RESUMEN
Early reports suggest that chimeric antigen receptor (CAR)-T therapy has remarkable potential for treating autoimmune disease. Current approaches rely on autologous CAR-T cells, creating a bottleneck to the broad deployment of this therapy. In this issue of Cell, Wang et al.1 report the first use of allogeneic CAR-T cells in three patients with systemic autoimmune disease.
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Enfermedades Autoinmunes , Receptores Quiméricos de Antígenos , Humanos , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Inmunoterapia Adoptiva/métodos , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
This review delves into the effects of autoimmune conditions like rheumatoid arthritis, inflammatory disorders such as irritable bowel syndrome, cardiovascular disease, diabetes, infectious ailments like human immunodeficiency virus, and their medications on periodontal therapy outcomes. It also explores the influence of hormones. Understanding these systemic factors is crucial for optimizing periodontal health and treatment efficacy. The review underscores the necessity of considering these variables in periodontal care. Other vital systemic factors are addressed elsewhere in this special edition.
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Enfermedades Periodontales , Humanos , Enfermedades Periodontales/terapia , Pronóstico , Enfermedades Cardiovasculares , Resultado del Tratamiento , Artritis Reumatoide , Síndrome del Colon Irritable/terapia , Enfermedades Autoinmunes , Infecciones por VIH/complicaciones , Diabetes Mellitus , Factores de RiesgoRESUMEN
Detection of cytosolic DNA by the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway provides immune defense against pathogens and cancer but can also cause autoimmunity when overactivated. The exonuclease three prime repair exonuclease 1 (TREX1) degrades DNA in the cytosol and prevents cGAS activation by self-DNA. Loss-of-function mutations of the TREX1 gene are linked to autoimmune diseases such as Aicardi-Goutières syndrome, and mice deficient in TREX1 develop lethal inflammation in a cGAS-dependent manner. In order to determine the type of cells in which cGAS activation drives autoinflammation, we generated conditional cGAS knockout mice on the Trex1-/- background. Here, we show that genetic ablation of the cGAS gene in classical dendritic cells (cDCs), but not in macrophages, was sufficient to rescue Trex1-/- mice from all observed disease phenotypes including lethality, T cell activation, tissue inflammation, and production of antinuclear antibodies and interferon-stimulated genes. These results show that cGAS activation in cDC causes autoinflammation in response to self-DNA accumulated in the absence of TREX1.
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Autoinmunidad , Células Dendríticas , Exodesoxirribonucleasas , Ratones Noqueados , Nucleotidiltransferasas , Fosfoproteínas , Animales , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/deficiencia , Exodesoxirribonucleasas/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/deficiencia , Células Dendríticas/inmunología , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/inmunología , Ratones , Autoinmunidad/inmunología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/patología , Inflamación/inmunología , Inflamación/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genéticaAsunto(s)
Síndromes Compartimentales , Enfermedades Orbitales , Humanos , Masculino , Síndromes Compartimentales/diagnóstico , Síndromes Compartimentales/etiología , Enfermedades Orbitales/diagnóstico , Vacuolas , Enfermedades Autoinmunes/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genéticaRESUMEN
BACKGROUND Statin-induced myopathy can present with symptoms ranging from mild myalgia to significant muscle weakness. Muscle-related adverse effects of statins have been very challenging in clinical practice and they necessitate high clinical suspicion. This case report highlights how statin-induced autoimmune myopathy often goes undiagnosed. CASE REPORT We present a 69-year-old man with a past medical history of coronary artery disease who presented with myalgia and progressive proximal muscle weakness for 2 months, with a creatinine kinase of 8323 U/L. Atorvastatin was held on admission and the patient received intravenous (IV) fluid as treatment for presumed rhabdomyolysis. Although CK was trending down, he did not show significant improvement in muscle weakness or myalgia. At this point, myositis was suspected, so a myositis panel including anti-HMG Co-A reductase antibody was ordered and he was started on IV steroids. Anti-HMG Co-A reductase antibody was positive, and the rest of myopathy workup was negative. Meanwhile, the patient's muscle weakness significantly improved with IV steroid. He was discharged on methylprednisolone with close outpatient rheumatology follow-up. CONCLUSIONS Muscle-related adverse effects of statins, including rhabdomyolysis and myopathy, can fail to respond to conservative management. It is crucial to identify and manage statin-induced autoimmune myopathy as a possible differential diagnosis in patients with muscle weakness and elevated CK while on statin therapy who do not respond to intravenous fluid alone.
