant, and antiviral properties. Various in vitro studies revealed the therapeutic significance of Nyctanthes arbortristis against COVID-19. However, the exact molecular mechanism remains unclarified. In the present study, a network pharmacology approach was employed to uncover the active ingredients, their potential targets, and signaling pathways in Nyctanthes arbortristis for the treatment of COVID-19. In the framework of this study, we explored the active ingredient-target-pathway network and figured out that naringetol, ursolic acid, betasitosterol, and daucosterol decisively contributed to the development of COVID-19 by affecting IL6, MAPK3, and MDM2 genes. The results of molecular docking analysis indicated that Nyctanthes arbortristis exerted effective binding capacity in COVID-19. Further, we disclosed the targets, biological functions, and signaling pathways of Nyctanthes arbortristis in COVID-19. The analysis indicated that Nyctanthes arbortristis could help treat COVID-19 through the enhancement of immunologic functions, inhibition of inflammatory reactions and regulation of the cellular microenvironment. In short, the current study used a series of network pharmacologybased and computational analyses to understand and characterize the binding capacity, biological functions, pharmacological targets and therapeutic mechanisms of Nyctanthes arbortristis in COVID-19. However, the findings were not validated in actual COVID-19 patients, so further investigation is needed to confirm the potential use of Nyctanthes arbortristis for treating COVID-19.

Size and Surface Properties of Functionalized Organosilica Particles Impact Cell-Particle Interactions Including Mitochondrial Activity.

Understanding of the interactions between macrophages and multifunctional nanoparticles is important for development of novel macrophage-based immunotherapies. Here, we investigated the effects of fluorescent thiol-organosilica particle size and surface properties on cell-particle interactions, including mitochondrial activity, using the mouse macrophage cell line J774A.1. Three different sizes of thiol-organosilica particles (150, 400, and 680 nm in diameter) containing fluorescein (OS/F150, OS/F400, and OS/F680) and particles surface functionalized with polyethylenimine (PEI) (OS/F150PEI, OS/F400PEI, and OS/F680PEI) were prepared. Flow cytometric analysis, time-lapse imaging, and single-cell analysis of particle uptake and mitochondrial activity of J774A.1 cells demonstrated variations in uptake and kinetics depending on the particle size and surface as well as on each individual cell. Cells treated with OS/F150 and OS/F150PEI showed higher uptake and mitochondrial activity than those treated with other particles. The interaction between endosomes and mitochondria was observed using 3D fluorescent imaging and was characterized by the involvement of iron transport into mitochondria by iron-containing proteins adsorbed on the particle surface. Scanning electron microscopy of the cells treated with the particles revealed alterations in cell membrane morphology, depending on particle size and surface. We performed correlative light and electron microscopy combined with time-lapse and 3D imaging to develop an integrated correlation analysis of particle uptake, mitochondrial activity, and cell membrane morphology in single macrophages. These cell-specific characteristics of macrophages against functional particles and their evaluation methods are crucial for understanding the immunological functions of individual macrophages and developing novel immunotherapies.

Predicting radiation-induced immune suppression in lung cancer patients treated with stereotactic body radiation therapy.

Stereotactic body radiation therapy (SBRT) is known to modulate the immune system and contribute to the generation of anti-tumor T cells and stimulate T cell infiltration into tumors. Radiation-induced immune suppression (RIIS) is a side effect of radiation therapy that can decrease immunological function by killing naive T cells as well as SBRT-induced newly created effector T cells, suppressing the immune response to tumors and increasing susceptibility to infections. RIIS varies substantially among patients and it is currently unclear what drives this variability. Models that can accurately predict RIIS in near real time based on treatment plan characteristics would allow treatment planners to maintain current protocol specific dosimetric criteria while minimizing immune suppression. In this paper, we present an algorithm to predict RIIS based on a model of circulating blood using early stage lung cancer patients treated with SBRT. This Python-based algorithm uses DICOM data for radiation therapy treatment plans, dose maps, patient CT data sets, and organ delineations to stochastically simulate blood flow and predict the doses absorbed by circulating lymphocytes. These absorbed doses are used to predict the fraction of lymphocytes killed by a given treatment plan. Finally, the time dependence of absolute lymphocyte count (ALC) following SBRT is modeled using longitudinal blood data up to a year after treatment. This model was developed and evaluated on a cohort of 64 patients with 10-fold cross validation. Our algorithm predicted post-treatment ALC with an average error of cells/L with 89% of the patients having a prediction error below 0.5×109 cells/L. The accuracy was consistent across a wide range of clinical and treatment variables. Our model is able to predict post-treatment ALC<0.8 (grade 2 lymphopenia), with a sensitivity of 81% and a specificity of 98%. This model has a ∼38-s end-to-end prediction time of post treatment ALC. Our model performed well in predicting RIIS in patients treated using lung SBRT. With near-real time model prediction time, it has the capability to be interfaced with treatment planning systems to prospectively reduce immune cell toxicity while maintaining national SBRT conformity and plan quality criteria.

