(PQC3) Immunological Basis of Health Disparities in Multiple Myeloma

(PQC3) 多发性骨髓瘤健康差异的免疫学基础

• 批准号: 9054822
• 负责人: MANUEL L PENICHET
• 金额: $ 20.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054822
• 关键词: Acute; Adult; Affect; Affinity; African; African American; Allergens; Allergic; Allergic Reaction; American; Americas; Antibodies; Antigen Targeting; Antigens; Apoptotic; Autoimmune Diseases; B-Cell Activation; B-Lymphocytes; Benign; Binding; Biological Response Modifiers; Blood; CD4 Positive T Lymphocytes; Cell Communication; Cell Degranulation; Cell Survival; Cell-Mediated Cytolysis; Cells; Cellular Structures; Chronic; DNA; Development; Disease; Education; Electronics; Enzyme Activation; Epitopes; Etiology; European; Event; Flow Cytometry; Future; Generations; Genes; Glycocalyx; Goals; Health; Helper-Inducer T-Lymphocyte; Hematologic Neoplasms; Hematopoietic Neoplasms; Histamine; Histamine Release; Human; Hypersensitivity; IgE; IgE Receptors; Immune response; Immunotherapeutic agent; Incidence; Individual; Inflammatory; Inflammatory Response; Interleukin-6; Lead; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Microscopy; Molecular Profiling; Monitor; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mutate; Mutation; Nature; Oncogenes; Plasma Cells; Play; Precancerous Conditions; Premalignant; Prevalence; Prevention therapy; Preventive; Probability; Process; Race; Risk; Role; Signal Transduction; Stimulus; Structure; Surface; System; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic; Tissues; Tumor Antigens; United States; activation-induced cytidine deaminase; allergic response; antitumor effect; base; cancer cell; cancer health disparity; crosslink; cytokine; fighting; health disparity; mast cell; peripheral blood; racial disparity; response; tumor

 DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable B-cell proliferative disorder of malignant plasma cells. MM is an example of a cancer health disparity with one of the highest African American/European American (AA/EA) incidence rate ratios of all cancers. The explanation for this race-related difference needs to be found in the etiology of the MM premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS), since the prevalence of MGUS in AA is much higher than that observed in EA, while the probability for transition from MGUS to MM is the same in both races. We postulate that this health disparity can be explained by differences in the IgE-(mast cell) system, which are the mediators of the allergic immune response. This response is due to the presence of mast cells (MC) in tissue that are sensitized by IgE antibodies, which when bound to a multivalent antigen (allergen) lead to the cross-linking of the high affinity IgE receptor I (FceRI) and degranulation f MC, resulting in the release of histamine and other mediators of the acute inflammatory (allergic) response. However, in addition to this well-known degranulating response, when bound to MC in the absence of antigens (monomeric IgE), IgE activates MC and prolongs their survival without inducing degranulation. Activated MC secrete the cytokine interleukin-6 (IL-6) and express CD40L on their surface, both of which provide strong signals that activate B cells and trigger their differentiation into plasma cells. Since B-cell activation involves the expressio of the DNA mutating enzyme activation-induced cytidine deaminase (AID), this would increase the probability of mutations that lead to abnormal plasma cells (MGUS). It is well known that the total IgE blood level is higher in AA compared to EA, with and without other pathological conditions associated with high IgE levels. Thus, we hypothesize that the higher IgE levels in AA result in a higher incidence of MGUS through enhanced chronic activation of the MC-(B-cell) axis. Interestingly, there are also differences in MC structure and enzymatic content between AA and EA, with unknown functional implications. Therefore, we also hypothesize that MC from AA have stronger stimulatory activity, compared to those from EA, when exposed to the same amount of monomeric IgE, or even without IgE. However, both hypotheses are not mutually exclusive. We have two specific aims: Aim 1: Define the differences in MC in AA and EA in the absence of IgE and Aim 2: Define the differences of MC in AA and EA in the presence of IgE. In addition to using antigen free (monomeric) IgE to monitor its efficacy to activate the MC:B-cell axis, we will also explore the use of a therapeutic IgE targeting an antigen on MM cells to trigger degranulation and anti-tumor activity, a process known as the "re-education of MC to fight cancer". This artificially induced event is possible because degranulating MC release pro-apoptotic molecules with anti-tumor effects and should not be confused with that induced by total levels of IgE activating the MC:B-cell axis. Thus, our proposal has relevant implications in both the prevention and therapy of MM.

 描述（由申请人提供）：多发性骨髓瘤（MM）是一种恶性浆细胞的不可治愈的B细胞增殖性疾病。MM是癌症健康差异的一个例子，在所有癌症中，非洲裔美国人/欧洲裔美国人（AA/EA）的发病率比率最高。这种种族相关差异的解释需要在MM癌前病变（称为意义不明的单克隆丙种球蛋白病（MGUS））的病因学中找到，因为AA中MGUS的患病率远高于EA中观察到的患病率，而从MGUS转变为MM的概率在两个种族中相同。我们假设，这种健康的差距可以解释的IgE-（肥大细胞）系统，这是过敏性免疫反应的介质的差异。这种反应是由于组织中存在被IgE抗体致敏的肥大细胞（MC），当IgE抗体与多价抗原（过敏原）结合时，导致高亲和力IgE受体I（FceRI）的交联和MC的脱粒，导致组胺和急性炎症（过敏）反应的其他介质的释放。然而，除了这种众所周知的脱粒反应外，当在不存在抗原（单体IgE）的情况下与MC结合时，IgE激活MC并抑制其存活而不诱导脱粒。活化的MC分泌细胞因子白细胞介素-6（IL-6）并在其表面上表达CD 40 L，这两者都提供了激活B细胞并触发其分化为浆细胞的强信号。由于B细胞活化涉及DNA突变酶活化诱导的胞苷脱氨酶（AID）的表达，这将增加导致异常浆细胞（MGUS）的突变的可能性。众所周知，与EA相比，AA中的总IgE血液水平更高，有和没有与高IgE水平相关的其他病理状况。因此，我们假设AA中较高的IgE水平通过增强MC-（B细胞）轴的慢性激活导致MGUS的发生率较高。有趣的是，AA和EA之间的MC结构和酶含量也存在差异，具有未知的功能影响。因此，我们还假设，MC从AA有更强的刺激活性，相比，从EA，当暴露于相同量的单体IgE，甚至没有IgE。然而，这两种假设并不相互排斥。我们有两个具体目标：目标1：目的2：确定在IgE存在下AA和EA中MC的差异。除了使用无抗原（单体）IgE来监测其激活MC：B细胞轴的功效之外，我们还将探索使用靶向MM细胞上的抗原的治疗性IgE来触发MC：B细胞轴的激活。 这一过程被称为“MC的再教育以对抗癌症”。这种人工诱导的事件是可能的，因为脱粒MC释放具有抗肿瘤作用的促凋亡分子，不应与激活MC：B细胞轴的总IgE水平诱导的事件混淆。因此，我们的建议对MM的预防和治疗具有相关意义。