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\begin{document}

\title{Does vitamin D cause atopy?}



\author[1]{Valeria Andrea Zúñiga}%
\author[2]{Blanca Bazan-Perkins}%
\affil[1]{Instituto Tecnologico y de Estudios Superiores de Monterrey Escuela de Medicina y Ciencias de la Salud}%
\affil[2]{Instituto Nacional de Enfermedades Respiratorias}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Due to the Covid-19 pandemic, the intake of vitamin D (VD) has
increased. Vitamin D has multiple regulatory effects in the human body,
including immunological. Evidence accentuates the generation of a
pro-tolerogenic T helper (Th) 2 cell state with VD, suppressing a Th1
inflammatory response. Th2 cell polarization is characteristic of atopy.
However, VD promotes a balanced state through the action of regulatory T
cells, controlling cytokines, both pro-inflammatory and
anti-inflammatory, and by reducing B cell proliferation and
differentiation, thus preventing the development of atopy.%
\end{abstract}%



\sloppy


\selectlanguage{ngerman}\emph{VALERIA A. ZÚÑIGA} (Orcid ID
:\emph{https://orcid.org/0000-0002-9327-6588})

\emph{BLANCA BAZAN-PERKINS} (Orcid ID
:\emph{https://orcid.org/0000-0003-1331-6349} )

Article type: Letter to the Editor

\textbf{Does vitamin D cause atopy?}

To the Editor,

Covid-19, caused by the severe acute respiratory syndrome coronavirus 2,
has brought threats to public health and has caused millions of deaths
to date. It is suggested that a cytokine storm in Covid-19 is associated
with greater mortality and clinical deterioration, attributing severe
cases to the increase of interleukin (IL) -1, tumor necrosis factor
(TNF) -\selectlanguage{english}a, interferon (IFN) -\selectlanguage{greek}γ \selectlanguage{english}and IL-6.\textsuperscript{1}

Since the onset of the pandemic due Covid-19, evidence has indicated
that vitamin D (VD) deficiency is associated with a preeminent incidence
of infection\textsuperscript{2} and severity of Covid-19. As a
consequence, sales of vitamin supplements have increased during the
pandemic, including VD, due to its possible prophylactic or therapeutic
value.\textsuperscript{3}

Prohormone and VD can be obtained from endogenous production prompted by
ultraviolet B radiation, from supplements, and from the diet. VD has
multiple regulatory effects in the human body (figure 1), since there is
evidence of the presence of its receptor in different
tissues.\textsuperscript{4} VD acts as a regulator of mineral
homeostasis considering its effects on parathyroids, bone and intestine
and has a variety of other biological functions, including
immunological.\textsuperscript{5}

For this reason, it is possible to have effects on innate and adaptive
immunity, allowing the induction of monocyte and macrophage signaling,
especially on antimicrobial peptides such as cathelicidins and
\selectlanguage{greek}β-\selectlanguage{english}defensin 2. Likewise, VD enables the inhibition of both B and T cells,
decreases IL-1, IL-6, TNF-a \selectlanguage{english}and reduces antigen presenting cells such as
dendritic cells.\textsuperscript{5} Evidence highlights that vitamin D3
generates a shift from an inflammatory T-helper (Th) 1-cell response to
a pro-tolerogenic Th2 response with an arrest of cytotoxic T lymphocyte
infiltration and an increase in CD4+ CD25+ T regulatory cells
(Tregs).\textsuperscript{5} Hence, the possible development of atopy is
suspected in people who consume VD in excess.

Atopy refers to the disposition of developing an immune
hyperresponsiveness against allergens and antigens, leading to CD4+ Th2
polarization and immunoglobulin E (IgE)
overproduction.\textsuperscript{6} However, an increase in atopy has not
been seen due to the consumption of this vitamin.

Scrutinizing with the aforementioned, VD inhibits maturation,
differentiation, and survival of dendritic cells. It also down-regulates
major histocompatibility complex type II and costimulatory receptors
CD40, CD80 and CD86\textsuperscript{5}, which are elevated in
atopy\textsuperscript{7}; hindering the interaction and activation of T
cells. Moreover, B cell proliferation and differentiation, even towards
IgE, is reduced.

