The Pathogenesis, Diagnosis, And Treatment Of Systemic Mast Cell Disorders

系统性肥大细胞疾病的发病机制、诊断和治疗

• 批准号: 9354692
• 负责人: Dean D Metcalfe
• 金额: $ 83.57万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9354692
• 关键词: Adult; Advisory Committees; Affect; Bone Marrow; Bone marrow biopsy; Bone remodeling; CD34 gene; Categories; Cell Count; Charge; Child; Child Care; Childhood; Classification; Clinical; Clinical Research; Coculture Techniques; Cutaneous; Cutaneous Mastocytosis; Development; Diagnosis; Diagnostic; Diffuse; Disease; Dysmyelopoietic Syndromes; Engraftment; Epigenetic Process; Evaluation; Excision; Flow Cytometry; Future; Gene Expression; Genetic Polymorphism; Hematopoiesis; Hematopoietic; Histopathology; Human; Indolent Systemic Mastocytosis; International; Intervention; Judgment; Lesion; Marrow; Mast Cell Neoplasm; Measures; Mediator of activation protein; Medical; Mesenchymal Stem Cells; Molecular Abnormality; Mus; Mutation; Myeloproliferative disease; Pathogenesis; Pathology; Patient Care; Patients; Population; Proliferating; Proto-Oncogene Protein c-kit; Puberty; Quality of life; Questionnaires; Role; Serum; Shapes; Skin; Stromal Cells; Symptoms; Systemic Mastocytosis; Systemic disease; Time; Tryptase; Tyrosine Kinase Inhibitor; Urticaria Pigmentosa; Variant; Visceromegaly; WNT Signaling Pathway; base; cohort; cytopenia; healthy volunteer; improved; instrument; leukemia; mast cell; mastocytosis; mutant; novel therapeutics; osteogenic; pediatric patients; peripheral blood; progenitor; response

The diagnostic criteria for pediatric mastocytosis are largely based on adult studies. We thus evaluated use of the WHO criteria for diagnosis of systemic disease in pediatric mastocytosis. One hundred and thirteen children with pediatric mastocytosis were evaluated. Complete bone marrow evaluations were performed in 50 cases. Marrows were analyzed by histopathology, flow cytometry, and for KIT D816V. Bone marrow biopsies displayed mild atypical hematopoietic maturation. There was no evidence of peripheral blood cytopenias, myelodysplastic syndrome, myeloproliferative neoplasm or leukemia within this cohort. Based on these observations, we reached the conclusion that WHO criteria are applicable to the diagnosis of systemic mastocytosis in the pediatric population. Although unsuspected bone marrow findings typically seen in myeloproliferative disorders were observed, children within this study remained clinically stable without progression to a more aggressive variant. We similarly examined clinical aspects of pediatric mastocytosis in relationship to serum tryptase and bone marrow pathology to provide practical guidance for management. In children with high tryptase and severe mediator symptoms, all with organomegaly had systemic disease; none without organomegaly had systemic disease. Serum tryptase values differed significantly between urticaria pigmentosa, diffuse cutaneous, and systemic mastocytosis, and in all three categories versus controls. Tryptase levels in most cases declined with time as did symptoms, and highly correlated with mast cell percent within the bone marrow of patients with systemic disease. Within our cohort, children within all categories of disease either remained stable or improved. Organomegaly was a strong indicator of who needed a bone marrow biopsy. Serum tryptase reflected bone marrow findings and sequential tryptase determinations were useful in supplementing clinical judgment as to disease course. Because SM results from a mutation in c-kit in mast cells, we questioned if the function of bone marrow stromal cells (BMSCs; also known as mesenchymal stem cells) might be affected by the invasion of bone marrow by mutant mast cells. In our patients, BMSCs from SM patients did not have a mutation in c-kit, but they proliferated poorly and osteogenic differentiation was deficient. Since the hematopoietic supportive abilities of BMSCs are also important, we studied the engraftment in NSG mice of human CD34(+) hematopoietic progenitors, after being co-cultured with BMSCs of healthy volunteers vs. BMSCs derived from patients with SM. BMSCs derived from the bone marrow of patients with SM were deficient in support of hematopoiesis. We also found significant differences between healthy and SM derived BMSCs in the expression of genes with a variety of functions, including the WNT signaling, ossification, and bone remodeling. These observations suggest that some findings associated with SM might be driven by epigenetic changes in BMSCs caused by dysfunctional mast cells in the bone marrow compartment. We also participated in two initiatives directly dealing with patient care issues. First, we participated in an international task force charged to up-date the classification of forms of cutaneous mastocytosis. This resulted in revised definitions and criteria for forms of mastocytosis in the skin. In particular, the typical maculopapular cutaneous lesions (urticaria pigmentosa) were subdivided into two variants, a monomorphic variant with small maculopapular lesions, typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, typically observed in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. Refinements also resulted in the removal of teleangiectasia macularis eruptive perstans from the current classification of cutaneous mastocytosis and removal of "solitary" from the term "mastocytoma". In a second initiative, we assisted in the development of the first mastocytosis quality of life questionnaire for adult patients with cutaneous and indolent systemic mastocytosis. This instrument will serve as a much needed measure of response to medical intervention in future clinical studies and in routine patient care.

