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Mast cell (MC) activation and the
subsequent release of inflammatory mediators has been historically
linked to allergic responses1. In this regard,
allergen-specific immunoglobulin E (sIgE) is a potent activator of MCs
through FceRI crosslinking after allergen ligation to the IgE bound to
FceRI on the surface of MCs. This activation pathway of MCs leads to
potentially life-threatening reactions such as anaphylaxis.
Nevertheless, MCs also respond to triggers other than sIgE. For example,
venoms from different insects can drive MC degranulation in both
antibody-dependent and -independent manners2, thus
providing efficient innate and adaptive protection against toxic
compounds. Moreover, healthy subjects can display IgE against toxins
from Staphylococcus aureus (SA)
(SA-sIgE)3. Therefore, MCs may also have a role in the
adaptive protection against venoms or toxins.
Following this idea, the so-called toxin
hypothesis 4,5 , Starkl et
al .6 investigated the contribution of MCs and sIgE to
the host’s resistance against SA. Using a mouse model, the authors
showed that the epicutaneous inoculation of SA induces an early serum
increase of functional SA-sIgG1/sIgE and total IgE. This is followed by
an expansion of T follicular helper (Tfh) cells in the inguinal lymph
nodes, especially of cell subsets directly involved in high-affinity IgE
production such as Tfh137,8. SA toxins also induced
peripheral CD4+ and CD8+ T-cell proliferation and IgE synthesis via
monoclonal and polyclonal mechanisms in the absence of live bacteria.
Interestingly, a single skin inoculation of SA suffices to mount a
systemic immune that yields SA-sIgE. Upon subsequent infections, MCs
from different organs release high amounts of bactericidal compounds and
chemoattractants through SA-sIgE-mediated mechanisms. Some of these
chemotactic factors (such as TNF and CXCL1/2)6 are
involved in neutrophil recruitment, thus reducing bacterial load and
improving SA clearance. Collectively, IgE immunity confers an
evolutionary advantage which translates into a higher survival rate and
a quicker recovery following severe SA infections, including pneumonia.
Curiously, bactericidal compounds are also released when MCs are
activated by antigens other than SA toxin, which generally confers
potential antibacterial activities to allergic reactions.
In addition to the adulthood, sIgE might also exert protective roles
from the embryological development. Msallam et al . have recently
investigated the interactions between fetal MCs and maternal sIgE to
shed light on their relationship in fetal priming of immune and allergic
responses in mice and humans9. Mouse fetal MCs acquire
a semi-mature phenotype according to FcεRI and heparin expression, and
increase in number during early development stages, which suggests that
they might be functional before birth. Of note, the skin and the airways
hosted significant mouse fetal MCs populations. Furthermore, the
neonatal Fc receptor (FcRN) can translocate maternal IgE to the fetus,
thus allowing the sensitization of mouse fetal MCs. Intriguing, the
authors also showed that maternal sIgE can induce degranulation of mouse
fetal MCs, but this effect was progressively lost during the 6 weeks
following the offspring’s birth. Moreover, the authors partially
replicated these findings in humans as they identified a subset of human
fetal MCs that were phenotypically mature (based on FcεRI and CD63)
since the second trimester of pregnancy. Lastly, they showed that human
fetal MCs can also be sensitized with IgE in utero .
Overall, these data suggest that the offspring of atopic mothers can
become passively sensitized in utero , thus being able to
experience allergic reactions during the perinatal period without
previous contact with the allergen. This passive sensitization
phenomenon event constitutes a novel and clinically-relevant concept in
newborns of allergic mothers. On the other hand, fetal MCs sensitization
with maternal IgE might provide temporary protection from toxins and
venoms. This defence may be of paramount importance during the first
weeks of life given that the offspring is still developing
immunity.
Future research should expand these findings and investigate how to
apply them for the development of antibacterial and antivenom approaches
without the risk of suffering allergic reactions. By and large, these
findings contribute to expand the growing list of homeostatic and
protective roles of IgE4,5,6,10.