RESUMEN
Neoantigen-based immunotherapy is an attractive potential treatment for previously intractable tumors. To effectively broaden the application of this approach, stringent biomarkers are crucial to identify responsive patients. ARID1A, a frequently mutated subunit of SWI/SNF chromatin remodeling complex, has been reported to determine tumor immunogenicity in some cohorts; however, mutations and deletions of ARID1A are not always linked to clinical responses to immunotherapy. In this study, we investigated immunotherapeutic responses based on ARID1A status in targeted therapy-resistant cancers. Mouse and human BRAFV600E melanomas with or without ARID1A expression were transformed into resistant to vemurafenib, an FDA-approved specific BRAFV600E inhibitor. Anti-PD-1 antibody treatment enhanced antitumor immune responses in vemurafenib-resistant ARID1A-deficient tumors but not in ARID1A-intact tumors or vemurafenib-sensitive ARID1A-deficient tumors. Neoantigens derived from accumulated somatic mutations during vemurafenib resistance were highly expressed in ARID1A-deficient tumors and promoted tumor immunogenicity. Furthermore, the newly generated neoantigens could be utilized as immunotherapeutic targets by vaccines. Finally, targeted therapy resistance-specific neoantigen in experimental human melanoma cells lacking ARID1A were validated to elicit T-cell receptor responses. Collectively, the classification of ARID1A-mutated tumors based on vemurafenib resistance as an additional indicator of immunotherapy response will enable a more accurate prediction to guide cancer treatment. Furthermore, the neoantigens that emerge with therapy resistance can be promising therapeutic targets for refractory tumors. Significance: Chemotherapy resistance promotes the acquisition of immunogenic neoantigens in ARID1A-deficient tumors that confer sensitivity to immune checkpoint blockade and can be utilized for developing antitumor vaccines, providing strategies to improve immunotherapy efficacy.
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Antígenos de Neoplasias , Proteínas de Unión al ADN , Resistencia a Antineoplásicos , Melanoma , Factores de Transcripción , Vemurafenib , Animales , Humanos , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Ratones , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Resistencia a Antineoplásicos/inmunología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/terapia , Inmunoterapia/métodos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/inmunología , Línea Celular Tumoral , Femenino , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Mutación , Terapia Molecular Dirigida/métodos , Ratones Endogámicos C57BLRESUMEN
Diversity is a key feature of B cell biology-from BCR rearrangement to the heterogeneity of memory B cells. In this issue of Immunity, Wang et al. show that the zinc-finger protein ZFP318 supports mitochondrial health in certain memory B cells, thereby facilitating potent recall upon rechallenge.
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Células B de Memoria , Humanos , Animales , Células B de Memoria/inmunología , Mitocondrias/inmunología , Mitocondrias/metabolismo , Memoria Inmunológica/inmunología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/inmunología , Factores de Transcripción/metabolismo , Factores de Transcripción/inmunología , Linfocitos B/inmunologíaRESUMEN
Maxwell et al. show that ARID1A loss enhances antitumor immunity by triggering a type I IFN response through the cGAS-STING pathway, thereby promoting T cell infiltration and cytotoxicity. These findings highlight SWI/SNF inhibitors as a strategy to augment immunotherapy efficacy by potentially transforming non-responsive tumors into responders and advancing approaches to cancer treatment.
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Proteínas de Unión al ADN , Inmunoterapia , Neoplasias , Factores de Transcripción , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Inmunoterapia/métodos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/inmunología , Animales , Mutación , Transducción de Señal , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/inmunologíaRESUMEN
Histone demethylation by PHF8 initiates innate immune signaling in acute myeloid leukemia, elucidating a novel therapeutic strategy.