儿童肥大细胞增多症的诊断标准主要基于成人研究。因此，我们对WHO诊断儿童肥大细胞增多症全身性疾病的标准进行了评估。对113例儿童肥大细胞增多症进行了评估。对50例患者进行了完整的骨髓检查。用组织病理学、流式细胞术和试剂盒D816V对骨髓进行分析。骨髓活检显示轻度不典型的造血成熟。在该队列中没有外周血细胞减少症、骨髓增生异常综合征、骨髓增生性肿瘤或白血病的证据。根据这些观察，我们得出结论，WHO标准适用于儿童人群中系统性肥大细胞增多症的诊断。尽管观察到了骨髓增殖性疾病中常见的意外骨髓表现，但本研究中的儿童临床上保持稳定，没有进展为更具侵袭性的变异。 我们类似地检查了儿童肥大细胞增多症的临床方面与血清类胰蛋白酶和骨髓病理的关系，以提供实用的治疗指导。在有高类胰酶和严重介体症状的儿童中，所有器质性肥大的儿童都有系统性疾病；没有器质性肥大的儿童都有系统性疾病。血清类胰蛋白酶在色素性荨麻疹、弥漫性皮肤肥大细胞增生症和全身性肥大细胞增生症之间存在显著差异，并且在所有三种类型中都与对照组有显著差异。在大多数情况下，类胰蛋白酶水平随着时间的推移而下降，症状也是如此，并且与系统性疾病患者骨髓中肥大细胞的百分比高度相关。在我们的队列中，所有疾病类别的儿童要么保持稳定，要么有所改善。器官肿大是一个强烈的指标，表明谁需要骨髓活检。血清类胰蛋白酶反映了骨髓的表现，连续的类胰蛋白酶测定有助于补充临床对病程的判断。 由于SM是肥大细胞c-kit突变的结果，我们质疑突变的肥大细胞对骨髓的侵袭是否会影响骨髓基质细胞(BMSCs；也称为间充质干细胞)的功能。在我们的患者中，来自SM患者的BMSCs没有c-kit突变，但它们增殖较差，成骨分化不足。由于BMSCs的造血支持能力也很重要，我们研究了人CD34(+)造血祖细胞与健康志愿者BMSCs和SM患者BMSCs共培养后在NSG小鼠体内的植入情况。SM患者骨髓来源的BMSCs缺乏对造血的支持。我们还发现，健康和SM来源的BMSCs在多种功能基因的表达上存在显著差异，包括WNT信号、成骨和骨重建。这些观察表明，与SM相关的一些发现可能是由骨髓间隔室肥大细胞功能障碍引起的BMSCs的表观遗传学变化所驱动的。 我们还参与了两项直接处理病人护理问题的倡议。首先，我们参加了一个国际工作组，负责更新皮肤肥大细胞增多症的分类。这导致了对皮肤肥大细胞增多症形式的定义和标准的修订。特别是，典型的斑丘性皮肤病变(色素性荨麻疹)被细分为两种变异体，一种是单形性变异体，具有小的斑丘性病变，通常见于成人患者，另一种是多态变异体，具有较大的病变，其大小和形状可变，通常见于儿童患者。临床观察表明，如果在儿童中发生单态变异，通常会持续到成年，而多态变异可能会在青春期前后消失。改进还导致从目前的皮肤肥大细胞增生症的分类中去除了斑点状毛细血管扩张症，并从术语“肥大细胞瘤”中去除了“孤立的”。在第二项倡议中，我们协助开发了第一份针对皮肤和惰性系统性肥大细胞增多症成人患者的肥大细胞增多症生活质量问卷。在未来的临床研究和常规病人护理中，该仪器将作为对医疗干预反应的一种迫切需要的测量。