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PubMed2025

Targeting IDH2 promotes antitumor immunity through epigenetic activation of cGAS-STING pathway.

Reductive carboxylation is critical for the proliferation of cancer cells and the differentiation of T cells. However, the role of this reaction in cancer cell-mediated tumor immunity remains unclear. Analysis of TCGA database showed a negative correlation between IDH2 expression and the presence of CD8+ T cells in lung and breast cancers, whereas IDH1 expression didn't show such a correlation. Further GSEA analysis revealed a significant enrichment of immune-related genes within IDH2-associated genes, specifically those in the type Ⅰ interferon pathway. In lung cancer cells, the depletion of IDH2 expression indeed could induce the activation of the immune-related and specially type Ⅰ interferon pathway. Targeting IDH2 with shRNA or its inhibitor AGI-6780 caused an increase in intracellular α-ketoglutarate concentration and a decrease in ATP and SAM levels, leading to a reduction in the methylation of STING promoter and elevated levels expression of STING. The increase of STING expression underlies the activation of type I interferon pathway observed in IDH2 compromised tumor cells and increased defense responses in the tumors in mice. These results identify IDH2 as a potential target to enhance cancer immune therapy.

Humans↗
PubMed2025

A choanoflagellate cGLR-STING pathway reveals evolutionary links between bacterial and animal immunity.

Animal innate immunity evolved from ancient pathways in bacterial anti-phage defense. How bacterial immune components were first acquired and adapted within eukaryotic cells remains poorly understood. Here we identify a complete cGLR-STING signaling axis in choanoflagellates, the closest living relatives of animals, that exhibits a mosaic of features from both bacterial and animal immunity. Comparative genomics reveals choanoflagellate cGLR and STING genes organized in operon-like arrangements reminiscent of bacterial defense loci. Reconstitution of choanoflagellate cGLR-STING signaling in vitro demonstrates that activation occurs through the conserved nucleotide immune signal 2'3'-cGAMP. Structural analysis of a choanoflagellate STING-2'3'-cGAMP complex explains how retention of bacterial-like features in early eukaryotic proteins shapes ligand specificity and receptor activation. We analyze cGLR and STING evolution in unicellular eukaryotes and identify further STING homologs in choanoflagellates and fungi that support additional independent acquisition events. Our results reveal molecular fossils that bridge bacterial and animal immunity and illuminate early eukaryotic immune system evolution.

Journal Article↗
PubMed2026

Loss of XRCC1 promotes cGAS/STING mediated innate immune signaling in gastric cancer.

BACKGROUND: One of the most defining features of gastric cancer (GC) is harboring deficiency in DNA repair that subsequently contributes to carcinogenesis. The X-ray repair cross complementing 1 (XRCC1) protein is a key molecular scaffold required for efficient repair of DNA single-strand breaks (SSBs) to maintain genomic stability. However, further investigation is needed to uncover the role of XRCC1 in innate immune signaling and inflammation in GC. METHODS: We evaluated how loss of XRCC1 leads to accumulation of cytosolic DNA using immunofluorescence localization assay and measuring DNA from cytosolic extract. We applied ON-TARGETplus™ SMARTpool siRNAs to knockdown XRCC1 in gastric cell lines and examined the innate immune siganling and inflammation with and without ATM inhibitor treatment. Further, we examined Type I interferon gene expression in various gastric cancer cell lines and assessed its role in cGAS-STING signaling using RT-qPCR, RNA-Seq, and immunoblot analysis. In addition, we generated conditional knockout XRCC1 mice and characterized the innate immune signaling from stomach tissue extract using RT-qPCR, western blot. Further, the DNA damage and histological analysis was done by immunohistochemistry. RESULTS: In this work, we examined the role of XRCC1 in modulating the innate immune signaling axis via cGAS/STING pathway. We find that XRCC1 deficient gastric cancer cell lines and mouse stomach tissue shows activation of cGAS/STING signaling. Further, ATM inhibition enhances robust cGAS/STING mediate innate immune signaling and PD-L1 expression in XRCC1 deficient gastric cancer cells. CONCLUSIONS: Results from this work demonstrate that XRCC1 is essential to maintain innate immune homeostasis. Further, this work suggest that ATM inhibitors may provide a potential therapeutic strategy to enhance the PD-L1 expression that could increase the efficacy of an immune checkpoint blockade (ICB) in XRCC1 deficient or low expressing GC.

