Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Querubismo/genética , Querubismo/patologia , Infecções/imunologia , Inflamação/genética , Macrófagos/imunologia , Animais , Querubismo/imunologia , Modelos Animais de Doenças , Heterozigoto , Infecções/genética , Infecções/patologia , Inflamação/patologia , Camundongos , Camundongos Knockout , Mutação de Sentido IncorretoRESUMO
Autoinflammatory bone disease is a new branch of autoinflammatory diseases caused by seemingly unprovoked activation of the innate immune system leading to an osseous inflammatory process. The inflammatory bone lesions in these disorders are characterized by chronic inflammation that is typically culture negative with no demonstrable organism on histopathology. The most common autoinflammatory bone diseases in childhood include chronic nonbacterial osteomyelitis (CNO), synovitis, acne, pustulosis, hyperostosis, osteitis syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist, and cherubism. In this article, the authors focus on CNO and summarize the distinct genetic autoinflammatory bone syndromes.
Assuntos
Doenças Ósseas/imunologia , Doenças Hereditárias Autoinflamatórias/imunologia , Acne Vulgar/diagnóstico , Acne Vulgar/imunologia , Acne Vulgar/terapia , Síndrome de Hiperostose Adquirida/diagnóstico , Síndrome de Hiperostose Adquirida/imunologia , Síndrome de Hiperostose Adquirida/terapia , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/imunologia , Anemia Diseritropoética Congênita/terapia , Doenças Ósseas/diagnóstico , Doenças Ósseas/terapia , Querubismo/diagnóstico , Querubismo/imunologia , Querubismo/terapia , Doença Crônica , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/terapia , Humanos , Hiperostose/diagnóstico , Hiperostose/imunologia , Hiperostose/terapia , Síndromes de Imunodeficiência , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Osteíte/diagnóstico , Osteíte/imunologia , Osteíte/terapia , Osteomielite/diagnóstico , Osteomielite/imunologia , Osteomielite/terapia , Síndrome , Sinovite/diagnóstico , Sinovite/imunologia , Sinovite/terapiaRESUMO
Autoinflammatory bone disorders are characterized by chronic non-infectious osteomyelitis and inflammation-induced bone resorption and result from aberrant activation of the innate immune system. Sporadic chronic non-bacterial osteomyelitis (CNO) is the most common disease subtype. The clinical picture is highly variable and the exact underlying pathophysiology remains to be determined. Recently, novel insights in the pathophysiology of sterile bone inflammation have been gathered by analyzing patients with rare, monogenic inflammatory diseases. In this overview CNO and Majeed syndrome, cherubism, hypophosphatasia and primary hypertrophic osteoarthropathy will be discussed. For the latter four disorders, a genetic cause affecting bone metabolism and leading to chronic bone inflammation has been described. The exact pathophysiology of CNO remains to be determined. Insights from monogenic autoinflammatory bone diseases and the identification of distinct inflammatory pathways may help to understand the pathogenesis of bone inflammation and inflammation-induced bone resorption in more common diseases.
Assuntos
Doenças Ósseas/genética , Doenças Ósseas/imunologia , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/imunologia , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/imunologia , Querubismo/genética , Querubismo/imunologia , Doença Crônica , Predisposição Genética para Doença , Humanos , Hipofosfatasia/genética , Hipofosfatasia/imunologia , Síndromes de Imunodeficiência , Inflamação/genética , Inflamação/imunologia , Camundongos , Osteoartropatia Hipertrófica Primária/genética , Osteoartropatia Hipertrófica Primária/imunologia , Osteomielite/genética , Osteomielite/imunologia , Doenças Raras/genéticaRESUMO
Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Querubismo/genética , Querubismo/fisiopatologia , Inflamação/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Reabsorção Óssea/genética , Reabsorção Óssea/imunologia , Reabsorção Óssea/fisiopatologia , Calcineurina/metabolismo , Querubismo/imunologia , Modelos Animais de Doenças , Mutação em Linhagem Germinativa , Humanos , Inflamação/genética , Inflamação/fisiopatologia , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/imunologia , Osteoclastos/metabolismo , Fosforilação , Ativação TranscricionalRESUMO
PURPOSE OF REVIEW: This review provides an update on clinical, genetic, and immunologic aspects of the autoinflammatory bone disorders. RECENT FINDINGS: Chronic noninfectious inflammation of the bone is a clinical feature of both chronic recurrent multifocal osteomyelitis and (to a lesser degree) cherubism. The genes responsible for Majeed syndrome (LPIN2), murine chronic multifocal osteomyelitis (pstpip2), and cherubism (SH3BP2 and possibly PTPN11) have been identified. Murine models of both chronic recurrent multifocal osteomyelitis and cherubism have demonstrated that the bone inflammation is mediated by hematopoietically derived cells and can occur in the absence of a functioning adaptive immune system. As the immunologic defects become better defined, the cells of the myeloid lineage are emerging as the primary players. SUMMARY: Chronic multifocal osteomyelitis and cherubism are hereditary chronic inflammatory disorders in which bone is the primary inflammatory target. Recent genetic and immunologic discoveries demonstrate involvement of the innate immune system, which places these entities in the category of autoinflammatory disorders.
