Since the first clinical approval in 2017, chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most powerful modalities for redirecting the immune response against cancer. Building on decades of foun...Since the first clinical approval in 2017, chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most powerful modalities for redirecting the immune response against cancer. Building on decades of foundational discoveries in T cell biology and synthetic immunoengineering, CAR T cell therapy has transformed the treatment of B cell malignancies, resulting in durable remissions in patients with B cell leukaemias, lymphomas and multiple myeloma. Next-generation CAR designs are now expanding the reach of this approach into autoimmune disease and solid tumours. Innovations in gene editing, allogeneic manufacturing and in vivo delivery are improving the scalability, safety and accessibility of CAR T cell therapies, although challenges persist in overcoming antigen heterogeneity and tumour microenvironmental barriers and in promoting the long-term persistence of CAR T cells. In this Review, we summarize the key discoveries that laid the foundations for CAR T cell therapies and provide a broad overview of the current principles of CAR design, their clinical development and emerging strategies aimed at enhancing efficacy, broadening indications and achieving durable immune control across disease types.
Macrophages are essential components of the innate immune system and have crucial roles in host defence, tissue homeostasis and inflammation. Embryonic macrophages are specialized populations of macrophages that arise ea...Macrophages are essential components of the innate immune system and have crucial roles in host defence, tissue homeostasis and inflammation. Embryonic macrophages are specialized populations of macrophages that arise early during development and contribute to tissue organization, immune system development and homeostasis. These cells originate from yolk sac and fetal liver progenitors and colonize various tissues during embryogenesis, becoming long-lived tissue-resident macrophages. In the embryo, macrophages are involved in a wide range of developmental processes, including the clearance of apoptotic cells, regulation of organogenesis and establishment of tissue integrity. They are also pivotal in the early establishment of immune tolerance and in the development of the fetal haematopoietic and immune systems. Plenty of literature covers the role of yolk sac-derived macrophages in adult tissues, whereas less is known about their functions in the embryo itself. This Review highlights our emerging understanding of embryonic macrophages, their origin and their roles in organogenesis and development in mice and humans.
Psoriatic disease is characterised by persistent immune activation that is closely linked to tissue context and clinical severity. How immune metabolism is organised within inflamed skin and across systemic immune compar...Psoriatic disease is characterised by persistent immune activation that is closely linked to tissue context and clinical severity. How immune metabolism is organised within inflamed skin and across systemic immune compartments remains incompletely elucidated. Here, spatial transcriptomics and CITE-seq datasets were analysed to characterise immune metabolic niche organisation across skin and circulation. Two metabolic constraint axes capturing oxygen redox and nutrient limitation were used to define metabolically constrained and permissive immune niches within leukocyte-rich tissue regions and circulating immune lineages. Psoriatic lesions exhibited a pronounced shift towards metabolically constrained immune niches that distinguished psoriasis from atopic dermatitis. This imbalance showed strong spatial organisation, with dominance within the epidermis and close alignment with immune activation programmes. Epidermal metabolic organisation scaled with clinical severity and was accompanied by increased immune activation in severely affected tissue, while dermal organisation remained comparatively stable. Extending these observations to circulation, immune metabolic states were further skewed towards constraint in psoriatic patients with joint involvement, consistent with higher systemic inflammatory burden, with prominent effects observed in CD4 T cells. Together, these findings identify immune metabolic niche organisation as a spatially and systemically structured feature of psoriatic disease that links tissue architecture, immune activation and clinical severity.
T cell engagers (TCEs) are antibody-based, bispecific or multi-specific constructs that can reprogramme T cells to eliminate target cells expressing a defined surface antigen. Originally developed for cancer therapy, TCE...T cell engagers (TCEs) are antibody-based, bispecific or multi-specific constructs that can reprogramme T cells to eliminate target cells expressing a defined surface antigen. Originally developed for cancer therapy, TCEs are now being investigated for the treatment of autoimmune diseases, with promising initial results. The interest in using TCEs for autoimmune diseases is rapidly growing given their comparable potency with cellular therapies, combined with the advantages of biologics, including ease of manufacturing, off-the-shelf availability, better safety and more convenient delivery. Here we review the history of TCEs, focus on distinct aspects of the mechanism of action of TCEs and explain design principles. We also discuss key challenges for future TCE development in autoimmunity, including enhanced safety, high convenience and complete target cell elimination. Finally, we provide an overview of the preclinical and clinical development landscape and give an outlook on next-generation TCEs that are optimized to treat a wide variety of autoimmune diseases.
