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Type 2 immunity in allergic diseases
Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.
The guided fire from within: intratumoral administration of mRNA-based vaccines to mobilize memory immunity and direct immune responses against pathogen to target solid tumors
We investigated a novel cancer immunotherapy strategy that effectively suppresses tumor growth in multiple solid tumor models and significantly extends the lifespan of tumor-bearing mice by introducing pathogen antigens into tumors via mRNA-lipid nanoparticles. The pre-existing immunity against the pathogen antigen can significantly enhance the efficacy of this approach. In mice previously immunized with BNT162b2, an mRNA-based COVID-19 vaccine encoding the spike protein of the SARS-CoV-2 virus, intratumoral injections of the same vaccine efficiently tagged the tumor cells with mRNA-expressed spike protein. This action rapidly mobilized the pre-existing memory immunity against SARS-CoV-2 to kill the cancer cells displaying the spike protein, while concurrently reprogramming the tumor microenvironment (TME) by attracting immune cells. The partial elimination of tumor cells in a normalized TME further triggered extensive tumor antigen-specific T cell responses through antigen spreading, eventually resulting in potent and systemic tumor-targeting immune responses. Moreover, combining BNT162b2 treatment with anti-PD-L1 therapy yielded a more substantial therapeutic impact, even in “cold tumor” types that are typically less responsive to treatment. Given that the majority of the global population has acquired memory immunity against various pathogens through infection or vaccination, we believe that, in addition to utilizing the widely held immune memory against SARS-CoV-2 via COVID-19 vaccine, mRNA vaccines against other pathogens, such as Hepatitis B Virus (HBV), Common Human Coronaviruses (HCoVs), and the influenza virus, could be rapidly transitioned into clinical use and holds great promise in treating different types of cancer. The extensive selection of pathogen antigens expands therapeutic opportunities and may also overcome potential drug resistance.
Third-party evaluators perceive AI as more compassionate than expert humans
Empathy connects us but strains under demanding settings. This study explored how third parties evaluated AI-generated empathetic responses versus human responses in terms of compassion, responsiveness, and overall preference across four preregistered experiments. Participants (N = 556) read empathy prompts describing valenced personal experiences and compared the AI responses to select non-expert or expert humans. Results revealed that AI responses were preferred and rated as more compassionate compared to select human responders (Study 1). This pattern of results remained when author identity was made transparent (Study 2), when AI was compared to expert crisis responders (Study 3), and when author identity was disclosed to all participants (Study 4). Third parties perceived AI as being more responsive—conveying understanding, validation, and care—which partially explained AI’s higher compassion ratings in Study 4. These findings suggest that AI has robust utility in contexts requiring empathetic interaction, with the potential to address the increasing need for empathy in supportive communication contexts.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
TCR catch bonds nonlinearly control CD8 cooperation to shape T cell specificity
Naturally evolved T-cell receptors (TCRs) exhibit remarkably high specificity in discriminating non-self antigens from self-antigens under dynamic biomechanical modulation. In contrast, engineered high-affinity TCRs often lose this specificity, leading to cross-reactivity with self-antigens and off-target toxicity. The underlying mechanism for this difference remains unclear. Our study reveals that natural TCRs exploit mechanical force to form optimal catch bonds with their cognate antigens. This process relies on a mechanically flexible TCR–pMHC binding interface, which enables force-enhanced CD8 coreceptor binding to MHC-α1α2 domains through sequential conformational changes induced by force in both the MHC and CD8. Conversely, engineered high-affinity TCRs create rigid, tightly bound interfaces with cognate pMHCs of their parental TCRs. This rigidity prevents the force-induced conformational changes necessary for optimal catch-bond formation. Paradoxically, these high-affinity TCRs can form moderate catch bonds with non-stimulatory pMHCs of their parental TCRs, leading to off-target cross-reactivity and reduced specificity. We have also developed comprehensive force-dependent TCR–pMHC kinetics-function maps capable of distinguishing functional and non-functional TCR–pMHC pairs and identifying toxic, cross-reactive TCRs. These findings elucidate the mechano-chemical basis of the specificity of natural TCRs and highlight the critical role of CD8 in targeting cognate antigens. This work provides valuable insights for engineering TCRs with enhanced specificity and potency against non-self antigens, particularly for applications in cancer immunotherapy and infectious disease treatment, while minimizing the risk of self-antigen cross-reactivity.
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