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Histonas , Inmunidad Innata , Leucemia Mieloide Aguda , Inmunidad Innata/inmunología , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/genética , Histonas/inmunología , Histonas/metabolismo , Animales , Desmetilación , Factores de Transcripción/inmunología , Transducción de Señal/inmunología , Histona Demetilasas/inmunología , Histona Demetilasas/metabolismoRESUMEN
Dermatomyositis (DM) presents with inflammatory myopathy and distinct skin manifestations, often linked to specific autoantibodies. Anti-transcriptional intermediary factor-1 gamma (TIF-1γ) antibodies (Abs) are typically linked to DM in older patients and malignancy in 15% to 40% of cases. We highlight a case of a 24-year-old female who presented with weakness of proximal muscles, periorbital edema, heliotrope rash, erosions on oral mucosa, and painful scaly rash on the lower extremities. Transcriptional intermediary factor-1 gamma Abs were positive, confirming inflammatory myopathy. Treatment with steroid pulse therapy and immunoglobulin led to improvement. Evaluation for malignancy yielded unremarkable results. This case underscores the importance of recognizing and managing DM with TIF-1γ Ab positive, even in atypical demographics, and highlights the need for comprehensive malignancy evaluation.
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Autoanticuerpos , Dermatomiositis , Factores de Transcripción , Humanos , Femenino , Dermatomiositis/inmunología , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/diagnóstico , Autoanticuerpos/sangre , Adulto Joven , Factores de Transcripción/inmunologíaAsunto(s)
Dermatomiositis , Factores de Transcripción , Humanos , Dermatomiositis/inmunología , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/diagnóstico , Dermatomiositis/complicaciones , Resultado del Tratamiento , Factores de Transcripción/inmunología , Autoanticuerpos/sangre , Femenino , Neumatosis Cistoide Intestinal/diagnóstico , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Masculino , Biomarcadores/sangre , Tomografía Computarizada por Rayos X , Persona de Mediana EdadRESUMEN
The relevance of the problem of immunoinflammatory rheumatic diseases (IIRD) for modern medicine is determined by their high prevalence in the population, the difficulty of early diagnosis, the rapid development of disability and poor life prognosis. Recent data on the significance of anti-DFS70 have opened up new possibilities for optimizing the step-by-step diagnosis of IIRD. The detection of these antibodies can help in the interpretation of a positive result for antinuclear antibodies (ANA) by indirect immunofluorescence assay on HEp-2 cells (IIFA-HEp-2) in the absence of autoantibodies specific for IIRD. Detection of anti-DFS70 in antinuclear factor (ANF) seropositive patients without clinical and/or serological markers characteristic of a certain disease from the IIRD group can be considered as a potential marker that excludes this group of diseases.
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Proteínas Adaptadoras Transductoras de Señales , Anticuerpos Antinucleares , Enfermedades Reumáticas , Humanos , Enfermedades Reumáticas/inmunología , Anticuerpos Antinucleares/inmunología , Anticuerpos Antinucleares/sangre , Proteínas Adaptadoras Transductoras de Señales/inmunología , Factores de Transcripción/inmunología , Biomarcadores/sangre , Masculino , Femenino , Persona de Mediana Edad , Adulto , Relevancia ClínicaRESUMEN
OBJECTIVES: To report the association of zinc finger and SCAN domain containing 1 antibodies (ZSCAN1-abs) with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome in patients without tumor. METHODS: Patients with symptoms compatible with ROHHAD syndrome but without an associated tumor were selected from our database. Serum and CSF samples were examined for the presence of ZSCAN1-abs by an in-house cell-based assay. In addition, samples from 149 patients with several inflammatory and noninflammatory disorders and 50 healthy participants served as controls. RESULTS: Thirteen patients with ROHHAD syndrome were identified. Of these, we had paired serum/CSF samples from 6 patients and only serum from the other 7. Five of 6 patients (83.3%) with paired serum/CSF (4 children, 1 adult) had ZSCAN-abs only in CSF and 1 had antibodies in serum and CSF. ZSCAN1-abs were not detected in the remaining 7 patients with ROHHAD with only serum available or in any of the 199 control samples. DISCUSSION: Patients with ROHHAD syndrome should be investigated for the presence of ZSCAN1-abs in CSF. The antibodies do not necessarily predict the presence of a tumor. The detection of ZSCAN1-abs in an adult patient suggests that this condition also occurs beyond the pediatric age.