Kalu NA, Olaniyan MF, Omosigho PO
… +7 more, Shuaib BI, Omoruyi EC, Yelwa IS, Innocent IG, Aka-Okeke CU, Abdullahi AM, Adamu IA
BMC Immunol
· 2026 Jun · PMID 42374168
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BACKGROUND: The high genetic diversity of HIV-1, persistent immune activation and rising antiretroviral drug resistance continue to hinder HIV treatment, especially in Sub-Saharan Africa. This study examined inflammatory...BACKGROUND: The high genetic diversity of HIV-1, persistent immune activation and rising antiretroviral drug resistance continue to hinder HIV treatment, especially in Sub-Saharan Africa. This study examined inflammatory responses in relation to HIV-1 genetic subtypes and antiretroviral drug (ARVD) resistance among patients experiencing virological failure in Minna, Niger State, Nigeria. METHODOLOGY: A cross-sectional design involved people living with HIV-1 (PLWH-1) on ART with virological failure (defined as repeated viral load ≥ 1000 copies/mL). Plasma levels of IL-6, IL-10, hs-CRP, and TNF-α were assessed as markers of inflammation; CD4 + counts and viral load served as immune and virological indicators. Genotypic analysis targeting the HIV-1 protease and reverse transcriptase regions was performed to identify subtypes and resistance mutations. RESULTS: HIV-1 subtypes G and CRF02_AG predominated. Subtype G was linked to elevated TNF-α and IL-6 levels and a higher frequency of drug resistance mutations, suggesting subtype-specific polymorphisms and elevated pro-inflammatory markers which correlated with poor treatment outcomes. Co-infections with HBV, HCV, and Mtb were also common, especially among individuals with heightened inflammatory markers and virological failure, complicating disease progression. IL-6, IL-10, hs-CRP, and TNF-α emerged as potential surrogate biomarkers for predicting virological failure and immune reconstitution inflammatory syndrome (IRIS). CONCLUSION: The findings underscore the importance of integrating inflammatory profiling and genotypic resistance testing to inform clinical decisions and improve ART outcomes. A personalized approach to HIV care, accounting for viral subtype, immune-inflammatory status, and resistance patterns are recommended to enhance treatment efficacy and reduce HIV-related morbidity and mortality in resource-limited settings.
Tchago EF, Nana CMM, Kemlong AT
… +4 more, Ngainang C, Tertullien ED, Bayibeki A, Megnekou R
BMC Immunol
· 2026 Jun · PMID 42350937
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BACKGROUND: Female genital schistosomiasis (FGS) remains an underdiagnosed consequence of Schistosoma haematobium (S. haematobium) infection, with limited understanding of its associated immunological responses. This stu...BACKGROUND: Female genital schistosomiasis (FGS) remains an underdiagnosed consequence of Schistosoma haematobium (S. haematobium) infection, with limited understanding of its associated immunological responses. This study investigated the prevalence of FGS-related cervical lesions and their relationship with systemic cytokine profiles, as well as soluble immune activation biomarkers, among women living in endemic areas of Cameroon. METHODS: A cross-sectional study was conducted between November-December 2023 and May-June 2024, in two endemic municipalities in Cameroon. Sexually active women were screened for S. haematobium infection using urine filtration microscopy. Cervical examination and digital imaging were performed to document FGS-associated lesions, which were classified into neovascularization (NVA), grainy sandy patches (GS), yellow sandy patches (YS), and rubbery papules (RP). Blood samples were collected and plasma concentrations of cytokines (IFN-α, TNF-α, IL-10, IL-13, IL-17A, IL-33) and soluble immune activation biomarkers (sCD25, sCD163) were quantified using a magnetic Luminex assay. RESULTS: A total of 218 women agreed to participate in this study, of whom 54 (24.8%) were infected with S. haematobium. Infected women presented significantly higher proportions of FGS (81.5%), NVA (53.7%), GS (42.6%), YS (7.4%), and RP (9.3%) compared with uninfected women (0.61%-13.4%; p ≤ 0.014). Itching and pelvic pain were not associated with the presence of FGS-related cervical lesions. S. haematobium infection was associated with increased plasma levels of IL-17A (p = 0.039). Women with FGS, NVA, and GS lesions exhibited significantly higher IL-17A and IFN-α concentrations (0.0001 ≤ p ≤ 0.039). IL-17A levels strongly correlated positively with NVA (r = 0.568, p < 0.0001), while levels of IFN-α correlated with both NVA (r = 0.390, p < 0.0001) and GS (r = 0.500, p < 0.0001). Interesting, the immune activation biomarker sCD25 negatively and significantly correlated with RP (r=-0,228, p = 0,042). CONCLUSION: S. haematobium infection is associated with FGS-related cervical lesions, which occur independently of common symptoms such as itching or pelvic pain. Elevated IL-17A and IFN-α levels and their strong correlation with lesion types suggest that these cytokines may play key roles in FGS immunopathogenesis. These findings highlight the need to improve screening strategies by taking into account immunological markers to better detect and manage FGS in endemic areas.
