Laboratory Assessment of Patients with Systemic Mastocytosis

系统性肥大细胞增多症患者的实验室评估

基本信息

  • 批准号:
    8952884
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
  • 资助国家:
    美国
  • 起止时间:
  • 项目状态:
    未结题

项目摘要

The wast majority of patients with mastocytosis carry somatic KIT mutations. Mastocytosis associated with germline KIT activating mutations is exceedingly rare. We investigated the unique clinicopathologic features of a patient with systemic mastocytosis caused by a de novo germline KIT K509I mutation. We sought to investigate the effect of the germline KIT K509I mutation on human mast cell development and function. Primary human mast cells derived from CD34(+) peripheral blood progenitors were examined for growth, development, survival, and IgE-mediated activation. In addition, a mast cell transduction system that stably expressed the KIT K509I mutation was established. KIT K509I biopsied mast cells were round, CD25(-), and well differentiated. KIT K509I progenitors cultured in stem cell factor (SCF) demonstrated a 10-fold expansion compared with progenitors from healthy subjects and developed into mature hypergranular mast cells with enhanced antigen-mediated degranulation. KIT K509I progenitors cultured in the absence of SCF survived but lacked expansion and developed into hypogranular mast cells. A KIT K509I mast cell transduction system revealed SCF-independent survival to be reliant on the preferential splicing of KIT at the adjacent exonic junction. We concluded that germline KIT mutations associated with mastocytosis drive a well-differentiated mast cell phenotype distinct to that of somatic KIT D816V disease, the oncogenic potential of which might be influenced by SCF and selective KIT splicing. Within the mast cell compartment, both germline and somatic mutations in KIT have been identified in patients with rare familial presentations of mastocytosis. While seeking to characterize patients with unique, inherited allergic phenotypes among patients referred for evaluation of severe allergic skin, airway, or gastrointestinal disease or systemic mastocytosis (SM), we identified 9 atopic subjects with persistent increases in serum basal tryptase levels in the absence of evidence for a clonal mast cell disorder. Thorough clinical evaluations were undertaken, total and fractionated serum tryptase levels were obtained, in vitro basophil activation was assayed, and bone marrow biopsies were performed in 5 of these index patients. Increased basal serum tryptase levels were found to segregate with distinct clinical features, and it was noted that multiple family members of each index patient shared elements of this phenotype. An autosomal dominant inheritance pattern of increased basal total serum tryptase levels was revealed in all 9 families. The mean basal total serum tryptase level measured during a resting state was 21.6 ng/mL among subjects with inherited tryptasemia; however, tryptase fractionation in a subset of 18 affected patients further revealed that mature tryptase in serum was undetectable (<1 ng/mL), suggesting increase in protryptase levels. Prominent among features segregating with basal serum tryptase level increases were symptoms consistent with chronic and episodic mast cell degranulation, with 26 of 33 subjects reporting episodic urticaria, flushing, and/or cramping abdominal pain frequently associated with urgency, diarrhea, or both. A history of anaphylaxis was reported in 10 of 33 subjects from 6 different families. Gastrointestinal manifestations, whether chronic or episodic, were another prominent feature seen in 28 of 33 subjects with increased tryptase levels. Atopic symptoms were present in 31 of 33 tryptasemic subjects, with environmental allergies and asthma being reported among 28 of 33 affected subjects. Connective tissue abnormalities were present in 23 of 33 subjects with increased tryptase levels from 8 of 9 families, and chronic musculoskeletal pain was present among 11 of 33 tryptasemic