Unmet needs in AbAID with autoreactive IgE and concluding remarks
Important current challenges need to be addressed to better characterize IgE AAb as pathogenic factors and therapeutic targets. First, the extremely low concentration of these antibodies can make their quantification difficult. In this regard, new IgE detection methods are being developed, such as isotype-specific agglutination-PCR (ISAP)173 and luciferase-linked immunosorbent assay (LuLISA)174, which can both detect specific IgE in 1 µL of sample. Both methods have so far only been tested for measurement of IgE against allergens, but could be and should be extended to autoantigens. The high sensitivity of these approaches could allow screening of multiple potential autoantigens, and may be used for further epitope mapping studies once important autoantigens have been identified. IgE AAb detection may also be improved by purifying IgE to remove IgG AAb competing for the same antigen and epitope175.
Better functional tests are also needed to assess IgE AAb and their antigens for their effects on FcεRI-bearing cells. Basophil activation tests are useful to screen potential autoantigens for IgE-mediated degranulation176, but can be challenging to implement given the low frequency of these cells in blood samples. As an alternative approach, mast cell activation assays are now being developed177, and the availability of novel mast cell models such as human mast cells derived from pluripotent stem cells and mouse mast cells expressing the human FcεRI may facilitate screening of potential autoallergens178,179.
A deeper knowledge of the diversity and specificity of IgE repertoires in CSU and other autoimmune diseases is needed in order to identify key IgE clones that are likely to drive autoallergic responses. However, studying IgE repertoires is challenging due to the extremely low frequency of circulating IgE-producing B cells, making their isolation almost impossible using standard flow cytometry sorting strategies. However, Croote and colleagues have recently reported the first successful paired variable heavy (VH) and light (VL) chain sequencing of IgE+ B cells from allergic subjects180. A similar approach could be applied to CSU, AD and other autoimmune diseases in order to gain knowledge on the diversity of IgE repertoires in these diseases. Importantly, once identified, these paired VH-VL sequences could be used to produce recombinant IgE to further assess characteristics of these mAbs (affinity, epitope mapping analysis, ability to induce mast cell degranulation), and to serve as positive controls for future standardized IgE detection methods.
IgE targeting benefits many CSU patients, shows encouraging results in SLE and some limitations in subsets of type IIb autoimmune CSU, AD and BP patients. Despite the fact that IgE and FcεRI-bearing cells are clearly involved in the pathophysiology of these diseases, they are not the only nor the main pathogenic factors in all patients. Hence, targeting other pathogenic factors along with IgE may provide quicker and more efficient clinical benefits. For instance, IgG AAb are pathogenic in SLE and BP either through Fc receptor-mediated or complement-mediated mechanisms7,113. In BP, targeting B cells with rituximab (anti-CD20 mAb), IgE with OMZ, or IL-4Rα with dupilumab may lead to similar clinical benefits181. Combining rituximab with OMZ as an adjuvant treatment (in a small cohort of patients) showed promising add-on effects in refractory BP patients182. Thus, similar approaches in other AbAID, where autoreactive IgE and IgG are pathogenic and where IgE or IgG targeting are not efficacious enough, may represent a promising therapeutic strategy.
Other chronic inflammatory diseases such as vasculitis or cardiovascular diseases may involve IgE AAb and FcεRI-bearing cells in their pathophysiology. Further investigations with recently developed tools may thus identify other conditions where targeting IgE AAb could be beneficial to improve patient care. Taken together, autoreactive IgE is involved in the pathophysiology of multiple immune-mediated diseases. This rapidly evolving knowledge holds strong potential for improving diagnosis, prediction of disease course and personalized treatment approaches.