LPS was also inversely associated with atopic sensitization (Weber et al. 2015).
Interestingly, the more the microbiome of a Finnish home resembles that of the farm
environment rich in species of animal origin, the lower the risk of asthma in the
children (Kirjavainen et al. 2019). Other studies had also shown that contact with
cows and pigs protects against allergic disorders (Riedler et al. 2001; Sozanska et al.
2014). Moreover, the peripheral blood cells of children from homes with farm-like
microbiomes released lower levels of inflammatory cytokines in response to bacterial cell wall components in vitro (Kirjavainen et al. 2019).
We now understand that signals provided in early life by conserved microbial
components such as LPS are necessary for two distinct reasons. First, they set up the
appropriate background level of innate immune system activation, sometimes
referred to as “trained immunity”, via a series of epigenetic mechanisms elegantly
reviewed elsewhere (Netea et al. 2016). Secondly, and crucially, they set up antiinflammatory and immunoregulatory pathways, and it is these mechanisms rather
than trained immunity that are the focus of this review.
18.4.5.1 Endotoxin Tolerance and Immunoregulation
The first glimpse of these mechanisms was interpreted as “endotoxin tolerance”. It
was observed that animals would survive a lethal dose of endotoxin if they had
previously been exposed to one or more lower doses. More recently we understand
that this is not really what endotoxin tolerance is about (Fig. 18.3). In an animal
model LPS was shown to induce Treg via tolerogenic dendritic cells and TGF-β (Jia
et al. 2018). Endotoxin in dust protects against allergy through induction of A20 in
lung epithelial cells (Schuijs et al. 2015). A20, the product of the TNFAIP3 gene, is a
potent inhibitor of the NF-κB signalling pathway. The relevance of this to immunoregulation in humans is demonstrated by the observation that mutations in the
TNFAIP3 gene that lead to A20 deficiency cause an early-onset auto-inflammatory
disease (Zhou et al. 2016).
LPS also sets up immunoregulatory circuits via the gut. Autoimmune and allergic
disorders are much more prevalent in Finland and Estonia than in genetically similar
populations in Russia. It has emerged that the LPS of the dominant Gram-negative
bacteria in the guts of Finnish and Estonian children fails to trigger TLR4 and so fails
to set up endotoxin tolerance and the accompanying immunoregulatory mechanisms,
while the Russian children have organisms that provide a potent TLR4 agonist
(Vatanen et al. 2016).
18.4.5.2 Tolerance to TLR2 Agonists and Immunoregulation
Endotoxin is not the only microbial component to which tolerance can be induced,
and that can help to set up immunoregulatory circuits, including Treg (Fig. 18.3). It
is also possible to induce tolerance to TLR2 agonists such as lipoproteins from
Gram-negative and Gram-positive bacteria, lipoteichoic acid from Gram-positive
342
G. A. W. Rook
Interestingly, the more the microbiome of a Finnish home resembles that of the farm
environment rich in species of animal origin, the lower the risk of asthma in the
children (Kirjavainen et al. 2019). Other studies had also shown that contact with
cows and pigs protects against allergic disorders (Riedler et al. 2001; Sozanska et al.
2014). Moreover, the peripheral blood cells of children from homes with farm-like
microbiomes released lower levels of inflammatory cytokines in response to bacterial cell wall components in vitro (Kirjavainen et al. 2019).
We now understand that signals provided in early life by conserved microbial
components such as LPS are necessary for two distinct reasons. First, they set up the
appropriate background level of innate immune system activation, sometimes
referred to as “trained immunity”, via a series of epigenetic mechanisms elegantly
reviewed elsewhere (Netea et al. 2016). Secondly, and crucially, they set up antiinflammatory and immunoregulatory pathways, and it is these mechanisms rather
than trained immunity that are the focus of this review.
18.4.5.1 Endotoxin Tolerance and Immunoregulation
The first glimpse of these mechanisms was interpreted as “endotoxin tolerance”. It
was observed that animals would survive a lethal dose of endotoxin if they had
previously been exposed to one or more lower doses. More recently we understand
that this is not really what endotoxin tolerance is about (Fig. 18.3). In an animal
model LPS was shown to induce Treg via tolerogenic dendritic cells and TGF-β (Jia
et al. 2018). Endotoxin in dust protects against allergy through induction of A20 in
lung epithelial cells (Schuijs et al. 2015). A20, the product of the TNFAIP3 gene, is a
potent inhibitor of the NF-κB signalling pathway. The relevance of this to immunoregulation in humans is demonstrated by the observation that mutations in the
TNFAIP3 gene that lead to A20 deficiency cause an early-onset auto-inflammatory
disease (Zhou et al. 2016).
LPS also sets up immunoregulatory circuits via the gut. Autoimmune and allergic
disorders are much more prevalent in Finland and Estonia than in genetically similar
populations in Russia. It has emerged that the LPS of the dominant Gram-negative
bacteria in the guts of Finnish and Estonian children fails to trigger TLR4 and so fails
to set up endotoxin tolerance and the accompanying immunoregulatory mechanisms,
while the Russian children have organisms that provide a potent TLR4 agonist
(Vatanen et al. 2016).
18.4.5.2 Tolerance to TLR2 Agonists and Immunoregulation
Endotoxin is not the only microbial component to which tolerance can be induced,
and that can help to set up immunoregulatory circuits, including Treg (Fig. 18.3). It
is also possible to induce tolerance to TLR2 agonists such as lipoproteins from
Gram-negative and Gram-positive bacteria, lipoteichoic acid from Gram-positive
342
G. A. W. Rook