RESUMEN
The ability of Staphylococcus aureus (S. aureus) to survive within macrophages is a critical strategy for immune evasion, contributing to the pathogenesis and progression of osteomyelitis. However, the underlying mechanisms remain poorly characterized. This study discovered that inhibiting the MEK1/2 pathway reduced bacterial load and mitigated bone destruction in a mouse model of S. aureus osteomyelitis. Histological staining revealed increased phosphorylated MEK1/2 levels in bone marrow macrophages surrounding abscess in the mouse model of S. aureus osteomyelitis. Activation of MEK1/2 pathway and its roles in impairing macrophage bactericidal function were confirmed in primary mouse bone marrow-derived macrophages (BMDMs). Transcriptome analysis and in vitro experiments demonstrated that S. aureus activates the MEK1/2 pathway through EGFR signaling. Moreover, we found that excessive activation of EGFR-MEK1/2 cascade downregulates mitochondrial reactive oxygen species (mtROS) levels by suppressing Chek2 expression, thereby impairing macrophage bactericidal function. Furthermore, pharmacological inhibition of EGFR signaling prevented upregulation of phosphorylated MEK1/2 and restored Chek2 expression in macrophages, significantly enhancing S. aureus clearance and improving bone microstructure in vivo. These findings highlight the critical role of the EGFR-MEK1/2 cascade in host immune defense against S. aureus, suggesting that S. aureus may reduce mtROS levels by overactivating the EGFR-MEK1/2 cascade, thereby suppressing macrophage bactericidal function. Therefore, combining EGFR-MEK1/2 pathway blockade with antibiotics could represent an effective therapeutic approach for the treatment of S. aureus osteomyelitis.
Asunto(s)
Receptores ErbB , MAP Quinasa Quinasa 1 , Macrófagos , Osteomielitis , Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Osteomielitis/microbiología , Osteomielitis/inmunología , Osteomielitis/metabolismo , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiología , Ratones , Staphylococcus aureus/inmunología , Receptores ErbB/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Transducción de SeñalRESUMEN
Systemic autoinflammatory diseases (SAIDs) arise from dysregulated innate immune system activity, which leads to systemic inflammation. These disorders, encompassing a diverse array of genetic defects classified as inborn errors of immunity, are significant diagnostic challenges due to their genetic heterogeneity and varied clinical presentations. Although recent advances in genetic sequencing have facilitated pathogenic gene discovery, approximately 40% of SAIDs patients lack molecular diagnoses. SAIDs have distinct clinical phenotypes, and targeted therapeutic approaches are needed. This review aims to underscore the complexity and clinical significance of SAIDs, focusing on prototypical disorders grouped according to their pathophysiology as follows: (i) inflammasomopathies, characterized by excessive activation of inflammasomes, which induces notable IL-1ß release; (ii) relopathies, which are monogenic disorders characterized by dysregulation within the NF-κB signaling pathway; (iii) IL-18/IL-36 signaling pathway defect-induced SAIDs, autoinflammatory conditions defined by a dysregulated balance of IL-18/IL-36 cytokine signaling, leading to uncontrolled inflammation and tissue damage, mainly in the skin; (iv) type I interferonopathies, a diverse group of disorders characterized by uncontrolled production of type I interferons (IFNs), notably interferon α, ß, and ε; (v) anti-inflammatory signaling pathway impairment-induced SAIDs, a spectrum of conditions characterized by IL-10 and TGFß anti-inflammatory pathway disruption; and (vi) miscellaneous and polygenic SAIDs. The latter group includes VEXAS syndrome, chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis, Schnitzler syndrome, and Still's disease, among others, illustrating the heterogeneity of SAIDs and the difficulty in creating a comprehensive classification. Therapeutic strategies involving targeted agents, such as JAK inhibitors, IL-1 blockers, and TNF inhibitors, are tailored to the specific disease phenotypes.
