RESUMEN
Autoimmune diseases (ADs) showcase the intricate balance between the immune system's protective functions and its potential for self-inflicted damage. These disorders arise from the immune system's erroneous targeting of the body's tissues, resulting in damage and disease. The ability of T cells to distinguish between self and non-self-antigens is pivotal to averting autoimmune reactions. Perturbations in this process contribute to AD development. Autoreactive T cells that elude thymic elimination are activated by mimics of self-antigens or are erroneously activated by self-antigens can trigger autoimmune responses. Various mechanisms, including molecular mimicry and bystander activation, contribute to AD initiation, with specific triggers and processes varying across the different ADs. In addition, the formation of neo-epitopes could also be implicated in the emergence of autoreactivity. The specificity of T cell responses centers on the antigen recognition sequences expressed by T cell receptors (TCRs), which recognize peptide fragments displayed by major histocompatibility complex (MHC) molecules. The assortment of TCR gene combinations yields a diverse array of T cell populations, each with distinct affinities for self and non-self antigens. However, new evidence challenges the traditional notion that clonal expansion solely steers the selection of higher-affinity T cells. Lower-affinity T cells also play a substantial role, prompting the "two-hit" hypothesis. High-affinity T cells incite initial responses, while their lower-affinity counterparts perpetuate autoimmunity. Precision treatments that target antigen-specific T cells hold promise for avoiding widespread immunosuppression. Nevertheless, detection of such antigen-specific T cells remains a challenge, and multiple technologies have been developed with different sensitivities while still harboring several drawbacks. In addition, elements such as human leukocyte antigen (HLA) haplotypes and validation through animal models are pivotal for advancing these strategies. In brief, this review delves into the intricate mechanisms contributing to ADs, accentuating the pivotal role(s) of antigen-specific T cells in steering immune responses and disease progression, as well as the novel strategies for the identification of antigen-specific cells and their possible future use in humans. Grasping the mechanisms behind ADs paves the way for targeted therapeutic interventions, potentially enhancing treatment choices while minimizing the risk of systemic immunosuppression.
RESUMEN
BACKGROUND AND AIMS: There is increased interest in utilizing dietary interventions to alter the progression of autoimmune diseases. These efforts are driven by associations of gut microbiota/metabolites with levels of short-chain fatty acids (SCFAs). Propionate is a key SCFA that is commonly used as a food preservative and is endogenously generated by bacterial fermentation of non-digestible carbohydrates in the gut. A thesis has suggested that a diet rich in propionate and other SCFAs can successfully modulate autoimmunity. Herein, we investigated the effect of long-term administration of propionylated high-amylose resistant starches (HAMSP) on the course of murine primary biliary cholangitis. MATERIALS AND METHODS: Groups of female ARE-Del mice were fed an HAMSP diet either before or after disease onset. A detailed immunobiological analysis was performed involving autoantibodies and rigorous T-cell phenotyping, including enumeration of T-cell subsets in the spleen, liver, intestinal intraepithelial lymphocytes and lamina propria by flow cytometry. Histopathological scores were used to assess the frequency and severity of liver inflammation and damage to hepatocytes and bile ducts. RESULTS: Our results demonstrate that a long-term propionate-yielding diet re-populated the T-cell pool with decreased naïve and central memory T-cell subsets and an increase in the effector memory T cells in mice. Similarly, long-term HAMSP intake reduced CD4+CD8+ double-positive T cells in intraepithelial lymphocytes and the intestinal lamina propria. Critically, HAMSP consumption led to moderate-to-severe hepatocellular steatosis in ARE-Del mice, independent of the stage of autoimmune cholangitis. CONCLUSIONS: Our data suggest that administration of HAMSP induces both regulatory and effector T cells. Furthermore, HAMSP administration resulted in hepatocellular steatosis. Given the interest in dietary modulation of autoimmunity and because propionate is widely used as a food preservative, these data have significant implications. This study also provides new insights into the immunological and pathological effects of chronic propionate exposure.
RESUMEN
Autoimmune regulator (Aire) and TGF-ß signaling play important roles in central tolerance and peripheral tolerance, respectively, by eliminating or suppressing the activity of autoreactive T cells. We previously demonstrated that dnTGFßRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)-like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGFßRII Aire-/- mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA-seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFßRII Aire-/- mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8+ T cell infiltrates. Depleting CD8+ T cells using an anti-CD8α antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA-seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice developed an autoreactive CD8+ T-cell-mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH-PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. © 2023 The Pathological Society of Great Britain and Ireland.
