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\begin{document}

\title{You might owe your mother more than you think}



\author[1]{Leticia De las Vecillas }%
\author[2]{Ibon Eguiluz-Gracia}%
\author[3]{Mattia Giovannini}%
\affil[1]{Hospital Universitario Marques de Valdecilla}%
\affil[2]{IBIMA-Regional University Hospital of Málaga, UMA, Malaga}%
\affil[3]{Anna Meyer Chidren's University Hospital}%


\vspace{-1em}



  
  \date{May 29, 2024}


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\textbf{News and Views: Groundbreaking Discoveries in Immunology}

\textbf{Title: You might owe your mother more than you think}

\textbf{Authors:} Leticia de las Vecillas\textsuperscript{1}, Ibon
Eguiluz-Gracia\textsuperscript{2}, Mattia Giovannini\textsuperscript{3}

\textsuperscript{1}Allergy Department, Marqu\selectlanguage{ngerman}és de Valdecilla University
Hospital-Instituto de Investigación Marqués de Valdecilla (IDIVAL),
Santander, Spain. leticia.delasveci@gmail.com; ORCID
0000-0003-4969-5678\textsuperscript{2}Allergy Unit, ARADyAL,
IBIMA\selectlanguage{english}-Hospital Regional Universitario de Malaga\selectlanguage{english}-UMA, Malaga, Spain.
iboneguiluz@gmail.com; ORCID 0000-0002-3774-931X

\textsuperscript{3}Allergy Unit, Department of Pediatrics, Meyer
Children's University Hospital, Florence, Italy.
mattia.giovannini@unifi.it; ORCID 0000-0001-9568-6882

\textbf{Correspondence to} : Leticia de las Vecillas, Allergy
Department, Marques de Valdecilla University Hospital-Instituto de
Investigacion Marques de Valdecilla (IDIVAL), Santander, Spain. Email:
leticia.delasveci@gmail.com; ORCID 0000-0003-4969-5678. Mattia
Giovannini, Allergy Unit, Department of Pediatrics, Meyer Children's
University Hospital, Florence, Italy. mattia.giovannini@unifi.it; ORCID
0000-0001-9568-6882

\textbf{Word count: 653}

\textbf{Number of tables:} 0

\textbf{Number of figures:} 1

\textbf{Keywords:} IgE; mast cells; protection;
\emph{Staphylococcusaureus;} allergy; murine models; pediatrics,
transplacental transfer, toxin hypothesis.

\textbf{Abbreviations:} CXCL1/2, chemokine (C-X-C motif) ligand 1/2;
Fc\selectlanguage{greek}ε\selectlanguage{english}RI, high-affinity receptor for the Fc region of IgE; FcRN, neonatal
Fc receptor; MC, mast cell; SA, \emph{Staphylococcus} \emph{aureus} ;
sIgE, specific immunoglobulin E; Tfh13, T follicular helper 13; TNF,
tumor necrosis factor.

\textbf{Statement of conflict of interest:} the authors declare no
conflict of interest in relation to this work.

\textbf{Statement of contribution} : LV and MG conceptualized the
article and wrote the manuscript. IEG supervised the work of the rest of
the authors and reviewed the final version of the article.

\textbf{Statement of funding} : This work was supported by the Instituto
de Salud Carlos III of the Spanish Ministry of Science and
Competitiveness (grants co-funded by the European Regional Development
Fund) through the research contract ``Juan Rodes'' for IEG (JR19/00029),
and the program of Redes Tem\selectlanguage{ngerman}áticas de Investigación Colaborativa en
Salud (RETICS): Asma, Reacciones Adversas y Alérgicas-ARADyAL
(RD16/0006/0001).

\textbf{Ethical approval and trial registration:} Not applicable.

\textbf{Consent for publication:} Not applicable.

\textbf{Data sharing and data accessibility:} Not applicable.

\textbf{Acknowledgements:} The authors want to thank Dr. Anna Globinska
for Figure 1 design and Dr. Jiménez-Saiz for critical review of the
manuscript.

\textbf{Abstract:} Not applicable.