Asunto(s)
Enfermedades Autoinflamatorias Hereditarias , Humanos , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Inflamasomas/genética , Inflamación/genética , Transducción de Señal , Interleucina-18/genética , Interleucina-1beta/genética , Interleucina-1beta/antagonistas & inhibidores , FN-kappa B , Anemia Diseritropoyética Congénita/genética , Anemia Diseritropoyética Congénita/terapia , Anemia Diseritropoyética Congénita/diagnóstico , Síndrome de Schnitzler/genética , Síndrome de Schnitzler/tratamiento farmacológico , Síndrome de Schnitzler/diagnóstico , Osteomielitis/genética , Osteomielitis/tratamiento farmacológico , Osteomielitis/inmunología , Deficiencia de Mevalonato Quinasa/genética , Deficiencia de Mevalonato Quinasa/tratamiento farmacológico , Deficiencia de Mevalonato Quinasa/diagnóstico , Síndromes de InmunodeficienciaRESUMEN
More frequent among adults, phenocopies may be caused by somatic mutations or anti-cytokine autoantibodies, mimicking the phenotypes of primary immunodeficiencies. A fourteen-year-old girl was referred for a two-year history of weight loss and multiple recurrent abscesses, complicated recurrent pneumonia, pyelonephritis, osteomyelitis, and septic shock, without fever. She had started with nausea, hyporexia, and weight loss, then with abscesses in her hands, knee, ankle, and spleen. She also developed a rib fracture and left thoracic herpes zoster. The patient was cachectic, with normal vital signs, bilateral crackles on chest auscultation, tumefaction of the knee joint, and poorly healed wounds in hands and chest, oozing a yellowish fluid. Chest computed tomography revealed multiple bilateral bronchiectases. Laboratory workup reported chronic anemia, leukocytosis, neutrophilia, mild lymphopenia, thrombocytosis, pan-hypergammaglobulinemia, and elevated acute serum reactants. Lymphocyte subsets were low but present. Mycobacterium tuberculosis was detected via polymerase chain reaction in a bone biopsy specimen from ankle osteomyelitis. Whole-exome sequencing failed to identify a monogenic defect. Interleukin-12 was found markedly elevated in the serum of the patient. Phosphorylation of STAT4, induced by increasing doses of IL-12, was neutralized by patient serum, confirming the presence of anti-IL12 autoantibodies. IL-12 and IL-23 are crucial cytokines in the defense against intracellular microorganisms, the induction of interferon-gamma production by lymphocytes, and other inflammatory functions. Patients who develop neutralizing serum autoantibodies against IL12 manifest late in life with weight loss, multiple recurrent abscesses, poor wound healing, and fistulae. Treatment with anti-CD20 monoclonal antibodies was effective.
Asunto(s)
Absceso , Autoanticuerpos , Humanos , Femenino , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Adolescente , Absceso/inmunología , Subunidad p40 de la Interleucina-12/inmunología , Recurrencia , Osteomielitis/inmunologíaRESUMEN
BACKGROUND: Osteomyelitis (OM) is recognized as a significant challenge in orthopedics due to its complex immune and inflammatory responses. The prognosis heavily depends on timely diagnosis, accurate classification, and assessment of severity. Thus, the identification of diagnostic and classification-related genes from an immunological standpoint is crucial for the early detection and tailored treatment of OM. METHODS: Transcriptomic data for OM was sourced from the Gene Expression Omnibus (GEO) database, leading to the identification of autophagy- and immune-related differentially expressed genes (AIR-DEGs) through differential expression analysis. Diagnostic and classification models were subsequently developed. The CIBERSORT algorithm was utilized to examine immune cell infiltration in OM, and the relationship between OM clusters and various immune cells was explored. Key AIR-DEGs were further validated through the creation of OM animal models. RESULTS: Analysis of the transcriptomic data revealed three AIR-DEGs that played a significant role in immune responses and pathways. Nomogram and receiver operating characteristic curve analyses were performed, demonstrating excellent diagnostic capability for differentiating between OM patients and healthy individuals, with an area under the curve of 0.814. An unsupervised clustering analysis discerned two unique patterns of autophagy- and immune-related genes, as well as gene patterns. Further exploration into immune infiltration exhibited notable variances across different subtypes, especially between OM cluster 1 and gene cluster A, highlighting their potential role in mitigating inflammatory responses by regulating immune activities. Moreover, the mRNA and protein expression levels of three AIR-DEGs in the animal model were aligned with those in the training and validation data sets. CONCLUSIONS: From an immunological perspective, a diagnostic model was successfully developed, and two distinct clustering patterns were identified. These contributions offer a significant resource for the early detection and personalized immunotherapy of patients with OM.
Asunto(s)
Autofagia , Biomarcadores , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Osteomielitis , Osteomielitis/diagnóstico , Osteomielitis/inmunología , Osteomielitis/genética , Animales , Autofagia/genética , Autofagia/inmunología , Humanos , Ratones , TranscriptomaRESUMEN
BACKGROUND: Age-associated impairments in innate immunity are believed to be a causative factor responsible for severe pathogenesis of Staphylococcus aureus (S. aureus) infection in the bone tissue. However, the basis for age-associated decline in innate immune response upon S. aureus infection remains poorly understood. RESULTS: Our transcriptional data (GEO: GSE166522) from a mouse model of S. aureus osteomyelitis show up-regulated CXCL9 and CXCL10 (CXCL9/10), which is further confirmed in vitro and in vivo by the present study. Notably, monocytes are a main source for CXCL9/10 production in bone marrow upon S. aureus challenge, but this response declines in middle-aged mice. Interestingly, conditional medium of bone marrow monocytes from middle-aged mice has a strikingly decreased effect on bactericidal functions of neutrophils and macrophages compares with that from young mice. We further show that activation of CXCL9/10-CXCR3 axis between monocytes and macrophages/neutrophils promotes the bactericidal function of the cells, whereas blocking the axis impairs such function. Importantly, treatment with either exogenous CXCL9 or CXCL10 in a middle-aged mice model enhances, while pharmacological inhibition of CXCR3 in young mice model impairs, bacterial clearance and bone marrow structure. CONCLUSIONS: These findings demonstrate that bone marrow monocytes act as a critical promotor of innate immune response via the CXLCL9/10-CXCR3 axis upon S. aureus infection, and that the increased susceptibility to S. aureus infection in skeleton in an aged host may be largely attributable to the declined induction of CXCR9/10 in monocytes.
