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.
Multiple myeloma (MM) is an incurable blood cancer that disproportionally affects African Americans compared to European Americas (whites) and all other racial groups; however, the basis for this race-related difference is unknown. The main goal of this project is to understand the causes of a premalignant (benign) condition known as 'monoclonal gammopathy of undetermined significance' (MGUS) that precedes MM and is the key to understanding this cancer health disparity. The present proposal aims to discover the immunological basis of MGUS focusing on key players of the allergic immune response that may promote this premalignant condition (mast cells and IgE antibody) and also aims to reprogram this immune response to eventually eliminate MM.
| Jensen-Jarolim, E; Bax, H J; Bianchini, R et al. (2018) AllergoOncology: Opposite outcomes of immune tolerance in allergy and cancer. Allergy 73:328-340 |
