Immuno, Volume 5, Issue 1 (March 2025) – 10 articles

Hematopoietic stem cell transplantation is one of the most intricate immune therapies used for patients with hematological diseases or immune disorders. In addition to the inherent immunosuppression from their primary condition, many of these patients usually receive cytotoxic chemotherapy, radiation therapy, broad-spectrum antibiotics, or experience extended nutritional perturbations. These factors collectively lead to inflammation and the disruption of gut microbiota. Additionally, about 40–60% of patients undergoing fully HLA-matched allogeneic transplantation are expected to develop acute graft-versus-host disease (aGVHD), even with prophylactic measures such as calcineurin inhibitors, methotrexate/mycophenolate, or post-transplant cyclophosphamide treatment. Recent research has elucidated the complex interplay between immune effectors in the gastrointestinal tract and microbial populations within a proinflammatory peri-transplant environment, revealing its significant effect on survival and post-transplant complications such as aGVHD. This review will explore the relationship between dysbiosis during allogeneic transplantation and mechanisms that can help clarify the link between gut microbiota and the risk of GVHD, along with emerging therapeutic strategies aimed at addressing dysbiosis during hematopoietic stem cell transplantation. Full article

The immune system’s ability to detect and eliminate transformed cells is a critical factor in suppressing cancer development. However, immune surveillance in tumors is often disrupted by various immune escape mechanisms, many of which remain poorly understood. The Natural Killer Group 2D (NKG2D) receptor is an activating receptor expressed on natural killer (NK) cells and cytotoxic T lymphocytes. It can recognize and bind with varying affinities to a wide range of structurally diverse ligands, including MHC class I chain-related proteins A and B (MICA and MICB) and members of the ULBP family (ULBP1-6). The expression of these ligands plays a crucial role in immune antitumor responses and cancer immunoevasion mechanisms. Some evidence suggests that functional polymorphisms in the NKG2D receptor and the genes encoding its ligands significantly influence HLA-independent cancer immunosurveillance. Consequently, the NKG2D-NKG2D ligands (NKG2DLs) axis represents a promising target for developing novel therapeutic strategies. This review aims to provide a general overview of the role of NKG2D and its ligands in various malignancies and explore their potential in advancing personalized cancer treatment protocols. Full article

NK cells have traditionally been classified as effectors of innate immunity, even though they also exhibit some features of adaptive immunity such as memory. NK cells contribute to the lysis and growth inhibition of cancer, mediating direct cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) and regulating the functions of other immune cells, respectively. NK cells regulate the function of other immune cells via the release of inflammatory cytokines and chemokines. Currently, NK cell therapeutics in oral cancer have been less efficient due to several limitations, as follows: (a) lower percentages of NK cells in peripheral blood immune cells; (b) limited survival and decreased function of NK cells, especially in the tumor microenvironment; and (c) a lack of tools or methodologies to expand and activate NK cells to the levels that are required for the effective targeting of oral cancer. To overcome these limitations, we established and demonstrated a novel technology for activating and expanding highly functional NK cells coined as supercharged NK (sNK) cells. This review summarizes the characteristics of sNK cells and highlights their superior anti-cancer activity when compared to primary activated NK cells. Full article

T cell phenotypes and kinetics are emerging as crucial factors associated with immunotherapeutic responses in a wide range of solid cancer types. However, challenges remain in understanding the spatial and temporal profiles of T cells with differential phenotypes due to difficulties in single-cell analysis with preserved tissue structures. Here, we provide an optimized 12-marker multiplex immunohistochemical (IHC) panel and single-cell-based quantitative assessment to identify the spatial distributions of T cell phenotypes in formalin-fixed paraffin-embedded sections. This panel revealed differential T cell populations with spatial localizations in human tonsil tissue, where the percentages of CD8⁺ T cell-expressing programmed death receptor-1 (PD-1), T cell immunoglobulin and mucin domain 3 (TIM3), and other T cell phenotypic markers vary by tonsillar tissue components such as follicles, parenchyma, and epithelium. A specimen from salivary gland adenocarcinoma during hyper-progression, followed by anti-PD-1 treatment, exhibited the exclusion of CD8⁺ T cells from the intratumoral regions. Although the vast majority of peritumoral CD8⁺ T cells exhibited proliferative effector T cell phenotypes with PD-1⁻TIM3⁻Ki67⁺CD45RA⁺, intratumoral CD8⁺ T cells showed exhausted phenotypes with PD-1⁺TIM3⁻ and increased Eomes expression, which might be related to poor therapeutic response in this case. To verify these findings in the context of temporal changes, we analyzed six longitudinal samples from a single patient with maxillary sinus cancer, observing increased T cell exhaustion along with metastasis and progression. Together, highly multiplexed IHC can be applied to analyze the spatiotemporal phenotypes of T cells, potentially contributing to the understanding of the mechanisms of resistance to immunotherapy. Full article