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Enfermedades Autoinmunes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Debilidad Muscular , Enfermedades Musculares , Humanos , Masculino , Anciano , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Debilidad Muscular/inducido químicamente , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/diagnóstico , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/diagnóstico , Atorvastatina/efectos adversos , Miositis/inducido químicamente , Miositis/diagnósticoAsunto(s)
Enfermedades Autoinmunes , Antígeno de Maduración de Linfocitos B , Inmunosupresores , Linfocitos T , Humanos , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Antígeno de Maduración de Linfocitos B/inmunología , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Anticuerpos Biespecíficos/administración & dosificación , Femenino , Adulto , Persona de Mediana Edad , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Resultado del TratamientoRESUMEN
A bibliometric analysis of studies dedicated to autoimmune gastritis (AIG) recently published demonstrated a noteworthy surge in publications over the last three years. This can be explained by numerous publications from different regions of the world reporting the results of several studies that stimulated reassessment of our view of AIG as a precancerous condition. Follow-up studies and retrospective analyses showed that the risk of gastric cancer (GC) in AIG patients is much lower than expected if the patients ever being infected with Helicobacter pylori (H. pylori) were excluded. The low prevalence of precancerous lesions, such as the incomplete type of intestinal metaplasia, may explain the low risk of GC in AIG patients because the spasmolytic polypeptide-expressing metaplasia commonly observed in AIG does not involve clonal reprogramming of the gastric gland and can be considered as an adaptive change rather than a true precancerous lesion. However, changes in gastric secretion due to the progression of gastric atrophy during the course of AIG cause changes in the gastric mic-robiome, stimulating the growth of bacterial species such as streptococci, which may promote the development of precancerous lesions and GC. Thus, Streptococcus anginosus exhibited a robust proinflammatory response and induced the gastritis-atrophy-metaplasia-dysplasia sequence in mice, reproducing the well-established process for carcinogenesis associated with H. pylori. Prospective studies in H. pylori-naïve patients evaluating gastric microbiome changes during the long-term course of AIG might provide an explanation for the enigmatic increase in GC incidence in the last decades in younger cohorts, which has been reported in economically developed countries.
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Enfermedades Autoinmunes , Bibliometría , Mucosa Gástrica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Lesiones Precancerosas , Neoplasias Gástricas , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/epidemiología , Humanos , Gastritis/inmunología , Gastritis/microbiología , Gastritis/epidemiología , Gastritis/patología , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/inmunología , Helicobacter pylori/patogenicidad , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Lesiones Precancerosas/epidemiología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/epidemiología , Mucosa Gástrica/patología , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Metaplasia , Factores de Riesgo , Estómago/patología , Estómago/inmunología , Estómago/microbiología , Microbioma Gastrointestinal/inmunología , RatonesRESUMEN
Autoimmune rheumatic diseases comprise a group of immune-related disorders characterized by non-organ-specific inflammation. These diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, among others. Typically involving the hematologic system, these diseases may also affect multiple organs and systems. The pathogenesis of autoimmune rheumatic immune diseases is complex, with diverse etiologies, all associated with immune dysfunction. The current treatment options for this type of disease are relatively limited and come with certain side effects. Therefore, the urgent challenge remains to identify novel therapeutic targets for these diseases. Sterol regulatory element-binding proteins (SREBPs) are basic helix-loop-helix-leucine zipper transcription factors that regulate the expression of genes involved in lipid and cholesterol biosynthesis. The expression and transcriptional activity of SREBPs can be modulated by extracellular stimuli such as polyunsaturated fatty acids, amino acids, glucose, and energy pathways including AKT-mTORC and AMP-activated protein kinase (AMPK). Studies have shown that SREBPs play roles in regulating lipid metabolism, cytokine production, inflammation, and the proliferation of germinal center B (GCB) cells. These functions are significant in the pathogenesis of rheumatic and immune diseases (Graphical abstract). Therefore, this paper reviews the potential mechanisms of SREBPs in the development of SLE, RA, and gout, based on an exploration of their functions.