Asunto(s)
Quimiocina CXCL10 , Quimiocina CXCL9 , Modelos Animales de Enfermedad , Inmunidad Innata , Monocitos , Osteomielitis , Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Osteomielitis/microbiología , Osteomielitis/inmunología , Osteomielitis/metabolismo , Osteomielitis/patología , Monocitos/inmunología , Monocitos/metabolismo , Quimiocina CXCL9/metabolismo , Quimiocina CXCL9/genética , Staphylococcus aureus/inmunología , Ratones , Quimiocina CXCL10/metabolismo , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patología , Infecciones Estafilocócicas/metabolismo , Ratones Endogámicos C57BL , Receptores CXCR3/metabolismo , Receptores CXCR3/genética , Envejecimiento/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismoRESUMEN
Introduction: Osteomyelitis (OMS) is a bone infection causing bone pain and severe complications. A balanced immune response is critical to eradicate infection without harming the host, yet pathogens manipulate immunity to establish a chronic infection. Understanding OMS-driven inflammation is essential for disease management, but comprehensive data on immune profiles and immune cell activation during OMS are lacking. Methods: Using high-dimensional flow cytometry, we investigated the detailed innate and adaptive systemic immune cell populations in OMS and age- and sex-matched controls. Results: Our study revealed that OMS is associated with increased levels of immune regulatory cells, namely T regulatory cells, B regulatory cells, and T follicular regulatory cells. In addition, the expression of immune activation markers HLA-DR and CD86 was decreased in OMS, while the expression of immune exhaustion markers TIM-3, PD-1, PD-L1, and VISTA was increased. Members of the T follicular helper (Tfh) cell family as well as classical and typical memory B cells were significantly increased in OMS individuals. We also found a strong correlation between memory B cells and Tfh cells. Discussion: We conclude that OMS skews the host immune system towards the immunomodulatory arm and that the Tfh memory B cell axis is evident in OMS. Therefore, immune-directed therapies may be a promising alternative for eradication and recurrence of infection in OMS, particularly in individuals and areas where antibiotic resistance is a major concern.
Asunto(s)
Osteomielitis , Humanos , Osteomielitis/inmunología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Linfocitos T Reguladores/inmunología , Anciano , Activación de Linfocitos , Biomarcadores , Inmunidad Innata , Células B de Memoria/inmunología , Células T Auxiliares Foliculares/inmunología , Agotamiento del Sistema InmunológicoRESUMEN
Las betalactamasas de espectro extendido (BLEE) son enzimas producidas por bacilos gram negativos capaces de hidrolizar las cefalosporinas de amplio espectro y los monobactámicos. La mayoría pertenece a la familia de Enterobacteriae, tales como Klebsiella pneumoniae y Escherichia coli: Sin embargo, se asocian también con otras bacterias como Proteus, Serratia, Salmonella, Pseudomonas aeruginosa y Acinetobacter. Las enterobacterias productoras de carbapenemasas no sólo han sido aisladas en el ambiente hospitalario, sino que también provienen de la comunidad. Se presenta una paciente de sexo femenino con antecedentes de sida y osteomielitis secundaria a artritis séptica producida por una Klebsiella pneumoniae BLEE de la comunidad. Un tratamiento oportuno y eficaz puede evitar la opción quirúrgica, disminuyendo la morbimortalidad asociada con esta afección
Extended-spectrum beta-lactamases (ESBL) are enzymes produced by gram-negative rods capable of hydrolyzing broad-spectrum cephalosporins and monobactams. Most belong to the Enterobacteriae family, such as Klebsiella pneumoniae and Escherichia coli. However, they are also associated with other bacteria such as Proteus, Serratia, Salmonella, Pseudomonas aeruginosa and Acinetobacter. Carbapenemase-producing Enterobacteriaceae have not only been isolated from the hospital environment, but also from the community. We present a female patient with a history of AIDS and secondary osteomyelitis to septic arthritis caused by a community Klebsiella pneumoniae ESBL. It is concluded that a timely and effective treatment can avoids the surgical option, reducing the morbidity and mortality of this condition.