Asunto(s)
Colangitis , Hepatitis Autoinmune , Cirrosis Hepática Biliar , Ratones , Animales , Hepatitis Autoinmune/genética , Hepatitis Autoinmune/metabolismo , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/metabolismo , Linfocitos T CD8-positivos , Colangitis/genética , Colangitis/metabolismoRESUMEN
The gastrointestinal tract is home to the largest microbial population in the human body. The gut microbiota plays significant roles in the development of the gut immune system and has a substantial impact on the maintenance of immune tolerance beginning in early life. These microbes interact with the immune system in a dynamic and interdependent manner. They generate immune signals by presenting a vast repertoire of antigenic determinants and microbial metabolites that influence the development, maturation and maintenance of immunological function and homeostasis. At the same time, both the innate and adaptive immune systems are involved in modulating a stable microbial ecosystem between the commensal and pathogenic microorganisms. Hence, the gut microbial population and the host immune system work together to maintain immune homeostasis synergistically. In susceptible hosts, disruption of such a harmonious state can greatly affect human health and lead to various auto-inflammatory and autoimmune disorders. In this review, we discuss our current understanding of the interactions between the gut microbiota and immunity with an emphasis on: a) important players of gut innate and adaptive immunity; b) the contribution of gut microbial metabolites; and c) the effect of disruption of innate and adaptive immunity as well as alteration of gut microbiome on the molecular mechanisms driving autoimmunity in various autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes , Microbioma Gastrointestinal , Humanos , Ecosistema , Sistema Inmunológico , Inmunidad Adaptativa , Tolerancia Inmunológica , DisbiosisRESUMEN
BACKGROUND AND AIMS: The increased frequency of urinary tract infections in patients with primary biliary cholangitis (PBC) and the cross-reactivity between the lipoyl domains (LD) of human pyruvate dehydrogenase complex (hPDC-E2) and Escherichia coli PDC-E2 (ePDC-E2) have long suggested a role of E. coli in causality of PBC. This issue, however, has remained speculative. We hypothesized that by generating specific constructs of human and E. coli PDC-E2, we would be able to assess the specificity of autoantibody responses and define whether exposure to E. coli in susceptible hosts is the basis for the antimitochondrial antibody (AMA) response. APPROACH AND RESULTS: Importantly, the reactivity of hPDC-E2 LD (hPDC-E2LD) affinity-purified antibodies against hPDC-E2LD could only be removed by prior absorption with hPDC-E2LD and not ePDC-E2, suggesting the presence of unique human PDC-E2 epitopes distinct from E. coli PDC-E2. To identify the autoepitope(s) present in hPDC-E2LD, a more detailed study using a variety of PDC-E2 constructs was tested, including the effect of lipoic acid (LA) on ePDC-E2 conformation and AMA recognition. Individual recombinant ePDCE2 LD domains LD1, LD2 and LD3 did not react with either AMA or antibodies to LA (anti-LA), but in contrast, anti-LA was readily reactive against purified recombinant LD1, LD2, and LD3 expressed in tandem (LP); such reactivity increased when LP was precultured with LA. Moreover, when the three LD (LD1, LD2, LD3) domains were expressed in tandem in pET28a or when LD1 was expressed in another plasmid pGEX, they were lipoylated and reactive to PBC sera. CONCLUSIONS: In conclusion, our data are consistent with an exposure to E. coli that elicits specific antibody to ePDC-E2 resulting in determinant spreading and the classic autoantibody to hPDC-E2LD. We argue this is the first step to development of human PBC.