Systemic autoimmune diseases (SAIDs) affect millions worldwide, presenting significant clinical challenges due to their complex pathogenesis and limited treatment options. Traditional immunosuppressive therapies, while effective, often lack precision, leading to significant side effects and inadequate disease control. Recent advances in synthetic immunology offer promising avenues for precise, targeted interventions in SAIDs. This review examines the latest innovations in synthetic immunology for treating autoimmune diseases, focusing on engineered immune cells, synthetic biologics, and gene-editing technologies. It explores the therapeutic potential of these approaches to modulate immune tolerance, reduce systemic inflammation, and enhance patient-specific treatment efficacy. However, despite these promising developments, challenges remain, including immune system complexity, safety concerns, and regulatory hurdles that may hinder clinical translation. This review aims to consolidate current advancements, address existing barriers, and outline potential future directions for synthetic immunology in autoimmune disease management, highlighting synthetic immunology’s role in transforming the therapeutic landscape for SAIDs. Full article

Social behavior restrictions, social distancing, and promotion of non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic have significantly reduced the incidence of many epidemic infections in the world, especially in children. Resurges of infectious diseases vary depending on the biological characteristics of each infectious pathogen and differences in culture, lifestyle, and infection control mitigation policies by country or region. Although the gapping of infectious disease outbreaks can cause children who were uninfected during that period to become more susceptible to infection after the pandemic, resulting in a slightly older age of infected children, there are no conclusive reports that suggest a definite impact on the development of children’s immune maturation or its balance. Insufficient immune challenges in early life may influence the risk of developing immune-mediated conditions such as allergies or autoimmune diseases later in life, though evidence for this is still emerging. Future observational studies are needed to determine the long-term impact of the epidemic gap caused by the COVID-19 pandemic as well as the long-term impact of COVID-19 infection itself on the immune function or balance of children. Full article

Sex-based differences in innate immunity may play a crucial role in susceptibility to and progression of tuberculosis (TB), a disease that disproportionately affects men. This study aimed to examine whether early host–pathogen interactions contribute to the heightened vulnerability of males to Mycobacterium tuberculosis (Mtb) infection. Using recombination activating gene 2 knockout (RAG2 KO) mice, which lack adaptive immunity, we were able to isolate and analyze innate immune responses to Mtb without the influence of T and B cells. Surprisingly, and in stark contrast to wild-type mice that reflect the male bias as observed in humans, female RAG2 KO mice were more susceptible to Mtb than their male counterparts. Increased lung CFU in females was accompanied by a significant rise in inflammation, indicated by elevated levels of inflammatory cytokines and chemokines, as well as a massive influx of neutrophils into the lungs. In contrast, male mice exhibited higher levels of IFN-γ and CCL5, along with a greater presence of NK cells in their lungs, suggesting that, in the absence of adaptive immunity, males benefit from a more robust NK cell response, potentially offering greater protection by better controlling inflammation and slowing disease progression. Full article