Asunto(s)
Humanos , Femenino , Adulto , Osteomielitis/inmunología , Infecciones por Klebsiella/terapia , Artritis Infecciosa/terapia , Imipenem/uso terapéutico , Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Artrocentesis , Traumatismos de la Rodilla/terapiaRESUMEN
A number of human autoinflammatory diseases manifest with severe inflammatory bone destruction. Mouse models of these diseases represent valuable tools that help us to understand molecular mechanisms triggering this bone autoinflammation. The Pstpip2cmo mouse strain is among the best characterized of these; it harbors a mutation resulting in the loss of adaptor protein PSTPIP2 and development of autoinflammatory osteomyelitis. In Pstpip2cmo mice, overproduction of interleukin-1ß (IL-1ß) and reactive oxygen species by neutrophil granulocytes leads to spontaneous inflammation of the bones and surrounding soft tissues. However, the upstream signaling events leading to this overproduction are poorly characterized. Here, we show that Pstpip2cmo mice deficient in major regulator of Src-family kinases (SFKs) receptor-type protein tyrosine phosphatase CD45 display delayed onset and lower severity of the disease, while the development of autoinflammation is not affected by deficiencies in Toll-like receptor signaling. Our data also show deregulation of pro-IL-1ß production by Pstpip2cmo neutrophils that are attenuated by CD45 deficiency. These data suggest a role for SFKs in autoinflammation. Together with previously published work on the involvement of protein tyrosine kinase spleen tyrosine kinase, they point to the role of receptors containing immunoreceptor tyrosine-based activation motifs, which after phosphorylation by SFKs recruit spleen tyrosine kinase for further signal propagation. We propose that this class of receptors triggers the events resulting in increased pro-IL-1ß synthesis and disease initiation and/or progression.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Interleucina-1beta/inmunología , Antígenos Comunes de Leucocito/inmunología , Neutrófilos/inmunología , Osteomielitis/inmunología , Transducción de Señal/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Interleucina-1beta/genética , Antígenos Comunes de Leucocito/genética , Ratones , Ratones Noqueados , Neutrófilos/patología , Osteomielitis/genética , Osteomielitis/patología , Índice de Severidad de la Enfermedad , Transducción de Señal/genética , Receptores Toll-Like/genética , Receptores Toll-Like/inmunologíaRESUMEN
Preventing deep bacterial infection and simultaneously enhancing osteogenic differentiation are in great demand for osteomyelitis. Microwave (MW) dynamic therapy is attracting attention due to its excellent penetration ability, but the mechanism of MW-induced reactive oxygen species (ROS) is still unknown. Herein, MW-responsive engineered pseudo-macrophages (M-Fe3 O4 /Au nanoparticles (NPs)) are fabricated to clear Staphylococcus aureus infections and induce M2 polarization of macrophages to improve osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs) under MW irradiation. Fe3 O4 /Au NPs can generate ·O2 - and heat under MW irradiation in a saline solution, and the mechanism is put forward via finite element modeling and density functional theory calculations. Due to the gap plasmon, electromagnetic hotspots are produced at Fe3 O4 -Au interface at 2.45 GHz. Because of these induced electromagnetic hotspots, the sodium species is field-ionized and subsequently reacts with oxygen to produce ·O2 - . Meanwhile, the Fe3 O4 /Au NPs have a stronger ability than Fe3 O4 NPs to fix oxygen, favoring the production of ROS. Additionally, MW-treated macrophages diminish to secrete inflammatory cytokines, resulting in the decrease of ROS production in MSCs and thus enhancing their osteogenic differentiation. These engineered pseudo-macrophages will be promising for effectively treating bacterial infections and promoting osteoblast differentiation simultaneously in deep tissues under MW irradiation.
