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OBJECTIVES: The clinical symptoms and complications of JDM differ depending on the type of muscle-specific autoantibodies (MSAs) present. We aimed to identify protein expression profiles specific for MSAs that characterize various clinical features by comprehensively analyzing the proteins present in the serum of patients with JDM. METHODS: We analysed sera from patients with JDM that were positive for anti-melanoma differentiation-associated protein 5 (MDA5) antibodies (n = 5), anti-nuclear matrix protein 2 (NXP2) antibodies (n = 5) and anti-transcriptional intermediary factor 1 alpha or gamma subunit (TIF1-γ) antibodies (n = 5), and evaluated healthy controls (n = 5) via single-shot liquid chromatography-tandem mass spectrometry (MS) in data-independent acquisition mode, which is superior for comparative quantitative analysis. We identified different protein groups based on MSAs and performed pathway analysis to understand their characteristics. RESULTS: We detected 2413 proteins from serum MS analysis; 508 proteins were commonly altered in MSAs, including many myogenic enzymes and IFN-regulated proteins. Pathway analysis using the top 50 proteins that were upregulated in each MSA group revealed that the type I IFN and proteasome pathways were significantly upregulated in the anti-MDA5 antibody group alone. CONCLUSION: Although JDM serum contains many proteins commonly altered in MSAs, the pathways associated with clinical features of MSAs differ based on protein accumulation. In-depth serum protein profiles associated with MSAs may be useful for developing therapeutic target molecules and biomarkers.
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Dermatomiositis , Miositis , Humanos , Autoanticuerpos , Proteómica , Biomarcadores , Músculos/metabolismoRESUMEN
Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, and GATA2. We identified a heterozygous missense variation in OAS1, encoding 2,'5'-oligoadenylate synthetase 1 (OAS1) in three affected siblings, but not in unaffected family members. Deep sequence analysis with next-generation sequencing indicated 3.81% mosaicism of this variant in DNA from their mother's peripheral blood leukocytes, suggesting that PAP observed in this family could be inherited as an autosomal-dominant trait from the mother. We identified two additional de novo heterozygous missense variations of OAS1 in two unrelated simplex individuals also manifesting infantile-onset PAP with hypogammaglobulinemia. PAP in the two simplex individuals resolved after hematopoietic stem cell transplantation, indicating that OAS1 dysfunction is associated with impaired surfactant catabolism due to the defects in AMs.
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2',5'-Oligoadenilato Sintetasa/genética , Agammaglobulinemia/complicaciones , Agammaglobulinemia/genética , Proteinosis Alveolar Pulmonar/complicaciones , Proteinosis Alveolar Pulmonar/genética , 2',5'-Oligoadenilato Sintetasa/química , Secuencia de Aminoácidos , Secuencia de Bases , Demografía , Evolución Molecular , Familia , Femenino , Heterocigoto , Humanos , Lactante , Masculino , Modelos Moleculares , MutaciónRESUMEN
OBJECTIVES: This study aimed to investigate the clinical characteristics, treatment and prognosis of juvenile idiopathic inflammatory myopathies (JIIM) in Japan for each myositis-specific autoantibody (MSA) profile. METHODS: A multicentre, retrospective study was conducted using data of patients with JIIM at nine paediatric rheumatology centres in Japan. Patients with MSA profiles, determined by immunoprecipitation using stored serum from the active stage, were included. RESULTS: MSA were detected in 85 of 96 cases eligible for the analyses. Over 90% of the patients in this study had one of the following three MSA types: anti-melanoma differentiation-associated protein 5 (MDA5) (n = 31), anti-transcriptional intermediary factor 1 alpha and/or gamma subunits (TIF1γ) (n = 25) and anti-nuclear matrix protein 2 (NXP2) (n = 25) antibodies. Gottron papules and periungual capillary abnormalities were the most common signs of every MSA group in the initial phase. The presence of interstitial lung disease (ILD) was the highest risk factor for patients with anti-MDA5 antibodies. Most patients were administered multiple drug therapies: glucocorticoids and MTX were administered to patients with anti-TIF1γ or anti-NXP2 antibodies. Half of the patients with anti-MDA5 antibodies received more than three medications including i.v. CYC, especially patients with ILD. Patients with anti-MDA5 antibodies were more likely to achieve drug-free remission (29 vs 21%) and less likely to relapse (26 vs 44%) than others. CONCLUSION: Anti-MDA5 antibodies are the most common MSA type in Japan, and patients with this antibody are characterized by ILD at onset, multiple medications including i.v. CYC, drug-free remission, and a lower frequency of relapse. New therapeutic strategies are required for other MSA types.