Additionally, VD induces regulatory T-lymphocytes,\textsuperscript{5}the
latter being able to exhort immune tolerance by enhancing the secretion
of IL-10 and transforming growth factor \selectlanguage{greek}β.\selectlanguage{english}\textsuperscript{7}

The deterioration or absence of development of an allergic or atopic
disease by people who consume VD, can be explained by the action of
Tregs. The latter can subdue proliferation and activation of effector Th
cells, such as Th2 or Th17, and impede functions and migration of Th1,
thus IFN-\selectlanguage{greek}γ, \selectlanguage{english}Th2, Th9 and Th17 cells.\textsuperscript{7} Responsively,
Th2 cytokines get suppressed\textsuperscript{8} by action of Tregs
during atopy, including mast cells, IgE, basophils, and
eosinophils,\textsuperscript{9} as shown in figure 2.

Tregs have suppressive mechanisms mediated by its inhibitory cytokines
and its stimulatory signals such as CTLA-4. This receptor implements an
immunoregulatory function, restraining T cell response by avoiding the
union of CD28 T-cell costimulatory molecule with its ligands CD80 and
CD86.

In conclusion, VD promotes immune homeostasis through Tregs, reducing
pro-inflammatory cytokines clustering, regulating levels of
anti-inflammatory cytokines and enhancing the production of
antimicrobial peptides. In this way, the derivation of an atopic disease
as a result of a supposed increase in Th2 lymphocytes is avoided due to
the consumption of this vitamin.

\textbf{ACKNOWLEDGEMENTS}

None.

\textbf{CONFLICTS OF INTEREST}

The authors report no conflicts of interest.

\textbf{AUTHORS}

Valeria Andrea Z\selectlanguage{ngerman}úñiga\textsuperscript{1}

Blanca Bazan-Perkins \textsuperscript{2,3}

\textsuperscript{1} Instituto Tecnológico y de Estudios Superiores de
Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo
León, México

\textsuperscript{2} Instituto Nacional de Enfermedades Respiratorias,
Ismael Cosío Villegas, Ciudad de México, Mexico

\textsuperscript{3} Instituto Tecnológico de Estudios Superiores de
Monterrey, Escuela de Medicina y Ciencias de la Salud, Ciudad de México,
México

Correspondence

Email:\emph{valeria.andrea.zuniga@gmail.com}

\textbf{ORCID}

\emph{Valeria Andrea Zúñiga} (Orcid
ID:\emph{https://orcid.org/0000-0002-9327-6588})

\emph{Blanca Bazan-Perkins} (Orcid
ID:\emph{https://orcid.org/0000-0003-1331-6349} )

\textbf{REFERENCES}

\begin{enumerate}
\tightlist
\item
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\item
  Martens, P. J., Gysemans, C., Verstuyf, A., \& Mathieu, A. C. (2020).
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  1248. https://doi.org/10.3390/nu12051248
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  Justiz Vaillant, A. A., Modi, P., \& Jan, A. (2021). Atopy.
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  Boonpiyathad, T., Sözener, Z. C., Akdis, M., \& Akdis, C. A. (2020).
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\end{enumerate}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{FIGURE 1.} Vitamin D (VD) synthesis and its effects.

VD is obtained through the skin production or by alimentary consumption.
7-dehydrocholesterol, which can be transformed to
cholesterol,\textsuperscript{A} converts to previtamin
D3\textsuperscript{B,C} through ultraviolet B radiation. Via spontaneous
isomeration,\textsuperscript{D} precholecalciferol changes to
cholecalciferol.\textsuperscript{E} VD can be obtained from food, both
of animal (cholecalciferol) and plant origin
(ergocalciferol).\textsuperscript{E} Cholecalciferol is metabolized in
the liver to 25-hydroxyvitamin D.\textsuperscript{F,G} The active form
of VD, 1,25-dihydroxyvitamin D, is obtained in the kidneys by the enzyme
25-Hydroxyvitamin D-1\selectlanguage{greek}α-\selectlanguage{english}hydroxylase (which, in turn, is regulated by
stimuli).\textsuperscript{C} Calcitriol has diverse effects on different
tissues.\textsuperscript{C}

