(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（由适用提供）：多发性骨髓瘤（MM）是一种无法治愈的恶性血浆细胞增殖疾病。 MM是癌症健康差异的一个例子，其是所有癌症的最高非裔美国/欧美（AA/EA）发病率比例之一。对于种族相关差异的解释需要在MM预立句疾病的病因中找到，称为单克隆性γ-具有不确定意义的单克隆性伽马病（MGUS），因为AA中MGU的流行率远高于EA中观察到的，而从MGUS到MM的过渡概率是两个种族中的过渡。我们假设这种健康差异可以通过IgE（肥大细胞）系统的差异来解释，这是过敏免疫反应的介体。这种响应是由于组织中存在肥大细胞（MC），而IgE抗体敏感，而IgE抗体与多价抗原（过敏原）绑定导致高亲和力IgE受体I（FCERI）（FCERI）和脱粒F MC的交联，从而导致组胺释放和其他抗炎症（抗炎症）释放（导致）。然而，除了在没有抗原（单体IgE）的情况下与MC结合的这种众所周知的脱粒反应外，IgE还激活MC并延长其存活而没有诱导的脱粒。激活的MC秘密在其表面上激活了细胞因子白介素-6（IL-6）和表达CD40L，这两者都提供了强大的信号，可激活B细胞并触发其分化为浆细胞。由于B细胞激活涉及DNA突变酶激活诱导的胞苷死亡酶（AID）的表达，因此这将增加导致异常血浆细胞（MGUS）的突变的可能性。众所周知，与EA相比，AA的总IgE血液水平更高，并且具有与高IgE水平相关的其他病理状况。这就是我们假设AA中较高的IgE水平通过增强MC-（B细胞）轴的慢性激活而导致MGU的发生率更高。有趣的是，AA和EA之间的MC结构和酶促含量也存在差异，功能含义未知。因此，我们还假设来自AA的MC具有强大的刺激活性，与EA相比，当暴露于相同数量的单体IgE时，甚至没有IgE。但是，这两个假设都不相互排斥。我们有两个具体的目标：目标1：在没有IgE和AIG的情况下定义AA和EA中MC的差异：在IgE存在下定义AA和EA中MC的差异。除了使用无抗原（单体）IGE监测其激活MC：B细胞轴的有效性外，我们还将探索针对MM细胞上抗原的治疗IgE的使用来触发抗原 脱粒和抗肿瘤活性，这一过程被称为“ MC重新抗击癌症”。这种人为诱发的事件是可能的，因为脱粒MC释放了具有抗肿瘤作用的促凋亡分子，并且不应与由IgE激活MC的总水平激活MC：B细胞轴的诱导的脱粒事件。这，我们的提议对MM的预防和治疗都具有相关的影响。