(PQC3) Immunological Basis of Health Disparities in Multiple Myeloma

 描述(申请人提供)：多发性骨髓瘤(MM)是一种无法治愈的恶性浆细胞B细胞增生性疾病。多发性骨髓瘤是癌症健康差距的一个例子，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。这种种族相关的差异需要在MM癌前疾病的病因学中找到解释，这被称为未确定意义的单克隆性伽马病(MGUS)，因为MGUS在AA中的患病率远远高于EA，而从MGUS过渡到MM的概率在两个种族中是相同的。我们推测，这种健康差异可以通过IgE(肥大细胞)系统的差异来解释，IgE-(肥大细胞)系统是过敏免疫反应的中介。这种反应是由于在被IgE抗体致敏的组织中存在肥大细胞(MC)，当肥大细胞与多价抗原(过敏原)结合时，会导致高亲和力IgE受体I(FceRI)的交联和MC的脱颗粒，导致组胺和其他急性炎症(过敏)反应的介质释放。然而，除了这种众所周知的脱颗粒反应外，当在没有抗原(单体IgE)的情况下与MC结合时，IgE激活MC并延长其存活时间，而不会导致脱颗粒。活化的MC分泌细胞因子白介素6(IL-6)，并在其表面表达CD40L，两者都提供了激活B细胞并触发其向浆细胞分化的强烈信号。由于B细胞的激活涉及DNA突变酶激活诱导的胞苷脱氨酶(AID)的表达，这将增加突变导致异常浆细胞(MGUS)的概率。众所周知，与EA相比，AA患者的血总IgE水平更高，无论是否有其他与高IgE水平相关的病理情况。因此，我们假设再生障碍性贫血患者中较高的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在MC结构和酶含量上也存在差异，其功能含义尚不清楚。因此，我们还假设，与EA的MC相比，AA来源的MC在暴露于相同数量的单体IgE时，甚至在没有IgE的情况下，具有更强的刺激活性。然而，这两种假设并不是相互排斥的。我们有两个具体的目标：目标1：确定在不存在IgE的情况下AA和EA的MC的差异，以及目标2：确定AA和EA在存在IgE时的MC的差异。除了使用无抗原(单体)IgE来监测其激活MC：B细胞轴的有效性外，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 脱颗粒和抗肿瘤活性，这一过程被称为“MC抗癌的再教育”。这种人工诱导的事件是可能的，因为脱颗粒MC释放了具有抗肿瘤作用的促凋亡分子，不应与总水平的IgE激活MC：B细胞轴引起的事件混淆。因此，我们的建议在MM的预防和治疗方面都有相关的意义。

 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.