Daily diary engagement among caregivers of patients undergoing hematopoietic stem cell transplant.

e23064 Background: Caregivers of allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients bear significant responsibilities involving commitment to be available 24/7 up to at least 100 days post-transplant to provide emotional and physical support to their patients. Caregiving for such an extended duration is associated with reduced quality of life, compromised psychological well-being, and dysregulated metabolic and immunological functioning. Ecological momentary assessment (EMA) may allow a better understanding of the dynamic day-to-day experiences of this unique population. However, no prior research on EMA exists in this population. This study reports on the feasibility of delivering EMAs in the form of a daily diary (DD) and how completion of the DD relates to the patient’s course of treatment and caregiver’s demographics among the caregivers of allo-HSCT caregivers. Results are part of an ongoing 3-arm randomized controlled trial (71% enrolled to date) of those individuals randomized to the usual care condition. Methods: Caregivers (n = 46) received DD prompts for 6 weeks during their patient’s active treatment phase: before transplant (week 1), transplant through discharge (weeks 2 and 3), after discharge (weeks 3 through 6). The DD included six affect items from the Positive and Negative Affect Schedule (stressed, overwhelmed, frustrated, drained, guilty, and hopeful), three state mindfulness items (attention, non-judgement, and decentering), and one item related to caregiver’s self-efficacy in patient care. Results: Among 46 caregivers (mean age = 55.8 [SD = 15.7], 74% female, 32% retired), the overall completion rate (CR = total number of prompts completed/total number of prompts received) was 65.5%, with 72% of participants completing &gt; 50% and 22% of participants completing &gt; 85% of the prompts. For the duration before transplant, the overall CR was 63.2%, with 66.7% of participants completing &gt; 50%, and 33.3% completing &gt; 85% of the prompts. For the duration between transplant through discharge, the overall CR was 65.57%, with 76% of participants completing &gt; 50%, and 26% completing &gt; 85% of the prompts. Similarly, for the duration after discharge, the overall CR was 65.14%, with 66.7% completing &gt; 50%, and 28.9% completing &gt; 85% of the prompts. DD completion was not related to the caregiver’s age, sex, or employment status ( ps &gt; 0.1). Conclusions: The completion rate for the DD was very similar across the patient’s course of treatment, suggesting EMA completion is not excessively burdensome for caregivers potentially experiencing dynamic distress. Furthermore, EMA completion was not associated with age, sex, or employment status, indicating that all caregivers, regardless of demographics, were amenable to completing EMAs. Our findings suggest that delivering EMAs is feasible in this population. Clinical trial information: NCT05078229 .

Co-infection with Mycobacterium tuberculosis and Mycobacterium avium in an HIV-positive patient – Case Report

Abstract Introduction: The association between Mycobacterium tuberculosis and the Human Immunodeficiency Virus can accelerate the deterioration of immunological functions. The risks are even more accentuated in the situation of a Non-tuberculous Mycobacterium and Mycobacterium tuberculosis co-infection. Case presentation: We present the case of a 59-year-old male patient, who was admitted at the hospital with non-specific symptoms. Further investigations reveal a remarkable particularity about the case: The infection with Mycobacterium tuberculosis was urogenital, whereas the one with Non-tuberculous mycobacteria was pulmonary. Conclusion: Both Mycobacterium tuberculosis and Non-tuberculous strains can exist within the same infection, posing great difficulties for diagnosis, as well as the treatment scheme.

Association of gut dysbiosis with first‑episode psychosis (Review).

The gut‑microbiota‑brain axis is a complex bidirectional communication system linking the gastrointestinal tract to the brain. Changes in the balance, composition and diversity of the gut‑microbiota (gut dysbiosis) have been found to be associated with the development of psychosis. Early‑life stress, along with various stressors encountered in different developmental phases, have been shown to be associated with the abnormal composition of the gut microbiota, leading to irregular immunological and neuroendocrine functions, which are potentially responsible for the occurrence of first‑episode psychosis (FEP). The aim of the present narrative review was to summarize the significant differences of the altered microbiome composition in patients suffering from FEP vs. healthy controls, and to discuss its effects on the occurrence and intensity of symptoms in FEP.

#2932 Our experience in combined and simultaneous liver-kidney transplantation: recipient and kidney graft survival