Asunto(s)
Autoantígenos/inmunología , Acetiltransferasa de Residuos Dihidrolipoil-Lisina/inmunología , Infecciones por Escherichia coli/complicaciones , Escherichia coli/inmunología , Cirrosis Hepática Biliar/microbiología , Mitocondrias/inmunología , Proteínas Mitocondriales/inmunología , Autoanticuerpos/sangre , Estudios de Casos y Controles , Reacciones Cruzadas/inmunología , Epítopos/inmunología , Escherichia coli/enzimología , Hepatitis Autoinmune/sangre , Humanos , Lipoilación , Conformación Molecular/efectos de los fármacos , Ácido Tióctico/inmunología , Ácido Tióctico/farmacologíaRESUMEN
Treating macaques with an anti-α4ß7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4ß7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4ß7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4ß7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4ß7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed-some animals exhibited large fluctuations in viral load after cART cessation-the model suggests that anti-α4ß7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antivirales/uso terapéutico , Integrinas/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Animales , Anticuerpos Monoclonales/inmunología , Antivirales/farmacología , Linfocitos T CD8-positivos/inmunología , Terapia Combinada , Depleción Linfocítica , Macaca , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Carga Viral/efectos de los fármacos , Carga Viral/inmunologíaRESUMEN
Deglycosylated, live-attenuated SIV vaccines elicited protective immune responses against heterologous SIVsmE543-3, which differs from the vaccine strain SIVmac239 to levels similar to those across HIV-1 clades. Two thirds of the vaccinees contained the chronic SIVsmE543-3 infection (controllers), whereas one third did not (noncontrollers). In this study, we investigated immune correlates of heterologous challenge control in rhesus macaques of Burmese origin. Because depletion of CD8+ cells in the controllers by administration of anti-CD8α Ab abrogated the control of viral replication, CD8+ cells were required for the protective immune response. However, classical SIV-specific CD8+ T cells did not account for the protective immune response in all controllers. Instead, IL-15-responding CD8α+ cells, including CD8+ T and NK cells, were significantly higher in the controllers than those in the noncontrollers, before and after vaccination with deglycosylated SIV. It is well established that IL-15 signal transduction occurs through "trans-presentation" in which IL-15 complexed with IL-15Rα on monocytes, macrophages, and dendritic cells binds to IL-15 Rß/γ expressed on CD8+ T and NK cells. Accordingly, levels of IL-15 stimulation were strongly affected by the depletion of monocytes from PBMCs, implying key roles of innate immune cells. These results suggest that intrinsic IL-15 responsiveness may dictate the outcome of protective responses and may lead to optimized formulations of future broadly protective HIV vaccines.
Asunto(s)
Inmunidad Innata/inmunología , Interleucina-15/inmunología , Vacunas contra el SIDAS/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas Atenuadas/inmunología , Animales , Anticuerpos Antivirales/inmunología , Linfocitos T CD8-positivos/inmunología , Células Asesinas Naturales/inmunología , Macaca mulatta , Masculino , Monocitos/inmunología , Transducción de Señal/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Vacunación/métodos , Carga Viral/inmunología , Replicación Viral/inmunologíaRESUMEN
The diverse clinical manifestations of COVID-19 is emerging as a hallmark of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. While the initial target of SARS-CoV-2 is the respiratory tract, it is becoming increasingly clear that there is a complex interaction between the virus and the immune system ranging from mild to controlling responses to exuberant and dysfunctional multi-tissue directed autoimmune responses. The immune system plays a dual role in COVID-19, being implicated in both the anti-viral response and in the acute progression of the disease, with a dysregulated response represented by the marked cytokine release syndrome, macrophage activation, and systemic hyperinflammation. It has been speculated that these immunological changes may induce the loss of tolerance and/or trigger chronic inflammation. In particular, molecular mimicry, bystander activation and epitope spreading are well-established proposed mechanisms to explain this correlation with the likely contribution of HLA alleles. We performed a systematic literature review to evaluate the COVID-19-related autoimmune/rheumatic disorders reported between January and September 2020. In particular, we investigated the cases of incident hematological autoimmune manifestations, connective tissue diseases, antiphospholipid syndrome/antibodies, vasculitis, Kawasaki-like syndromes, acute arthritis, autoimmune-like skin lesions, and neurologic autoimmune conditions such as Guillain-Barré syndrome. We screened 6263 articles and report herein the findings of 382 select reports which allow us to conclude that there are 2 faces of the immune response against SARS-CoV-2, that include a benign virus controlling immune response and a many faceted range of dysregulated multi-tissue and organ directed autoimmune responses that provides a major challenge in the management of this viral disease. The number of cases for each disease varied significantly while there were no reported cases of adult onset Still disease, systemic sclerosis, or inflammatory myositis.