Asunto(s)
Nanopartículas de Magnetita/química , Microondas , Osteomielitis/terapia , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de la radiación , Citocinas/metabolismo , Teoría Funcional de la Densidad , Óxido Ferrosoférrico/química , Oro/química , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Nanopartículas de Magnetita/toxicidad , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Osteogénesis/efectos de los fármacos , Osteogénesis/efectos de la radiación , Osteomielitis/inmunología , Células RAW 264.7 , Conejos , Especies Reactivas de Oxígeno/metabolismo , Staphylococcus aureus/efectos de los fármacosRESUMEN
Staphylococcus aureus is the predominant pathogen causing osteomyelitis. Unfortunately, no immunotherapy exists to treat these very challenging and costly infections despite decades of research, and numerous vaccine failures in clinical trials. This lack of success can partially be attributed to an overreliance on murine models where the immune correlates of protection often diverge from that of humans. Moreover, S. aureus secretes numerous immunotoxins with unique tropism to human leukocytes, which compromises the targeting of immune cells in murine models. To study the response of human immune cells during chronic S. aureus bone infections, we engrafted non-obese diabetic (NOD)-scid IL2Rγnull (NSG) mice with human hematopoietic stem cells (huNSG) and analyzed protection in an established model of implant-associated osteomyelitis. The results showed that huNSG mice have increases in weight loss, osteolysis, bacterial dissemination to internal organs, and numbers of Staphylococcal abscess communities (SACs), during the establishment of implant-associated MRSA osteomyelitis compared to NSG controls (p < 0.05). Flow cytometry and immunohistochemistry demonstrated greater human T cell numbers in infected versus uninfected huNSG mice (p < 0.05), and that T-bet+ human T cells clustered around the SACs, suggesting S. aureus-mediated activation and proliferation of human T cells in the infected bone. Collectively, these proof-of-concept studies underscore the utility of huNSG mice for studying an aggressive form of S. aureus osteomyelitis, which is more akin to that seen in humans. We have also established an experimental system to investigate the contribution of specific human T cells in controlling S. aureus infection and dissemination.
Asunto(s)
Absceso/inmunología , Osteólisis/inmunología , Osteomielitis/inmunología , Infecciones Relacionadas con Prótesis/inmunología , Infecciones Estafilocócicas/inmunología , Absceso/microbiología , Absceso/patología , Animales , Modelos Animales de Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Ratones , Osteólisis/microbiología , Osteólisis/patología , Osteomielitis/microbiología , Osteomielitis/patología , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Relacionadas con Prótesis/patología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patología , Staphylococcus aureus/inmunología , Quimera por Trasplante/inmunologíaRESUMEN
Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2. It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature. The early descriptions of Majeed syndrome reported severely affected children with recurrent fevers, severe multifocal osteomyelitis, failure to thrive, and marked elevations of blood inflammatory markers. As more affected families have been identified, it has become clear that there is significant phenotypic variability. Data supports that disruption of the phosphatidic acid phosphatase activity in LIPIN2 results in immune dysregulation due to aberrant activation of the NLRP3 inflammasome and overproduction of proinflammatory cytokines including IL-1ß, however, these findings did not explain the bone phenotype. Recent studies demonstrate that LPIN2 deficiency drives pro-inflammatory M2-macrophages and enhances osteoclastogenesis which suggest a critical role of lipin-2 in controlling homeostasis at the growth plate in an inflammasome-independent manner. While there are no approved medications for Majeed syndrome, pharmacologic blockade of the interleukin-1 pathway has been associated with rapid clinical improvement.
Asunto(s)
Anemia Diseritropoyética Congénita/genética , Anemia Diseritropoyética Congénita/inmunología , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Osteomielitis/genética , Osteomielitis/inmunología , Anemia Diseritropoyética Congénita/patología , Predisposición Genética a la Enfermedad , Homeostasis , Humanos , Síndromes de Inmunodeficiencia/patología , Inflamasomas/metabolismo , Modelos Biológicos , Mutación/genética , Osteomielitis/patologíaRESUMEN
We report a case of septic polyarthritis caused by Ureaplasma urealyticum in a woman with neuromyelitis optica who was receiving rituximab. Her case exemplifies some of the unique characteristics of invasive Ureaplasma infections that can lead to delayed diagnosis as well as treatment challenges including recurrence following antibiotic discontinuation.
Asunto(s)
Artritis Infecciosa/microbiología , Huésped Inmunocomprometido , Factores Inmunológicos/efectos adversos , Neuromielitis Óptica/tratamiento farmacológico , Osteomielitis/microbiología , Rituximab/efectos adversos , Ureaplasma urealyticum/aislamiento & purificación , Artritis Infecciosa/diagnóstico , Artritis Infecciosa/inmunología , Artritis Infecciosa/terapia , Artroscopía , Errores Diagnósticos , Doxiciclina/uso terapéutico , Femenino , Gonorrea/diagnóstico , Gonorrea/tratamiento farmacológico , Humanos , Articulación de la Rodilla/cirugía , Imagen por Resonancia Magnética , Técnicas de Amplificación de Ácido Nucleico , Osteomielitis/diagnóstico , Osteomielitis/inmunología , Osteomielitis/terapia , Articulación del Hombro/cirugía , Líquido Sinovial , Irrigación Terapéutica , Adulto JovenRESUMEN
BACKGROUND: Invasive fungal infection (IFI) is one of the most challenging complications in children undergoing acute lymphoblastic leukaemia (ALL) treatment, but acute fungal osteomyelitis (OM) is rarely encountered. CASE PRESENTATION: Here, we describe a case of Candida tropicalis osteomyelitis in a 10-year-old patient with Philadelphia chromosome (Ph)-positive ALL. He was on remission induction therapy at the time of neutropenia, and an abscess developed in his right arm. The blood and bone cultures were positive for C. tropicalis. Antibiotics and antifungals were administered. Magnetic resonance imaging of the arm revealed an intraosseous abscess, suggestive of OM. Surgical irrigation and debridement of the bone were performed immediately. The patient was effectively treated with antifungal therapy and ALL treatment. He has fully recovered into complete clinical remission but with visible sequelae on magnetic resonance imaging (MRI). He took oral posaconazole for consolidation until disappearance of the lesion shadows on MRI and received subsequent cycles of chemotherapy in parallel. CONCLUSIONS: In the successful management of Ph-positive ALL, dasatinib, a second-generation Abl-tyrosine kinase inhibitor, is crucial. The recommended treatment for Candida osteomyelitis in Ph-positive ALL patients is a fungicidal agent combined with surgery and modification chemotherapy with dasatinib. The use of combined modalities of treatment seems to be crucial in the successful management of Ph-positive ALL.