BMC Immunol
· 2026 Jun · PMID 42343224
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BACKGROUND: Severe pneumonia in children typically presents with the most prominent early lesion being damage to the bronchial mucosa. AIM: To explore the diagnostic value of hsa_circ_0077658 in pediatric severe pneumoni...BACKGROUND: Severe pneumonia in children typically presents with the most prominent early lesion being damage to the bronchial mucosa. AIM: To explore the diagnostic value of hsa_circ_0077658 in pediatric severe pneumonia and its possible mechanism of action. MATERIALS AND METHODS: 116 children with severe pneumonia, 87 children with pneumonia, and 60 healthy children were included. Lipopolysaccharide (LPS) was used to stimulate BEAS-2B cells to establish a pneumonia cell model. Reverse Transcription quantitative PCR (RT-qPCR) was performed to detect the expression levels of hsa_circ_0077658, miR-15a-5p and Neurofibromatosis type 1(NF1). The Enzyme-Linked Immunosorbent Assay (ELISA) method was performed to detect the levels of oxidative stress markers and inflammatory factors. The Annexin V/PI and Cell Counting Kit-8 (CCK-8) kits were used to assess the apoptosis and proliferation levels of BEAS-2B cells, respectively. Person's correlation analysis, dual luciferase assays and RNA Binding Protein Immunoprecipitation (RIP) experiments were performed to demonstrate the relationship between genes. RESULTS: Hsa_circ_0077658 and NF1 were downregulated in patients with pneumonia and in LPS-induced BEAS-2B cells, while miR-15a-5p was upregulated. Hsa_circ_0077658 showed excellent diagnostic performance, with an AUC of 0.820 (95% CI: 0.749-0.890) in healthy vs. pneumonia children comparison and 0.931 (95% CI: 0.894-0.966) for distinguishing pneumonia children from severe pneumonia children. Following exposure to LPS, BEAS-2B cells exhibited heightened oxidative stress, apoptosis, and inflammatory responses, while cellular proliferation was suppressed. Hsa_circ_0077658 targets miR-15a-5p, and NF1 is the downstream effect target of miR-15a-5p. Overexpression of hsa_circ_0077658 can alleviate the oxidative stress, apoptosis and inflammatory response in LPS-BEAS-2B cells, thereby promoting proliferation. This effect was reversed by overexpression of miR-15a-5p. Furthermore, overexpression of NF1 can reverse the exacerbating effect of miR-15a-5p overexpression on the damage caused by LPS to BEAS-2B cells. CONCLUSION: Hsa_circ_0077658 may be a biomarker for pediatric severe pneumonia, potentially influencing disease progression via the miR-15a-5p/NF1 axis.
