Assuntos
Anticorpos , Vacinas contra COVID-19 , COVID-19 , Proteína Antagonista do Receptor de Interleucina 1 , Miocardite , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Miocardite/etiologia , Miocardite/imunologia , SARS-CoV-2 , VacinaçãoRESUMO
The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1ß, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.
Assuntos
Inflamação , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1 , Animais , COVID-19 , Inflamação/imunologia , Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-1/genética , Interleucina-1/imunologia , Lipídeos , Camundongos , RNA , Vacinas Sintéticas , Vacinas de mRNA/efeitos adversos , Vacinas de mRNA/metabolismoRESUMO
The novel coronavirus pandemic has emerged as one of the significant medical-health challenges of the current century. The World Health Organization has named this new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first detection of SARS-CoV-2 in November 2019 in Wuhan, China, physicians, researchers, and others have made it their top priority to find drugs and cures that can effectively treat patients and reduce mortality rates. The symptoms of Coronavirus Disease 2019 (COVID-19) include fever, dry cough, body aches, and anosmia. Various therapeutic compounds have been investigated and applied to mitigate the symptoms in COVID-19 patients and cure the disease. Degenerative virus analyses of the infection incidence and COVID-19 have demonstrated that SARS-CoV-2 penetrates the pulmonary alveoli's endothelial cells through Angiotensin-Converting Enzyme 2 (ACE2) receptors on the membrane, stimulates various signaling pathways and causes excessive secretion of cytokines. The continuous triggering of the innate and acquired immune system, as well as the overproduction of pro-inflammatory factors, cause a severe condition in the COVID-19 patients, which is called "cytokine storm". It can lead to acute respiratory distress syndrome (ARDS) in critical patients. Severe and critical COVID-19 cases demand oxygen therapy and mechanical ventilator support. Various drugs, including immunomodulatory and immunosuppressive agents (e.g., monoclonal antibodies (mAbs) and interleukin antagonists) have been utilized in clinical trials. However, the studies and clinical trials have documented diverging findings, which seem to be due to the differences in these drugs' possible mechanisms of action. These drugs' mechanism of action generally includes suppressing or modulating the immune system, preventing the development of cytokine storm via various signaling pathways, and enhancing the blood vessels' diameter in the lungs. In this review article, multiple medications from different drug families are discussed, and their possible mechanisms of action are also described.
Assuntos
Antivirais/imunologia , Tratamento Farmacológico da COVID-19 , Agentes de Imunomodulação/farmacologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Antivirais/farmacologia , Azetidinas/imunologia , Azetidinas/farmacologia , COVID-19/etiologia , Dexametasona/imunologia , Dexametasona/farmacologia , Famotidina/imunologia , Famotidina/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Infliximab/imunologia , Infliximab/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Melatonina/imunologia , Melatonina/farmacologia , Purinas/imunologia , Purinas/farmacologia , Pirazóis/imunologia , Pirazóis/farmacologia , Sulfonamidas/imunologia , Sulfonamidas/farmacologiaRESUMO
Tuberculosis (TB) remains a major public health problem and we lack a comprehensive understanding of how Mycobacterium tuberculosis (M. tb) infection impacts host immune responses. We compared the induced immune response to TB antigen, BCG and IL-1ß stimulation between latently M. tb infected individuals (LTBI) and active TB patients. This revealed distinct responses between TB/LTBI at transcriptomic, proteomic and metabolomic levels. At baseline, we identified a novel immune-metabolic association between pregnane steroids, the PPARγ pathway and elevated plasma IL-1ra in TB. We observed dysregulated IL-1 responses after BCG stimulation in TB patients, with elevated IL-1ra responses being explained by upstream TNF differences. Additionally, distinct secretion of IL-1α/IL-1ß in LTBI/TB after BCG stimulation was associated with downstream differences in granzyme mediated cleavage. Finally, IL-1ß driven signalling was dramatically perturbed in TB disease but was completely restored after successful treatment. This study improves our knowledge of how immune responses are altered during TB disease, and may support the design of improved preventive and therapeutic tools, including host-directed strategies.
Assuntos
Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1 , Tuberculose , Humanos , Vacina BCG , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-1/genética , Interleucina-1/imunologia , Redes e Vias Metabólicas , Proteômica , Tuberculose/tratamento farmacológico , Tuberculose/genética , Tuberculose/imunologiaRESUMO
A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1ß, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR-15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.