\textbf{Main text}

Mast cell (MC) activation and the subsequent release of inflammatory
mediators has been historically linked to allergic
responses\textsuperscript{1}. 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 manners\textsuperscript{2}, thus
providing efficient innate and adaptive protection against toxic
compounds. Moreover, healthy subjects can display IgE against toxins
from \emph{Staphylococcus} \emph{aureus} (SA)
(SA-sIgE)\textsuperscript{3}. Therefore, MCs may also have a role in the
adaptive protection against venoms or toxins.

Following this idea, the so-called \emph{toxin hypothesis}
\textsuperscript{4,5} , Starkl \emph{et al} .\textsuperscript{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 Tfh13\textsuperscript{7,8}. 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)\textsuperscript{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 \emph{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 humans\textsuperscript{9}. Mouse fetal MCs acquire
a semi-mature phenotype according to Fc\selectlanguage{greek}ε\selectlanguage{english}RI 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 Fc\selectlanguage{greek}ε\selectlanguage{english}RI and CD63)
since the second trimester of pregnancy. Lastly, they showed that human
fetal MCs can also be sensitized with IgE \emph{in utero} .

Overall, these data suggest that the offspring of atopic mothers can
become passively sensitized \emph{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 IgE\textsuperscript{4,5,6,10}.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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\textbf{Figure 1} . Scheme of IgE's vertical transmission and the
sensitization of fetal MCs for allergen-specific degranulation by IgE of
maternal origin through the neonatal Fc receptor (FcRN) (left side).
Prenatal sensitization may include protective functions in the offspring
described by the ``Toxin hypothesis'', in which mast cells confer
adaptive protection against venoms and bacterial toxins (left side).

\textbf{References}

1. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med.
2012;18:693--704.

2. Anderson E, Stavenhagen K, Kolarich D, Sommerhoff CP, Maurer M, Metz
M. Human Mast Cell Tryptase Is a Potential Treatment for Snakebite
Envenoming Across Multiple Snake Species. Front Immunol. 2018;9:1532.
Available from:
https://www.frontiersin.org/article/10.3389/fimmu.2018.01532

3. Sintobin I, Siroux V, Holtappels G, Pison C, Nadif R, Bousquet J, et
al. Sensitization to staphylococcal enterotoxins and asthma severity: a
longitudinal study in the EGEA cohort. Eur Respir J. 2019;54:1900198.
Available from: http://erj.ersjournals.com/content/54/3/1900198.abstract

4. Profet M. The function of allergy: immunological defense against
toxins. Q Rev Biol. 1991;66:23--62.

5. Galli SJ, Starkl P, Marichal T, Tsai M. Mast cells and IgE in defense
against venoms: Possible ``good side'' of allergy? Allergol Int.
2016;65:3--15. Available from:
http://dx.doi.org/10.1016/j.alit.2015.09.002

6. Starkl, P., Watzenboeck, M. L., Popov, L. M., Zahalka, S., Hladik,
A., Lakovits, K., \ldots{} \& Knapp, S. (2020). IgE Effector Mechanisms,
in Concert with Mast Cells, Contribute to Acquired Host Defense against
Staphylococcusaureus. Immunity, 53(4), 793-804.7. Chen JS, Grassmann
JDS, Gowthaman U, Olyha SJ, Simoneau T, Berin MC, et al. Flow cytometric
identification of Tfh13 cells in mouse and human. J Allergy Clin
Immunol. 2021;147(2):470-483. Available from:
https://doi.org/10.1016/j.jaci.2020.04.063

8. Jim\selectlanguage{ngerman}énez-Saiz R, Bruton K, Jordana M. Follicular T cells: From
stability to failure. Allergy. 2020;75(4):1006-1007. doi:
10.1111/all.14167. Epub 2020 Feb 5. PMID: 31883377.

9. Msallam R, Balla J, Rathore APS, Kared H, Malleret B, Saron WAA, et
al. Fetal mast cells mediate postnatal allergic responses dependent on
maternal IgE. Science. 2020;370:941--50.

10. Ferastraoaru D., Bax H.J., Bergmann C., Capron M., Castells M.,
Dombrowicz D., Fiebiger E., Gould H.J., Hartmann K., Jappe U., et al.
AllergoOncology: Ultra-Low IgE, a potential novel biomarker in
cancer---A Position Paper of the European Academy of Allergy and
Clinical Immunology (EAACI) Clin. Transl. Allergy. 2020;10:1--16. doi:
10.1186/s13601-020-00335-w.\selectlanguage{english}
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