Allotey EA, Adedia D, Amponsah JA
… +12 more, Boakye AA, Frimpong A, Gyamfi J, Ninsin E, Offei H, Kwansa-Bentum H, Kpeli GS, Tetteh JKA, Amegan-Aho KH, Atadja PW, Mosi L, Duedu KO
BMC Immunol
· 2026 Jun · PMID 42343201
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BACKGROUND: Sickle cell disease (SCD) is characterized by chronic inflammation, yet the inflammatory landscape defining the clinically defined steady state remains poorly characterized, particularly in African population...BACKGROUND: Sickle cell disease (SCD) is characterized by chronic inflammation, yet the inflammatory landscape defining the clinically defined steady state remains poorly characterized, particularly in African populations where the disease burden is highest. Understanding baseline cytokine and chemokine signatures during the steady state is important for distinguishing physiological disease equilibrium from transitions toward acute complications. METHODS: We conducted a cross-sectional study of 129 children aged 2-17 years in Ghana, including 63 children with SCD in steady state and 66 healthy controls. Serum concentrations of 23 cytokines and chemokines were quantified using multiplex immunoassays alongside full blood count parameters. Comparative analyses and cytokine ratio assessments were performed to characterize steady-state SCD inflammatory signatures. RESULTS: Most pro-inflammatory cytokines and chemokines were significantly elevated in children with SCD compared with controls. However, IL-12p70 and IL-23p40 levels were significantly reduced in the SCD cohort, while CCL2 and IL-1β showed no significant differences between groups. Ratio analyses revealed lower IL-12p70/IL-4, IL-23p40/IL-4, and IL-1β/IL-10 ratios, alongside increased IL-1α/IL-4, IL-17A/IL-10, IL-3/IL-10, CCL3/IL-10, and GM-CSF/IL-10 ratios, indicating an imbalanced inflammatory milieu dominated by pro-inflammatory signals. Discriminant analyses using cytokine and hematological parameters further demonstrated clear separation between children with SCD and controls. CONCLUSIONS: Steady-state SCD in African children is characterized by a distinct cytokine and chemokine profile marked by persistent pro-inflammatory activation alongside regulatory counterbalances. Reduced ratios of IL-12p70 and IL-23p40 relative to anti-inflammatory cytokines may contribute to maintaining the steady-state inflammatory equilibrium. These findings provide reference signatures that may support future studies investigating inflammatory biomarkers.
The thymus is a primary lymphoid organ where antigen-presenting cells (APCs) orchestrate the development of a self-tolerant and functional T-cell repertoire. Herein, we elucidate the pivotal role of thymic selection defe...The thymus is a primary lymphoid organ where antigen-presenting cells (APCs) orchestrate the development of a self-tolerant and functional T-cell repertoire. Herein, we elucidate the pivotal role of thymic selection defects in autoimmune pathogenesis and evaluate targeted therapeutic strategies for these mechanisms. This review synthesises recent advances in understanding how cortical thymic epithelial cells (cTECs), medullary thymic epithelial cells (mTECs), dendritic cells (DCs), and B cells collaboratively mediate positive and negative selection. cTECs drive positive selection through thymus-specific antigen processing machinery, including the β5t-containing thymoproteasome and cathepsin L, which generate self-peptide-MHC complexes with moderated affinity. mTECs broadly express tissue-restricted antigens (TRAs) under the control of AIRE, establishing a foundational self-antigen landscape for central tolerance. DCs execute efficient clonal deletion via cross-presentation and antigen transfer, while B cells contribute to tolerance against soluble antigens through BCR-mediated uptake. We further quantify the relative contributions of these APC subsets during thymic selection and discuss how defects in these processes underlie autoimmune diseases and immunodeficiencies. Finally, we highlight emerging therapeutic strategies that target thymic selection mechanisms, including AIRE modulation, tolerogenic DC vaccines, and thymic tissue engineering. These insights not only advance our understanding of T-cell development but also offer novel avenues for immune reprogramming in disease.
Immune evasion remains one of the key hallmarks in cancer survival by which tumours avoid immune system response. Mechanism of immune evasion involved modulation of immune related cytokines, modulation of tumour microenv...Immune evasion remains one of the key hallmarks in cancer survival by which tumours avoid immune system response. Mechanism of immune evasion involved modulation of immune related cytokines, modulation of tumour microenvironment and immune checkpoints. Intrinsic workings of these mechanisms lead to a network of 'on' and 'off' switches which could modulate immune activity. Interestingly in leukaemia, a complex network is involved as immune masking occurred concomitantly with leukaemogenesis within the same microenvironment, which makes immune evasion a more elusive hallmark for this disease. Dysregulation of these mechanisms not only facilitates disease persistence and progression but also contributes to resistance against conventional therapies. Therefore, understanding the role of leukaemic immune checkpoints is essential for identifying novel therapeutic targets and improving the efficacy of immunomodulatory treatment strategies. Here, we focus on the leukaemic immune checkpoints as these consist of crucial surface molecules, receptors, ligands, and immunosuppressive cells which interact within the tumour environment to enable leukaemia to elude immune response.