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Autoanticuerpos , Enfermedades Hipotalámicas , Humanos , Masculino , Adulto , Femenino , Niño , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Enfermedades Hipotalámicas/inmunología , Enfermedades Hipotalámicas/sangre , Enfermedades Hipotalámicas/líquido cefalorraquídeo , Adolescente , Factores de Transcripción/inmunología , Hipoventilación/sangre , Hipoventilación/inmunología , Hipoventilación/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Autónomo/inmunología , Enfermedades del Sistema Nervioso Autónomo/sangre , Obesidad/inmunología , Adulto Joven , Persona de Mediana Edad , Preescolar , SíndromeRESUMEN
BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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Proteína AIRE , Interferón gamma , Inhibidores de las Cinasas Janus , Poliendocrinopatías Autoinmunes , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Proteína AIRE/deficiencia , Proteína AIRE/genética , Proteína AIRE/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Quimiocina CXCL9/genética , Interferón gamma/genética , Interferón gamma/inmunología , Inhibidores de las Cinasas Janus/uso terapéutico , Ratones Noqueados , Nitrilos/uso terapéutico , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/tratamiento farmacológico , Poliendocrinopatías Autoinmunes/inmunología , Pirazoles/uso terapéutico , Pirazoles/farmacología , Pirimidinas/uso terapéutico , Linfocitos T/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Proyectos Piloto , Modelos Animales de Enfermedad , Niño , Adolescente , Persona de Mediana EdadAsunto(s)
Dermatomiositis , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/complicaciones , Dermatomiositis/inmunología , Dermatomiositis/diagnóstico , Dermatomiositis/sangre , Dermatomiositis/complicaciones , Factores de Transcripción/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Masculino , Femenino , Persona de Mediana Edad , AncianoRESUMEN
Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Double strand RNA is an important ligand that stimulates tumor immunity via interferon responses. Differentiation of embryonic stem cells to pluripotent epithelial cells activates the interferon response during development, raising the question of whether epithelial vs. mesenchymal gene signatures in cancer potentially regulate the interferon pathway as well. Here, using genomics and signaling approaches, we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes type-I and -III interferon responses to double-strand RNA. GRHL2 enhanced the activation of IRF3 and relA/NF-kB and the expression of IRF1; a functional GRHL2 binding site in the IFNL1 promoter was also identified. Moreover, time to recurrence in breast cancer correlated positively with GRHL2 protein expression, indicating that GRHL2 is a tumor recurrence suppressor, consistent with its enhancement of interferon responses. These observations demonstrate that epithelial cell identity supports interferon responses in the context of cancer.
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Neoplasias de la Mama , Proteínas de Unión al ADN , Factores de Transcripción , Animales , Femenino , Humanos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Regulación Neoplásica de la Expresión Génica , Factor 1 Regulador del Interferón/metabolismo , Factor 1 Regulador del Interferón/genética , Factor 1 Regulador del Interferón/inmunología , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Interferones/metabolismo , Interferones/inmunología , Interferones/genética , Recurrencia Local de Neoplasia/inmunología , ARN Bicatenario/inmunología , Transducción de Señal/inmunología , Factor de Transcripción ReIA/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/inmunologíaRESUMEN
Targeted protein degradation is an innovative therapeutic strategy to selectively eliminate disease-causing proteins. Exemplified by proteolysis-targeting chimeras (PROTACs), they have shown promise in overcoming drug resistance and targeting previously undruggable proteins. However, PROTACs face challenges, such as low oral bioavailability and limited selectivity. The recently published PROxAb Shuttle technology offers a solution enabling the targeted delivery of PROTACs using antibodies fused with PROTAC-binding domains derived from camelid single-domain antibodies (VHHs). Here, a modular approach to quickly generate PROxAb Shuttles by enzymatically coupling PROTAC-binding VHHs to off-the-shelf antibodies was developed. The resulting conjugates retained their target binding and internalization properties, and incubation with BRD4-targeting PROTACs resulted in formation of defined PROxAb-PROTAC complexes. These complexes selectively induced degradation of the BRD4 protein, resulting in cytotoxicity specifically to cells expressing the antibody's target. The chemoenzymatic approach described herein provides a versatile and efficient solution for generating antibody-VHH conjugates for targeted protein degradation applications, but it could also be used to combine antibodies and VHH binders to generate bispecific antibodies for further applications.