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Autoanticuerpos/inmunología , Miositis/inmunología , Adenosina Trifosfatasas/inmunología , Adolescente , Proteínas Reguladoras de la Apoptosis/inmunología , Niño , Preescolar , Proteínas de Unión al ADN/inmunología , Femenino , Humanos , Inmunoprecipitación , Lactante , Recién Nacido , Helicasa Inducida por Interferón IFIH1/inmunología , Japón , Masculino , Miositis/diagnóstico , Proteínas Nucleares/inmunología , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVES: To assess the performance of the EULAR/ACR idiopathic inflammatory myopathies (IIMs) classification criteria to classify juvenile IIMs (JIIMs) in an Asian paediatric population. METHODS: Sixty-eight JIIM patients and 49 non-JIIM patients diagnosed at seven major paediatric rheumatology centres in Japan between 2008 and 2015 were enrolled. Retrospective data were collected, and each patient's data form was submitted. The expert group reviewed the forms and re-examined the diagnoses. The EULAR/ACR criteria were then applied and the probability of having JIIM was determined for each case. The sensitivity and specificity of the EULAR/ACR criteria were compared with those of other existing criteria. RESULTS: The sensitivity/specificity of the EULAR/ACR classification criteria were 92.1/100% with muscle biopsy data (n = 38); 86.7/100% without muscle biopsy data (n = 30) and 89.7/100% in our total cohort (n = 68). The sensitivity of Bohan and Peter's criteria and Tanimoto's criteria were 80.9 and 64.7% in our total cohort, respectively. Among 68 physician-diagnosed JIIM patients, seven cases (three JDM and four overlap myositis) were not classified as JIIM because the probability did not reach the cut-off point (55%). The three JDM patients all presented with only one of the three skin manifestations that are listed in the criteria: Gottron's sign. CONCLUSION: Our validation study with Japanese JIIM cases indicates that the EULAR/ACR classification criteria for IIM generally perform better than existing diagnostic criteria for myositis.
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Clasificación/métodos , Servicios de Diagnóstico/normas , Músculo Esquelético/patología , Miositis , Edad de Inicio , Biopsia/métodos , Niño , Servicios de Diagnóstico/estadística & datos numéricos , Femenino , Humanos , Japón/epidemiología , Masculino , Miositis/clasificación , Miositis/diagnóstico , Miositis/epidemiología , Selección de Paciente , Sensibilidad y EspecificidadRESUMEN
Juvenile dermatomyositis is the most common type of juvenile idiopathic inflammatory myopathy mainly affecting the skin and proximal muscles. We have published the Japanese version of 'Clinical practice guidance for juvenile dermatomyositis (JDM) 2018 'consisting of a review of articles in the field and evidence-informed consensus-based experts' opinion on the treatment strategy in collaboration with The Pediatric Rheumatology Association of Japan and The Japan College of Rheumatology under the financial support by 'Research on rare and intractable diseases, Health and Labor Sciences Research Grants'. This article is a digest version of the Japanese guidance.
