Jul 2026· Expert Review of Clinical Immunology· Vol 22, pp. 731 - 740· 0 citations· 82 references
Medicine
TL;DR
These findings challenge the traditional immune-centric model and support a more integrated view of disease progression, emphasizing the interplay between beta cell vulnerability and immune activation.
Abstract
ABSTRACT Introduction Type 1 diabetes (T1D) has long been viewed as an immune-driven disease characterized by the destruction of otherwise healthy pancreatic beta cells. However, growing evidence indicates that beta cells may actively contribute to disease initiation. Intrinsic dysfunction – such as impaired protein processing, endoplasmic reticulum stress, neoantigen formation, and early upregulation of major histocompatibility complex (MHC) class I – could increase beta-cell immunogenicity and promote autoimmune recognition. This emerging paradigm has significant implications for prevention and therapeutic strategies. Areas covered This review synthesizes experimental, translational, and clinical evidence supporting beta cell stress and dysfunction as central components of T1D pathogenesis. It examines intrinsic beta cell pathways, mechanisms of immune recognition, and therapeutic approaches aimed at preserving beta-cell integrity. These findings challenge the traditional immune-centric model and support a more integrated view of disease progression, emphasizing the interplay between beta cell vulnerability and immune activation. Expert opinion Effective prevention will likely require combination strategies that address both beta cell stress and autoimmunity. Approaches integrating beta cell protective agents with antigen-specific tolerance therapies may delay or prevent progression when applied early. Stage-adapted interventions targeting both beta cell resilience and immune modulation may redefine T1D prevention and improve management of pre-symptomatic individuals.
Beta-cell stress is traditionally viewed as a downstream consequence of autoimmune destruction in type 1 diabetes (T1D). This review examines evidence supporting an alternative interpretation in which intrinsic beta-cell stress precedes and contributes to immune activation. We synthesize findings from experimental models, human islet studies, and recent spatial transcriptomic analyses to describe how endoplasmic reticulum stress, mitochondrial dysfunction, and cGAS-STING signaling may promote major histocompatibility complex class I upregulation, chemokine production, damage-associated molecular pattern release, and neoantigen generation before organized insulitis develops. We further discuss how sustained inflammatory signaling may facilitate tertiary lymphoid structure (TLS) formation, creating a persistent local immune niche that reinforces disease progression. Based on these observations, we present a stage-dependent conceptual framework linking beta-cell stress, innate immune activation, and TLS-mediated stabilization of chronic inflammation. This framework provides a rationale for the limited durability of current immune-targeted therapies and identifies experimentally testable hypotheses using existing human resources, including HPAP, TrialNet, and spatial transcriptomics. Although direct evidence that beta-cell stress precedes immune infiltration in humans remains limited, this perspective offers an integrative framework for interpreting T1D pathogenesis and guiding future translational research.
Unknown authors· Diabetes Research and Clinic...· 0 citations
Immunosenescence, characterized by functional decline and altered phenotypes of immune cells with age, can disturb immune tolerance and promote autoreactive responses. Type 1 diabetes (T1D) has traditionally been viewed as a disease of immune dysregulation that leads to the autoimmune destruction of pancreatic β-cells. Emerging evidence suggests that senescence contributes to both the onset and progression of T1D. Autoreactive T cells are associated not only with β-cell death but also with the induction of β-cell senescence. In parallel, senescent β-cells acquire a senescence-associated secretory phenotype that amplifies local inflammation and increases β-cell vulnerability. These interlinked processes position senescence as a mechanistic bridge between aging, immune dysfunction, and autoimmunity. Importantly, a bidirectional loop appears to exist, in which T1D accelerates immune aging while immunosenescence further exacerbates autoimmunity. Recognizing this interplay highlights senescence as a promising and underexplored therapeutic target. Here, we synthesize current knowledge on immunosenescence and cellular senescence, examine their convergence in T1D pathogenesis, and outline future directions where interventions against senescent pathways could open new opportunities for treatment and prevention.
