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The Consortium of Eosinophilic Gastrointestinal disease Researchers (CEGIR) and The International Gastrointestinal Eosinophil Researchers (TIGERS) organized a day-long symposium at the 2024 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured new discoveries in basic and translational research and debates on the mechanisms and management of eosinophilic gastrointestinal diseases (EGIDs). Updates on recent clinical trials and consensus guidelines were also presented. Herein, we summarize the updates on EGIDs presented at the symposium.
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PURPOSE OF REVIEW: Aspirin-exacerbated respiratory disease (AERD) is a syndrome of high type 2 inflammation and is known to critically involve mast cell activation. The mast cell is an important cell in the baseline inflammatory processes in the upper and lower airway by maintaining and amplifying type 2 inflammation. But it also is prominent in the hypersensitivity reaction to COX-1 inhibition which defines this condition. RECENT FINDINGS: Recent work highlights the mast cell as a focal point in AERD pathogenesis. Using AERD as a specific model of both high type 2 asthma and chronic sinusitis, the role of mast cell activity can be better understood in other aspects of airway inflammation. Further dissecting out the mechanism of COX-1-mediated mast cell activation in AERD will be an important next phase in our understanding of NSAID-induced hypersensitivity as well as AERD pathophysiology.
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Asma Induzida por Aspirina , Pólipos Nasais , Sinusite , Humanos , Mastócitos/patologia , Sinusite/induzido quimicamente , Sinusite/patologia , Inflamação/patologia , Aspirina/efeitos adversosRESUMO
The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in ß-amyloid (Aß) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aß clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive-innate immunity cross talk and accelerated disease progression.
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Adaptação Fisiológica , Doença de Alzheimer/fisiopatologia , Microglia/patologia , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Imunoglobulina G/sangue , Camundongos , FagocitoseRESUMO
After spinal cord injury (SCI), the neurogenic bladder is observed to develop asynchronous bladder and external urethral sphincter (EUS) contractions in a condition known as detrusor-sphincter dyssnergia (DSD). Activation of the EUS spinal controlling center located at the upper lumbar spinal cord may contribute to reduce EUS dyssynergic contractions and decrease urethral resistance during voiding. However, this mechanism has not been well studied. This study aimed at evaluating the effects of epidural stimulation (EpS) over the spinal EUS controlling center (L3) in combination with a serotonergic receptor agonist on EUS relaxation in naive rats and chronic (6-8 wk) T8 SCI rats. Cystometrogram and EUS electromyography (EMG) were obtained before and after the intravenous administration of 5HT-1A receptor agonist and antagonist. The latency, duration, frequency, amplitude, and area under curve of EpS-evoked EUS EMG responses were analyzed. EpS on L3 evoked an inhibition of EUS tonic contraction and an excitation of EUS intermittent bursting/relaxation correlating with urine expulsion in intact rats. Combined with a 5HT-1A receptor agonist, EpS on L3 evoked a similar effect in chronic T8 SCI rats to reduce urethral contraction (resistance). This study examined the effect of facilitating the EUS spinal controlling center to switch between urine storage and voiding phases by using EpS and a serotonergic receptor agonist. This novel approach of applying EpS on the EUS controlling center modulates EUS contraction and relaxation as well as reduces urethral resistance during voiding in chronic SCI rats with DSD.