Harman E, Çölkesen F, Gerek ME
… +6 more, Sağun F, Kolak S, Savaş ŞA, Yiğitdöl İ, Ergün ÜY, Arslan Ş
BMC Immunol
· 2026 Jun · PMID 42332566
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BACKGROUND: Gastrointestinal (GI) involvement is a common and clinically significant manifestation of common variable immunodeficiency (CVID); however, its relationship with immunological parameters remains incompletely...BACKGROUND: Gastrointestinal (GI) involvement is a common and clinically significant manifestation of common variable immunodeficiency (CVID); however, its relationship with immunological parameters remains incompletely understood. OBJECTIVE: This study aimed to evaluate the association between GI involvement and immunological markers, particularly serum immunoglobulin levels and B-cell subsets, and to assess their discriminative performance. METHODS: In this single-center retrospective study, 109 adult patients with CVID were included and categorized based on GI involvement. Clinical, endoscopic, histopathological, and immunological data were analyzed. Multivariable logistic regression analysis was performed to identify factors independently associated with GI involvement. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate discriminative performance. RESULTS: GI involvement was present in 58.7% of patients. Patients with GI involvement had significantly lower serum IgA and IgM levels, as well as reduced percentages of CD19⁺CD27⁺IgD⁻ switched memory B cells. In multivariable analysis, low IgM levels (OR = 0.161, 95% CI: 0.041-0.633, p = 0.009) and decreased switched memory B-cell percentage (OR = 0.918, 95% CI: 0.855-0.986, p = 0.019) were independently associated with GI involvement. ROC analysis demonstrated good discriminative ability for serum IgM (AUC = 0.799, 95% CI: 0.708-0.889) and moderate discriminative performance for switched memory B cells (AUC = 0.695, 95% CI: 0.589-0.802). Endoscopic abnormalities were detected in 87.7% of evaluated patients, with inflammatory bowel disease-like patterns being the most common histopathological finding. CONCLUSION: GI involvement is common in CVID and is independently associated with reduced IgM levels and decreased switched memory B cells, suggesting a potential role of impaired B-cell maturation in its pathophysiology. These findings may help identify patients at higher risk and support the clinical utility of immunophenotyping. Prospective multicenter studies are needed to validate these findings and to establish clinically relevant cutoff values.
Senescent cells accumulate in chronically diseased liver tissues and are known to actively contribute to disease pathology. To date, these studies have predominantly focussed on senescence in epithelial cells, such as he...Senescent cells accumulate in chronically diseased liver tissues and are known to actively contribute to disease pathology. To date, these studies have predominantly focussed on senescence in epithelial cells, such as hepatocytes and biliary epithelial cells, and senescence in liver endothelial cells remains largely understudied. Here, we utilise publicly available single-cell RNA-sequencing data, immunohistochemical and immunofluorescent staining to detect senescent endothelial cells within chronically diseased human liver tissues. Next, we develop a novel protocol for the induction of paracrine senescence in primary human liver endothelial cells and explore their functionality. We demonstrate that senescent liver endothelial cells exhibit a reduced scavenging capacity but are still able to support lymphocyte recruitment under physiological flow conditions in vitro. Mechanistically, we determine that inducible T cell costimulator ligand (ICOSL) is an important factor in the specific recruitment of CD4 T cells, but antibody blockade, genetic knockdown and genetic overexpression of ICOSL in endothelial cells has no effect on CD8 T cell recruitment. Finally, we show that ICOSL gene expression is upregulated in chronically diseased tissues, present in scar-associated endothelial cells and correlates to CD4 T cell infiltration. This is the first study to demonstrate that senescent human liver endothelial cells can potentially shape the liver immune microenvironment in chronic liver disease. Targeting senescent endothelial cells could present new therapeutic opportunities to treat chronic liver diseases.