subjects from 6 of 9 families. Autonomic dysfunction, manifesting as postural orthostatic tachycardia syndrome, was reported in 10 of 33 affected subjects, and a neuropsychiatric diagnosis was present in 17 of 33 affected subjects. These 5 clusters of clinical characteristics (cutaneous, connective tissue, gastrointestinal, atopic, and neuropsychiatric) were independently and significantly associated with increased tryptase levels. Because some of the reported symptoms in tryptasemic subjects could have been consistent with the familial presentation of a clonal mast cell disorder, index patients in 5 of 9 families underwent bone marrow biopsy. A significant increase in mast cell numbers was observed (P < .05; mean, 9.6 cells/high-power field hpf; range, 4-19.4 cells/hpf) compared with that seen in healthy volunteers (mean, 2.5 cells/hpf; range, 1-5 cells/hpf). However, none of the patients met the World Health Organization established criteria for a diagnosis of SM or monoclonal mast cell activation. Mast cell aggregates were not present, aberrant expression of CD2/CD25 was absent, and KIT D816V mutation test results were negative in all 5 patients. Spindled-shaped mast cells (>25%) were observed in a single patient. In vitro basophil activation was assessed in affected subjects from 6 of 9 families. Basophils from affected subjects demonstrated reduced activation, as measured based upon CD203c mean fluorescence intensity after stimulation with anti-IgE or N-formyl-methionylleucyl-phenylalanine. However, CD63 induction within the CD203c basophil population, although variable, was not significantly different between patients and paired control subjects. Additional genetic study is ongoing, and as the dysfunctional pathways in these families are elucidated, we might gain additional insights into the hypermobile connective tissue phenotype, atopic disease, autonomic dysfunction, and neuropsychiatric illness and their interface with mast cell mediators.
大多数肥大细胞增多症患者携带体细胞 KIT 突变。与种系 KIT 激活突变相关的肥大细胞增多症极为罕见。我们调查了一名由新生种系 KIT K509I 突变引起的系统性肥大细胞增多症患者的独特临床病理特征。我们试图研究种系 KIT K509I 突变对人类肥大细胞发育和功能的影响。 对源自 CD34(+) 外周血祖细胞的原代人肥大细胞进行了生长、发育、存活和 IgE 介导的激活的检查。此外,还建立了稳定表达KIT K509I突变的肥大细胞转导系统。 KIT K509I活检肥大细胞呈圆形、CD25(-)且分化良好。与健康受试者的祖细胞相比,在干细胞因子 (SCF) 中培养的 KIT K509I 祖细胞表现出 10 倍的扩增,并发育成成熟的超颗粒肥大细胞,具有增强的抗原介导的脱颗粒作用。在不存在 SCF 的情况下培养的 KIT K509I 祖细胞存活下来,但缺乏扩增并发育成低颗粒肥大细胞。 KIT K509I 肥大细胞转导系统显示,不依赖于 SCF 的存活依赖于 KIT 在相邻外显子连接处的优先剪接。 我们得出的结论是,与肥大细胞增多症相关的种系 KIT 突变驱动了与体细胞 KIT D816V 疾病不同的分化良好的肥大细胞表型,其致癌潜力可能受到 SCF 和选择性 KIT 剪接的影响。 在肥大细胞室内,在具有罕见家族性肥大细胞增多症的患者中,已鉴定出 KIT 的种系突变和体细胞突变。在寻求对转诊评估严重过敏性皮肤、气道或胃肠道疾病或系统性肥大细胞增多症 (SM) 的患者中描述具有独特的遗传性过敏表型的患者特征时,我们在没有克隆性肥大细胞疾病证据的情况下,确定了 9 名血清基础类胰蛋白酶水平持续升高的特应性受试者。我们进行了彻底的临床评估,获得了总血清类胰蛋白酶水平和分级血清类胰蛋白酶水平,测定了体外嗜碱性粒细胞活化,并对其中 5 名指标患者进行了骨髓活检。发现基础血清类胰蛋白酶水平升高具有不同的临床特征,并且值得注意的是,每个指标患者的多个家庭成员都具有这种表型的元素。在所有 9 个家族中都揭示了基础总血清类胰蛋白酶水平增加的常染色体显性遗传模式。患有遗传性类胰蛋白酶血症的受试者在静息状态下测得的平均基础总血清类胰蛋白酶水平为 21.6 ng/mL;然而,对 18 名受影响患者的子集进行类胰蛋白酶分级分离进一步显示,血清中检测不到成熟类胰蛋白酶 (<1 ng/mL),表明原类胰蛋白酶水平有所增加。与基础血清类胰蛋白酶水平升高相关的突出特征是与慢性和偶发性肥大细胞脱颗粒一致的症状,33 名受试者中有 26 名报告偶发性荨麻疹、潮红和/或痉挛性腹痛,通常与尿急、腹泻或两者兼而有之。来自 6 个不同家庭的 33 名受试者中有 10 名报告有过敏反应史。胃肠道表现,无论是慢性的还是间歇性的,是 33 名类胰蛋白酶水平升高的受试者中的 28 名受试者中观察到的另一个显着特征。 33 名胰蛋白酶血症受试者中有 31 名出现特应性症状,33 名受影响受试者中有 28 名报告有环境过敏和哮喘。 9 个家庭中有 8​​ 个家庭的 33 名类胰蛋白酶水平升高的受试者中有 23 名存在结缔组织异常,9 个家庭中有 6 个的 33 名类胰蛋白酶血症受试者中有 11 名存在慢性肌肉骨骼疼痛。 33 名受影响受试者中有 10 名报告有自主神经功能障碍,表现为体位性直立性心动过速综合征,33 名受影响受试者中有 17 名有神经精神诊断。这 5 组临床特征(皮肤、结缔组织、胃肠道、特应性和神经精神)与类胰蛋白酶水平升高独立且显着相关。由于胰蛋白酶血症受试者中报告的一些症状可能与克隆性肥大细胞疾病的家族表现一致,因此 9 个家庭中有 5 个的指标患者接受了骨髓活检。与健康志愿者中观察到的肥大细胞数量(平均值,2.5 个细胞/hpf;范围,1-5 个细胞/hpf)相比,观察到肥大细胞数量显着增加(P < .05;平均值,9.6 个细胞/高倍视野 hpf;范围,4-19.4 个细胞/hpf)。然而,没有一名患者符合世界卫生组织制定的 SM 或单克隆肥大细胞激活诊断标准。 5 名患者均不存在肥大细胞聚集体,不存在 CD2/CD25 异常表达,KIT D816V 突变检测结果均为阴性。在一名患者中观察到纺锤形肥大细胞(>25%)。对来自 9 个家庭中 6 个家庭的受影响受试者进行了体外嗜碱性粒细胞活化评估。根据抗 IgE 或 N-甲酰基亮氨酰苯丙氨酸刺激后的 CD203c 平均荧光强度测量,来自受影响受试者的嗜碱性粒细胞表现出活化降低。然而,CD203c 嗜碱性粒细胞群体内的 CD63 诱导虽然存在差异,但在患者和配对对照受试者之间没有显着差异。其他基因研究正在进行中,随着这些家族的功能障碍途径得到阐明,我们可能会对过度活动结缔组织表型、特应性疾病、自主神经功能障碍和神经精神疾病及其与肥大细胞介质的相互作用获得更多见解。