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Enfermedades Autoinmunes , Enfermedades Reumáticas , Proteínas de Unión a los Elementos Reguladores de Esteroles , Humanos , Enfermedades Reumáticas/inmunología , Enfermedades Reumáticas/etiología , Enfermedades Reumáticas/genética , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/genética , Proteínas de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteínas de Unión a los Elementos Reguladores de Esteroles/genética , Metabolismo de los Lípidos , Regulación de la Expresión Génica , Transducción de SeñalRESUMEN
The pathophysiology of dengue may be influenced by antibodies released during infection. Several autoimmune diseases are accompanied by antinuclear antibodies (ANAs) but 8-10% of the general population have positive ANA tests. To test the hypothesis that an ANA-positive test indicates an immune dysregulated state that modifies the risk for certain clinical disorders in people with or without an autoimmune disease, we examined the various ANA profiles and their relationships to various autoimmune disorders, as well as the severity of these relationships, in patients infected with dengue fever. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) methods were used. Indirect immunofluorescence assay (IIFA) and line immunoassay (LIA) were performed to detect and differentiate the ANAs among dengue infected patients. Out of 135 dengue virus-positive patients, 94.07% were positive by ELISA and 5.93% positive by RT-PCR method. ANAs by IIFA and LIA were detected in 54.8% and 18.5% of the dengue positive patients, respectively, and 10.3% and 7.1% of the 126 dengue negative patients, respectively. This study showed that dengue was associated with an increased risk of autoimmune myositis and mixed connective tissue disease (MCTD), a rare complication of dengue. The risk of other autoimmune diseases did not seem to increase after DENV infection.
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Anticuerpos Antinucleares , Enfermedades Autoinmunes , Dengue , Ensayo de Inmunoadsorción Enzimática , Humanos , Anticuerpos Antinucleares/sangre , Dengue/sangre , Dengue/inmunología , Dengue/diagnóstico , India/epidemiología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/diagnóstico , Masculino , Adulto , Femenino , Persona de Mediana Edad , Adulto Joven , Adolescente , Técnica del Anticuerpo Fluorescente Indirecta , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Anciano , Niño , Virus del Dengue/inmunologíaRESUMEN
The THαß host immunological pathway contributes to the response to infectious particles (viruses and prions). Furthermore, there is increasing evidence for associations between autoimmune diseases, and particularly type 2 hypersensitivity disorders, and the THαß immune response. For example, patients with systemic lupus erythematosus often produce anti-double stranded DNA antibodies and anti-nuclear antibodies and show elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 throughout the disease course. These cytokines and antibody isotypes are associated with the THαß host immunological pathway. Similarly, the type 2 hypersensitivity disorders myasthenia gravis, Graves' disease, graft-versus-host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjögren's syndrome have also been linked to the THαß pathway. Considering the potential associations between these diseases and dysregulated THαß immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferon α/ß could be explored for effective management.
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Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/complicaciones , Síndrome de Sjögren/inmunología , Enfermedad Injerto contra Huésped/inmunología , Enfermedades Autoinmunes/inmunología , Citocinas/inmunología , Miastenia Gravis/inmunología , Anemia Hemolítica Autoinmune/inmunología , Enfermedad de Graves/inmunología , Enfermedad de Graves/complicaciones , Dermatomiositis/inmunologíaRESUMEN
Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics.
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Asma , Estudio de Asociación del Genoma Completo , Inmunoglobulina G , Polimorfismo de Nucleótido Simple , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina G/genética , Adulto , Femenino , Masculino , Asma/genética , Asma/inmunología , Asma/sangre , Niño , Adolescente , Receptores de IgG/genética , Persona de Mediana Edad , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/sangre , Alelos , Adulto Joven , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/sangre , Cromosomas Humanos Par 17/genética , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Antígenos HLA/inmunología , Proteínas de la MembranaRESUMEN
Myocarditis is a potentially life-threatening inflammatory disease of the myocardium, often resulting from infectious and immune-mediated responses. Clinical presentation in severe cases often results in a devastating illness requiring extracorporeal membrane oxygenation support as a result of cardiogenic shock. Although endomyocardial biopsy is still considered the gold standard for diagnosis, it often reveals nonspecific lymphocytic infiltration. Because the precise cause is usually unknown, the initial treatment typically involves immunosuppression and frequent assessment of myocardial contractility. This report presents 3 rare cases of autoimmune diseases (polymyositis, immunoglobulin G4-related disease, and systemic lupus erythematosus) that require extracorporeal membrane oxygenation support as a result of fulminant myocarditis, including their follow-up periods.