X-ray Repair Cross Complementing Protein 1↗
PubMedDate not supplied

Immunity against the venom of Mexican scorpion Centruroides lumpidus limpidus induced by some proteins from this venom.

A protein fraction, which consisted of at least 12 proteins, was obtained from the venom of Mexican scorpion Centruroides limpidus limpidus. The molecular weights of these proteins ranged between 9,800 and 163,000 daltons. This fraction was separated from the rest of the venom components, which were almost all neurotoxins, by chromatographying the venom obtained by electrical stimulation through a Sephadex G-50M column. This fraction was non-toxic for mice, even at dose of 200 micrograms/mouse. The most important is that it was able to induce immunity against C. l. limpidus venom, since 92.8% of the animals inoculated with three doses survived after the challenge with 39.2 micrograms of venom (2 DL50 for mice of 20 g); on the contrary, 88 min after the challenge, 100% of the control mice had already died. In another experiment, this immunogen was inoculated into mice three times at variable doses. Seven days after the last injection, each mouse was challenged with 19.6 micrograms of venom. In all controls the typical envenomation picture produced by scorpion venom was developed, and death was registered in 19% of the animals. In contrast, 87% of mice immunized with the highest dose failed to show signs of envenomation or died throughout the observation time. Only two immunized animals (13%) showed mild tachycardia and hyperpnea at 120 min post-challenge. Immunoelectrophoresis and immunodiffusion tests revealed that these proteins induced antibodies against components of the most toxic fraction.

Animals↗
PubMed1976

Allergy to insect stings. II. Phospholipase A: the major allergen in honeybee venom.

In order to determine the proteins of major allergenic importance in honeybee venom (Apis mellifera) it was chromatographed on G-50 Sephadex. The four major protein peaks eluted were identified as hyaluronidase, phospholipase, melittin, and apamin. Testing these preparations on the leukocytes of 6 honeybee-sensitive patients, with the in vitro method of histamine release, revealed that all individuals were most sensitive to phospholipase A. IgE antibodies against phospholipase A (RAST) were found in the sera of honeybee-sensitive patients and IgG antibodies to this venom component were found in the sera from beekeepers and venom-treated patients. Melittin appeared to be allergenic in several patients, but the results were variable and were possibly due to contamination with phospholipase. All patients were insensitive to the hyaluronidase and apamin preparations. We conclude that phospholipase A is the major allergen of honeybee venom and, since this protein is readily available, it should be useful for diagnostic and therapeutic studies as well as for the standardization of materials used in the management of honeybee-sensitive patients.

Allergens↗
PubMed1977

Urticaria. An updated review.

Urticaria can result from many different stimuli, and numerous factors, both immunologic and nonimmunologic, are involved in its pathogenesis. Most commonly considered of immunologic mechanisms is the type I hypersensitivity state mediated by IgE. Another immunologic mechanism involves the activation of the complement cascade, which produces anaphylatoxins that can release histamine. Immunologic, nonimmunologic, genetic, and modulating factors converge on mast cells and basophils to release mediators capable of producing urticarial lesions. In addition to the clinical and laboratory diagnosis and treatment regimens, we review such mediators as histamine, kinins, serotonin, slow-reacting substance of anaphylaxis, prostaglandins, acetylcholine, fibrin degradation products, and anaphylatoxins that increase vascular permeability and can thereby produce wheals. Special consideration is given to histamine and the factors that regulate is secretory release from mast cells and basophils, including the modulating role of intracellular levels of cyclic adenosine monophosphate.

Bites and Stings↗
PubMed1978

Sensitization following Hymenoptera whole body extract therapy.