Asunto(s)
Candidiasis/inmunología , Candidiasis/microbiología , Dasatinib/uso terapéutico , Osteomielitis/inmunología , Osteomielitis/microbiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Antifúngicos/uso terapéutico , Antineoplásicos/uso terapéutico , Candida tropicalis , Candidiasis/terapia , Niño , Terapia Combinada , Desbridamiento , Humanos , Imagen por Resonancia Magnética , Masculino , Osteomielitis/terapia , Cromosoma Filadelfia , Inducción de Remisión , Irrigación TerapéuticaRESUMEN
The cell membrane-coated nanoparticles (MNPs) showed great potential in treating infectious disease due to their superior biofunctions in improving biocompatibility of nanoparticles and neutralization of pathogen or toxins. However, bone infection is accompanied with severe inflammation and bone loss, which also requires anti-inflammatory and osteoconductive treatment. The conventional membrane coating method has to undergo ultrasonication and extrusion procedures, which reduces the functionality of cell membrane and limits the choice of nanoparticles. In this study, we proposed an electroporation-based membrane coating strategy to facilitate the synthesis of MNPs to tackle those problems. Methods: Magnetic composite nanoparticles with osteoconductive Ca3(PO4)2 and bactericidal TiO2 were assembled into macrophages through phagocytosis and then collected to expose in electric field for obtaining macrophage membrane-coating nanoparticles. By using molecular dynamics simulation and materials characterizations, the cell membrane coating efficiency was confirmed. The in vitro anti-bacterial and anti-inflammatory abilities were tested by bacteria culturing and immune cells activation. Then drug-resistant bacteria induced bone infection model was established to verify its in vivo therapeutic effects. Results: The coated membrane prepared through electroporation reserved the integrality of membrane structure and right-sidedness, with more functional proteins. Those led to the superior properties of recognition and adsorption with bacteria, toxins and inflammatory cytokines. Owing to the benefits of electroporation, the MNPs exhibited significant better antibacterial and anti-inflammatory abilities for enhancing the tissue repair process. Conclusion: This study provides a novel self-assembly cell membrane coating strategy by electroporation to construct multifunctional membrane-coating nanoparticles for bone infection treatment. This strategy not only improves the functions of coated membrane, but is also proved to be universal for varies nanoparticles or cells, indicating a great potential for future applications in the bioengineering field.
Asunto(s)
Antiinflamatorios/farmacología , Membrana Celular/química , Materiales Biocompatibles Revestidos/farmacología , Electroporación/métodos , Nanopartículas/administración & dosificación , Osteomielitis/prevención & control , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Femenino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Ratones , Nanopartículas/química , Osteomielitis/inmunología , Osteomielitis/microbiología , Infecciones Estafilocócicas/complicaciones , Infecciones Estafilocócicas/microbiologíaRESUMEN
Family history is one key in diagnosing inborn errors of immunity (IEI); however, disease status is difficult to determine in deceased relatives. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is one of the hyper IgM syndromes that is caused by a hypomorphic variant in the nuclear factor kappa beta essential modulator. We identified a novel IKBKG variant in a 7-month-old boy with pneumococcal rib osteomyelitis and later found that his mother has incontinentia pigmenti. Genetic analysis of preserved umbilical cords revealed the same variant in two of his deceased maternal uncles. Analysis of preserved umbilical cord tissue from deceased relatives can provide important information for diagnosing IEI in their descendants.