Asunto(s)
Enfermedades Autoinmunes/epidemiología , COVID-19/epidemiología , Quinasas Janus/metabolismo , SARS-CoV-2/fisiología , Animales , Enfermedad Crónica , Humanos , Inmunidad , Incidencia , InflamaciónRESUMEN
The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin α4ß7, a gut-homing receptor. Using both cell-surface expressed α4ß7 and a soluble α4ß7 heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of α4ß7 in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to α4ß7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, α4ß7 antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to α4ß7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to α4ß7. It includes the canonical LDV/I α4ß7 binding site, a cryptic epitope that lies 7-9 amino acids amino terminal to the LDV/I, and residues K169 and I181. These two residues were identified in a sieve analysis of the RV144 vaccine trial as sites of vaccine -mediated immune pressure. HIV and SIV V2 mAbs elicited by both vaccination and infection that recognize this peptide block V2-α4ß7 interactions. These mAbs recognize conformations absent from the ß- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-α4ß7 interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.
Asunto(s)
Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/prevención & control , Integrinas/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Vacunas contra el SIDA/química , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/metabolismo , Animales , Anticuerpos Monoclonales , Sitios de Unión/inmunología , Línea Celular Tumoral , Epítopos/química , Epítopos/inmunología , Anticuerpos Anti-VIH/química , Anticuerpos Anti-VIH/inmunología , Anticuerpos Anti-VIH/metabolismo , Infecciones por VIH/inmunología , VIH-1/inmunología , Macaca , Unión Proteica , Dominios y Motivos de Interacción de Proteínas/inmunología , Vacunas contra el SIDAS/química , Vacunas contra el SIDAS/inmunología , Vacunas contra el SIDAS/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunación/métodosRESUMEN
The Coronavirus-associated disease, that was first identified in 2019 in China (CoViD-19), is a pandemic caused by a bat-derived beta-coronavirus, named SARS-CoV2. It shares homology with SARS and MERS-CoV, responsible for past outbreaks in China and in Middle East. SARS-CoV2 spread from China where the first infections were described in December 2019 and is responsible for the respiratory symptoms that can lead to acute respiratory distress syndrome. A cytokine storm has been shown in patients who develop fatal complications, as observed in past coronavirus infections. The management includes ventilatory support and broad-spectrum antiviral drugs, empirically utilized, as a targeted therapy and vaccines have not been developed. Based upon our limited knowledge on the pathogenesis of CoViD-19, a potential role of some anti-rheumatic drugs may be hypothesized, acting as direct antivirals or targeting host immune response. Antimalarial drugs, commonly used in rheumatology, may alter the lysosomal proteases that mediates the viral entry into the cell and have demonstrated efficacy in improving the infection. Anti-IL-1 and anti-IL-6 may interfere with the cytokine storm in severe cases and use of tocilizumab has shown good outcomes in a small cohort. Baricitinib has both antiviral and anti-inflammatory properties. Checkpoints inhibitors such as anti-CD200 and anti-PD1 could have a role in the treatment of CoViD-19. Rheumatic disease patients taking immunosuppressive drugs should be recommended to maintain the chronic therapy, prevent infection by avoiding social contacts and pausing immunosuppressants in case of infection. National and international registries are being created to collect data on rheumatic patients with CoViD-19.
Asunto(s)
Terapia Biológica , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/complicaciones , Neumonía Viral/tratamiento farmacológico , Enfermedades Reumáticas/complicaciones , Enfermedades Reumáticas/terapia , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antimaláricos/uso terapéutico , Antirreumáticos/uso terapéutico , Azetidinas/uso terapéutico , Betacoronavirus/efectos de los fármacos , COVID-19 , Infecciones por Coronavirus/prevención & control , Citocinas/inmunología , Humanos , Inmunosupresores/uso terapéutico , Interleucina-1/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Pandemias/prevención & control , Neumonía Viral/prevención & control , Purinas , Pirazoles , SARS-CoV-2 , Sulfonamidas/uso terapéutico , Internalización del Virus/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
The genus Ebolavirus from the family Filoviridae is composed of five species including Sudan ebolavirus, Reston ebolavirus, Bundibugyo ebolavirus, Taï Forest ebolavirus, and Ebola virus (previously known as Zaire ebolavirus). These viruses have a large non-segmented, negative-strand RNA of approximately 19 kb that encodes for glycoproteins (i.e., GP, sGP, ssGP), nucleoproteins, virion proteins (i.e., VP 24, 30,40) and an RNA dependent RNA polymerase. These viruses have become a global health concern because of mortality, their rapid dissemination, new outbreaks in West-Africa, and the emergence of a new condition known as "Post-Ebola virus disease syndrome" that resembles inflammatory and autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus and spondyloarthritis with uveitis. However, there are many gaps in the understanding of the mechanisms that may induce the development of such autoimmune-like syndromes. Some of these mechanisms may include a high formation of neutrophil extracellular traps, an uncontrolled "cytokine storm", and the possible formation of auto-antibodies. The likely appearance of autoimmune phenomena in Ebola survivors suppose a new challenge in the management and control of this disease and opens a new field of research in a special subgroup of patients. Herein, the molecular biology, pathogenesis, clinical manifestations, and treatment of Ebola virus disease are reviewed and some strategies for control of disease are discussed.
