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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,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
disorders2.
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+ plasmablasts to the small
intestine.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 et al. describe a novel method for isolating human GALT
that allows thorough profiling of immune cells in
ILFs.4 The conventional isolation method has
identified the existence of plasma cells, naïve B and T cells in colonic
cell suspensions. The novel isolation method proposed by Fenton 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.4Using mass cytometry, CyTOF, they also demonstrated that the composition
of T and B cells in the GALT was distinct from the GALT-free LP;
CD57hiPD-1hi Tfh-like cells and
CD4+CD25+CD127-IL-2-Treg cells primarily localized in the GALT while cytokine-producing T
cell subsets mostly localized within the GALT-free
LP.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 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.5 Moreover, the work by Fenton 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.6 Allergen
sensitization studies in mice using bovine lactoglobulin also
demonstrated suppression in intestinal allergen-specific sIgA and number
of IgA+ B cells in PP compared with tolerant
mice.7 However, a recent clinical study showed
contradicting findings whereby a weak correlation was observed between
IgA deficiency and food allergy.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).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.