Background: Anaphylaxis is an acute and life-threatening allergic response. Classically and most commonly, it can be mediated by the crosslinking of allergens to immunoglobulin E (IgE)- high affinity IgE receptor (FcεRI) complex found mostly on mast cells. However, there is another pathway of anaphylaxis that is less well-studied. This pathway known as the alternative pathway is mediated by IgG and its Fc gamma receptor (Fcγ). Though it was not documented in human anaphylaxis, a few studies have found that IgG-mediated anaphylaxis can happen as demonstrated in rodent models of anaphylaxis. In these studies, a variety of soluble mediators were being evaluated and they differ from each study which causes confusion in the suitability, and reliability of choice of soluble mediators to be analyzed for diagnosis or therapeutic purposes. Hence, the objective of this meta-analysis is to identify the potential soluble mediators that are involved in an IgG-mediated anaphylaxis reaction. Methods: Studies related to IgG-mediated anaphylaxis were sourced from five search engines namely PubMed, Scopus, Ovid, Cochrane Library, and Center for Agricultural Bioscience International (CABI) regardless of publication year. Relevant studies were then reviewed based on specific inclusion factors. The means and standard deviations of each soluble mediator studied were then extracted using ImageJ or Get Data Graph Digitiser software and the data were subjected to meta-analysis. Results: From our findings, we found that histamine, serotonin, platelet activating factor (PAF), β-hexosaminidase, leukotriene C4 (LTC4), mucosal mast cell protease-1 (MMCP-1), interleukins (IL)-4,-6, and-13; tumor necrosis factor alpha (TNF-α), and macrophage inflammatory protein-1α (MIP-1α) were often being analyzed. Out of these soluble mediators, histamine, PAF, β-hexosaminidase, IL-6, and-13, MIP-1α and TNF-α were more significant with positive effect size and p < 0.001. As study effect was relatively small, we performed publication bias and found that there was publication bias and this could be due to the small sample size studied. Conclusion: As such, we proposed that through meta-analysis, the potential soluble mediators involved in rodent IgG-mediated anaphylaxis to be histamine, PAF, β-hexosaminidase, IL-6 and-13 and MIP-1α, and TNF-α but will require further studies with larger sample size.
tHGA, a geranyl acetophenone compound originally isolated from a local shrub called Melicope ptelefolia, has been previously reported to prevent ovalbumin-induced allergic airway inflammation in a murine model of allergic asthma by targeting cysteinyl leukotriene synthesis. Mast cells are immune effector cells involved in the pathogenesis of allergic diseases including asthma by releasing cysteinyl leukotrienes. The anti-asthmatic properties of tHGA could be attributed to its inhibitory effect on mast cell degranulation. As mast cell degranulation is an important event in allergic responses, this study aimed to investigate the anti-allergic effects of tHGA in cellular and animal models of IgE-mediated mast cell degranulation. For in vitro model of IgE-mediated mast cell degranulation, DNP-IgE-sensitized RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA to induce degranulation. For IgE-mediated passive systemic anaphylaxis, Sprague Dawley rats were sensitized by intraperitoneal injection of DNP-IgE before challenged with DNP-BSA. Both in vitro and in vivo models showed that tHGA significantly inhibited the release of preformed mediators (β-hexosaminidase and histamine) as well as de novo mediators (interleukin-4, tumour necrosis factor-α, prostaglandin D2 and leukotriene C4). Pre-treatment of tHGA also prevented IgE-challenged RBL-2H3 cells and peritoneal mast cells from undergoing morphological changes associated with mast cell degranulation. These findings indicate that tHGA possesses potent anti-allergic activity via attenuation of IgE-mediated mast cell degranulation and inhibition of IgE-mediated passive systemic anaphylaxis. Thus, tHGA may have the potential to be developed as a mast cell stabilizer for the treatment of allergic diseases in the future.
Mast cells (MCs), a type of immune effector cell, have recently become recognized for their ability to cause vascular leakage during dengue virus (DENV) infection. Although MC stabilizers have been reported to attenuate DENV induced infection in animal studies, there are limited in vitro studies on the use of MC stabilizers against DENV induced MC degranulation. 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA) has been reported to be a potential MC stabilizer by inhibiting IgE-mediated MC activation in both cellular and animal models. The present study aims to establish an in vitro model of DENV3-induced RBL-2H3 cells using ketotifen fumarate as a control drug, as well as to determine the effect of tHGA on the release of MC mediators upon DENV infection. Our results demonstrated that the optimal multiplicities of infection (MOI) were 0.4 × 10-2 and 0.8 × 10-2 focus forming units (FFU)/cell. Ketotifen fumarate was proven to attenuate DENV3-induced RBL-2H3 cells degranulation in this in vitro model. In contrast, tHGA was unable to attenuate the release of both β-hexosaminidase and tumor necrosis factor (TNF)-α. Nonetheless, our study has successfully established an in vitro model of DENV3-induced RBL-2H3 cells, which might be useful for the screening of potential MC stabilizers for anti-dengue therapies.