Asunto(s)
Ebolavirus/inmunología , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/virología , Animales , Anticuerpos Antivirales/inmunología , Autoanticuerpos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/virología , HumanosRESUMEN
Glycosylation of antibodies, particularly in the Fc domain, critically modulate the ability of antibodies to bind to FcRs, maintaining immune quiescence to achieve a finely orchestrated immune response. The removal of sialic acid and galactose residues dramatically alters the physiological function of IgGs, and alterations of Ig glycosylation have been associated with several autoimmune disorders. However, Ig glycosylation has not been extensively studied in autoimmune cholangitis. We applied triple quadruple mass spectroscopy with subsequent multiple reaction monitoring to elucidate the profile, composition and linkage of sugar residues of antibody glycans in patients with primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and healthy controls (HC). Agalactosylated, HexNAc terminated IgG1 glycoforms were enriched in both PBC and PSC. Levels of IgM glycans at site N439 and fucosylated glycans in J chain, were significantly decreased in PBC compared to PSC and HC. PSC patients had decreased bisecting glycoforms and increased biantennary glycoforms on IgA compared to PBC. Importantly, our data demonstrate the association of distinct branching and composition patterns of Ig glycoforms with disease severity and liver cirrhosis, which highlight the importance of glycan biology as a potential mechanism and/or a disease specific signal of inflammation.
Asunto(s)
Autoanticuerpos/metabolismo , Enfermedades Autoinmunes/diagnóstico , Colangitis Esclerosante/diagnóstico , Inmunoglobulina G/metabolismo , Cirrosis Hepática Biliar/diagnóstico , Adulto , Anciano , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , Biomarcadores/sangre , Biomarcadores/metabolismo , Estudios de Casos y Controles , Colangitis Esclerosante/sangre , Colangitis Esclerosante/inmunología , Femenino , Glicómica/métodos , Glicosilación , Voluntarios Sanos , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/inmunología , Masculino , Persona de Mediana Edad , Polisacáridos/inmunología , Polisacáridos/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Neumonía Viral/inmunología , Inmunidad Adaptativa/genética , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/virología , Betacoronavirus/aislamiento & purificación , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/terapia , Enfermedad Crítica , Síndrome de Liberación de Citoquinas/diagnóstico , Síndrome de Liberación de Citoquinas/terapia , Síndrome de Liberación de Citoquinas/virología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Inmunidad Innata/genética , Inmunización Pasiva/métodos , Mediadores de Inflamación/sangre , Mediadores de Inflamación/inmunología , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Masculino , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Neumonía Viral/terapia , Factores de Riesgo , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Factores Sexuales , Sueroterapia para COVID-19RESUMEN
Infusion of a simianized anti-α4ß7 mAb (Rh-α4ß7) just before and following SIV infection protected rhesus macaques from developing AIDS and partially from vaginal SIV acquisition. Recently, short-term treatment with Rh-α4ß7 in combination with cART was found to lead to prolonged viral suppression after withdrawal of all therapeutic interventions. The humanized form of Rh-α4ß7, vedolizumab, is a highly effective treatment for inflammatory bowel disease. To clarify the mechanism of action of Rh-α4ß7, naive macaques were infused with Rh-α4ß7 and sampled in blood and tissues before and after treatment to monitor several immune cell subsets. In blood, Rh-α4ß7 increased the CD4+ and CD8+ T cell counts, but not B cell counts, and preferentially increased CCR6+ subsets while decreasing CD103+ and CD69+ lymphocytes. In mucosal tissues, surprisingly, Rh-α4ß7 did not impact integrin α4+ cells, but decreased the frequencies of CCR6+ and CD69+ CD4+ T cells and, in the gut, Rh-α4ß7 transiently decreased the frequency of memory and IgA+ B cells. In summary, even in the absence of inflammation, Rh-α4ß7 impacted selected immune cell subsets in different tissues. These data provide new insights into the mechanisms by which Rh-α4ß7 may mediate its effect in SIV-infected macaques with implications for understanding the effect of treatment with vedolizumab in patients with inflammatory bowel disease.