Abstract Background and Aims Simultaneous combined liver-kidney transplantation is a definitive treatment in patients with terminal failure of both organs, but sometimes, assessing the indication for said combined transplantation can be difficult. The liver from the same donor as the kidney graft protects the kidney immunologically and this provides long-term follow-up with a lower risk of rejection. No such protection is observed when both organs come from different cadaveric donors. There are no differences in graft survival in simultaneous or isolated transplants (liver or kidney), being prolonged in both cases. However, patient survival is lower, due to the complexity of this procedure and the clinical characteristics of the patients. The main aim is to analyze the evolution of patients with combined and simultaneous liver-kidney transplantation in our center in terms of graft survival and overall survival of the recipient. Method It is a retrospective observational study. The computerized clinical history of 50 patients with combined liver-kidney transplantation was reviewed from August 1998 to November 2023. The data were recorded in an Excell-type database. Descriptive and inferential statistics were performed for the analysis. Results 50 combined liver-kidney transplants have been performed, of which 28 (56%) died, and 23 of them (82%) with the kidney graft functioning. The main causes of death were neoplasms (11 patients) and infections (7 patients). The survival of the patients at 5 years was approximately 70%. There were 5 cases of kidney graft loss, excluding death. Chronic rejection was the main cause (70-80%) of kidney graft loss. 60% received a kidney transplant again and died with the graft functioning; 20% died while on hemodialysis; and the remaining 20% are awaiting hemodialysis and are being studied for another kidney transplant. Conclusion Simultaneous liver and kidney transplantation is a good therapeutic option for patients with terminal disease of both organs. However, it is a complex procedure in patients with multiple comorbidities, which affects overall survival. In contrast, kidney graft survival is prolonged and many recipients die with functioning grafts. It seems to be related to the immunological protective function of the liver. Consequently, there are few rejections and, the vast majority are chronic rejection.

Variable Syndromic Immunodeficiency in Patients with Biallelic PRIM1 Mutations

Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.

Immunotherapy in the context of sepsis-induced immunological dysregulation.

Sepsis is a clinical syndrome caused by uncontrollable immune dysregulation triggered by pathogen infection, characterized by high incidence, mortality rates, and disease burden. Current treatments primarily focus on symptomatic relief, lacking specific therapeutic interventions. The core mechanism of sepsis is believed to be an imbalance in the host's immune response, characterized by early excessive inflammation followed by late immune suppression, triggered by pathogen invasion. This suggests that we can develop immunotherapeutic treatment strategies by targeting and modulating the components and immunological functions of the host's innate and adaptive immune systems. Therefore, this paper reviews the mechanisms of immune dysregulation in sepsis and, based on this foundation, discusses the current state of immunotherapy applications in sepsis animal models and clinical trials.

The IL-12 family of heterodimeric cytokines in polycystic ovarian syndrome: biological role in induction, regulation, and treatment.

Polycystic ovary syndrome (PCOS) is a diverse endocrine disorder widely recognized as the prevailing metabolic condition among women in their reproductive years. The precise pathophysiological mechanisms underlying PCOS remain incompletely understood. However, existing evidence suggests that the development of PCOS may be linked to factors such as abdominal obesity, hyperandrogenism, and insulin resistance (IR). Excessive central adiposity in women with PCOS may lead to the development of a chronic, low-grade inflammation characterized by the activation of proinflammatory cytokines. The cytokines that belong to the IL-12 family are a collection of distinct heterodimeric cytokines that include IL-12, IL-23, IL-27, and IL-35. Recent research has provided further evidence regarding the significance of IL-12 cytokines in influencing both innate and adaptive immune responses in different diseases. Additionally, these studies have discovered diverse roles for certain members of the IL-12 family, encompassing multiple immunological functions that can either act as effectors or regulators. In this discourse, we examine the distinctive and atypical structural and functional attributes of this particular cytokine family. This study aims to offer a comprehensive overview of the pathophysiological significance of the IL-12 family cytokines in PCOS patients. Additionally, the therapeutic potential of the cytokines as novel approaches for PCOS treatment will be proposed.

An ovine model for investigation of the microenvironment of the male mammary gland.

The specific biology of the male breast remains relatively unexplored in spite of the increasing global prevalence of male breast cancer. Delineation of the microenvironment of the male breast is restricted by the low availability of human samples and a lack of characterisation of appropriate animal models. Unlike the mouse, the male ovine gland persists postnatally. We suggest that the male ovine mammary gland constitutes a promising adjunctive model for the male breast. In this study, we evaluate the male ovine mammary gland microenvironment, comparing intact and neutered males. Assessment of the glandular histo-anatomy highlights the resemblance of the male gland to that of neonatal female sheep and confirms the presence of rudimentary terminal duct lobular units. Irrespective of neutered status, cell proliferation in epithelial and stromal compartments is similarly low in males, and cell proliferation in epithelial cells and in the intralobular stroma is significantly lower than in pubertal female sheep. Between 42% and 72% of the luminal mammary epithelial cells in the male gland express the androgen receptor and expression is significantly reduced by neutering. Luminal epithelial cells within the intact and neutered male gland also express oestrogen receptor alpha, but minimal progesterone receptor expression is observed. The distribution of leukocytes within the ducts and stroma is similar to the mammary gland of female sheep and females of other species. Both macrophages and T lymphocytes are intercalated in the epithelial bilayer and are more abundant in the intralobular stroma than the interlobular stroma, suggesting that they may have a protective immunological function within the vestigial glandular tissue of the male sheep. Mast cells are also observed within the stroma. These cells cluster near the glandular tissue and are frequently located adjacent to blood vessels. The abundance of mast cells is significantly higher in intact males compared to neutered males, suggesting that hormone signalling may impact mast cell recruitment. In this study, we demonstrate the utility of the male ovine mammary gland as a model for furthering our knowledge of postnatal male mammary biology.