Assuntos
COVID-19/complicações , Citocinas/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/imunologia , SARS-CoV-2/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Estudos de Casos e Controles , Citocinas/efeitos dos fármacos , Metilação de DNA , Feminino , Humanos , Imunofenotipagem , Técnicas In Vitro , Proteína Antagonista do Receptor de Interleucina 1/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Interleucina-8/efeitos dos fármacos , Interleucina-8/imunologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Regiões Promotoras Genéticas , Síndrome de COVID-19 Pós-AgudaRESUMO
The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.
Assuntos
Inibidores de Adenilil Ciclases/farmacologia , Adenilil Ciclases/genética , Antineoplásicos/farmacologia , AMP Cíclico/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Inibidores de Adenilil Ciclases/síntese química , Adenilil Ciclases/imunologia , Animais , Antineoplásicos/síntese química , Compostos de Benzil/química , AMP Cíclico/imunologia , AMP Cíclico/metabolismo , Ésteres , Feminino , Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Injeções Intralesionais , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Micelas , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/patologia , Peptídeos/química , Ácido Poliglutâmico/química , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Sarcosina/análogos & derivados , Sarcosina/química , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Carga Tumoral/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.
Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-1beta/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diferenciação Celular/imunologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/imunologia , Ligante RANK/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.
Assuntos
Proteínas de Ligação a DNA/genética , Doenças Hereditárias Autoinflamatórias/genética , Doenças Inflamatórias Intestinais/genética , Macrófagos/imunologia , Fatores de Transcrição/genética , Animais , Calgranulina A/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Lipocalina-2/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th17/imunologia , Transcrição Gênica/genética , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismoRESUMO
Systemic inflammation induced by periodontitis is suggested to be the link between periodontitis and cardiovascular disease. The aim of this work was to explore the oral microbiome in periodontitis in relation to disease severity and systemic inflammation. The saliva and subgingival microbiome from periodontal pocket samples of patients with severe (n = 12) and mild periodontitis (n = 13) were analyzed using metagenomic shotgun sequencing. The taxa and pathways abundances were quantified. The diversity was assessed and the abundances to phenotype associations were performed using ANCOM and linear regression. A panel of inflammatory markers was measured in blood and was associated with taxa abundance. The microbial diversity and species richness did not differ between severe and mild periodontitis in either saliva or periodontal pockets. However, there were significant differences in the microbial composition between severe and mild periodontitis in the subgingival microbiome (i.e., pocket samples) and, in a lower grade, in saliva, and this is positively associated with systemic inflammatory markers. The "red complex" and "cluster B" abundances in periodontal pockets were strongly associated with inflammatory markers interleukin-6 and the white blood cell count. Our data suggest that systemic inflammation in severe periodontitis may be driven by the oral microbiome and may support the indirect (inflammatory) mechanism for the association between periodontitis and cardiovascular disease.
Assuntos
Metagenoma , Microbiota/genética , Periodontite/microbiologia , Periodonto/microbiologia , Idoso , Biomarcadores/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/patologia , Feminino , Expressão Gênica , Variação Genética , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Leucócitos/imunologia , Leucócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Periodontite/complicações , Periodontite/imunologia , Periodontite/patologia , Periodonto/imunologia , Periodonto/patologia , Fenótipo , Filogenia , Índice de Gravidade de DoençaRESUMO
Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders.
Assuntos
Imunogenicidade da Vacina/imunologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Células T Auxiliares Foliculares/metabolismo , Animais , Anticorpos/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Antígenos/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Humanos , Imunidade Humoral/imunologia , Imunogenicidade da Vacina/fisiologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/imunologia , Receptores de Interleucina-1/metabolismo , Células T Auxiliares Foliculares/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinação/métodosRESUMO
The IL-1 receptor antagonist, anakinra, may represent a therapeutic option for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19). In this study, COVID-19 ARDS patients admitted to the Azienda Socio Sanitaria Territoriale of Lecco, Italy, between March 5th to April 15th, 2020, and who had received anakinra off-label were retrospectively evaluated and compared with a cohort of matched controls who did not receive immunomodulatory treatment. The primary end point was survival at day 28. The population consisted of 112 patients (56 treated with anakinra and 56 controls). Survival at day 28 was obtained in 69 patients (61.6%) and was significantly higher in anakinra-treated patients than in the controls (75.0 versus 48.2%, p = 0.007). When stratified by continuous positive airway pressure support at baseline, anakinra-treated patients' survival was also significant compared with the controls (p = 0.008). Univariate analysis identified anakinra usage (odds ratio, 3.2; 95% confidence interval, 1.47-7.17) as a significant survival predictor. This was not supported by multivariate modeling. The rate of infectious-related adverse events was similar between groups. In conclusion, anakinra improved overall survival and invasive ventilation-free survival and was well tolerated in patients with ARDS associated with COVID-19.