Asunto(s)
Integrinas/antagonistas & inhibidores , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Receptores CCR6/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Macaca mulatta , Especificidad de Órganos/inmunologíaRESUMEN
OBJECTIVE: A close relationship between gut microbiota and some chronic liver disorders has recently been described. Herein, we systematically performed a comparative analysis of the gut microbiome in primary biliary cholangitis (PBC) and healthy controls. DESIGN: We first conducted a cross-sectional study of 60 ursodeoxycholic acid (UDCA) treatment-naïve patients with PBC and 80 matched healthy controls. Second, an independent cohort composed of 19 treatment-naïve patients and 34 controls was used to validate the results. Finally, a prospective study was performed in a subgroup of 37 patients with PBC who underwent analysis before and after 6â months of UDCA treatment. Faecal samples were collected, and microbiomes were analysed by 16S ribosomal RNA gene sequencing. RESULTS: A significant reduction of within-individual microbial diversity was noted in PBC (p=0.03). A signature defined by decreased abundance of four genera and increased abundance of eight genera strongly correlated with PBC (area under curve=0.86, 0.84 in exploration and validation data, respectively). Notably, the abundance of six PBC-associated genera was reversed after 6â months of UDCA treatment. In particular, Faecalibacterium, enriched in controls, was further decreased in gp210-positive than gp210-negative patients (p=0.002). Of interest was the finding that the increased capacity for the inferred pathway, bacterial invasion of epithelial cells in PBC, highly correlated with the abundance of bacteria belonging to Enterobacteriaceae. CONCLUSIONS: This study presents a comprehensive landscape of gut microbiota in PBC. Dysbiosis was found in the gut microbiome in PBC and partially relieved by UDCA. Our study suggests that gut microbiota is a potential therapeutic target and diagnostic biomarker for PBC.
Asunto(s)
Bacterias , Colagogos y Coleréticos/uso terapéutico , Colangitis/microbiología , Disbiosis/microbiología , Microbioma Gastrointestinal , Ácido Ursodesoxicólico/uso terapéutico , Adulto , Anciano , Anticuerpos/sangre , Biomarcadores , Estudios de Casos y Controles , Colangitis/complicaciones , Colangitis/tratamiento farmacológico , Estudios Transversales , Disbiosis/complicaciones , Heces/microbiología , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Complejo Poro Nuclear/inmunología , Estudios Prospectivos , Adulto JovenRESUMEN
Dengue virus (DENV) infection is considered one of the most important mosquito-borne diseases. It causes a spectrum of illness that could be due to qualitative and/or quantitative difference(s) of the natural killer (NK) cell responses during acute DENV infection. This view prompted us to perform a detailed phenotypic comparative characterization of NK cell subsets from DENV-infected patients with dengue fever (DF), patients with dengue haemorrhagic fever (DHF) and healthy controls. The activation/differentiation molecules, CD69 and CD57 and a variety of tissue homing molecules were analysed on the CD56hi CD16- and CD56lo CD16+ NK cells. Although there was no increase in the frequency of the total NK cells during DENV infection compared with the healthy individuals, there was a significant increase in the frequency of the CD56hi CD16- subset and the frequency of CD69 expression by both NK cell subsets during the febrile phase of infection. We also found an increase in the frequencies of cells expressing CD69 and CD57 in the CD56lo CD16+ subset compared with those in the CD56hi CD16- subset. Moreover, although the CD56lo CD16+ subset contained a high frequency of cells expressing skin-homing markers, the CD56hi CD16- subset contained a high frequency of cells expressing bone marrow and lymph node trafficking markers. Interestingly, no differences of these NK cell subsets were noted in samples from patients with DF versus those with DHF. These findings suggest that activation and differentiation and the patterns of tissue homing molecules of the two major NK cell subsets are different and that these might play a critical role in the immune response against acute DENV infection.