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Oxigenación por Membrana Extracorpórea , Miocarditis , Humanos , Miocarditis/terapia , Miocarditis/diagnóstico , Miocarditis/fisiopatología , Miocarditis/inmunología , Oxigenación por Membrana Extracorpórea/métodos , Masculino , Femenino , Adulto , Biopsia , Persona de Mediana Edad , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/complicaciones , Miocardio/patología , Miocardio/inmunología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/terapia , Choque Cardiogénico/terapia , Choque Cardiogénico/etiología , Choque Cardiogénico/diagnóstico , Resultado del Tratamiento , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/terapia , Enfermedad Relacionada con Inmunoglobulina G4/complicacionesRESUMEN
Despite great therapeutic advances in the field of biologics, small synthetic molecules such as thiopurines, including azathioprine, mercaptopurine, and thioguanine, remain an important therapeutic pillar in the treatment of inflammatory bowel disease, other autoimmune disorders, and cancer. This review presents the latest guidelines for thiopurine administration, highlighting the importance of individualized therapy guided by pharmacogenomics. It emphasizes dose adjustment based on nudix hydrolase 15 (NUDT15) and thiopurine S-methyltransferase (TPMT) genotype, along side thiopurine S-methyltransferase activity and thiopurine metabolic profile. In addition, the article takes a critical look at emerging research in the field of thiopurine pharmaco genomics featuring novel genetic markers and technological developments in genetic testing. Finally, the potential of integrated approaches that combine genetic, meta bolic, and clinical factors to further individualize thiopurine therapy is highlighted.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Mercaptopurina , Metiltransferasas , Medicina de Precisión , Humanos , Medicina de Precisión/métodos , Metiltransferasas/metabolismo , Metiltransferasas/genética , Mercaptopurina/uso terapéutico , Mercaptopurina/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Azatioprina/administración & dosificación , Farmacogenética , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Genotipo , Tioguanina , Hidrolasas NudixRESUMEN
Maintaining peripheral immune tolerance and preventing harmful autoimmune reactions is a fundamental task of the immune system. However, these essential functions are significantly compromised during autoimmune disorders, creating a major challenge in treating these conditions. In this context, we provide an overview of research on small spleen polypeptides (SSPs) that naturally regulate peripheral immune tolerance. Alongside outlining the observed effects of SSPs, we summarize here the findings on the cellular and molecular mechanisms that underlie their regulatory impact. Specifically, SSPs have demonstrated remarkable effectiveness in halting the progression of developing or established autoimmune disorders like psoriasis or arthritis in animal models. They primarily target dendritic cells (DCs), swiftly prompting the production of extracellular ATP, which is then degraded and sensed by adenosine receptors. This process triggers the mTOR signaling cascade, similar to powerful immune triggers, but instead of a rapid and intense reaction, it leads to a moderate yet significant activation of the mTOR signaling cascade. This induces a tolerogenic state in dendritic cells, ultimately leading to the generation of Foxp3+ immunosuppressor Treg cells. In addition, SSPs may indirectly attenuate the autoimmune response by reducing extracellular ATP synthesis in non-immune cells, such as endothelial cells, when exposed to elevated levels of proinflammatory cytokines. SSPs thus have the potential to contribute to the restoration of peripheral immune tolerance and may offer valuable therapeutic benefits in treating autoimmune diseases.