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Dermatomiositis/diagnóstico , Guías de Práctica Clínica como Asunto , Adolescente , Niño , Consenso , Dermatomiositis/tratamiento farmacológico , Humanos , Japón , Reumatología/organización & administración , Sociedades Médicas/normasRESUMEN
PURPOSE: We report normal neutrophil count in a mother, who carries the same ELANE mutation as her daughter with severe congenital neutropenia. We hypothesized that the mother possessed wild- and mutant-type clones and the wild-type clones could generate neutrophils, whereas the mutant clones could not. METHODS: We confirmed mutant variant ratio by sequence signals and measured the frequency of the mutant allele by subcloning in various cell types. We established the ELANE-mutated and non-mutated induced pluripotent stem cells (iPSCs) from the mother's T cells and compared granulopoiesis between these iPSCs. RESULTS: In the sequence analysis of isolated peripheral blood (PB), nail and hair, the mutant variant was detected in approximately 40-60% of lymphocytes, monocytes, hematopoietic progenitor cells, and hair as well as in a small percentage of nail, but in none of the neutrophils. In the subcloning analysis of extracted DNA from CD3+ and CD34+ cells, the mutant allele was identified in 37.5% and 38.1%, respectively. We reprogrammed the mother's PB cells and established the ELANE-mutated and non-mutated iPSCs. Granulopoiesis from mutated iPSCs revealed little sensitivity to granulocyte colony-stimulating factor in comparison with non-mutated iPSCs. CONCLUSIONS: These observations strongly suggest that mutant-carrying neutrophils did not appear in the mother's PB because mutated clones could not differentiate into neutrophils. The mother's normal hematological phenotype could be explained by the perseverance of normal, non-mutated granulopoiesis.
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Elastasa de Leucocito/genética , Mutación/genética , Alelos , Línea Celular , Preescolar , Femenino , Factor Estimulante de Colonias de Granulocitos/genética , Humanos , Células Madre Pluripotentes Inducidas/inmunología , Recuento de Leucocitos/métodos , Elastasa de Leucocito/inmunología , Monocitos/inmunología , Mosaicismo , Madres , Mutación/inmunología , Neutrófilos/inmunología , Linfocitos T/inmunologíaRESUMEN
OBJECTIVE: Primary systemic vasculitis (PSV) is a rare disorder in children and difficult to distinguish from other diseases. However, appropriate diagnosis and prompt treatment will affect on the morbidity and mortality of intractable PSV. In this study, we conducted a nationwide survey in Japan, to clarify epidemiology and clinical outcome of PSV. METHODS: We had sent survey questionnaires to most of the Japanese institutions that employed pediatricians, requesting the number of patients with refractory PSV who were diagnosed and treated between 2007 and 2011. Respondents were asked to provide detailed information on the clinical and laboratory features of each case they had managed. Those with Kawasaki disease or Henoch-Shönlein purpura vasculitis (IgA vasculitis) were excluded. RESULTS: Of all the institutions surveyed, 1123 (37.3%) patients responded, finally, total of 49 patients with intractable PSV, defined by those with resistant to treatment and steroid-dependent, or with any complication associated with prognosis, were selected. The diagnosis was Takayasu arteritis in 31, polyarteritis nodosa in 11, granulomatosis with polyangitis in 2, microscopic polyangitis in 1, and ANCA negative microscopic polyangitis in 1. In those with Takayasu arteritis, 67% were treated with an immunosuppressive agent, 22% with biological modifiers, and 16% with surgical procedures. In other types of disease, 88% of the patients were treated with an immunosuppressive agent, and 12% with biological modifiers. Two with Takayasu arteritis died being terminally ill. CONCLUSION: This nationwide survey establishes the heterogeneous characteristics of PSV in children. Although questionnaire-based, the results of our analysis should be useful in planning prospective studies to identify the most effective therapy for each subtype of multifaceted disease.
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Vasculitis Sistémica/epidemiología , Niño , Femenino , Humanos , Japón , Masculino , Encuestas y Cuestionarios , Vasculitis Sistémica/tratamiento farmacológico , Vasculitis Sistémica/patologíaRESUMEN
IRF4/MUM1-positive lymphoma is a new subgroup of germinal center-derived B-cell lymphoma, predominantly involving the Waldeyer ring (WR) in children. CD5 expression is rare in these lymphomas. We report a 7-year-old Chinese male with B-cell lymphoma. Evaluation of his specimen by morphology, immunohistochemistry, and FISH analysis demonstrated IRF4/MUM1-positive lymphoma with strong and extensive CD5 and CD10 positivity. Despite the lack of t(14;18)(q32;q21) rearrangement, BCL2 protein was expressed. Our report highlights the clinicopathologic features of IFR4/MUM1-positive lymphoma in WR with co-expression of CD5 and CD10, and thereby provides insight into this newly recognized disease entity.