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Anticuerpos Biespecíficos , Proteolisis , Humanos , Anticuerpos Biespecíficos/química , Anticuerpos Biespecíficos/inmunología , Factores de Transcripción/metabolismo , Factores de Transcripción/inmunología , Proteínas de Ciclo Celular/inmunología , Proteínas de Ciclo Celular/metabolismo , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/inmunología , Proteínas que Contienen BromodominioRESUMEN
Conventional type 1 dendritic cells (cDC1) are the essential antigen-presenting DC subset in antitumor immunity. Suppressing B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) inhibits tumor growth and boosts immune responses against cancer. However, whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely understood. Here, we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into tumor. Pharmacological inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9z96 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8+ T cell responses. Mechanistically, targeting BCL9/BCL9L promoted antigen presentation in tumors. This is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 axis. Importantly, using single-cell transcriptomics analysis, we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type (WT) cDC1 at activation and antigen presentation via NF-κB/IRF1 signaling. Together, we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens, as well as CD8+ T cell activation and tumor infiltration. Targeting BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.
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Presentación de Antígeno , Células Dendríticas , Animales , Humanos , Ratones , Presentación de Antígeno/inmunología , Presentación de Antígeno/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Células Dendríticas/inmunología , Células Dendríticas/patología , Ratones Noqueados , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/patología , Receptores de Quimiocina , Factores de Transcripción/genética , Factores de Transcripción/inmunologíaRESUMEN
BACKGROUND: ELF4 deficiency has been recently recognized as a novel disorder within the spectrum of inborn errors of immunity (IEIs), specifically categorized as a "disease of immune dysregulation." Cases of this condition, reported by our team and others, are very limited worldwide. As such, our current knowledge of this new disease remains preliminary. This review aims to provide a brief overview of the clinical manifestations, pathogenesis, and treatment strategies for this novel IEI. DATA SOURCES: A comprehensive review was conducted after an extensive literature search in the PubMed/Medline database and websites concerning transcriptional factor ELF4 and reports concerning patients with ELF4 deficiency. Our search strategy was "ELF4 OR ETS-related transcription factor Elf-4 OR EL4-like factor 4 OR myeloid Elf-1-like factor" as of the time of manuscript submission. RESULTS: The current signature manifestations of ELF4 deficiency disorder are recurrent and prolonged oral ulcer, abdominal pain, and diarrhea in pediatric males. In some cases, immunodeficiency and autoimmunity can also be prominent. Targeted Sanger sequencing or whole exome sequencing can be used to detect variation in ELF4 gene. Western blotting for ELF4 expression of the patient's cells can confirm the pathogenic effect of the variant. To fully confirm the pathogenicity of the variant, further functional test is strongly advised. Glucocorticoid and biologics are the mainstream management of ELF4 deficiency disorder. CONCLUSIONS: Pediatric males presenting with recurring ulcerations in digestive tract epithelium with or without recurrent fever should be suspected of DEX. When atypical presentations are prominent, variations in ELF4 gene should be carefully evaluated functionally due to the complex nature of ELF4 function. Experience of treating DEX includes use of glucocorticoid and biologics and more precise treatment needs more patients to identify and further mechanistic study.
