Aqueous zinc-iodine batteries (AZIBs) hold great promise for sustainable energy storage, yet their practical viability is hindered by the uncontrolled shuttling of soluble polyiodide intermediates (e.g., I3 [-] and I5 [-]), which causes severe cathode active-material loss and zinc anode corrosion. Herein, hydroxypropyl trimethyl ammonium chloride chitosan (HTCC), a quaternized biomass derivative, is developed as a cationic binder that fundamentally suppresses the polyiodide shuttle effect. Unlike binders with weak hydrogen bonding that can only immobilize I3 [-], HTCC immobilizes both I3 [-] and I5 [-] through strong electrostatic interactions, complemented by hydrogen-bonding interactions. The optimized aqueous AZIBs exhibit exceptional antiself-discharge performance, as demonstrated by a stable open-circuit voltage of 1.322 V and a Coulombic efficiency above 96.2% after a 72 h rest. Furthermore, they deliver a highly specific capacity of 216.4 mAh g[-1] at 0.1 A g[-1] and outstanding long-term cycling stability, retaining 90.1% of their initial capacity after nearly 40,000 cycles at 5.0 A g[-1]. Mechanistic studies reveal the functionality of HTCC in mitigating polyiodide shuttling and zinc anode corrosion, owing to substantially enhanced adsorption energies and accelerated iodine conversion kinetics. This work highlights the great potential of cationic biomass binders for high-performance, sustainable aqueous iodine-based energy storage.

FoxP3[+] regulatory T cells (Tregs) maintain immune homeostasis by suppressing excessive antiself-immunity of effector T cells (Teffs) and thereby regulate autoimmunity and inhibit antitumor immune responses. Thus, Treg-targeting is a popular therapeutic strategy for both autoimmune diseases and cancer treatment. However, specific regulators of Tregs are needed to bypass adverse effects elicited by strategies that target molecules with overlapping expression between Tregs and other T cell subsets. We aim to identify small molecules that specifically target the key Treg lineage-defining transcription factor FoxP3. Here, we describe a high-throughput, flow-cytometry-based phenotypic screening assay, its data processing pipeline, and downstream methods for compound validation. We developed a set of algorithms to easily exclude compounds with high toxicity and to filter out autofluorescent compounds. Our screening assay is performed on human primary T cells by measuring FoxP3 levels in CD4[+] T cells, using an automated liquid handling pipeline. Selected hit candidates from the screening were validated and assessed through functional analyses. From screening a library of approved drugs, we identified several candidates that regulate Treg functions through FoxP3. Seventeen chemical analogs of one hit compound were identified and characterized in cell-based assays, revealing structure-activity relationships and identifying compounds with more potent effects on the regulation of FoxP3 levels and Treg function. We conclude that this novel screening method could successfully identify FoxP3 regulators with an effect on Treg functions.

First considered as a negative epiphenomenon in autoimmune and inflammatory diseases, with possible deleterious consequences through the production of pathological autoantibodies and antiself T cells, tertiary lymphoid structures (TLS) have gained major scientific and clinical interest in cancer due to their association with better clinical outcomes and improved responses to immunotherapy. Studies have investigated the structure and plasticity of TLS in the context of tumors and the role of the TLS B-cell compartment in contributing to the favorable clinical outcome of cancer patients. Identifying biomarkers that indicate the presence of TLS in tumors in a noninvasive manner could therefore represent a major advance in the diagnosis and treatment decision-making for these patients. Also, the interplay between TLS, tumor cells, and microbiota opens new avenues for deciphering the role of microorganisms in cancer development. Their use as TLS inducers further underlines the need for continued research in this field. Moreover, emerging data have emphasized the critical role of sensory and sympathetic nerves in regulating TLS formation and function. Finally, humanized mice may serve as valuable tools for developing preclinical models to study the role of human TLS in cancer, a much-needed goal. These different topics are discussed in the present review.

The measurement of serum antibodies that specifically recognize self-antigens is a critical diagnostic in autoimmunity. A limitation of such an approach is sensitivity to detect the antibody, particularly when abundant self-antigens in the body may bind and sequester circulating specific antibodies. The presence of specific memory B cells (Bmem) may provide a more sensitive and robust indicator of an autoimmune response, as is suggested for certain anti-viral responses. B cell enzyme-linked ImmunoSpot (ELISPOT) is capable of detecting antigen-specific Bmem cells in blood at the single cell level, following stimulation of peripheral blood mononuclear cells (PBMCs) to expand and differentiate the Bmem cells into functional antibody-secreting cells (ASCs). While this assay has been widely utilized in infectious diseases and vaccination, detection is more difficult for autoantigens due to self-tolerance and specific tissue compartmentalization of immune responses, making autoantigen-specific B cells rare in the circulation. The cycles of re-activation of Bmem cells to become ASCs, that may reflect disease flare-ups in autoimmunity, are not well defined. For several autoimmune diseases (ADs), the targeting of B cells via depleting monoclonal antibodies has proven to be an effective treatment, where Bmem cells are likely being targeted. The measurement of autoantigen-reactive Bmem cells may aid in diagnosis and staging of clinical severity, or be a metric for efficacious treatments, thus providing an additional informative biomarker of ADs. How B cell ELISPOT has been utilized to characterize Bmem cells in human ADs is described here, including the advantages and disadvantages of the assay.