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Antígenos CD5/metabolismo , Factores Reguladores del Interferón/metabolismo , Linfoma/patología , Neprilisina/metabolismo , Neoplasias Tonsilares/patología , Antígenos CD5/genética , Niño , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Factores Reguladores del Interferón/genética , Linfoma/clasificación , Linfoma/metabolismo , Masculino , Neprilisina/genética , Pronóstico , Neoplasias Tonsilares/metabolismoRESUMEN
Severe combined immunodeficiency (SCID) is a defect in the differentiation and function of T cells. An increased malignancy risk, mainly lymphatic malignancy, has been described in patients with SCID. We report a patient with X-linked SCID who developed acute myeloid leukemia, derived from the recipient with somatic NRAS mutation 4 months after cord blood transplantation (CBT). Loss of heterozygosity phenomenon of the recipient at 6q14 locus was observed at 2 months post-CBT and progressed to 6q deletion (6q-) chromosome abnormality. Somatic NRAS mutation was detected at 3 months post-CBT. Thus, 6q- and NRAS mutation were strongly associated with the leukemic transformation in our patient.
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Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/complicaciones , Deleción Cromosómica , Cromosomas Humanos Par 6 , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Hibridación Fluorescente in Situ , Lactante , Subunidad gamma Común de Receptores de Interleucina/genética , Pérdida de Heterocigocidad , Masculino , Mutación , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/diagnóstico , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/terapiaAsunto(s)
Anticuerpos Monoclonales Humanizados , Antirreumáticos , Artritis Juvenil , Enfermedades Pulmonares Intersticiales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Juvenil/complicaciones , Artritis Juvenil/tratamiento farmacológico , Preescolar , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Resultado del TratamientoRESUMEN
BACKGROUND: Heterozygous mutations of SFTPC, the gene-encoding surfactant protein C (SP-C), result in interstitial lung disease (ILD). However, characterization of mutations located in the mature domain of precursor SP-C (proSP-C) is limited. This study examined the molecular pathogenesis of such a mutation of ILD. METHODS: We employed sequencing of SFTPC and established A549 cells stably expressing several proSP-C mutants. Histopathology and transmission electron microscopy (TEM) of lung tissue from a pediatric patient with ILD were assessed. Effects of mutant proSP-C were evaluated by western blotting, immunofluorescence, and TEM. RESULTS: Sequencing of SFTPC revealed a novel heterozygous mutation, c.163C>T (L55F). In lung tissue, abnormal localization of proSP-C was observed by immunohistochemistry, and small and dense lamellar bodies (LBs) in type II alveolar epithelial cells (AECs) were detected by TEM. TEM of A549 cells stably expressing proSP-C(L55F) displayed abnormal cytoplasmic organelles. ProSP-C(L55F) exhibited a band pattern similar to that of proSP-C(WT) for processed intermediates. Immunofluorescence studies demonstrated that proSP-C(L55F) partially colocalized in CD63-positive cytoplasmic vesicles of A549 cells, which was in contrast to proSP-C(WT). CONCLUSION: We detected a novel c.163C>T mutation located in the mature domain of SFTPC associated with ILD that altered the subcellular localization of proSP-C in A549 cells.