Treatment of an insect-sensitive patient with Hymenoptera whole body extracts (WBE) led, on five occasions, to a serum sickness--like syndrome which did not recur after therapy was stopped. The patient was found to be sensitive by skin test, histamine release, and radioallergosorbent test (RAST) to both venom and WBE as well as to venomless bee body preparations. Subsequent therapy with honeybee and yellow jacket venoms was without sequelae, and after treatment the patient did not react to a sting. In order to assess the frequency of sensitivity to irrelevant body proteins in patients treated with WBE we carried out WBE RASTs on sera from 15 such patients and compared them with those from 15 nontreated insect-allergic patients who had similar venom-specific IgE antibody levels. None of the patients allergic to insects who had not been treated with WBE had detectable IgE anti-WBE antibodies, while about 50% of those treated with WBE had developed IgE antibodies against these proteins. It appears that sensitization to nonvenom WBE proteins in terms of the development of IgE antibody is a common result of this therapy, and, rarely, repeated challenge with this complex antigenic mixture can also lead to clinical illness.

Adolescent↗
PubMed1979

Comparison of the atopic background between allergic and non-allergic beekeepers.

A study was carried out on beekeepers and their families. 34 subjects with a history of bee sting allergy and also a positive radioallergosorbent test (RAST) to honey bee venom were compared with 47 subjects with neither. 16 subjects in the bee allergy group (47%) had a history of atopic diseases as compared to 6 (13%) in the control group (p less than 0.01). 15 in the bee allergy group (44%) had at least one positive RAST to three common inhalant allergens as compared to 5 (11%) in the control group (p less than 0.01). These results suggest that, although bee sting allergy frequently affects non-atopic subjects, sensitization among beekeepers and their families occurs more readily in atopics. It is notable that a large proportion of patients injected with foreign proteins (the control group) either never develop venom-specific IgE antibodies or have suppressed their production.

Adult↗
PubMed2022

An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2.

Elevated levels of cytokines IL-1β and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1β released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARS-CoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1β release. Nuclease treatment, STING, and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1β release. After release, IL-1β stimulates IL-6 secretion from HAE. Therefore, infection alone does not increase IL-1β secretion by either cell type. Rather, bi-directional interactions between the SARS-CoV-2-infected epithelium and immune bystanders stimulates both IL-1β and IL-6, creating a pro-inflammatory cytokine circuit. Consistent with these observations, patient autopsy lungs show elevated myeloid inflammasome gene signatures in severe COVID-19.

Humans↗
PubMed2025

Divergent viral phosphodiesterases for immune signaling evasion.

Cyclic dinucleotides (CDNs) and other short oligonucleotides play fundamental roles in immune system activation in organisms ranging from bacteria to humans. In response, viruses use phosphodiesterase (PDE)-mediated oligonucleotide cleavage for immune evasion, a strategy whose diversity has not yet been explored. Here, we use a canonical 2H PDE (2H PDE) structure-based search of prokaryotic and eukaryotic viral sequences to identify an exceptional diversity of 2H PDEs across the virome, including enzymes not detectable with sequence search methods alone. Despite active site conservation, biochemical experiments reveal remarkable substrate specificity of these PDEs that corresponds to variations in the core 2H fold. This nuanced specificity allows 2H PDEs to selectively degrade oligonucleotide messengers to avoid interfering with host nucleotide signaling. Together, these findings nominate viral 2H PDEs as key regulators of CDN signaling across the tree of life.

Immune Evasion↗
PubMed1976

Allergy to insect sting. III. Allergenic cross-reactivity among the vespid venoms.

