Editorial: From Trained Immunity to Rheumatic Diseases: Updated Evidence

Infectious and rheumatic diseases continue to be major global health concerns, despite the advancements in vaccines that have reduced mortality from many infectious diseases [1]. Trained immunity in rheumatic diseases refers to the innate immune system's ability to develop a form of “memory” after exposure to certain vaccines or artificial stimuli. This enhanced, non-specific immune response may help modulate disease activity by reducing inflammation or preventing infections, potentially offering therapeutic benefits in managing autoimmune conditions [2]. Emerging pathogens highlight the need to improve current vaccinology strategies. Trained immunity (TI) is a novel concept where the innate immune system acquires memory through epigenetic and metabolic changes. This results in enhanced responsiveness to a wide range of pathogens, offering non-specific protection. Trained immunity-based vaccines (TIbV) aim to induce TI and provide broad-spectrum protection, particularly beneficial for vulnerable populations or where conventional vaccines are unavailable. TI has potential applications in both infections and allergic diseases, offering a new avenue for vaccine development [1]. The mechanisms of trained immunity in rheumatic diseases involve epigenetic and metabolic reprogramming of innate immune cells, such as monocytes and macrophages, after exposure to an initial inflammatory or pathogenic stimulus. Epigenetic changes, such as histone modifications (e.g., H3K4me3), promote the transcription of pro-inflammatory genes in trained cells. These changes are often paired with a shift in metabolism toward glycolysis, enabling cells to meet the energy demands of sustained inflammation [3]. Key metabolic pathways, such as the mTOR pathway, promote glycolysis, driving the enhanced immune responses seen in rheumatic conditions. Sustained mTOR activation perpetuates glycolysis even in the absence of acute stimuli, resulting in chronic energy provision for ongoing cytokine production. This persistent metabolic state supports the survival and activation of pro-inflammatory cells, thereby maintaining low-grade systemic inflammation characteristic of chronic rheumatic diseases [4]. These metabolic and epigenetic alterations result in increased production of pro-inflammatory cytokines like Tumor Necrosis Factor (TNF), Interleukin- 6 (IL-6), and IL-1β, which are central to the pathogenesis of rheumatic diseases. In conditions like rheumatoid arthritis (RA), autoantibodies and immune complexes exacerbate trained immunity, leading to tissue damage and synovial inflammation. Similarly, in Systemic Lupus Erythematosus (SLE), nuclear antigens from apoptotic cells stimulate monocytes, leading to trained immune responses that contribute to disease flares [2]. These molecular adaptations—particularly persistent metabolic reprogramming and histone modification—sustain the hyperinflammatory state seen in RA and SLE, driving disease progression from preclinical immune activation to clinically overt inflammation and tissue damage [3]. The mechanisms behind trained immunity in RA involve metabolic shifts toward glycolysis, which provide the energy needed for sustained inflammation. Additionally, epigenetic changes, such as histone modifications (e.g., H3K4me3), enable these cells to maintain an activated state, ready to produce high levels of inflammatory mediators when re-stimulated. Autoantibodies, especially anti-citrullinated protein antibodies (ACPA), can induce trained immunity in monocytes, enhancing their inflammatory activity [5]. Mechanistically, ACPA immune complexes are taken up by Fcγ receptors on monocytes, leading to inflammasome activation and chromatin remodeling. This cascade reinforces pro-inflammatory gene expression patterns through sustained histone modification and upregulation of glycolytic enzymes [6]. This leads to excessive production of pro-inflammatory cytokines like TNF-α and IL-6, which activate PI3K/AKT signaling. This results in phosphorylation and inactivation of Tuberous sclerosis protein (TSC)1/2, permitting Ras homolog enriched in the brain (Rheb)-GTP to switch on the mTOR complex (mTORC)1 pathway. Likewise, Damage-associated molecular patterns in the joint (e.g., fibronectin fragments, HMGB1) engage Toll-like receptors (TLRs) on macrophages and fibroblast-like synoviocytes (FLS), which trigger MyD88/NF-κB and also recruit PI3K/AKT [7]. The mTOR activation ends up producing more pro-inflammatory cytokines. Trained immunity may begin early in the disease, even before symptoms are evident, especially in individuals with ACPA-positive arthralgia. The hyperresponsiveness of monocytes due to trained immunity could drive the transition from early RA to more established disease, leading to progressive joint damage. This early activation suggests that targeting trained immunity could be a preventive strategy in RA [5, 6]. Trained immunity refers to a state in which innate immune cells undergo long-term changes that enhance their response to future threats. These changes are driven by epigenetic reprogramming, allowing the innate immune system to “remember” past encounters with pathogens or stimuli. Initially studied in infectious disease contexts, trained immunity was observed