项目成果

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Irina Maric其他文献

Irina Maric的其他文献

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{{ truncateString('Irina Maric', 18)}}的其他基金

Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases
肿瘤和非肿瘤疾病的骨髓组织病理学变化
  • 批准号:
    8565402
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Hypereosinophilic Syndrome
嗜酸性粒细胞增多综合征患者的实验室评估
  • 批准号:
    8565378
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Hypereosinophilic Syndrome
嗜酸性粒细胞增多综合征患者的实验室评估
  • 批准号:
    9555574
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Systemic Mastocytosis
系统性肥大细胞增多症患者的实验室评估
  • 批准号:
    10019275
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Hypereosinophilic Syndrome
嗜酸性粒细胞增多综合征患者的实验室评估
  • 批准号:
    10684570
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases
肿瘤和非肿瘤疾病的骨髓组织病理学变化
  • 批准号:
    10255219
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Systemic Mastocytosis
系统性肥大细胞增多症患者的实验室评估
  • 批准号:
    9354088
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases
肿瘤和非肿瘤疾病的骨髓组织病理学变化
  • 批准号:
    9154156
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Hypereosinophilic Syndrome
嗜酸性粒细胞增多综合征患者的实验室评估
  • 批准号:
    8952883
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Laboratory Assessment of Patients with Chronic Myeloproliferative Diseases
慢性骨髓增生性疾病患者的实验室评估
  • 批准号:
    7593142
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

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