Allopurinol, widely used in gout treatment, is the most common cause of severe cutaneous adverse drug reactions. The risk of developing such life-threatening reactions is increased particularly for HLA-B*58:01 positive individuals. However the mechanism of action between allopurinol and HLA remains unknown. We demonstrate here that a Lamin A/C peptide KAGQVVTI which is unable to bind HLA-B*58:01 on its own, is enabled to form a stable peptide-HLA complex only in the presence of allopurinol. Crystal structure analysis reveal that allopurinol non-covalently facilitated KAGQVVTI to adopt an unusual binding conformation, whereby the C-terminal isoleucine does not engage as a PΩ that typically fit deeply in the binding F-pocket. A similar observation, though to a lesser degree was seen with oxypurinol. Presentation of unconventional peptides by HLA-B*58:01 aided by allopurinol contributes to our fundamental understanding of drug-HLA interactions. The binding of peptides from endogenously available proteins such as self-protein lamin A/C and viral protein EBNA3B suggest that aberrant loading of unconventional peptides in the presence of allopurinol or oxypurinol may be able to trigger anti-self reactions that can lead to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Whereas T cells in the tumor microenvironment have been the main focus as cancer controlling cells and targets of immunotherapies, B cells have recently gained strong attention. Being associated to Tertiary Lymphoid Structures (TLS) located at the vicinity of tumor nests, the fate of B cell depends on TLS maturity. In immature TLS they may evolve as regulatory B cells producing immunosuppressive cytokines and promote tumor growth. In mature TLS with a germinal center, B cells are selected, amplified, undergo affinity maturation and isotypic switching, resulting in plasma cell generation and production of anti-tumor antibodies. In that case, they are associated with longer patient's survival and therapeutic response to immunotherapy. Identification of tumor specific, or tumor overexpressed, antigens recognized by "in situ" produced antibodies and their discrimination from self-antigens induced by ICI treatments is a major challenge to develop novel antibody-based immunotherapies.

Haemoglobin (Hb) has well-documented inflammatory effects and is normally efficiently scavenged; clearance mechanisms can be overwhelmed during erythrocyte lysis. Whether Hb is preferentially inflammatory in lupus and triggers broad anti-self responses was assessed. Peripheral blood mononuclear cells (PBMCs) derived from SLE patients secreted higher levels of lupus-associated inflammatory cytokines when incubated with human Hb than did PBMCs derived from healthy donors, an effect negated by haptoglobin. Ferric murine Hb triggered the preferential release of lupus-associated cytokines from splenocytes, B cells, CD4 T cells, CD8 T cells and plasmacytoid dendritic cells isolated from ageing, lupus-prone NZM2410 mice, and also had mitogenic effects on B cells. Pull-downs, followed by mass spectrometry, revealed interactions of Hb with several lupus-associated autoantigens; co-incubation of ferric Hb with apoptotic blebs (structures that contain packaged autoantigens) revealed synergies-in terms of cytokine release and autoantibody production in vitro-that were also restricted to the lupus genotype. Murine ferric Hb activated multiple signalling pathways and, in combination with apoptotic blebs, preferentially triggered MAP kinase signalling specifically in splenocytes isolated from lupus-prone mice. Infusion of murine ferric Hb into lupus-prone mice led to enhanced release of lupus-associated cytokines, the generation of a spectrum of autoantibodies and enhanced-onset glomerulosclerosis. Given that the biased recognition of ferric Hb in a lupus milieu, possibly in concert with lupus-associated autoantigens, triggers inflammatory responses and the generation of lupus-associated cytokines, and also stimulates the generation of potentially pathogenic lupus-associated autoantibodies, neutralization of Hb could have beneficial effects.