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Células Epiteliales Alveolares/ultraestructura , Enfermedades Pulmonares Intersticiales/genética , Mutación Missense , Mutación Puntual , Proteinosis Alveolar Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/deficiencia , Células Epiteliales Alveolares/química , Sustitución de Aminoácidos , Línea Celular , Gránulos Citoplasmáticos/química , Exones/genética , Femenino , Heterocigoto , Humanos , Lactante , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/patología , Enfermedades Pulmonares Intersticiales/cirugía , Trasplante de Pulmón , Lisosomas/química , Microscopía Electrónica , Precursores de Proteínas/análisis , Procesamiento Proteico-Postraduccional , Estructura Terciaria de Proteína , Proteinosis Alveolar Pulmonar/diagnóstico por imagen , Proteinosis Alveolar Pulmonar/patología , Proteinosis Alveolar Pulmonar/cirugía , Alveolos Pulmonares/patología , Proteína C Asociada a Surfactante Pulmonar/análisis , Proteína C Asociada a Surfactante Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/metabolismo , Radiografía , Proteínas Recombinantes/análisis , Análisis de Secuencia de ADN , Fracciones Subcelulares/química , TransfecciónRESUMEN
OBJECTIVE: Kawasaki disease (KD) is the most commonly encountered inflammatory disease in children. However, its pathogenesis and diagnostic biomarkers have not been fully investigated. We examined the activation of neutrophils and monocytes in KD. METHODS: We studied the expression of the Fcγ-receptors CD64 and CD16 on neutrophils and monocytes in KD before and after the treatment with intravenous infusion of high dose immunoglobulin (IVIG). Bacterial infections were addressed as well. RESULTS: CD64 expression on neutrophils and monocytes was dramatically increased at the onset of KD flare-ups, but later decreased just after IVIG. Similarly, CD16-positive monocytes were observed at the onset and were less apparent after therapy. The addition of immunoglobulin did not block the expression of CD64 or CD16 in vitro. Serum G-CSF in the majority of patients, and IFN-γ in some patients, were elevated during flares but decreased after treatment. CONCLUSION: Our findings demonstrate that remarkable CD64 expression during KD flare-ups may serve as a biomarker for diagnosis. Evaluation of CD64 is also potentially useful for the determination of treatment efficacy in KD.
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Monocitos/metabolismo , Síndrome Mucocutáneo Linfonodular/metabolismo , Neutrófilos/metabolismo , Receptores de IgG/metabolismo , Biomarcadores/metabolismo , Preescolar , Citocinas/sangre , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Monocitos/efectos de los fármacos , Síndrome Mucocutáneo Linfonodular/sangre , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Neutrófilos/efectos de los fármacosRESUMEN
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects of nicotinamide adenine dinucleotide phosphate oxidase. Catalase-positive bacteria and fungi are phagocytosed, but persist within phagocytes, resulting in granulomatous inflammation. Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CGD, HSCT sometimes leads to fatal outcomes related to the exacerbation of persistent infectious or post-infectious inflammatory diseases, particularly in adolescent and young adult patients with a history of recurrent infections and/or multiple granulomas in organs. Here, we present the case of a young adult with X-linked CGD in whom multiple lesions were found in lungs and lymph nodes on both computed tomography and positron emission tomography (PET) scans before allogeneic HSCT, but all the lesions disappeared only on PET scan 5 months after HSCT. Monitoring the activity of multiple pre-existing lesions with PET scan may be beneficial to adolescent and young adult CGD-patients undergoing allogeneic HSCT.
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Enfermedad Granulomatosa Crónica/diagnóstico por imagen , Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas , Aloinjertos , Fluorodesoxiglucosa F18 , Humanos , Masculino , Tomografía de Emisión de Positrones , Radiofármacos , Adulto JovenRESUMEN
UNLABELLED: : Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. OBJECTIVE: To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. METHODS: NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. RESULTS: A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. CONCLUSIONS: We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.