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Tolerancia Inmunológica , Bazo , Humanos , Animales , Bazo/inmunología , Bazo/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Células Dendríticas/inmunología , Péptidos/inmunología , Péptidos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
Background: To clarify the controversy between inflammatory or autoimmune skin diseases and thyroid diseases, we performed two-sample Mendelian randomization (MR) analyses. Participants: Genetic data on factors associated with atopic dermatitis (AD, n=40,835), seborrheic dermatitis (SD, n=339,277), acne (n=363,927), rosacea (n=299,421), urticaria (n=374,758), psoriasis (n=373,338), psoriasis vulgaris (n=369,830), systemic lupus erythematosus (SLE, n=14,267), vitiligo (n=353,348), alopecia areata (AA, n=361,822), pemphigus (n=375,929), bullous pemphigoid (BP, n=376,274), systemic sclerosis (SSc, n=376,864), localized scleroderma (LS, n=353,449), hypothyroidism (n=314,995 or n=337,159), and hyperthyroidism (n=281,683 or n=337,159) were derived from genome-wide association summary statistics of European ancestry. Main measures: The inverse variance weighted method was employed to obtain the causal estimates of inflammatory or autoimmune skin diseases on the risk of thyroid diseases, complemented by MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Key results: AD, SLE, SD, and psoriasis vulgaris were associated with an increased risk of hypothyroidism, whereas BP was associated with a lower risk of hypothyroidism (all with p < 0.05). The multivariable MR analyses showed that AD (OR = 1.053; 95%CI: 1.015-1.092; p = 0.006), SLE (OR = 1.093; 95%CI: 1.059-1.127; p < 0.001), and SD (OR = 1.006; 95%CI: 1.002-1.010; p = 0.006) independently and predominately contributed to the genetic causal effect on hypothyroidism after adjusting for smoking. The results showed no causal effects of inflammatory or autoimmune skin diseases on hyperthyroidism. Conclusion: The findings showed a causal effect of AD, SLE, SD on hypothyroidism, but further investigations should be conducted to explore the pathogenic mechanisms underlying these relationships.
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Enfermedades Autoinmunes , Análisis de la Aleatorización Mendeliana , Enfermedades de la Piel , Enfermedades de la Tiroides , Humanos , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/epidemiología , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/epidemiología , Enfermedades de la Piel/genética , Enfermedades de la Piel/epidemiología , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad , Inflamación/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Liquid biopsies based on peripheral blood offer a minimally invasive alternative to solid tissue biopsies for the detection of diseases, primarily cancers. However, such tests currently consider only the serum component of blood, overlooking a potentially rich source of biomarkers: adaptive immune receptors (AIRs) expressed on circulating B and T cells. Machine learning-based classifiers trained on AIRs have been reported to accurately identify not only cancers but also autoimmune and infectious diseases as well. However, when using the conventional "clonotype cluster" representation of AIRs, individuals within a disease or healthy cohort exhibit vastly different features, limiting the generalizability of these classifiers. This study aimed to address the challenge of classifying specific diseases from circulating B or T cells by developing a novel representation of AIRs based on similarity networks constructed from their antigen-binding regions (paratopes). Features based on this novel representation, paratope cluster occupancies (PCOs), significantly improved disease classification performance for infectious disease, autoimmune disease, and cancer. Under identical methodological conditions, classifiers trained on PCOs achieved a mean AUC of 0.893 when applied to new individuals, outperforming clonotype cluster-based classifiers (AUC 0.714) and the best-performing published classifier (AUC 0.777). Surprisingly, for cancer patients, we observed that "healthy-biased" AIRs were predicted to target known cancer-associated antigens at dramatically higher rates than healthy AIRs as a whole (Z scores >75), suggesting an overlooked reservoir of cancer-targeting immune cells that could be identified by PCOs.