Asunto(s)
Antígenos CD/inmunología , Dengue/inmunología , Células Asesinas Naturales/inmunología , Enfermedad Aguda , Adolescente , Anticuerpos Monoclonales/inmunología , Biomarcadores , Niño , Preescolar , Dengue/sangre , Virus del Dengue/inmunología , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
The detection of viral dynamics and localization in the context of controlled HIV infection remains a challenge and is limited to blood and biopsies. We developed a method to capture total-body simian immunodeficiency virus (SIV) replication using immunoPET (antibody-targeted positron emission tomography). The administration of a poly(ethylene glycol)-modified, (64)Cu-labeled SIV Gp120-specific antibody led to readily detectable signals in the gastrointestinal and respiratory tract, lymphoid tissues and reproductive organs of viremic monkeys. Viral signals were reduced in aviremic antiretroviral-treated monkeys but detectable in colon, select lymph nodes, small bowel, nasal turbinates, the genital tract and lung. In elite controllers, virus was detected primarily in foci in the small bowel, select lymphoid areas and the male reproductive tract, as confirmed by quantitative reverse-transcription PCR (qRT-PCR) and immunohistochemistry. This real-time, in vivo viral imaging method has broad applications to the study of immunodeficiency virus pathogenesis, drug and vaccine development, and the potential for clinical translation.
Asunto(s)
Antirretrovirales/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Virus de la Inmunodeficiencia de los Simios , Imagen de Cuerpo Entero/métodos , Adenina/análogos & derivados , Adenina/uso terapéutico , Animales , Radioisótopos de Cobre , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Emtricitabina , Inmunohistoquímica , Masculino , Glicoproteínas de Membrana/metabolismo , Naftiridinas/uso terapéutico , Organofosfonatos/uso terapéutico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y Especificidad , Tenofovir , Proteínas del Envoltorio Viral/metabolismo , Viremia , Replicación ViralRESUMEN
Glycosylation of Env defines pathogenic properties of simian immunodeficiency virus (SIV). We previously demonstrated that pathogenic SIVmac239 and a live-attenuated, quintuple deglycosylated Env mutant (Δ5G) virus target CD4+ T cells residing in different tissues during acute infection. SIVmac239 and Δ5G preferentially infected distinct CD4+ T cells in secondary lymphoid organs (SLOs) and within the lamina propria of the small intestine, respectively (C. Sugimoto et al., J Virol 86:9323-9336, 2012, https://doi.org/10.1128/JVI.00948-12). Here, we studied the host responses relevant to SIV targeting of CXCR3+ CCR5+ CD4+ T cells in SLOs. Genome-wide transcriptome analyses revealed that Th1-polarized inflammatory responses, defined by expression of CXCR3 chemokines, were distinctly induced in the SIVmac239-infected animals. Consistent with robust expression of CXCL10, CXCR3+ T cells were depleted from blood in the SIVmac239-infected animals. We also discovered that elevation of CXCL10 expression in blood and SLOs was secondary to the induction of CD14+ CD16+ monocytes and MAC387+ macrophages, respectively. Since the significantly higher levels of SIV infection in SLOs occurred with a massive accumulation of infiltrated MAC387+ macrophages, T cells, dendritic cells (DCs), and residential macrophages near high endothelial venules, the results highlight critical roles of innate/inflammatory responses in SIVmac239 infection. Restricted infection in SLOs by Δ5G also suggests that glycosylation of Env modulates innate/inflammatory responses elicited by cells of monocyte/macrophage/DC lineages.IMPORTANCE We previously demonstrated that a pathogenic SIVmac239 virus and a live-attenuated, deglycosylated mutant Δ5G virus infected distinct CD4+ T cell subsets in SLOs and the small intestine, respectively (C. Sugimoto et al., J Virol 86:9323-9336, 2012, https://doi.org/10.1128/JVI.00948-12). Accordingly, infections with SIVmac239, but not with Δ5G, deplete CXCR3+ CCR5+ CD4+ T (Th1) cells during the primary infection, thereby compromising the cellular immune response. Thus, we hypothesized that distinct host responses are elicited by the infections with two different viruses. We found that SIVmac239 induced distinctly higher levels of inflammatory Th1 responses than Δ5G. In particular, SIVmac239 infection elicited robust expression of CXCL10, a chemokine for CXCR3+ cells, in CD14+ CD16+ monocytes and MAC387+ macrophages recently infiltrated in SLOs. In contrast, Δ5G infection elicited only modest inflammatory responses. These results suggest that the glycosylation of Env modulates the inflammatory/Th1 responses through the monocyte/macrophage subsets and elicits marked differences in SIV infection and clinical outcomes.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Quimiocina CXCL10/biosíntesis , Macrófagos/inmunología , Monocitos/inmunología , Receptores CXCR3/análisis , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Subgrupos de Linfocitos T/virología , Animales , Linfocitos T CD4-Positivos/química , Expresión Génica , Perfilación de la Expresión Génica , Inmunidad Innata , Macaca mulatta , Masculino , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Subgrupos de Linfocitos T/químicaRESUMEN