Asunto(s)
Displasia Ectodérmica/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Quinasa I-kappa B/genética , Osteomielitis/diagnóstico , Infecciones Neumocócicas/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Cordón Umbilical/patología , Análisis Mutacional de ADN , Diagnóstico Tardío , Displasia Ectodérmica/complicaciones , Displasia Ectodérmica/genética , Displasia Ectodérmica/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Lactante , Masculino , Osteomielitis/genética , Osteomielitis/inmunología , Osteomielitis/microbiología , Linaje , Infecciones Neumocócicas/genética , Infecciones Neumocócicas/inmunología , Infecciones Neumocócicas/microbiología , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Streptococcus pneumoniae/inmunología , Streptococcus pneumoniae/aislamiento & purificaciónRESUMEN
OBJECTIVE: To estimate the incidence rate (IR) of psoriasis in children with inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), and chronic noninfectious osteomyelitis (CNO) with tumor necrosis factor inhibitor (TNFi) exposure as compared to children without TNFi exposure and to the general pediatric population. METHODS: This was a single-center retrospective cohort study of children with IBD, JIA, or CNO from 2008 to 2018. TNFi exposure was defined as a prescription for adalimumab, etanercept, infliximab, certolizumab, or golimumab, and the primary outcome was incident psoriasis. IRs and standardized incidence ratios (SIRs) were calculated. Cox proportional hazards models were used to assess the association of psoriasis with TNFi exposure and other risk factors. RESULTS: Of the 4,111 children who met inclusion criteria, 1,614 (39%) had TNFi exposure and 2,497 (61%) did not, with 4,705 and 6,604 person-years of follow-up, respectively. There were 58 cases (IR 12.3 per 1,000 person-years) and 25 cases (IR 3.8 per 1,000 person-years) of psoriasis in children with and without TNFi exposure, respectively. The SIR was 18 (95% confidence interval [95% CI] 15-22) overall, 30 (95% CI 23-39) for children with TNFi exposure, and 9.3 (95% CI 6.3-14) for children without TNFi exposure. The hazard ratio of psoriasis comparing TNFi exposure to no TNFi exposure was 3.84 (95% CI 2.28-6.47; P < 0.001). CONCLUSION: Children with IBD, JIA, and CNO had an increased rate of psoriasis compared to the general pediatric population, with the highest rate in those with TNFi exposure.
Asunto(s)
Artritis Juvenil/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Osteomielitis/tratamiento farmacológico , Psoriasis/inducido químicamente , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Adolescente , Factores de Edad , Artritis Juvenil/diagnóstico , Artritis Juvenil/inmunología , Niño , Enfermedad Crónica , Bases de Datos Factuales , Femenino , Humanos , Incidencia , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/inmunología , Masculino , Osteomielitis/diagnóstico , Osteomielitis/inmunología , Psoriasis/diagnóstico , Psoriasis/epidemiología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Anemia Diseritropoyética Congénita/genética , Síndromes de Inmunodeficiencia/genética , Inflamación/genética , Macrófagos/inmunología , Proteínas Nucleares/genética , Osteogénesis/genética , Osteomielitis/genética , Anemia Diseritropoyética Congénita/tratamiento farmacológico , Anemia Diseritropoyética Congénita/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Estudios de Casos y Controles , Preescolar , Síndromes Periódicos Asociados a Criopirina/genética , Síndromes Periódicos Asociados a Criopirina/inmunología , Femenino , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/inmunología , Heterocigoto , Humanos , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Síndromes de Inmunodeficiencia/inmunología , Inflamación/inmunología , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/inmunología , MAP Quinasa Quinasa 4/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Factores de Transcripción NFATC/metabolismo , Proteínas Nucleares/inmunología , Osteomielitis/tratamiento farmacológico , Osteomielitis/inmunología , Familia-src Quinasas/metabolismoRESUMEN
The major limitations of clinical outcome predictions of osteomyelitis mediated by Staphylococcus aureus (S. aureus) are not specific and definitive. To this end, current studies aim to investigate host immune responses of trend changes of the iron-regulated surface determinant (Isd) of IsdA, IsdB, IsdH, cell wall-modifying proteins of amidase (Amd) and glucosaminidase (Gmd), and secreted virulence factor of chemotaxis inhibitory protein S. aureus (CHIPS) and staphylococcal complement inhibitor (SCIN) longitudinally to discover their correlationship with clinical outcomes. A total of 55 patients with confirmed S. aureus infection of the long bone by clinical and laboratory methods were recruited for the study. Whole blood was collected at 0, 6, 12 months for the serum that was used to test IsdA, IsdB, IsdH, Gmd, Amd, CHIPS, and SCIN using a customized Luminex assay after clinical standard care parameters were collected. The patients were then divided into two groups: (1) infection controlled versus (2) adverse outcome based on clinical criteria for statistical analysis. We found that standard clinical parameters were unable to distinguish therapeutic outcomes. Significant overexpression of all antigens was confirmed in infection patients at 0-, 6-, and 12-month time points. A distinct expression trend and dynamic changes of IsdB, Amd, Gmd, and CHIPS were observed between infection controlled and adverse outcome patients, while the IsdA, IsdH, SCIN remained demonstrated no statistical significance. We conclude that dynamic changes of specific antigens could predict clinical outcomes of S. aureus osteomyelitis. Clinical Relevance: The trend changes of host immune responses to S. aureus specific antigens of IsdB, Gmd, Amd, and CHIPS could predict clinical outcomes of S. aureus osteomyelitis.