when certain cells, such as monocytes, macrophages, and natural killer cells, became more responsive after exposure to infections or vaccines. This enhanced immune readiness allows for a stronger and faster response upon subsequent exposure to similar pathogens [8]. Epigenetic modifications in hematopoietic progenitor cells enhance their adaptability to inflammatory and hematopoietic stress, leading to the production of myeloid cells that improve protection against future infections—a concept known as “trained innate immunity.” While beneficial against infections, internal stimuli can trigger harmful inflammation. In diseases like systemic lupus erythematosus (SLE) and systemic sclerosis, such inappropriate activation drives chronic inflammation and disease progression [8-10]. SLE pathogenesis is marked by complex immune dysregulation, including defective clearance of immune complexes and nucleic acid debris, leading to overactivation of the innate immune system via Toll-like receptors (TLRs) and type I interferons (IFN) [11]. Type I IFNs, particularly IFN-α, serve as both a consequence and amplifier of trained immunity in SLE. These cytokines further reprogram monocytes and progenitor cells epigenetically, enhancing their responsiveness to inflammatory stimuli and perpetuating the cycle of immune activation and flare-ups [9, 11]. Similar to RA, type I IFN in SLE may augment PI3K/AKT signaling and boost mTORC1 in T cells. This activation occurs through phosphorylation of insulin receptor substrate 1 (IRS1), which binds to the PI3K regulatory subunit p85, leading to activation of the catalytic subunit p110 [11]. This cascade results in the activation of mTORC1. Furthermore, B cell activating factor (BAFF) receptor signaling triggers PI3K/AKT and upregulates mTORC1. BAFF-R signaling also activates NF-κB/NIK, which can phosphorylate mTOR to sustain its activity [7]. Thus, high BAFF in SLE promotes mTOR-driven B-cell proliferation and plasma cell differentiation. Abnormal lymphocyte activation further exacerbates the condition. Neutropenia is common in SLE, with bone marrow showing reduced granulocyte–macrophage colony-forming units. SLE neutrophils have higher apoptosis rates, impaired phagocytosis, and altered oxidative metabolism, and gene expression studies reveal a granulopoiesis signature in the peripheral blood of these patients [10, 12], suggesting a compensatory response by the body to counteract the increased turnover and apoptosis of neutrophils [13]. This neutrophil dysregulation extends to the patients with active systemic lupus erythematosus (SLE), where bone marrow mononuclear cells exhibit gene expression profiles characteristic of both apoptosis and granulopoiesis. Recent work by Banchereau R. et al. demonstrated a progressive increase in neutrophil-related transcripts in the blood of pediatric SLE patients as lupus nephritis advanced. Among these, low-density granulocytes (LDGs), which are highly inflammatory and play a key role in sustaining the inflammatory subset of neutrophils, exhibit marked demethylation of interferon-related genes, amplifying type I IFN signaling and contributing to the elevated IFN signature observed in SLE. The accumulation and activation of LDGs in SLE highlight the interplay between immune dysregulation, increased neutrophil turnover, and sustained inflammation, underscoring the central role of neutrophils and IFN pathways in the disease's pathogenesis [14]. TIbVs represent a novel approach in immunology by harnessing the innate immune system's ability to develop “memory” through metabolic and epigenetic reprogramming. These vaccines offer broad-spectrum protection, extending beyond traditional vaccines that target specific pathogens. Future research will likely expand TIbV applications to not only infectious diseases but also autoimmune and allergic conditions. However, the clinical application of TIbVs remains in early stages. Potential risks include overstimulation of innate immunity leading to excessive inflammation or autoimmune flares, especially in genetically predisposed individuals. Regulatory challenges also exist, particularly in standardizing manufacturing, defining biomarkers of efficacy, and ensuring long-term safety. These aspects must be addressed in preclinical and phase I/II trials before widespread use [15]. Personalized vaccinology, utilizing epigenetic markers, could further tailor vaccines to individual needs, offering more precise and preventive solutions for diseases like RA and SLE. Moreover, TIbVs may address vaccine challenges in resource-limited areas by offering long-lasting, broad protection, especially for vulnerable populations. In allergic diseases, next-generation vaccines could reshape immune responses, promoting tolerance instead of sensitization. The potential for epigenetic inheritance also opens new research avenues, with implications for maternal and neonatal health. Overall, TIbVs have the potential to revolutionize vaccine strategies, bridging innate and adaptive immunity to provide more comprehensive disease protection. K.-C.C., Y.-H.H., Y.-A.T. drafted the original manuscript. P.-C.S., S.-B.Y. and C.-Y.Y. provided critical review and revised the manuscript. All authors read and approved the final manuscript. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.