Recent reports have indicated that venoms may be more beneficial than whole body extracts for the diagnosis and treatment of Hymenoptera sensitive patients. These studies were undertaken to determine the cross-reactivity among the vespid venoms. Eighteen patients who were anaphylactically sensitive to vespid venoms were studied using in vitro leukocyte histamine release. The results (venom concentration for 50% histamine release) were analyzed by linear regression analysis; there was no allergenic cross-reactivity between any of the venoms, except for a modest association between yellow hornet and white hornet venom. In spite of this result 13 of the 18 patients studied were sensitive to three or four of the venoms tested. There is no clear explanation for this observation, but it suggests the existence of multiple major allergens in the vespid venoms, some of which are cross-reactive. Since immunotherapy with inappropriate proteins may lead to the development of IgE and the possibility of clinical sensitivity and since the majority of patients were not sensitive to all venom preparations, we suggest that appropriate diagnostic studies be carried out before the institution of therapy.

Animals↗
PubMed2026

Venomous Lepidoptera: defensive toxin systems, venom composition, and clinical significance.

Venomous Lepidoptera constitute an underrecognized yet medically significant group of toxin-producing arthropods that employ contact-mediated defensive envenomation through specialized integumentary structures such as setae, spines, and scoli. Unlike actively stinging arthropods, these insects deliver venom passively upon contact, eliciting a diverse spectrum of clinical manifestations collectively termed lepidopterism. Clinical outcomes range from localized pain and dermatitis to severe systemic effects, including hemorrhagic syndromes, complement activation, and chronic inflammatory disorders. Recent advances in proteomic and transcriptomic technologies have transformed our understanding of lepidopteran venoms, revealing unexpectedly complex toxin repertoires comprising serine proteases, phospholipases, pore-forming proteins, disulfide-rich peptides, neuroactive RF-amide peptides, and immune-modulating components. These findings have provided new insights into the molecular basis of toxicity, host-pathogen interactions, and the evolutionary diversification of venom systems within Lepidoptera. This review synthesizes current knowledge on the morphology of venom-delivery structures, venom composition, mechanisms of action, and associated clinical manifestations, while highlighting medically important taxa, particularly species of the genus Lonomia. The successful development of antivenom against Lonomia envenomation underscores the translational relevance of lepidopteran toxin research and its potential for therapeutic innovation. By integrating molecular, clinical, and evolutionary perspectives, this review repositions venomous Lepidoptera as a legitimate and important component of arthropod toxinology. Furthermore, it identifies critical methodological limitations and key knowledge gaps, providing a framework for future investigations aimed at advancing our understanding of toxin biology, immunopathology, and the development of novel biomedical applications.

Animals↗
PubMed1979

Sensitization to nonvenom contaminants in a venom preparation.

An individual is described who appeared to be sensitive to nonvenom contaminants in a venom preparation. His IgE antibodies, measured by the immediate direct skin test and the radioallergosorbent test (RAST), reacted with a yellow jacket venom preparation obtained by "washing" of venom sacs. With yellow jacket venom obtained by electriral stimulation, there was a skin test reaction of equivocal significance and no serum antibodies were detected by the RAST. Moderate reactions were also found with yellow jacket body extracts. In contrast, sera obtained from patients with yellow jacket sting anaphylaxis showed strong reactions with the electrically stimulated venom preparation and only a few reacted with the body extract. In additional studies, the patient's serum reacted with yellow jacket extracts devoid of venom and a variety of hornet and wasp extracts. Analyses of the two yellow jacket venoms by gel diffusion using rabbit antisera showed the presence of body proteins in the venom obtained by venom sac "washing." Subsequent history revealed the presence of insect nests in the roof of the patient's bedroom, perhaps the source of inhalant exposure and sensitivity. This case history demonstrates the need for venom extracts that do not contain potentially sensitizing extraneous material.

Adolescent↗
PubMedDate not supplied

[Tick-bite meningoradiculitis (author's transl)].

Meningoradiculitis due to tick-bite is rare and poorly documented. Its etiology remains hypothetical, but is thought to be caused by a viral infection carried by the tick. It is characterized by a striking clinical picture, especially symptoms of a subjective nature. The involved area extends asymmetrically from the site of the bite with variable latency. The CSF is characteristic, showing definite lymphocytosis and a moderate protein reaction. The prognosis is excellent although recovery may take several months. In the event of facial paralysis, there is a risk of postparalytic spasms. Treatment is symptomatic; no drug has proved effective.

Aged↗