RESUMEN
We report herein a case of a 72-year-old man with pityriasis rubra pilaris (PRP) that was refractory to conventional therapies. His skin lesions progressed to generalized erythroderma despite anti-interleukin (IL)-17A antibody therapy. Topical corticosteroids, emollients, systemic retinoid, methotrexate, cyclosporin and phototherapy yielded no therapeutic response. However, blockade of IL-12/23 p40 dramatically improved his cutaneous lesions. Complete remission was achieved 4 weeks after the first injection of ustekinumab and maintained for more than 48 weeks. Our data indicate that IL-12 was associated with the onset of PRP in this patient, rather than IL-23. IL-12 is critical for the differentiation of T-helper (Th)1 cells. Thus, the Th1 pathway may be associated with the onset of PRP.
Asunto(s)
Dermatitis Exfoliativa/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Subunidad p40 de la Interleucina-12/antagonistas & inhibidores , Interleucina-17/antagonistas & inhibidores , Pitiriasis Rubra Pilaris/tratamiento farmacológico , Anciano , Dermatitis Exfoliativa/inmunología , Dermatitis Exfoliativa/patología , Fármacos Dermatológicos/farmacología , Progresión de la Enfermedad , Humanos , Masculino , Pitiriasis Rubra Pilaris/inmunología , Pitiriasis Rubra Pilaris/patología , Piel/inmunología , Piel/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Blau syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in nucleotide-binding oligomerization domain 2 (NOD2). The underlying mechanisms of Blau syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau syndrome. OBJECTIVES: To elucidate the mechanisms of autoinflammation in patients with Blau syndrome, we sought to clarify the relation between disease-associated mutant NOD2 and the inflammatory response in human samples. METHODS: Blau syndrome-specific induced pluripotent stem cell (iPSC) lines were established. The disease-associated NOD2 mutation of iPSCs was corrected by using a CRISPR-Cas9 system to precisely evaluate the in vitro phenotype of iPSC-derived cells. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the statuses of nuclear factor κB pathway and proinflammatory cytokine secretion were investigated. RESULTS: IFN-γ acted as a priming signal through upregulation of NOD2. In iPSC-derived macrophages with mutant NOD2, IFN-γ treatment induced ligand-independent nuclear factor κB activation and proinflammatory cytokine production. RNA sequencing analysis revealed distinct transcriptional profiles of mutant macrophages both before and after IFN-γ treatment. Patient-derived macrophages demonstrated a similar IFN-γ-dependent inflammatory response. CONCLUSIONS: Our data support the significance of ligand-independent autoinflammation in the pathophysiology of Blau syndrome. Our comprehensive isogenic disease-specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of patients with Blau syndrome.
Asunto(s)
Artritis/etiología , Artritis/metabolismo , Interferón gamma/metabolismo , Macrófagos/metabolismo , Células Madre Pluripotentes/metabolismo , Sinovitis/etiología , Sinovitis/metabolismo , Uveítis/etiología , Uveítis/metabolismo , Linaje de la Célula/genética , Citocinas/metabolismo , Análisis Mutacional de ADN , Exones , Marcación de Gen , Sitios Genéticos , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Mediadores de Inflamación/metabolismo , Interferón gamma/genética , Ligandos , Macrófagos/inmunología , Masculino , Mutación , FN-kappa B/metabolismo , Proteína Adaptadora de Señalización NOD2/genética , Fenotipo , Células Madre Pluripotentes/citología , SarcoidosisAsunto(s)
Hipertermia Inducida , Infecciones por Mycobacterium no Tuberculosas/terapia , Mycobacterium chelonae/crecimiento & desarrollo , Enfermedades Cutáneas Bacterianas/terapia , Anciano , Antibacterianos/uso terapéutico , Antiinflamatorios/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Humanos , Masculino , Minociclina/uso terapéutico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/patología , Mycobacterium chelonae/efectos de los fármacos , Mycobacterium chelonae/aislamiento & purificación , Infiltración Neutrófila , Ofloxacino/uso terapéutico , Prednisolona/uso terapéutico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/patología , Resultado del TratamientoRESUMEN
Pattern-recognition receptors are a first line of defense against invading pathogens. Recent advances in the understanding of innate immunity have revealed a novel family of cytosolic pattern-recognition receptors called Nods, which contain an amino-terminal effector-binding domain, a centrally located nucleotide-binding oligomerization domain (NOD) and a carboxy-terminal ligand recognition domain. Hereditary mutations of Nods have been reported in patients with certain inflammatory diseases; for example, Nod2 mutations are associated with the inflammatory granulomatous disorders, Crohn's disease and Blau syndrome. Missense mutations of Nod2 are also associated with early-onset sarcoidosis, a rare but sporadic disease. Because Nod2 is predominantly expressed in monocytes and recognizes a component of bacterial peptidoglycan, analysis of its function may help in understanding the role of the immune system in granuloma formation.