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.