ARTICLE HIGHLIGHTS
The relationship between type 1 diabetes (T1D) and immunosenescence has not been deeply investigated. T1D is characterized by immune activation, metabolic stress, and hyperglycemia, which induce chronic low-grade inflammation. These factors are well-established drivers of immunosenescence. We propose that T1D may induce a state of premature immunosenescence, even in relatively young individuals. Immunosenescence is associated with an impaired immune response, reduced tolerance, and production of proinflammatory mediators. These may further exacerbate autoimmunity, creating a self-reinforcing cycle between autoimmunity and immune aging mechanisms. Integrating these perspectives could expand our understanding of disease mechanisms and lead to novel treatment approaches for T1D.
D. Saavedra, Rahul Mittal, C. Blaschke et al.· Diabetes· 0 citations
ABSTRACT Latent autoimmune diabetes in adults (LADA) is a heterogeneous form of autoimmune diabetes characterised by adult onset, the presence of islet autoantibodies, and a slower progression to insulin dependence compared with classical type 1 diabetes. Positioned at the interface of type 1 and type 2 diabetes, LADA arises from complex interactions among genetic susceptibility, immune dysregulation, and metabolic stress. While autoreactive T cells are recognized as central mediators of β‐cell destruction, accumulating evidence indicates that B lymphocytes play a broader and dynamic role in disease pathogenesis than previously appreciated. Beyond autoantibody production, B cells contribute to LADA through antigen presentation, cytokine secretion, and regulation of T cell responses, thereby amplifying autoimmune circuits within pancreatic islets. Emerging studies further demonstrate perturbations in circulating B cell subsets, including expansion of memory B cells and plasmablasts and impairment of regulatory B cells. However, whether these alterations represent primary drivers of disease progression or secondary responses to ongoing β‐cell injury remains unresolved. In parallel, immunometabolic stress and β‐cell dysfunction promote neoantigen formation and may shape B cell activation and selection, linking metabolic perturbations to adaptive immune dysregulation. Together, these findings support a model in which B lymphocytes act as both effector and regulatory components within a dynamic immunometabolic network that determines disease heterogeneity and progression. Recent advances in molecular profiling have further revealed distinct LADA endotypes, particularly stratified by glutamic acid decarboxylase antibody levels, suggesting divergent autoimmune and metabolic contributions across patient subgroups. These insights provide a rationale for precision medicine approaches and highlight B lymphocyte‐targeted interventions as potential, although still investigational, therapeutic strategies aimed at preserving residual β‐cell function.
Aging is the primary risk factor for a wide spectrum of chronic diseases, ranging from infectious diseases and cancer to autoimmunity and neurodegeneration. One of the key drivers of this increased susceptibility is the progressive decline in immune function-immunosenescence that reshapes the host's inflammatory landscape. Emerging evidence points to an age-associated expansion of cytotoxic CD4+ T cells (CD4 CTLs), which can play context-dependent protective or pathogenic roles in host homeostasis and disease, reflecting their unique integration of helper and cytotoxic programs as well as their preferential expansion during aging. On the protective side, CD4 CTLs contribute to immune surveillance and host defense against viral infections and malignancies. Conversely, in selected settings, they can function as pathogenic effectors in autoimmune and neurodegenerative disorders. In this review, we synthesize the emerging biology of CD4 CTLs, highlighting their differentiation and dual roles in protection and pathology. Beyond a descriptive overview, we propose a conceptual framework that places age-associated CD4 CTL expansion at the intersection of aging and age-associated disease. Rather than viewing late-life pathologies as fully independent events, we suggest that at least a subset may be partially interconnected by recurrent CD4 CTL programs, while emphasizing that the strength of evidence and the degree of causality differ substantially by disease context. This framework provides a basis for asking when CD4 CTLs should be enhanced, restrained, or more precisely redirected to promote healthy longevity.