Assuntos
COVID-19 , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Respiração Artificial , SARS-CoV-2/imunologia , Síndrome Respiratória Aguda Grave , Idoso , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/terapia , Intervalo Livre de Doença , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/antagonistas & inibidores , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/mortalidade , Síndrome Respiratória Aguda Grave/terapia , Síndrome Respiratória Aguda Grave/virologia , Taxa de SobrevidaRESUMO
OBJECTIVE: To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. METHODS: Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA). RESULTS: A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1ß secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/ß, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade. CONCLUSION: We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.
Assuntos
Anemia Diseritropoética Congênita/genética , Síndromes de Imunodeficiência/genética , Inflamação/genética , Macrófagos/imunologia , Proteínas Nucleares/genética , Osteogênese/genética , Osteomielite/genética , Anemia Diseritropoética Congênita/tratamento farmacológico , Anemia Diseritropoética Congênita/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos de Casos e Controles , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/imunologia , Feminino , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Heterozigoto , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Inflamação/imunologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , MAP Quinase Quinase 4/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas Nucleares/imunologia , Osteomielite/tratamento farmacológico , Osteomielite/imunologia , Quinases da Família src/metabolismoRESUMO
BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).
Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Pneumonia Viral/imunologia , Síndrome do Desconforto Respiratório/imunologia , Sepse/imunologia , Adulto , Idoso , COVID-19 , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Síndrome da Liberação de Citocina/sangue , Citocinas/sangue , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-18/sangue , Interleucina-18/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Síndrome do Desconforto Respiratório/sangue , Sepse/sangue , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Identifying immune correlates of COVID-19 disease severity is an urgent need for clinical management, vaccine evaluation, and drug development. Here, we present a temporal analysis of key immune mediators, cytokines, and chemokines in blood of hospitalized COVID-19 patients from serial sampling and follow-up over 4 weeks. METHODS: A total of 71 patients with laboratory-confirmed COVID-19 admitted to Beijing You'an Hospital in China with either mild (53 patients) or severe (18 patients) disease were enrolled with 18 healthy volunteers. We measured 34 immune mediators, cytokines, and chemokines in peripheral blood every 4-7 days over 1 month per patient using a bioplex multiplex immunoassay. RESULTS: We found that the chemokine RANTES (CCL5) was significantly elevated, from an early stage of the infection, in patients with mild but not severe disease. We also found that early production of inhibitory mediators including IL-10 and IL-1RA were significantly associated with disease severity, and a combination of CCL5, IL-1 receptor antagonist (IL-1RA), and IL-10 at week 1 may predict patient outcomes. The majority of cytokines that are known to be associated with the cytokine storm in virus infections such as IL-6 and IFN-γ were only significantly elevated in the late stage of severe COVID-19 illness. TNF-α and GM-CSF showed no significant differences between severe and mild cases. CONCLUSION: Together, our data suggest that early intervention to increase expression of CCL5 may prevent patients from developing severe illness. Our data also suggest that measurement of levels of CCL5, as well as IL-1RA and IL-10 in blood individually and in combination, might be useful prognostic biomarkers to guide treatment strategies.
Assuntos
Quimiocina CCL5/imunologia , Infecções por Coronavirus/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-10/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Betacoronavirus , COVID-19 , Estudos de Casos e Controles , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Hospitalização , Humanos , Imunoensaio , Interferon gama/imunologia , Interleucina-6/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , SARS-CoV-2 , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/imunologiaRESUMO
PURPOSE OF THE REVIEW: Kawasaki disease (KD) is a childhood systemic vasculitis of unknown etiology that causes coronary artery aneurysms (CAA), and if left undiagnosed can result in long-term cardiovascular complications and adult cardiac disease. Up to 20% of KD children fail to respond to IVIG, the mainstay of therapy, highlighting the need for novel therapeutic strategies. Here we review the latest findings in the field regarding specific etiology, genetic associations, and advancements in treatment strategies to prevent coronary aneurysms. RECENT FINDINGS: Recent discoveries using the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model have accelerated the study of KD pathophysiology and have advanced treatment strategies including clinical trials for IL-1R antagonist, Anakinra. KD remains an elusive pediatric vasculitis syndrome and is the leading cause of acquired heart disease among children in the USA and developed countries. Advancements in combination treatment for refractory KD with further understanding of novel genetic risk factors serve as a solid foundation for future research endeavors in the field.