Lawsonia intracellularis is a Gram-negative, intracellular bacterium that can infect several animal species. In pigs, the bacteria cause porcine proliferative enteropathy, or ileitis. The wide spread of the pathogen produces a large impact on pig production worldwide. Saliva is a source of biomarkers that can help to monitor changes in the immune system after vaccination. The purpose of this study was to study the changes in haptoglobin (Hp), immunoglobulin G (IgG), and adenosine deaminase (ADA) in saliva after vaccination against Lawsonia intracellularis. In addition, productivity parameters were analysed to evaluate if vaccination and changes in salivary analytes could be associated with changes in these parameters. The pigs vaccinated against Lawsonia showed an improvement in the productive parameters and a reduction in food conversion and frequency of diseases. In addition, they showed lower values of Hp (p = 0.011), IgG (p < 0.01), and ADA (p < 0.003) in saliva during the first two months of the fattening period compared to non-vaccinated pigs. It could be concluded that in our experimental conditions, the vaccination against Lawsonia intracellularis produced a significant decrease in biomarkers of the immune response in saliva compared with the non-vaccinated pigs. This would indicate a reduction in the activation of the immune system, which could be postulated to be due to the increased defence ability of the organism against pathogens. This reduced activation of the immune system can lead to better food conversion and an increase in the productive parameters of these pigs. Overall, this report opens a new window for the possible use of saliva for non-invasive evaluation of the immune system after vaccination in pigs. Full article

Dendritic cells (DCs) play a crucial role in controlling viral infections. Little is known about the changes in frequencies of the DC subsets in patients with chronic hepatitis C (CHC), particularly in the era of interferon-free regimens. We aimed to evaluate the impact of sofosbuvir/daclatasvir on the frequency of different peripheral DC subsets, the expression of the inhibitory CD200R and its ligand CD200 on DC, and their relation to the treatment outcome. A total of 1000 patients with CHC were enrolled and treated with a fixed oral dose of 400 mg of sofosbuvir and 60 mg of daclatasvir for 12 weeks. A total of 940 patients achieved sustained virologic response (SVR), and only 60 patients were non-responders (NRs). The frequencies of the peripheral plasmacytoid (pDC) and myeloid (mDCs) subsets and their surface expressions of CD200R and CD200 molecules were analyzed using flow cytometry. This analysis included 60 non-responders (NR group), 60 randomly selected sustained virologic responders (SVR group) at baseline, and at the end of treatment, and 60 healthy controls. HCV infection was associated with a down-regulation in the frequency of mDC, compared to healthy controls. In addition, mDC in HCV-infected patients showed lower levels of CD200R. However, neither the pDC frequency nor their CD200R expression was significantly altered. Interestingly, by the end of therapy, the frequencies of circulating mDCs and CD200R⁺mDC increased significantly in the SVR group and were even comparable to healthy controls. The levels of these cells were not normalized in the NR group. Percentages of mDCs and CD200R⁺mDC subsets showed good prognostic accuracy for predicting virologic response to therapy. Our results showed that HCV infection was associated with modulation of the mDC frequency and their surface expression of CD200R. Successful daclatasvir and sofosbuvir combined therapy was associated with the normalization of the percentages of mDC and CD200R⁺mDC. Full article

Exostosin 1 (EXT1) encodes a type II transmembrane glycosyltransferase residing in the endoplasmic reticulum and plays an essential role in the elongation of heparan sulfate chain biosynthesis. Additionally, EXT1 may act as an oncogene that could promote cell proliferation as well as cancer cell metastasis. Herein, we investigated EXT1’s expression pattern and prognostic value in breast cancer, along with its immunological implications. Immunohistochemical staining of EXT1 was assessed in 85 breast cancer patients. Patients were categorized into molecular subtypes, namely luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2), along with triple-negative breast cancer (TNBC). Correlations of EXT1 immunostaining with clinicopathological parameters were evaluated. Furthermore, the correlations of EXT1 expression with tumor immune infiltration and immune cell surface markers were assessed using TIMER. Moreover, survival analysis was conducted to reveal EXT1’s prognostic value. EXT1 expression was markedly associated with the status of the estrogen receptor (ER), molecular subtypes, and recurrence status. In addition, high levels of EXT1 expression were associated with worse overall survival (OS) and relapse-free survival (RFS). Analysis of immune infiltration indicated that EXT1 expression was positively correlated with dendritic cells (DCs), macrophages, neutrophils, CD4⁺ T cells, and CD8⁺ T cells, although it showed a negative correlation with the tumor purity. Overall, this study suggests that the elevated EXT1 expression, particularly in TNBC, has a positive correlation with poor prognosis and with immune-infiltrated cells in breast cancer. Therefore, it may emerge as an independent prognostic biomarker, immunological marker, and potential future therapeutic target for the most aggressive TNBC subtype. Full article