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Proteínas de Unión al ADN , Factores de Transcripción , Humanos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Proteínas Proto-Oncogénicas c-ets/genética , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Enfermedades del Sistema Inmune/genéticaAsunto(s)
Autoanticuerpos , Dermatitis Exfoliativa , Dermatomiositis , Factores de Transcripción , Humanos , Dermatomiositis/inmunología , Dermatomiositis/complicaciones , Dermatomiositis/sangre , Dermatomiositis/diagnóstico , Dermatitis Exfoliativa/inmunología , Dermatitis Exfoliativa/etiología , Dermatitis Exfoliativa/diagnóstico , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Factores de Transcripción/inmunología , Femenino , Masculino , Persona de Mediana EdadRESUMEN
CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.
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Linfocitos T CD8-positivos , Matriz Extracelular , Sarcoma , Microambiente Tumoral , Proteínas Señalizadoras YAP , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Animales , Microambiente Tumoral/inmunología , Ratones , Proteínas Señalizadoras YAP/inmunología , Proteínas Señalizadoras YAP/genética , Humanos , Matriz Extracelular/inmunología , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Sarcoma/inmunología , Sarcoma/patología , Sarcoma/genética , Sarcoma/metabolismo , Colágeno Tipo VI/genética , Colágeno Tipo VI/inmunología , Colágeno Tipo VI/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/inmunología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/inmunología , Oncogenes , Proteínas de Neoplasias/inmunología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/inmunologíaRESUMEN
Anti-nuclear matrix protein 2 (NXP2) antibody-positive dermatomyositis (DM) is characterized by extensive and severe myositis. In this study, we evaluated which cytokines/chemokines involved with the activity of the myositis. We performed quantitative immunoassays using the MILLIPLEX® Multiplex Assays Using Luminex to evaluate serum levels of interferon-γ, interleukin (IL)-1ß, IL-6, IL-8, IL-12p40, and tumor necrosis factor-α in samples collected over time from a 9-year-old female with anti-NXP2 antibody-positive DM. In our case, the serum level of IL-8 was elevated when the myositis worsened, and decreased in accordance with the improvement of myositis, suggesting that the serum IL-8 levels were correlated with the myositis activity. Serum levels of IL-8 in samples from five patients with anti-NXP2 antibody-positive DM and five patients with anti-transcriptional intermediary factor 1γ (TIF1γ) antibody-positive DM without both interstitial lung disease (ILD) and malignancy before starting treatments, along with five healthy controls, were also evaluate by an enzyme-linked immunosorbent assay. Serum IL-8 levels were significantly elevated in anti-NXP2 or anti-TIF1γ antibody-positive DM patients with myositis but not ILD, than healthy controls. It was suggested that serum levels of IL-8 correlate with the activity of myositis in DM including anti-NXP2 antibody-positive DM.
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Autoanticuerpos , Dermatomiositis , Interleucina-8 , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenosina Trifosfatasas , Autoanticuerpos/sangre , Biomarcadores/sangre , Dermatomiositis/inmunología , Dermatomiositis/sangre , Proteínas de Unión al ADN , Interleucina-8/sangre , Miositis/inmunología , Miositis/sangre , Proteínas de Unión al ARN/inmunología , Factores de Transcripción/sangre , Factores de Transcripción/inmunologíaRESUMEN
This study is aimed at investigating the potential molecular features of allergic rhinitis (AR) and identifying gene signatures and related transcription factors using transcriptome analysis and in silico datasets. Transcriptome profiles were obtained using three independent cohorts (GSE101720, GSE19190, and GSE46171) comprising healthy controls (HC) and patients with AR. The pooled dataset (n = 82) was used to identify the critical signatures of AR compared with HC. Subsequently, key transcription factors were identified by a combined analysis using transcriptome and in silico datasets. Gene ontology: bioprocess (GO: BP) analysis using differentially expressed genes (DEGs) revealed that immune response-related genes were significantly enriched in AR compared with HC. Among them, IL1RL1, CD274, and CD44 were significantly higher in AR patients. We also identified key transcription factors between HC and AR using the in silico dataset and found that AR samples frequently express KLF transcription factor 4 (KLF4), which regulates immune response-related genes including IL1RL1, CD274, and CD44 in human nasal epithelial cells. Our integrative analysis of transcriptomic regulation provides new insights into AR, which may help in developing precision management for patients with AR.