Molecular mimicry is one of the leading mechanisms by which infectious or chemical agents may induce autoimmunity. It occurs when similarities between foreign and self-peptides favor an activation of autoreactive T or B cells by a foreign-derived antigen in a susceptible individual. However, molecular mimicry is unlikely to be the only underlying mechanism for autoimmune responses; other factors such as breach in central tolerance, non-specific bystander activation, or persistent antigenic stimuli (amongst others) may also contribute to the development of autoimmune diseases. Host genetics, exposure to microbiota and environmental chemicals are additional links to our understanding of molecular mimicry. Our current knowledge of the detailed mechanisms of molecular mimicry is limited by the issues of prolonged periods of latency before the appearance of disease, the lack of enough statistical power in epidemiological studies, the limitations of the potential role of genetics in human studies, the relevance of inbred murine models to the diverse human population and especially the limited technology to systematically dissect the human T-cell repertoire and B-cell responses. Nevertheless, studies on the role of autoreactive T-cells that are generated secondary to molecular mimicry, the diversity of the T-cell receptor repertoires of auto-reactive T-cells, the role of exposure to cryptic antigens, the generation of autoimmune B-cell responses, the interaction of microbiota and chemical adjuvants with the host immune systems all provide clues in advancing our understanding of the molecular mechanisms involved in the evolving concept of molecular mimicry and also may potentially aid in the prevention and treatment of autoimmune diseases.
Asunto(s)
Antígenos Bacterianos/inmunología , Antígenos Virales/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Autoinmunidad , Imitación Molecular/inmunología , Animales , Antígenos Bacterianos/genética , Antígenos Virales/genética , Autoanticuerpos/biosíntesis , Autoantígenos/genética , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/microbiología , Enfermedades Autoinmunes/virología , Linfocitos B/inmunología , Reacciones Cruzadas , Expresión Génica , Humanos , Ratones , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunologíaRESUMEN
Mucosal-associated invariant T (MAIT) cells are novel innate-like T cells constituting a significant proportion of circulating and hepatic T cells. Herein, we extensively examine the phenotypical and functional alterations of MAIT cells and their regulation in a cohort of 56 patients with Primary Biliary Cholangitis (PBC) and 53 healthy controls (HC). Additionally alterations of MAIT cells were assessed before and after UDCA treatment. Finally the localization of MAIT cell in liver was examined using specific tetramer staining and the underlying mechanisms of these alterations in PBC were explored. Our data demonstrated that the frequency and number of circulating MAIT cells were decreased, whereas hepatic MAIT cells were increased in PBC compared to HC. Moreover, circulating MAIT cells were more activated in PBC than HC, reflected by elevated expression levels of granzyme B. Six months of UDCA treatment significantly attenuated the circulating MAIT cells differences in PBC. Of note, the expression levels of IL-7 were significantly increased in both plasma and liver from PBC as compared to HC, which promoted the production of inflammatory cytokines and granzyme B by inducing signal transduction and activation of transcription 5 (STAT5) phosphorylation in MAIT cells. Finally, cholic acid, one of the major bile acids in liver, upregulated IL-7 expression in hepatocyte cell line L02 by inducing Farnesoid X Receptor (FXR) binding to the IL-7 promoter. Hence MAIT cells are activated and enriched in the liver of PBC. Cholic acid-induced IL-7 production in hepatocytes plays a critical role in regulating MAIT cell function, highlighting that hepatocytes may bridge cholangiocyte injury and innate immunity through a bile acid signaling pathway.