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Enfermedades Transmisibles , Neoplasias , Humanos , Neoplasias/inmunología , Enfermedades Transmisibles/inmunología , Receptores Inmunológicos/metabolismo , Aprendizaje Automático , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/diagnóstico , AutoinmunidadRESUMEN
A body develops an autoimmune illness when its immune system mistakenly targets healthy cells and organs. Eight million people are affected by more than 80 autoimmune diseases. The public's and individuals' well-being is put at risk. Type 1 diabetes, lupus, rheumatoid arthritis, and multiple sclerosisare autoimmune diseases. Tissue injury, nociceptive responses, and persistent inflammation are the results of these stresses. Concerns about healthcare costs, health, and physical limitations contribute to these issues. Given their prevalence, it is crucial to enhance our knowledge, conduct thorough research, and provide all-encompassing support to women dealing with autoimmune diseases. This will lead to better public health and better patient outcomes. Most bacteria's immune systems employ CRISPR-Cas, a state-of-the-art technique for editing genes. For Cas to break DNA with pinpoint accuracy, a guide RNA employs a predetermined enzymatic pathway. Genetic modifications started. After it was developed, this method was subjected to much research on autoimmune diseases. By modifying immune pathways, CRISPR gene editing can alleviate symptoms, promote immune system tolerance, and decrease autoimmune reactivity. The autoimmune diseases that CRISPR-Cas9 targets now have no treatment or cure. Results from early clinical trials and preclinical studies of autoimmune medicines engineered using CRISPR showed promise. Modern treatments for rheumatoid arthritis,multiple sclerosis, and type 1 diabetes aim to alter specific genetic or immune mechanisms. Accurate CRISPR editing can fix autoimmune genetic disorders. Modifying effector cells with CRISPR can decrease autoimmune reactions. These cells include cytotoxic T and B lymphocytes. Because of improvements in delivery techniques and kits, CRISPR medications are now safer, more effective, and more accurately targeted. It all comes down to intricate immunological reactions and unexpected side consequences. Revolutionary cures for autoimmune problems and highly personalized medical therapies have been made possible by recent advancements in CRISPR.
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Enfermedades Autoinmunes , Sistemas CRISPR-Cas , Humanos , Sistemas CRISPR-Cas/genética , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/inmunología , Animales , Edición Génica , Terapia Genética/métodosRESUMEN
Platelets are crucial for thrombosis and hemostasis. Importantly, they contain mitochondria that are responsible for energy generation and therefore vital for platelet survival and activation. Activated platelets can release mitochondria that may be free or encapsulated in platelet extracellular vesicles (EVs). Extruded mitochondria are a well-known source of mitochondrial DNA, and mitochondrial antigens that can be targeted by autoantibodies forming immune complexes (IC). Interaction of IC with the platelet cell surface FcγRIIA receptor results in platelet activation and release of platelet granule components. In this review, we summarize how platelets and mitochondria may contribute to the pathogenesis of different autoimmune and musculoskeletal diseases. Targeting key drivers of mitochondrial extrusion may ultimately lead to urgently needed targeted pharmacological interventions for treating inflammation and thrombotic diathesis, and halting organ damage in some of these rheumatological conditions.
Asunto(s)
Enfermedades Autoinmunes , Plaquetas , Mitocondrias , Enfermedades Musculoesqueléticas , Humanos , Plaquetas/inmunología , Plaquetas/metabolismo , Mitocondrias/metabolismo , Mitocondrias/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Musculoesqueléticas/inmunología , Animales , Activación Plaquetaria/inmunología , Autoanticuerpos/inmunologíaRESUMEN
OBJECTIVE: This study aimed to examine the reliability and validity of a newly developed questionnaire for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). The aim was to contribute to future standardisation of screening methods for symptoms and comorbidity, as well as the measurement of symptom severity, daily life impairment, and treatment effectiveness in individuals diagnosed with PANDAS/PANS. METHODS: 27 items from the PANDAS/PANS questionnaire concerning symptoms and comorbidities associated with PANDAS/PANS were divided into ten domains. To assess the external validity, 119 PANDAS/PANS questionnaires from a cohort of 65 children with PANDAS/PANS were correlated with three well-known validated questionnaires: the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS), and the Strengths and Difficulties Questionnaire (SDQ). The internal validity of the PANDAS/PANS questionnaire was assessed by correlating the PANDAS/PANS items with the domains. RESULTS: Internal consistency of the PANDAS/PANS questionnaire was high, measuring moderate to very strong correlations. The external correlations for the PANDAS/PANS questionnaire showed a higher correlation with the ADHD-RS and CY-BOCS (rs ≥ 0.60) than with the SDQ (rs < 0.40). CONCLUSION: The validity and clinical feasibility of the PANDAS/PANS questionnaire were confirmed as an effective tool for screening symptoms, assessing symptom severity, and evaluating comorbidity and daily life impairment in individuals with PANDAS/PANS. These findings can potentially enhance the management of PANDAS/PANS patients in both clinical and research settings.