\begin{enumerate}
\tightlist
\item
  Prabhu, A. V., Luu, W., Sharpe, L. J., \& Brown, A. J. (2016).
  Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase
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  Journal of biological chemistry}, \emph{291}(16),
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\item
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\item
  Baeke, F., Takiishi, T., Korf, H., Gysemans, C., \& Mathieu, C.
  (2010). Vitamin D: modulator of the immune system. \emph{Current
  opinion in pharmacology}, \emph{10}(4),
  482--496.\emph{https://doi.org/10.1016/j.coph.2010.04.001}
\item
  Tian, X. Q., \& Holick, M. F. (1995). Catalyzed thermal isomerization
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  complexation. \emph{The Journal of biological
  chemistry},\emph{270}(15),
  8706--8711.\emph{https://doi.org/10.1074/jbc.270.15.8706}
\item
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\item
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\item
  Martens, P. J., Gysemans, C., Verstuyf, A., \& Mathieu, A. C. (2020).
  Vitamin D's Effect on Immune Function. \emph{Nutrients}, \emph{12}(5),
  1248.\emph{https://doi.org/10.3390/nu12051248}
\end{enumerate}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{FIGURE 2.} Vitamin D's (VD) regulatory mechanisms in atopy.

T-helper (Th)-2 cells, an atopy feature, release
cytokines\textsuperscript{A} such as interleukin (IL)-4, that inhibits
Th1 cells generation,\textsuperscript{B} IL-5, IL-10 and IL-13.
Likewise, there is a notable elevation of antigens presentation,
CD80/CD86 expression, major histocompatibility complex II (MHCII)
action, mast cell (MC) release and eosinophils (EOS). VD regulates
atopy's hyperresponsiveness through T regulatory cells (Tregs)
differentiation,\textsuperscript{C} suppressing
EOS\textsuperscript{D}and impeding Th1 and Th2 functions, which
regulates cytokines of the latter.\textsuperscript{E} Additionally, VD
suppresses dendritic cells (DC)\textsuperscript{C} and B cell
differentiation,\textsuperscript{F}reducing antibody production,
including IgE, and antigen presentation.

\begin{enumerate}
\tightlist
\item
  Justiz Vaillant, A. A., Modi, P., \& Jan, A. (2021). Atopy.
  In\emph{StatPearls}. StatPearls Publishing.
\item
  Lazarski, C. A., Ford, J., Katzman, S. D., Rosenberg, A. F., \&
  Fowell, D. J. (2013). IL-4 attenuates Th1-associated chemokine
  expression and Th1 trafficking to inflamed tissues and limits pathogen
  clearance. \emph{PloS one}, \emph{8}(8),
  e71949.\emph{https://doi.org/10.1371/journal.pone.0071949}
\item
  Martens, P. J., Gysemans, C., Verstuyf, A., \& Mathieu, A. C. (2020).
  Vitamin D's Effect on Immune Function. \emph{Nutrients}, \emph{12}(5),
  1248.\emph{https://doi.org/10.3390/nu12051248}
\item
  Mart\selectlanguage{ngerman}ín-Orozco, E., Norte-Muñoz, M., \& Martínez-García, J. (2017).
  Regulatory T Cells in Allergy and Asthma. \emph{Frontiers in
  pediatrics}, \emph{5},
  117.\emph{https://doi.org/10.3389/fped.2017.00117}
\item
  Boonpiyathad, T., Sözener, Z. C., Akdis, M., \& Akdis, C. A. (2020).
  The role of Treg cell subsets in allergic disease. \emph{Asian Pacific
  journal of allergy and immunology}, \emph{38}(3),
  139--149.\emph{https://doi.org/10.12932/AP-030220-0754}
\item
  Charoenngam, N., \& Holick, M. F. (2020). Immunologic Effects of
  Vitamin D on Human Health and Disease. \emph{Nutrients}, \emph{12}(7),
  2097.\emph{https://doi.org/10.3390/nu12072097}
\end{enumerate}

\textbf{Hosted file}

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