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Proteínas Portadoras/genética , Síndromes Periódicos Asociados a Criopirina/genética , Mosaicismo , Adolescente , Pueblo Asiatico/genética , Preescolar , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Proteína con Dominio Pirina 3 de la Familia NLR , Análisis de Secuencia de ADN , Población Blanca/genéticaRESUMEN
OBJECTIVE: Rapidly progressive interstitial lung disease (RP-ILD) is a rare but potentially fatal complication of JDM. The aim of this study was to establish markers for the prediction and early diagnosis of RP-ILD associated with JDM. METHODS: The clinical records of 54 patients with JDM were retrospectively reviewed: 10 had RP-ILD (7 died, 3 survived), 19 had chronic ILD and 24 were without ILD. Routine tests included a high-resolution CT (HRCT) scan of the chest and measurement of serum levels of creatine phosphokinase, ferritin and Krebs von den Lungen-6 (KL-6). Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies and IL-18 levels were measured by ELISA. RESULTS: No differences were found in the ratio of juvenile clinically amyopathic DM between the three groups. Initial chest HRCT scan findings were variable and could not distinguish between RP-ILD and chronic ILD. Anti-MDA5 antibodies were positive in all 8 patients with RP-ILD and 10 of 14 with chronic ILD, but none of the patients without ILD. Serum levels of anti-MDA5 antibody, ferritin, KL-6 and IL-18 were significantly higher in the RP-ILD group than in the chronic ILD and non-ILD groups. Serum levels of IL-18 positively correlated with serum KL-6 (R = 0.66, P < 0.001). CONCLUSION: High serum levels of IL-18, KL-6, ferritin and anti-MDA5 antibodies (e.g. >200 units by ELISA) are associated with RP-ILD. These can be used as an indication for early intensive treatment. Both alveolar macrophages and autoimmunity to MDA5 are possibly involved in the development of RP-ILD associated with JDM.
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Dermatomiositis/sangre , Dermatomiositis/complicaciones , Progresión de la Enfermedad , Enfermedades Pulmonares Intersticiales/sangre , Enfermedades Pulmonares Intersticiales/diagnóstico , Adolescente , Anticuerpos Antiidiotipos/sangre , Biomarcadores/sangre , Niño , Preescolar , ARN Helicasas DEAD-box/inmunología , Dermatomiositis/etnología , Femenino , Ferritinas/sangre , Humanos , Lactante , Helicasa Inducida por Interferón IFIH1 , Interleucina-18/sangre , Japón , Enfermedades Pulmonares Intersticiales/mortalidad , Masculino , Mucina-1/sangre , Valor Predictivo de las Pruebas , Pronóstico , Estudios RetrospectivosRESUMEN
PURPOSE: Neutrophil-specific granule deficiency (SGD) is a rare, congenital disorder characterized by atypical neutrophil structure and function that results in frequent and severe bacterial infections. However, the clinical course of patients with SGD have not been described in detail because of the scarcity of the disease. We present the clinical course of an adult patient with SGD and propose a method for making an early diagnosis of SGD. PATIENT AND METHODS: A32-year-old Japanese woman with SGD had a small impetigo lesion on her face and experienced the rapid spread of a facial abscess to a pulmonary abscess via the blood stream. We also analyzed the expression of neutrophil granule proteins in our patient compared with a healthy control by flow cytometry. RESULTS: We confirmed defects of several neutrophil granule proteins in our patient by flow cytometry. CONCLUSION: Severe bacterial infections sometimes occur and spread rapidly in SGD. Detection of neutrophil granules by flow cytometry is useful for a rapid diagnosis and a screening of SGD.
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Síndromes de Inmunodeficiencia/diagnóstico , Impétigo/diagnóstico , Absceso Pulmonar/diagnóstico , Neutrófilos/metabolismo , Vesículas Secretoras/metabolismo , Proteínas de Fase Aguda/metabolismo , Adulto , Profilaxis Antibiótica , Péptidos Catiónicos Antimicrobianos/metabolismo , Proteínas Sanguíneas/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Desbridamiento , Defensinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/terapia , Impétigo/genética , Impétigo/terapia , Japón , Lactoferrina/metabolismo , Lipocalina 2 , Lipocalinas/metabolismo , Absceso Pulmonar/genética , Absceso Pulmonar/terapia , Mutación/genética , Neutrófilos/patología , Peroxidasa/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , CatelicidinasRESUMEN
BACKGROUND: Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency that affects phagocytic cells. CGD patients are susceptible to fungal infections, especially Aspergillus infections. The management of life-threatening Aspergillus infections in CGD is particularly difficult because some infections cannot be eradicated with standard antifungal treatments and, hence, result in death. CASE REPORT: A 2-week-old girl developed invasive pulmonary aspergillosis, which rapidly progressed to respiratory failure. Liposomal amphotericin B, micafungin, and voriconazole were not effective. At the age of 2 months, she was diagnosed with p67phox-deficient CGD. In addition to antifungal treatment, the patient received 21 granulocyte transfusions (GTX), which were obtained from 300- or 400-mL whole blood samples from healthy random donors who were not treated with granulocyte-colony-stimulating factor or dexamethasone. The median neutrophil count of the GTX was 1.88 × 10(8) /kg body weight. Rituximab was administered to reduce alloimmunization to human leukocyte antigens (HLA) after the eighth GTX, resulting in their absence of anti-HLA before and after cord blood transplantation (CBT). A marked improvement in her invasive pulmonary aspergillosis was achieved, although the first CBT was rejected. Complete hematopoietic recovery was obtained after the second CBT. CONCLUSION: Repeated GTX containing relatively low doses of neutrophils might be able to control severe Aspergillus infections in infants with CGD.