We have previously shown that obesity is associated with increased secretion of IgG antibodies with anti-self-reactivity. In this paper, we confirm and extend our previous findings. We show that the plasma of individuals with obesity is enriched in autoimmune antibodies whose levels are positively associated with blood frequencies of the subset of Double Negative (DN) B cells, which is the most pro-inflammatory B cell subset. We also show that DN B cells, significantly increased in the blood of obese versus lean individuals, are characterized by higher expression of immune activation markers and of the transcription factor T-bet, both associated with autoimmunity. The removal of DN B cells from the peripheral B cell pool significantly decreases in vitro secretion of anti-self IgG antibodies. These results altogether confirm the crucial role of DN B cells in the secretion of anti-self IgG antibodies in individuals with obesity.

Systemic administration of anti-programmed cell death 1 (PD-1) antibody (Ab) has achieved remarkable success in metastatic cancers. The blockade of PD-1-mediated signaling pathways sometimes cause immune-related adverse events (irAEs) due to restored anti-cancer as well as anti-self immunity. Although the liver is a preferential organ for irAEs, the immuno-pathogenesis underlying hepatic irAEs has been poorly understood. We describe a 57-year-old man with Stage IV lung cancer who underwent the first-line regimen composed of carboplatin and paclitaxel. Nivolumab treatment (3.2 mg/kg, every 3 weeks) was initiated when the disease progressed after the first chemotherapy. Sequential occurrence of irAEs involving the multiorgan systems was observed. He developed hepatic irAEs (Grade 3) after endocrine, lung, and cutaneous irAEs. Lobular hepatitis characterized by predominant infiltration of CD8+ T cells was seen in the liver biopsy specimens. Interestingly, defective accumulation of regulatory T cells (Tregs) expressing forkhead box protein P3 (FOXP3) was evident in this case with hepatic irAEs as compared with typical cases with autoimmune hepatitis. This case suggests that hepatic irAEs are characterized not only by lobular infiltration of CD8+ T cells but also by defective accumulation of FOXP3+ Tregs.

T cell receptor (TCR) signaling influences multiple aspects of CD4+ and CD8+ T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.

Cutaneous Lupus Erithematosus is one of the most common manifestation of Systemic Lupus Erithematosus and can be featured by the onset of cutaneous vasculitis which can bring to skin ulcers, expecially on the extremities. The "common" aetiopathogenesis can be summarized as following: 1) an antiself response to the endothelial cells which brings to frequent ischemic or thrombotic episodes, 2) the drugs therapy; recently authors have been demostrated a correlation between Metalloproteinase Matrix (MMP) and Cutaneous LES. Here we present the case of a 33 y.o. woman affected by a rheumatic disorder, which has developed a chronic ulcer on her left leg. After several and different unsuccessful approaches, as homologous and autologous skin graft, and considering both the refusal of other surgery even if enhanced by Negative Pressure Therapy and the compromised vascularization which contraindicated the use of flaps, we decided to use a dressing based on the TLC-NOSF (Technology Lipido-Colloid plus Nano-Oligo Saccharide Factor) protease inhibitor, a metalloproteinase regulator. The dressing was changed 2 times/week for the first 2 months and 1 time/week for other 2 months. The ulcer became smaller at every session and we obtained a full coverage at 4th month. KEY WORDS: Nano-oligo saccharide factor, Wound.

The genetic basis and mechanisms of disparate antitumor immune response was investigated in Diversity Outbred (DO) F1 mice that express human HER2. DO mouse stock samples nearly the entire genetic repertoire of the species. We crossed DO mice with syngeneic HER2 transgenic mice to study the genetics of an anti-self HER2 response in a healthy outbred population. Anti-HER2 IgG was induced by Ad/E2TM or naked pE2TM, both encoding HER2 extracellular and transmembrane domains. The response of DO F1 HER2 transgenic mice was remarkably variable. Still, immune sera inhibited HER2+ SKBR3 cell survival in a dose-dependent fashion. Using DO quantitative trait locus (QTL) analysis, we mapped the QTL that influences both total IgG and IgG2(a/b/c) Ab response to either Ad/E2TM or pE2TM. QTL from these four datasets identified a region in chromosome 17 that was responsible for regulating the response. A/J and NOD segments of genes in this region drove elevated HER2 Ig levels. This region is rich in MHC-IB genes, several of which interact with inhibitory receptors of NK cells. (B6xA/J)F1 and (B6xNOD)F1 HER2 transgenic mice received Ad/E2TM after NK cell depletion, and they produced less HER2 IgG, demonstrating positive regulatory function of NK cells. Depletion of regulatory T cells enhanced response. Using DO QTL analysis, we show that MHC-IB reactive NK cells exert positive influence on the immunity, countering negative regulation by regulatory T cells. This new, to our knowledge, DO F1 platform is a powerful tool for revealing novel immune regulatory mechanisms and for testing new interventional strategies.