Asunto(s)
Antígenos/sangre , Osteomielitis/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Adulto , China/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Osteomielitis/sangre , Osteomielitis/epidemiología , Infecciones Estafilocócicas/sangre , Infecciones Estafilocócicas/epidemiologíaRESUMEN
BACKGROUND: Glucosaminidase (Gmd) is known to be a protective antigen in animal models of Staphylococcus aureus osteomyelitis. We compared the endogenous anti-Gmd antibody levels in sera of patients with culture-confirmed S. aureus bone infections to their sera at 1 year after operative treatment of the infection. METHODS: A novel global biospecimen registry of 297 patients with deep-wound culture-confirmed S. aureus osteomyelitis was analyzed to assess relationships between baseline anti-Gmd serum titers (via custom Luminex assay), known host risk factors for infection, and 1-year postoperative clinical outcomes (e.g., infection control, inconclusive, refracture, persistent infection, septic nonunion, amputation, and septic death). RESULTS: All patients had measurable humoral immunity against some S. aureus antigens, but only 20 patients (6.7%; p < 0.0001) had high levels of anti-Gmd antibodies (>10 ng/mL) in serum at baseline. A subset of 194 patients (65.3%) who completed 1 year of follow-up was divided into groups based on anti-Gmd level: low (<1 ng/mL, 54 patients; 27.8%), intermediate (<10 ng/mL, 122 patients; 62.9%), and high (>10 ng/mL, 18 patients; 9.3%), and infection control rates were 40.7%, 50.0%, and 66.7%, respectively. The incidence of adverse outcomes in these groups was 33.3%, 16.4%, and 11.1%, respectively. Assessing anti-Gmd level as a continuous variable showed a 60% reduction in adverse-event odds (p = 0.04) for every tenfold increase in concentration. No differences in patient demographics, body mass index of >40 kg/m, diabetes status, age of ≥70 years, male sex, Charlson Comorbidity Index of >1, or Cierny-Mader host type were observed between groups, and these risk factors were not associated with adverse events. Patients with low anti-Gmd titer demonstrated a significant 2.68-fold increased odds of adverse outcomes (p = 0.008). CONCLUSIONS: Deficiency in circulating anti-Gmd antibodies was associated serious adverse outcomes following operative treatment of S. aureus osteomyelitis. At 1 year, high levels of anti-Gmd antibodies were associated with a nearly 3-fold increase in infection-control odds. Additional prospective studies clarifying Gmd immunization for osteomyelitis are needed. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Asunto(s)
Hexosaminidasas/inmunología , Inmunidad Humoral/inmunología , Osteomielitis/cirugía , Complicaciones Posoperatorias/etiología , Infecciones Estafilocócicas/etiología , Anciano , Anticuerpos Antibacterianos/inmunología , Femenino , Humanos , Masculino , Osteomielitis/inmunología , Osteomielitis/microbiología , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/microbiología , Sistema de Registros , Factores de Riesgo , Infecciones Estafilocócicas/inmunologíaRESUMEN
Development of quantitative analysis software has enabled application of several standardised uptake values (SUV) for bone analysis in single photon emission computed tomography (SPECT). The present retrospective study aimed to develop a reliable method of monitoring bone inflammatory activity in antiresorptive agent-related osteonecrosis of the jaw (ARONJ) using SPECT quantitative analysis software. Fifteen ARONJ patients underwent SPECT before and after anti-inflammatory therapy. We calculated the mean maximum SUV (SUVmax) of the bilateral cranial bones using quantitative analysis software and used this as the control [C]. We attempted to adjust the SUVmax of the lesion [L] as follows: adjusted SUVmax (aSUVmax) = [L] - [C]. The optimum threshold to calculate the metabolic bone volume (MBV) (cm3) was [C] + 3. The threshold values obtained for each case were input to calculate MBV at each osteomyelitis site. Retrospectively, we compared aSUVmax and MBV of each patient's ARONJ before and after anti-inflammatory therapy. The patients' high aSUVmax or large MBV of the ARONJ reduced rapidly, reflecting individual clinical findings after treatment. Application of SPECT quantitative analysis software to monitor bone inflammatory activity in ARONJ could improve the prognosis-deciding abilities of clinicians and enable them to treat ARONJ effectively.