Assuntos
Aneurisma Coronário/prevenção & controle , Imunossupressores/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Síndrome de Linfonodos Mucocutâneos , Miocardite , Vasculite , Animais , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/imunologia , Antirreumáticos/uso terapêutico , Aneurisma Coronário/etiologia , Modelos Animais de Doenças , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/imunologia , Infliximab/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Camundongos , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Síndrome de Linfonodos Mucocutâneos/etiologia , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Miocardite/etiologia , Miocardite/prevenção & controle , Vasculite/etiologia , Vasculite/prevenção & controleRESUMO
The IL1A and IL1B genes lie in close proximity on chromosome 2 near the gene for their natural inhibitor, IL1RN Despite diverse functions, they are all three inducible through TLR4 signaling but with distinct kinetics. This study analyzed transcriptional induction kinetics, chromosome looping, and enhancer RNA production to understand the distinct regulation of these three genes in human cells. IL1A, IL1B, and IL1RN were rapidly induced after stimulation with LPS; however, IL1B mRNA production was less inhibitable by iBET151, suggesting it does not use pause-release regulation. Surprisingly, chromatin looping contacts between IL1A and IL1B were highly intermingled, although those of IL1RN were distinct, and we focused on comparing IL1A and IL1B transcriptional pathways. Our studies demonstrated that enhancer RNAs were produced from a subset of the regulatory regions, that they were critical for production of the mRNAs, and that they bound a diverse array of RNA binding proteins, including p300 but not CBP. We, furthermore, demonstrated that recruitment of p300 was dependent on MAPKs. Integrator is another RNA binding protein recruited to the promoters and enhancers, and its recruitment was more dependent on NF-κB than MAPKs. We found that integrator and NELF, an RNA polymerase II pausing protein, were associated with RNA in a manner that facilitated interaction. We conclude that IL1A and IL1B share many regulatory contacts, signaling pathways, and interactions with enhancer RNAs. A complex of protein interactions with enhancer RNAs emphasize the role of enhancer RNAs and the overall structural aspects of transcriptional regulation.
Assuntos
Proteína p300 Associada a E1A/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Proteínas de Ligação a RNA/imunologia , Transcrição Gênica , Linhagem Celular , Proteína p300 Associada a E1A/genética , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Proteínas de Ligação a RNA/genética , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/imunologiaRESUMO
The inflammatory effects of IL-1α/ß are controlled by IL-1R antagonist (IL-1Ra). One IL-1Ra isoform is secreted, whereas three other isoforms (intracellular IL-1Ra [icIL-1Ra] 1, 2, and 3) are supposed to remain intracellular because of the absence of a signal peptide. In contrast to the well-characterized function of the secreted isoform, the biological role of the intracellular isoforms remains largely unclear. icIL-1Ra1 represents the major isoform in keratinocytes. We created icIL-1Ra1-/- mice and investigated the role of icIL-1Ra1 in Aldara (5% imiquimod)-induced psoriasis-like skin inflammation. Naive icIL-1Ra1-/- mice bred habitually and exhibited a normal phenotype. icIL-1Ra1 deficiency aggravated Aldara-induced skin inflammation, as demonstrated by increased ear thickness and increased mRNA levels of key proinflammatory cytokines. No intracellular effect of icIL-1Ra1 could be detected in isolated keratinocytes using RNA-sequencing analysis; however, Aldara treatment led to caspase 1/11-, caspase 8-, and RIPK3-independent keratinocyte cell death accompanied by the release of both icIL-1Ra1 and IL-1α. Furthermore, blocking IL-1α attenuated the clinical severity of Aldara-induced ear thickening in icIL-1Ra1-/- mice. Our data suggest that upon keratinocyte damage icIL-1Ra1 acts extracellularly as an antagonist of the alarmin IL-1α to immediately counteract its inflammatory effects.