Asunto(s)
Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/terapia , Enfermedad Granulomatosa Crónica/tratamiento farmacológico , Enfermedad Granulomatosa Crónica/terapia , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Enfermedades Pulmonares Fúngicas/terapia , Neutrófilos/citología , Terapia Combinada , Trasplante de Células Madre de Sangre del Cordón Umbilical , Femenino , Humanos , Recién NacidoRESUMEN
BACKGROUND: Severe combined immunodeficiency (SCID) is a heterogenous disorder with profound deficiency of T/B-cell functions. The best SCID therapy requires hematopoietic stem cell transplantation (HSCT) early in life. HSCT with conditioning is necessary to achieve a long-term reconstitution of B-cell functions. However, conditioning may aggravate pre-existing infection and cause transplant-related toxicity, especially in very young infants. Hence, the intensity of conditioning should be reduced to allow the reconstitution of immunity including B cells to the extent that prevents transplant-related toxicity and delayed complications. METHODS: An infant with a family history of X-linked SCID (X-SCID) was diagnosed with X-SCID disorder soon after birth. The infant exhibited cytomegalovirus (CMV) infection despite being strictly isolated. At 1.5â¯months of age, we performed an unrelated cord blood transplantation (CBT) with a less intensity conditioning regimen: fludarabine (125â¯mg/m2)â¯+â¯melphalan (80â¯mg/m2). We evaluated the efficacy of reconstitution by assessing B-cell function and growth and psychomotor development at 5â¯years and 7â¯months after CBT. RESULTS: The clinical course after CBT was uneventful after CBT. The CMV infection was fully controlled by ganciclovir or foscavir therapy, which was discontinued at day 55 after CBT. Furthermore, immunoglobulin (Ig) replacement therapy was also discontinued at 6â¯months after CBT. A sufficient proportion of CD27+ memory B cells was developed, which was essential for an effective vaccination and prevention of infections. While the B-cell chimerism became recipient-dominant, the Ig replacement therapy was substituted by very successful post-vaccine immunity acquisition after CBT. The analysis of the general developmental parameters showed that chemotherapy did not cause any delay in growth and psychomotor development. CONCLUSIONS: The CBT therapy with this conditioning regimen was well tolerated and induced an effective reconstitution of B-cell functions in an X-SCID infant under the 3â¯months of age.
RESUMEN
To investigate the quality of epilepsy care in a region in Japan that lacked specialised care, we retrospectively evaluated patients who visited our newly established epilepsy division between April 2018 and March 2021, and had been treated with anti-seizure medications (ASMs) for at least 1 year prior. Of the 231 patients included, 169 had ongoing seizure episodes at first visit (seizure-persist group) and 62 had no seizure episodes for more than a year (seizure-free group). Eighty-three patients in the seizure-persist group had not received specialised epilepsy care, 15 had been treated with unnecessary medications, and seven had experienced side effects from ASMs. Twelve patients in the seizure-free group had been treated with unnecessary ASMs, 10 had been treated with ASMs with teratogenic potential and four had experienced ASM side effects. These patients could be classified as having an advanced epilepsy treatment gap (ETG) because they had not previously received necessary specialised care. The progressive decline in the number of patients with advanced ETG suggests that our new epilepsy division has addressed this issue. This study highlights that a significant number of patients with advanced ETGs exist in Japan and that proper countermeasures are required to address this gap.