Introduction
Autoimmunity is defined by a break of tolerance to self-antigens leading
to either organ-specific or systemic diseases. This reactivity to self
is driven by autoreactive B and/or T cells that escaped negative
selection processes through mechanisms that are not yet fully
characterized. Several models explaining the loss of tolerance to some
self-antigens have been proposed concerning the expansion of both
autoreactive B and T cells1-6. Some autoimmune
diseases (AID) are characterized by the presence of pathogenic
autoreactive antibodies (AAb) produced by plasmablast and/or plasma
cells resulting from T cell-dependent and/or T cell-independent B cell
differentiation from both follicular and extrafollicular areas of
secondary or tertiary lymphoid organs3,7. Pathogenic
antibodies drive the development of organ injury in these
antibody-mediated AID (AbAID) through mechanisms involving Fc receptor
bearing cells and/or complement pathways8.
In organ-specific AbAID, AAb target tissue-expressed self-antigens which
leads to the development of signs and symptoms. For instance, in bullous
pemphigoid, AAb against BP-180 and BP-230 (BP Ag2 and BP Ag1,
respectively, key dermis-epidermis junction molecules) are responsible
for blister formation9. In systemic diseases, AAb
target non-organ specific antigens. In systemic lupus erythematosus
(SLE), for instance, AAb to nuclear antigens form circulating immune
complexes (CIC) that induce chronic and systemic inflammation by
depositing in target organs and by activating complement and innate
immune cells that amplify AAb production through various
mechanisms7.
AAb are prevalent in the general population and are thus not
systematically associated with clinical symptoms10.
However, in some individuals, through genetic, environmental and/or
hormonal mechanisms, a pro-inflammatory trigger can amplify their
production and modify their isotypes and glycosylation. Toll-like
receptors (TLR) and intracellular nucleic acid sensing molecules
engagement, through inflammatory signals, can lead to autoreactive B and
T cells proliferation and maturation1,3,10-12. Some of
these immune signals also initiate class switch recombination (CSR)
allowing B cells to switch the constant region of their BCR from IgM to
another isotype13,14.
While AAb of IgM isotype may generally be protective against AbAID, IgG
AAb are mostly pathogenic. IgG subclasses differ in the activation of
complement pathways and in engaging inhibitory and/or activating Fc
receptors for IgG (FcγR), and differences in post-translational
modifications influence their pro- or anti-inflammatory
properties8,10. The pathogenicity of IgA and IgD AAb
still needs further characterization, but recent evidence points to the
pathogenicity of IgE AAb and highlights IgE as a potent therapeutic
target in a number of AbAID15. Interleukin 4 (IL-4)
and IL-13 are the main cytokines promoting IgE CSR and the generation of
IgE-producing antibody-secreting cells14,16.
IgE binds with high affinity to FcεRI (Kd≈10-9 M),
which is expressed in its tetrameric form αβγ2 by mast cells and
basophils and, in humans, in its αγ2 trimeric form mainly by some
dendritic cell subsets, Langerhans cells, eosinophils and some monocytes
(either constitutively or induced)17. FcεRI-mediated
activation of mast cells and basophils leads to the immediate release of
granular pro-inflammatory preformed mediators and to neosynthesis and
release of arachidonic derivatives, cytokines, and
chemokines18. These effects can be toned down through
co-engagement of FcγRIIB (CD32B) or other inhibitory receptors that can
block degranulation and decrease cytokine
production19,20.
The lower affinity IgE receptor FcεRII (CD23,
Kd≈10-7-10-8 M) is mainly expressed
by some subsets of B cells and monocytes and is involved in the
regulation of IgE synthesis and, together with FcεRI, in IgE-mediated
facilitated antigen presentation14. Beyond its effects
on IgE synthesis, little is known about CD23-mediated pathogenicity of
IgE in AbAID. Its involvement in the regulation of allergic responses
has been recently reviewed14,21.
Autoreactive IgE can drive cellular activation of mast cells, basophils
and other types of FcεRI-bearing cells15 without
necessarily inducing their degranulation due to other factors
influencing their functional outcomes. Indeed, AbAID-affected patients
do not have chronic anaphylactic symptoms and systematically develop
pathogenic antibodies of multiple isotypes including IgG. Depending on
their subclass and their affinity to the autoantigen, autoreactive IgG
can induce inhibitory signals that will be integrated to FcεRI-mediated
activating signals leading to a specific cellular activation (or
inhibition) pattern of the targeted cell. This may result in mast cell
or basophil activation without degranulation but with the production of
cytokines, chemokines or other inflammation-related
compounds22 and may potentiate the TLR9-dependent
activation of dendritic cells23. Therefore, the term
autoallergy (or allergy to self) should be used cautiously when
referring to diseases where mast cell and basophil degranulation are not
induced by IgE AAb.
The present review summarizes the current knowledge on the pathogenicity
of autoreactive IgE in AbAID and will discuss the role of IgE as a
therapeutic target in these conditions. We will also highlight the need
to develop better assays for IgE AAb to validate their diagnostic and
prognostic values and allow further study of their pathophysiological
contribution to AbAID.