TCRαβCD4CD8 double negative T (TCRβDNT) cells are highly accumulated in human and murine lupus, although the origin and function of TCRβDNT cells remains largely elusive and controversy. Remarkably, conditional deletion...TCRαβCD4CD8 double negative T (TCRβDNT) cells are highly accumulated in human and murine lupus, although the origin and function of TCRβDNT cells remains largely elusive and controversy. Remarkably, conditional deletion of Egr2 in lymphocytes significantly reduced TCRβNK1.1 DNT cells, the dominant DNT type in B6/lpr mice. TCRβDNT cells of B6/lpr mice surprisingly had a lower expression of IFNγ, IL-17, and IL-10 compared to normal B6 mice, which was likely due to high CD138 expression in the TCRβDNT cells of B6/lpr mice. Conditionally deleting Egr2 in B6/lpr mice increased IFNγ and IL-10, but not IL-17 in TCRβDNT cells. Egr2 deletion suppressed IL-17 expression in TCRγδDNT cells, the major IL-17-expressing DNT cells in B6/lpr mice. The scRNA-seq analysis of DNT cells from Egr2B6/lpr (CD2-CreEgr2B6/lpr, EK) and control Egr2B6/lpr (EF) mice revealed a striking segregation of DNT clusters with distinct transcriptional profiles, identified as EK_dominant and EF_dominant DNT clusters. Egr2 deletion in B6/lpr mice seemingly normalised Helios, Ly6C, and Ly6A/E expression to levels similar to B6 mice, implying that inhibition of EGR2 can effectively correct the abnormalities in DNT cells of B6/lpr mice. Further, we found that conditional Egr2 deletion reduced TCRβDN thymocytes in B6/lpr mice and suppressed DNT-cell generation from in vitro cultured splenic CD8 T cells, suggesting that EGR2 might promote TCRβDNT cells in lpr mice at both the thymic and peripheral stages. Together, this study is the first to reveal a critical role of EGR2 in regulating the expansion, heterogeneity, and function of TCRβDNT cells in lupus mice.
Messenger RNA (mRNA) vaccines are a transformative platform for inducing antigen-specific T cell and B cell responses that are now being trialled in oncology. Here we propose an immunological framework that reconciles fo...Messenger RNA (mRNA) vaccines are a transformative platform for inducing antigen-specific T cell and B cell responses that are now being trialled in oncology. Here we propose an immunological framework that reconciles four axes controlling the efficacy of mRNA cancer vaccines: adjuvanticity versus immunopathology, antigen immunogenicity versus tolerance, adaptive immune memory versus exhaustion, and beneficial versus maladaptive trained immunity. We argue that mRNA vaccines should be viewed as programmable constructs in which nucleoside chemistry, delivery platforms and dosing schedules can be manipulated to tune these four axes by modulating antigen identity and decay, costimulation, cytokine tone and innate stimulation. By fitting recent mechanistic and translational insights into this framework, we outline design principles for positioning mRNA cancer vaccines within an optimal window of immune activation that supports durable, tumour-specific immunity while minimizing T cell exhaustion, tolerance and systemic toxicity.
Immune function across development, tissue repair, aging, and disease depends not only on signaling pathways but also on epigenetic architectures that determine whether coordinated transcriptional programs can be accesse...Immune function across development, tissue repair, aging, and disease depends not only on signaling pathways but also on epigenetic architectures that determine whether coordinated transcriptional programs can be accessed and resolved. Increasing evidence indicates that epigenetic gene networks regulate the accessibility and reversibility of semi-stable immune states, shaping plastic, homeostatic, reparative, and degenerative configurations. We propose the concept of epigenetic transition windows, defined as temporally and contextually restricted intervals during which epigenetic constraints are relaxed, permitting coordinated and reversible transitions between immune states. During development, these windows are broad and support immune tolerance and adaptive plasticity. In adulthood they become spatially and temporally restricted, preserving stability while enabling conditional adaptation. With aging, they progressively narrow, contributing to chronic inflammation, impaired repair, and increased vulnerability to neurodegeneration. Conversely, pathological persistence of regulatory permissiveness may underlie immune evasion and sustained plasticity in cancer. We outline operational genomic readouts for quantifying transition windows, including chromatin accessibility variance, enhancer switching dynamics, reversibility metrics, and cross-cell coordination indices, and derive experimentally testable predictions that distinguish this model from pathway-centric or damage-centric explanations. By reframing immune dysfunction as a failure of regulated state transition rather than excessive signaling alone, this framework integrates inflammaging, trained immunity, immune resolution failure, and tumor immune escape within a unified regulatory architecture and provides a systems-level perspective on immune adaptability across the lifespan.