Tatsuya Hasegawa, Kosei Nishitani, K. Kabashima· International Immunology· 0 citations
Type 1 diabetes (T1D) continues to be a complex, multifactorial autoimmune condition characterized by targeted destruction of pancreatic β-cells and permanent insulin dependence. How tremendous the change has been since the advent of insulin therapy, yet T1D patients remain at catastrophic risk from acute complications and chronic vascular injury, calling for more potent disease-modifying therapies. Developments in immunology and genetics have unraveled the interaction of environmental trigger events, including viral infection and gut microbiota, with genetic susceptibility, i.e., HLA class II alleles, on the aberration of immune tolerance and induction of β- cell autoimmunity. The last few decades have seen remarkable advances in the pathogenesis of T1D, including the discovery of β-cell autoantibodies and the pivotal role of autoreactive T cells. However, therapeutic trials in humans of immunomodulatory interventions, such as cyclosporine, anti-CD3 antibodies, and tolerogenic dendritic cells, have, to date, shown only temporary preservation of native insulin secretion, with safety limitations or failure to sustain efficacy being significant limitation. In parallel, efforts at inducing antigen-specific tolerance and microbiota modification have been promising in preclinical models but are still to be validated in humans. Technological advances, including continuous glucose monitoring and artificial pancreas systems, have enhanced glycemic management and quality of life without influencing causative autoimmunity. New strategies, β-cell replacement by transplant or xenograft, genetic engineering to favor immune evasion, and gene therapy for insulin production promise more definitive cures, but much remains in the path of safety, immune rejection, and long-term efficacy. Finally, in the years to come, the management of T1D will be a blend of early diagnosis, customized immunomodulation, improved sensing of glucose, and regeneration. Research on the genetic, immunologic, and environmental determinants for T1D and the creation of safer and more potent therapies will continue to be needed to advance beyond disease symptomatology management to disease modification and prevention.
Jasvinder Saini, Dushyant, Jagdeep Singh et al.· Current Topics in Medicinal...· 0 citations
RATIONALE
Type 1 diabetes mellitus (T1DM) involves immune-mediated destruction of pancreatic β cells, but the role of B cells in the islet immune microenvironment remains unclear. This study investigated how the long non-coding RNA X-inactive specific transcript (Xist) regulates islet immunity during T1DM progression.
METHODS
Single-cell RNA sequencing of non-obese diabetic (NOD) mice was used to characterize dynamic changes in islet immune cells. RNA pull-down, RNA immunoprecipitation, and ChIP-qPCR were performed to define the epigenetic mechanism of Xist and assess H3K27 acetylation at target gene promoters. In vitro co-culture systems and lentiviral intervention models were used to evaluate the effects of Xist-HDAC3 modulation on immune activation and islet injury.
RESULTS
Xist was specifically upregulated in pancreatic islet B cells during T1DM progression and was positively associated with B-cell activation and pro-inflammatory cytokine production. Mechanistically, Xist interacted with HDAC3 and altered H3K27ac levels at the promoters of CD40 and CD80, leading to their upregulation and enhancing B-cell antigen presentation and immunostimulatory capacity. This promoted CD8+ T-cell activation and the spread of islet inflammation. Modulation of the Xist-HDAC3 axis in vivo reduced immune-mediated injury, preserved islet structure, and improved glycemic control. In vitro findings further confirmed that Xist is a key regulator of B cell-mediated T-cell activation.
CONCLUSIONS
In T1DM, the present findings suggest a strong correlation between Xist expression and B-cell activation. Supported by in vitro and in vivo models, these data propose a potential mechanism in which Xist may influence B-cell immune dysregulation through HDAC3-mediated epigenetic pathways.
Yingxue Guo, Lin Lei, Guanghua Che et al.· Biochimica et Biophysica Act...· 0 citations
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