Assuntos
Alarminas/antagonistas & inibidores , Apoptose/imunologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/antagonistas & inibidores , Psoríase/imunologia , Alarminas/imunologia , Alarminas/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Imiquimode/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-1alfa/imunologia , Interleucina-1alfa/metabolismo , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , Psoríase/diagnóstico , Psoríase/patologia , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Pele/citologia , Pele/imunologia , Pele/patologiaRESUMO
Sexually transmitted infections (STIs) and vaginal dysbiosis (disturbed resident microbiota presenting with abnormal Nugent score or candidiasis) have been associated with mucosal inflammation and risk of HIV-1 infection, cancer and poor reproductive outcomes. To date, the temporal relationships between aberrant cervical innate immunity and the clinical onset of microbial disturbance have not been studied in a large population of reproductive age women. We examined data from a longitudinal cohort of 934 Ugandan and Zimbabwean women contributing 3,274 HIV-negative visits who had complete laboratory, clinical and demographic data. Among those, 207 women later acquired HIV, and 584 women were intermittently diagnosed with C. trachomatis (CT), N. gonorrhoeae (NG), genital herpes (HSV-2), T. vaginalis (TV), candidiasis, and abnormal intermediate (4-6) or high (7-10) Nugent score, i.e. bacterial vaginosis (BV). Immune biomarker concentrations in cervical swabs were analyzed by generalized linear and mixed effect models adjusting for site, age, hormonal contraceptive use (HC), pregnancy, breastfeeding, genital practices, unprotected sex and overlapping infections. High likelihood ratios (1.5-4.9) denoted the values of cervical immune biomarkers to predict onset of abnormal Nugent score and candidiasis at the next visits. When controlling for covariates, higher levels of ß-defensin-2 were antecedent to BV, CT and HSV-2, lower anti-inflammatory ratio IL-1RA:IL-1ß-to intermediate Nugent scores and candida, lower levels of the serine protease inhibitor SLPI-to candida, lower levels of the adhesion molecule ICAM-1 -to TV, and lower levels of the oxidative stress mitigator and endothelial activation marker VEGF-to NG. Changes in innate immunity following onset of dysbiosis and infections were dependent on HC use when controlling for all other covariates. In conclusion, imminent female genital tract dysbiosis or infection can be predicted by distinct patterns of innate immunity. Future research should characterize biotic and abiotic determinants of this pre-existing innate immunity state.
Assuntos
Disbiose/imunologia , Imunidade Inata/genética , Infecções Sexualmente Transmissíveis/imunologia , Vaginose Bacteriana/imunologia , Adolescente , Adulto , Biomarcadores/metabolismo , Colo do Útero/imunologia , Colo do Útero/microbiologia , Colo do Útero/patologia , Disbiose/epidemiologia , Disbiose/microbiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Estresse Oxidativo/imunologia , Gravidez , Infecções do Sistema Genital/epidemiologia , Infecções do Sistema Genital/imunologia , Inibidor Secretado de Peptidases Leucocitárias/imunologia , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/microbiologia , Uganda/epidemiologia , Vagina/imunologia , Vagina/microbiologia , Vaginose Bacteriana/epidemiologia , Vaginose Bacteriana/microbiologia , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Zimbábue/epidemiologiaRESUMO
Interleukin (IL)-1 receptor antagonist (IL-1Ra), a naturally occurring antagonist of IL-1α/IL-1ß signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells (MSCs). MSCs, in IL-1Ra-dependent manner, suppressed production of IL-1ß in dermal macrophages, induced their polarization in anti-inflammatory M2 phenotype, attenuated antigen-presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL-1ß in macrophages were mainly responsible for beneficial effects of MSC-derived IL-1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL-1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL-1Ra-dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL-1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC-treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL-1Ra-dependent inhibition of IL-1α/IL-1ß-signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC-derived IL-1Ra before IL-1Ra-overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.
Assuntos
Proliferação de Células/fisiologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Células-Tronco Mesenquimais/imunologia , Regeneração/imunologia , Regeneração/fisiologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Células-Tronco Mesenquimais/metabolismoRESUMO
There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N = 23) or decreased (N = 31) appetite and weight in their current depressive episode and healthy control participants (N = 42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.