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Terapia por Estimulação Elétrica/métodos , Traumatismos da Medula Espinal/complicações , Medula Espinal/fisiopatologia , Uretra/inervação , Bexiga Urinaria Neurogênica/terapia , Urodinâmica , Animais , Modelos Animais de Doenças , Eletromiografia , Feminino , Vértebras Lombares , Ratos Sprague-Dawley , Reflexo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Traumatismos da Medula Espinal/fisiopatologia , Fatores de Tempo , Uretra/efeitos dos fármacos , Bexiga Urinaria Neurogênica/etiologia , Bexiga Urinaria Neurogênica/fisiopatologia , Urodinâmica/efeitos dos fármacosRESUMO
Chronic hypoxia is an inciting factor for the development of pulmonary arterial hypertension. The mechanisms involved in the development of hypoxic pulmonary hypertension (HPH) include hypoxia-inducible factor 1 (HIF-1)-dependent transactivation of genes controlling pulmonary arterial smooth muscle cell (PASMC) intracellular calcium concentration ([Ca(2+)](i)) and pH. Recently, digoxin was shown to inhibit HIF-1 transcriptional activity. In this study, we tested the hypothesis that digoxin could prevent and reverse the development of HPH. Mice were injected daily with saline or digoxin and exposed to room air or ambient hypoxia for 3 wk. Treatment with digoxin attenuated the development of right ventricle (RV) hypertrophy and prevented the pulmonary vascular remodeling and increases in PASMC [Ca(2+)](i), pH, and RV pressure that occur in mice exposed to chronic hypoxia. When started after pulmonary hypertension was established, digoxin attenuated the hypoxia-induced increases in RV pressure and PASMC pH and [Ca(2+)](i). These preclinical data support a role for HIF-1 inhibitors in the treatment of HPH.
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Digoxina/farmacologia , Hipertensão Pulmonar/prevenção & controle , Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/complicações , Ativação Transcricional/fisiologia , Análise de Variância , Animais , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Digoxina/sangue , Hipertensão Pulmonar/etiologia , Hipertrofia Ventricular Direita/prevenção & controle , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Camundongos , Microscopia Confocal , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/citologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ativação Transcricional/efeitos dos fármacosRESUMO
The gastrointestinal system is a hollow organ affected by fibrostenotic diseases that cause volumetric compromise of the lumen via smooth muscle hypertrophy and fibrosis. Many of the driving mechanisms remain unclear. Yes-associated protein-1 (YAP) is a critical mechanosensory transcriptional regulator that mediates cell hypertrophy in response to elevated extracellular rigidity. In the type 2 inflammatory disorder, eosinophilic esophagitis (EoE), phospholamban (PLN) can induce smooth muscle cell hypertrophy. We used EoE as a disease model for understanding a mechanistic pathway in which PLN and YAP interact in response to rigid extracellular substrate to induce smooth muscle cell hypertrophy. PLN-induced YAP nuclear sequestration in a feed-forward loop caused increased cell size in response to a rigid substrate. This mechanism of rigidity sensing may have previously unappreciated clinical implications for PLN-expressing hollow systems such as the esophagus and heart.
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Proteínas de Ligação ao Cálcio , Hipertrofia , Mecanotransdução Celular , Miócitos de Músculo Liso , Proteínas de Sinalização YAP , Humanos , Miócitos de Músculo Liso/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Sinalização YAP/metabolismo , Animais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição/metabolismo , CamundongosRESUMO
Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene that alters cellular homeostasis, particularly in the striatum and cortex. Astrocyte signaling that establishes and maintains neuronal functions are often altered under pathological conditions. We performed single-nuclei RNA-sequencing on human HD patient-induced pluripotent stem cell (iPSC)-derived astrocytes and on striatal and cortical tissue from R6/2 HD mice to investigate high-resolution HD astrocyte cell state transitions. We observed altered maturation and glutamate signaling in HD human and mouse astrocytes. Human HD astrocytes also showed upregulated actin-mediated signaling, suggesting that some states may be cell-autonomous and human specific. In both species, astrogliogenesis transcription factors may drive HD astrocyte maturation deficits, which are supported by rescued climbing deficits in HD drosophila with NFIA knockdown. Thus, dysregulated HD astrocyte states may induce dysfunctional astrocytic properties, in part due to maturation deficits influenced by astrogliogenesis transcription factor dysregulation.
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Complement factor I deficiency (CFID; OMIM #610984) is a rare immunodeficiency caused by deficiencies in the serine protease complement factor I (CFI). CFID is characterized by predisposition to severe pneumococcal infection, often in infancy. We report a previously healthy adolescent male who presented with respiratory failure secondary to pneumococcal pneumonia and severe systemic inflammatory response. Rapid genome sequencing (rGS) identified compound heterozygous variants in CFI in the proband, with a novel maternally inherited likely pathogenic variant, a single nucleotide deletion resulting in premature stop (c.1646del; p.Asn549ThrfsTer25) and a paternally inherited novel likely pathogenic deletion (Chr 4:110685580-110692197del).
