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\begin{document}

\title{Uncovering the Immunological Properties of Isolated Lymphoid Follicles}



\author[1]{Janice Layhadi}%
\author[1]{Mohamed Shamji}%
\affil[1]{Imperial College London}%


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  \date{May 27, 2024}


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Article type: News and Views: Groundbreaking Discoveries in Immunology

\textbf{Title: Uncovering the Immunological Properties of Isolated
Lymphoid Follicles}

\textbf{Authors:} Janice A. Layhadi\textsuperscript{1} and Mohamed H.
Shamji\textsuperscript{1}

\textsuperscript{1}Immunomodulation and Tolerance Group, Allergy and
Clinical Immunology, National Heart and Lung Institute, Imperial College
London, UK

\textbf{Correspondence:} Janice Layhadi, Immunomodulation and Tolerance
Group, Allergy and Clinical Immunology, National Heart and Lung
Institute, Imperial College London, UK

Email address: Janice.lee-layhadi07@imperial.ac.uk

\textbf{Keywords:} ILF; GALT; secretory IgA; intestine; adaptive
immunity

\textbf{Abbreviations:} CyTOF, Mass Cytometry; GALT, Gut-Associated
Lymphoid Tissue; GC, Germinal Centre\textbf{;} ILF, Isolated Lymphoid
Follicles; PP, Peyer's patch\textbf{;} sIgA, secretory IgA\textbf{;}Tfh,
T follicular helper cells\textbf{;} Th, T helper cells\textbf{;}Treg, T
regulatory cells

\textbf{Acknowledgement:} We would like to thank Anna Globinska for her
assistance in generating the graphical figure.

\textbf{Main text}

The intestine is the largest organ of the body and exhibits the greatest
amount and diversity of immune cells. Intestinal homeostasis is tightly
controlled by the gut mucosal immune network, which involves
gut-associated lymphoid tissues (GALT), secretory IgA (sIgA), mucosal
immune cells (i.e. T helper (Th), T follicular (Tfh) and T regulatory
(Treg) cells), cytokines, chemokines and commensal
bacteria,\textsuperscript{1} among others. Unsurprisingly, crosstalk
between these cells and their local environment is crucial for the
maturation and function of the immune system, and the disruption of this
communication often leads to the development of immune
disorders\textsuperscript{2}.

GALT comprises of the Peyer's Patches (PP) as well as isolated lymphoid
follicles (ILFs), which are present throughout the human intestine. The
role of GALT in adaptive immune responses within the intestine has been
primarily reported in mice, with a recent report revealing a role for PP
in supplying IgA\textsuperscript{+} plasmablasts to the small
intestine.\textsuperscript{3} However, functional studies of human GALT
have been hampered due to the scarcity of established protocols for
isolation of pure cells and immunological profiling.

Fenton \emph{et al.} describe a novel method for isolating human GALT
that allows thorough profiling of immune cells in
ILFs.\textsuperscript{4} The conventional isolation method has
identified the existence of plasma cells, na\selectlanguage{ngerman}ïve B and T cells in colonic
cell suspensions. The novel isolation method proposed by Fenton \emph{et
al} . revealed that naïve lymphocytes and plasma cells were restricted
to ILFs and to GALT-free lamina propria (LP), respectively. This
cellular distribution indicates that ILFs (both mucosal and sub-mucosal)
function as inductive sites of the adaptive immune
response.\textsuperscript{4}Using mass cytometry, CyTOF, they also
demonstrated that the composition of T and B cells in the GALT was
distinct from the GALT-free LP;
CD57\textsuperscript{hi}PD-1\textsuperscript{hi} Tfh-like cells and
CD4\textsuperscript{+}CD25\textsuperscript{+}CD127\textsuperscript{-}IL-2\textsuperscript{-}Treg
cells primarily localized in the GALT while cytokine-producing T cell
subsets mostly localized within the GALT-free LP.\textsuperscript{4}
Moreover, GALT ILFs comprise of germinal centre (GC) and memory B cells
that express IgM, IgG, IgA1 and IgA2, which indicates that B cell class
switching occurs within the GC in these cell compartments and is a
source of intestinal IgA. IgA sequencing analysis revealed minimal
overlap in the IgA repertoire of GALT follicles. A low overlap of IgA
clones was observed between the PP and sub-mucosal ILFs suggesting a
distinct profile within the intestinal immune response. When the most
abundant clones of the sub-mucosal ILFs were further investigated, they
identified that these clones made up a huge fraction of the total clonal
repertoire of the colon LP. This suggests that sub-mucosal ILFs serve as
important adaptive-inductive sites in the colon.

