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，我们评估了世界卫生组织诊断小儿肥大细胞增多症全身性疾病标准的使用情况。对 113 名患有儿童肥大细胞增多症的儿童进行了评估。对50例进行了完整的骨髓评估。通过组织病理学、流式细胞术和 KIT D816V 分析骨髓。骨髓活检显示轻度非典型造血成熟。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。 基于这些观察，我们得出结论，世界卫生组织标准适用于儿科人群系统性肥大细胞增多症的诊​​断。尽管观察到了骨髓增生性疾病中常见的意想不到的骨髓检查结果，但本研究中的儿童仍保持临床稳定，没有进展为更具侵袭性的变异。 我们同样检查了儿科肥大细胞增多症与血清类胰蛋白酶和骨髓病理学的关系，为治疗提供实用指导。在类胰蛋白酶高且介导症状严重的儿童中，所有器官肿大均患有全身性疾病；没有器官肿大的人都没有患有全身性疾病。 与对照组相比，色素性荨麻疹、弥漫性皮肤病和系统性肥大细胞增多症以及所有三类疾病之间的血清类胰蛋白酶值存在显着差异。在大多数情况下，类胰蛋白酶水平随着时间的推移而下降，症状也随之下降，并且与全身性疾病患者骨髓内肥大细胞的百分比高度相关。在我们的队列中，所有类别疾病的儿童要么保持稳定，要么有所改善。器官肿大是判断谁需要进行骨髓活检的有力指标。血清类胰蛋白酶反映了骨髓检查结果，连续的类胰蛋白酶测定有助于补充对病程的临床判断。 由于 SM 是肥大细胞中 c-kit 突变的结果，我们怀疑突变型肥大细胞侵入骨髓是否会影响骨髓基质细胞（BMSC；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 BMSC 没有 c-kit 突变，但增殖不良且成骨分化不足。由于BMSCs的造血支持能力也很重要，我们研究了人CD34(+)造血祖细胞在与健康志愿者的BMSCs和来自SM患者的BMSCs共培养后在NSG小鼠中的植入情况。来自 SM 患者骨髓的 BMSC 缺乏支持造血功能。我们还发现健康和 SM 衍生的 BMSC 在具有多种功能的基因表达方面存在显着差异，包括 WNT 信号传导、骨化和骨重塑。这些观察结果表明，与 SM 相关的一些发现可能是由骨髓间质肥大细胞功能失调引起的 BMSC 的表观遗传变化驱动的。 我们还参与了两项直接处理患者护理问题的举措。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，典型的斑丘疹皮肤病变（色素性荨麻疹）被细分为两种变体，一种是具有小斑丘疹病变的单形变体，通常见于成人患者，另一种是具有不同大小和形状的较大病变的多形变体，通常见于儿童患者。临床观察表明，单态性变异如果在儿童中发生，通常会持续到成年期，而多态性变异可能会在青春期左右消退。 改进还导致从当前的皮肤肥大细胞增多症分类中删除了黄斑毛细血管扩张发疹性持久性，并从术语“肥大细胞瘤”中删除了“孤立性”。 在第二项举措中，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年患者的肥大细胞增多症生活质量调查问卷。该仪器将作为未来临床研究和常规患者护理中医疗干预反应急需的衡量标准。