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Fator I do Complemento , Adolescente , Humanos , Masculino , Genótipo , Mapeamento CromossômicoRESUMO
Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.
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Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Genômica , Células Mieloides , Sequências Reguladoras de Ácido Nucleico/genética , Alelos , Doença de Alzheimer/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Macrófagos , Microglia/metabolismo , TranscriptomaRESUMO
BACKGROUND: The immune system plays a major role in the pathogenesis of age-related dementia, including Alzheimer's disease (AD). An insight into age-associated changes in the immune response to amyloid-beta (Aß) in individuals without AD may be beneficial in identifying mechanisms preventing accumulation of Aß. METHODS: We examined the response of human monocyte-derived dendritic cells (DCs), T cells, and peripheral blood mononuclear cells (PBMCs) from healthy aged and young subjects to Aß peptide 1-42, Aß fibrils, and recombinant, nonaggregated tau-4 protein with a view to understand the role of peripheral immunity in AD. RESULTS: Our studies revealed that DCs from healthy aged subjects display weak reactivity towards the Aß peptide and no reactivity towards Aß fibrils and tau compared with their young counterparts. An analysis of old and young PBMCs revealed that there is no significant T-cell memory against Aß peptide, fibrils, or tau. Remarkably, the plasma levels of IgM antibodies specific to Aß peptide 1-42 were significantly increased in aged subjects compared with young subjects, while IgG levels were comparable. Aß peptide-specific IgM and IgG levels were also determined in the plasma of AD subjects compared with age-matched controls to demonstrate that the immune response against Aß is stronger in AD patients. A decline in Aß peptide-specific IgM antibodies was observed in AD patients compared with age-matched controls. In contrast, the levels of IgG as well as interleukin-21, the major cytokine involved in class switching, were increased in AD and patients with mild cognitive impairment, indicating a strong immune response against Aß. CONCLUSIONS: Collectively, low immunogenicity of Aß in healthy controls may prevent inflammation while the generation of specific IgM antibodies may help in the clearance of Aß in healthy subjects.
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Envelhecimento/sangue , Envelhecimento/imunologia , Peptídeos beta-Amiloides/imunologia , Imunoglobulina M/sangue , Fragmentos de Peptídeos/imunologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/farmacologia , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Humanos , Leucócitos Mononucleares , Masculino , Fragmentos de Peptídeos/farmacologia , Adulto Jovem , Proteínas tau/metabolismoRESUMO
To date, Alzheimer disease drug candidates have produced negative results in human trials, and progress in moving new targets out of the laboratory and into trials has been slow. However, based on 3 decades of previous work, there is reason to hope that amyloid-based and other novel therapies will move at a faster pace toward successful clinical trials. This article highlights selected preclinical research topics that are rapidly advancing in the laboratory.
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Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas E/genética , Inflamação/complicações , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Animais , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Colesterol/metabolismo , HumanosRESUMO
Brain aging and neurodegeneration are associated with prominent microglial reactivity and activation of innate immune response pathways, commonly referred to as neuroinflammation. One such pathway, the type I interferon response, recognizes viral or mitochondrial DNA in the cytoplasm via activation of the recently discovered cyclic dinucleotide synthetase cGAS and the cyclic dinucleotide receptor STING. Here we show that the FDA-approved antiviral drug ganciclovir (GCV) induces a type I interferon response independent of its canonical thymidine kinase target. Inhibition of components of the STING pathway, including STING, IRF3, Tbk1, extracellular IFNß, and the Jak-Stat pathway resulted in reduced activity of GCV and its derivatives. Importantly, functional STING was necessary for GCV to inhibit inflammation in cultured myeloid cells and in a mouse model of multiple sclerosis. Collectively, our findings uncover an unexpected new activity of GCV and identify the STING pathway as a regulator of microglial reactivity and neuroinflammation.
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Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica/genética , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Microglia/metabolismo , Animais , Animais Recém-Nascidos , Antivirais/uso terapêutico , Células Cultivadas , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/genética , Feminino , Adjuvante de Freund/toxicidade , Ganciclovir/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/imunologia , Toxina Pertussis/toxicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aß fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.