The study by Fenton \emph{et al} . advances the understanding of ILFs in
initiating the adaptive immune response and generating intestinal IgA,
especially in the context of allergic diseases. ILFs are commonly seen
on intestinal biopsies of young children, and hypertrophy of these
follicles has been associated with allergic
sensitization.\textsuperscript{5} Moreover, the work by Fenton \emph{et
al.} showing ILFs as a key source of intestinal IgA highlights their
potential role in the induction of immune tolerance and as a therapeutic
target. sIgA functions as a defence system against pathogen and toxins
and, its reduction has been associated with increased risk of allergy
development. This is supported by studies showing that low salivary and
intestinal sIgA levels resulted in an increased risk of allergic
manifestations during childhood.\textsuperscript{6} Allergen
sensitization studies in mice using bovine lactoglobulin also
demonstrated suppression in intestinal allergen-specific sIgA and number
of IgA\textsuperscript{+} B cells in PP compared with tolerant
mice.\textsuperscript{7} However, a recent clinical study showed
contradicting findings whereby a weak correlation was observed between
IgA deficiency and food allergy.\textsuperscript{8}

The interaction between sIgA and commensal bacteria in the intestine is
poorly understood. Children developing allergic manifestations such as
asthma have shown a lower proportion of IgA bound to faecal bacteria
compared to healthy children. This raises the possibility that sIgA
shapes the gut microbiota for inducing oral tolerance, in addition to
its role in maintaining homeostasis towards gut commensal bacteria.
Finally, as ILFs harbour GCs, identifying their role in allergic
diseases would be highly relevant because T and B cell interaction at
the GC is known to generate high-affinity, inflammatory antibodies
(IgE).\textsuperscript{9}

These novel findings show the role of human ILFs as a primary core for
regional immunity in the human intestine. Moreover, this study paves the
way towards a better understanding of the mechanisms involved in
maintaining the intestinal homeostatic network, allowing the development
of preventive and therapeutic approaches to immune disorders, including
allergic diseases.

\textbf{Total Word count: 747}

\textbf{Figure legend}

\textbf{Figure 1. Role of ILF within the GALT of the intestine.} ILF
consist of a heterogeneous population of immune cells that includes DCs,
T cells, Tfh-like cells and Treg cells. Moreover, they comprise of B
cells, IgA+ B cells, IgG+ B cells and IgM+ B cells, supporting their
role in the class switching of B cells. Human ILFs plays a role as
crucial immune inducer sites of adaptive immune response with an ability
to produce secretory IgA that plays a role in providing the first line
of defence in the intestinal tissue.

DCs, dendritic cells; Ig, Immunoglobulin; ILF, isolated lymphoid
follicles; Tfh, T follicular helper cells.

\textbf{References}

1. Tokuhara, D.\emph{, et al.} A comprehensive understanding of the gut
mucosal immune system in allergic inflammation. \emph{Allergol
Int}\textbf{68} , 17-25 (2019).

2. Durack, J. \& Lynch, S.V. The gut microbiome: Relationships with
disease and opportunities for therapy. \emph{J Exp Med} \textbf{216} ,
20-40 (2019).

3. Masahata, K.\emph{, et al.} Generation of colonic IgA-secreting cells
in the caecal patch. \emph{Nat Commun} \textbf{5} , 3704 (2014).

4. Fenton, T.M.\emph{, et al.} Immune Profiling of Human Gut-Associated
Lymphoid Tissue Identifies a Role for Isolated Lymphoid Follicles in
Priming of Region-Specific Immunity. \emph{Immunity} \textbf{52} ,
557-570 e556 (2020).

5. Kokkonen, J. \& Karttunen, T.J. Lymphonodular hyperplasia on the
mucosa of the lower gastrointestinal tract in children: an indication of
enhanced immune response? \emph{J Pediatr Gastroenterol Nutr}\textbf{34}
, 42-46 (2002).

6. Kukkonen, K.\emph{, et al.} High intestinal IgA associates with
reduced risk of IgE-associated allergic diseases. \emph{Pediatr Allergy
Immunol} \textbf{21} , 67-73 (2010).

7. Frossard, C.P., Hauser, C. \& Eigenmann, P.A. Antigen-specific
secretory IgA antibodies in the gut are decreased in a mouse model of
food allergy. \emph{J Allergy Clin Immunol} \textbf{114} , 377-382
(2004).

8. Aghamohammadi, A.\emph{, et al.} IgA deficiency: correlation between
clinical and immunological phenotypes. \emph{J Clin Immunol}\textbf{29}
, 130-136 (2009).

9. Gould, H.J., Takhar, P., Harries, H.E., Durham, S.R. \& Corrigan,
C.J. Germinal-centre reactions in allergic inflammation. \emph{Trends
Immunol} \textbf{27} , 446-452 (2006).

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