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Regulación de la Expresión Génica , Inmunidad , Factor 4 Similar a Kruppel , Rinitis Alérgica , Rinitis Alérgica/genética , Rinitis Alérgica/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Inmunidad/genética , Inmunidad/inmunología , Factor 4 Similar a Kruppel/genética , Factor 4 Similar a Kruppel/inmunología , Humanos , Regulación de la Expresión Génica/inmunología , Perfilación de la Expresión Génica , Línea CelularRESUMEN
Th9, a new subgroup of CD4+T cells is characterized by its specific cytokine IL-9, is a critical factor in allergic diseases, cancers and parasitic infections. This study aimed to explore the potential roles of Th9 cells in the immunopathogenesis of ECM. In splenocytes sourced from uninfected, PbA and Py infected mice, Th9 cells were characterised by flow cytometry, cell sorting and qPCR. Enhancement of CD4+IL-9+ (Th9) cells were observed in both the infections, which corroborated with increased expression of the differentiating transcription factors. Moreover, crucial cytokine receptors (IL-4R, TGF-ßR, IL-6R) as well as chemokine receptors (CCR3, CCR6 and CCR7) and activation marker (CD96), demonstrated elevation upon PbA infection in splenic Th9 cells. Furthermore, Neutralization of IL-9 along with IL-6 enhanced host survivability, reduced mean neurological score of ECM. However, anti- IL-9 treatment also down regulated frequency of Th17 cells, and its transcription factors pSTAT3, RORγT along with depleted Il-1ß and Il-6 expression. In sum, understanding how IL-9 producing CD4+ T-cells can alter Th17/Treg ratio and by that modulate host's immune response, could pave the way for developing immunomodulatory interventions against cerebral malaria.
Asunto(s)
Interleucina-9 , Malaria Cerebral , Células Th17 , Animales , Ratones , Interleucina-6/inmunología , Interleucina-9/inmunología , Malaria Cerebral/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Factores de Transcripción/inmunologíaRESUMEN
The E protein transcription factors E2A and HEB are critical for many developmental processes, including T cell development. We have shown that the Tcf12 locus gives rise to two distinct HEB proteins, with alternative (HEBAlt) and canonical (HEBCan) N-terminal domains, which are co-expressed during early T cell development. While the functional domains of HEBCan have been well studied, the nature of the HEBAlt-specific (Alt) domain has been obscure. Here we provide compelling evidence that the Alt domain provides a site for the molecular integration of cytokine signaling and E protein activity. Our results indicate that phosphorylation of a unique YYY motif in the Alt domain increases HEBAlt activity by 10-fold, and that this increase is dependent on Janus kinase activity. To enable in vivo studies of HEBAlt in the T cell context, we generated ALT-Tg mice, which can be induced to express a HA-tagged HEBAlt coding cassette in the presence of Cre recombinases. Analysis of ALT-Tg mice on the Vav-iCre background revealed a minor change in the ratio of ISP cells to CD8+ SP cells, and a mild shift in the ratio of T cells to B cells in the spleen, but otherwise the thymus, spleen, and bone marrow lymphocyte subsets were comparable at steady state. However, kinetic analysis of T cell development in OP9-DL4 co-cultures revealed a delay in early T cell development and a partial block at the DN to DP transition when HEBAlt levels or activity were increased. We also observed that HEBCan and HEBAlt displayed significant differences in protein stability that were resolved in the thymocyte context. Finally, a proteomic screen identified STAT1 and Xpo1 as potential members of HEBAlt-containing complexes in thymocytes, consistent with JAK-induced activation of HEBAlt accompanied by translocation to the nucleus. Thus, our results show that the Alt domain confers access to multiple layers of post-translational control to HEBAlt that are not available to HEBCan, and thus may serve as a rheostat to tune E protein activity levels as cells move through different thymic signaling environments during T cell development.