complex (MHC) genes so that they cannot activate T cells, there is rapid and severe
gut inflammation (unless the animals are germ free) that can be mitigated by
antibiotic treatment (Loschko et al. 2016). Similarly, selective IgA-deficiency,
although often superficially asymptomatic, is in fact accompanied by increased
incidences of infectious and inflammatory disorders. The microbiota of these individuals has decreased overall diversity as well as altered relative abundances of
specific microbial taxa (Catanzaro et al. 2019). Animal models have shown that the
role of IgA is subtle, and different for different bacterial species. Bacteroides fragilis
needs to be coated with IgA if it is to colonise the right niche (Donaldson et al. 2018).
Similarly, IgA bound to Lactobacillus rhamnosus enhanced the ability of those
bacteria to potentiate differentiation of Treg cells via TLR regulatory proteins,
RALDH2 and secretion of IL-10 and TGF-β (Mikulic et al. 2017) (The Toll-like
receptors, TLRs, are proteins that have a key role in the innate immune system and
they recognise structurally conserved molecules derived from microbes that usually
are expressed on sentinel cells such as macrophages and dendritic cells). On the
other hand colonisation by beneficial Clostridia was antagonised by inappropriate
IgA targeting (Petersen et al. 2019). It is interesting that chronic inflammation
associated with metabolic syndrome or inflammatory bowel disease is accompanied
by increased faecal levels of flagellin (Tran et al. 2019). Flagellin is the main
component of bacterial flagella and induces inflammatory gene expression via
TLR5 and the NLRC4 inflammasome, and also provides motility that helps bacteria
to penetrate the intestinal mucus layer. Intraperitoneal injections of flagellin have
been shown to induce intestinal anti-flagellin IgA, and to ameliorate diet-induced
obesity and protect against the colitis that normally appears in IL-10-deficient
animals (Tran et al. 2019). Thus, the adaptive immune system coordinates with the
innate immune system and is indeed involved in “farming” the microbiota, and we
should suspect that any input to the immune system that modifies the response to any
microbial component will inevitably modulate the microbiota too.
18.4.3 Low Dose Pathogen Exposure
It is inevitable that amongst the organisms that are breathed in there will be low
doses of potential pathogens (Fig. 18.2). This provides an opportunity for the
immune system to develop immunity to these organisms, particularly in early life
when the infant might still be protected by maternal antibody. The airways kill or
disarm the respired organisms which are then taken in by the lymphoid tissue of
Waldeyer’s ring, or exposed to acid in the stomach before being sampled by the
dendritic cells in small bowel (Schulz and Pabst 2013). The array of mechanisms
used by the airways to disarm the inhaled pathogens is impressive. Bacterial cell wall
LPS, acting via TLR4 induces release of nasal mucosa-derived exosomes containing
inducible nitric oxide synthase. These exosomes transfer the enzyme to
neighbouring epithelial cells which then increases release of nitric oxide (Nocera
et al. 2019). Bacterial attachment also leads to release of cathelicidin (also known as
18 Darwinian Medicine: We Evolved to Require Continuing Contact with the. . .
339
gut inflammation (unless the animals are germ free) that can be mitigated by
antibiotic treatment (Loschko et al. 2016). Similarly, selective IgA-deficiency,
although often superficially asymptomatic, is in fact accompanied by increased
incidences of infectious and inflammatory disorders. The microbiota of these individuals has decreased overall diversity as well as altered relative abundances of
specific microbial taxa (Catanzaro et al. 2019). Animal models have shown that the
role of IgA is subtle, and different for different bacterial species. Bacteroides fragilis
needs to be coated with IgA if it is to colonise the right niche (Donaldson et al. 2018).
Similarly, IgA bound to Lactobacillus rhamnosus enhanced the ability of those
bacteria to potentiate differentiation of Treg cells via TLR regulatory proteins,
RALDH2 and secretion of IL-10 and TGF-β (Mikulic et al. 2017) (The Toll-like
receptors, TLRs, are proteins that have a key role in the innate immune system and
they recognise structurally conserved molecules derived from microbes that usually
are expressed on sentinel cells such as macrophages and dendritic cells). On the
other hand colonisation by beneficial Clostridia was antagonised by inappropriate
IgA targeting (Petersen et al. 2019). It is interesting that chronic inflammation
associated with metabolic syndrome or inflammatory bowel disease is accompanied
by increased faecal levels of flagellin (Tran et al. 2019). Flagellin is the main
component of bacterial flagella and induces inflammatory gene expression via
TLR5 and the NLRC4 inflammasome, and also provides motility that helps bacteria
to penetrate the intestinal mucus layer. Intraperitoneal injections of flagellin have
been shown to induce intestinal anti-flagellin IgA, and to ameliorate diet-induced
obesity and protect against the colitis that normally appears in IL-10-deficient
animals (Tran et al. 2019). Thus, the adaptive immune system coordinates with the
innate immune system and is indeed involved in “farming” the microbiota, and we
should suspect that any input to the immune system that modifies the response to any
microbial component will inevitably modulate the microbiota too.
18.4.3 Low Dose Pathogen Exposure
It is inevitable that amongst the organisms that are breathed in there will be low
doses of potential pathogens (Fig. 18.2). This provides an opportunity for the
immune system to develop immunity to these organisms, particularly in early life
when the infant might still be protected by maternal antibody. The airways kill or
disarm the respired organisms which are then taken in by the lymphoid tissue of
Waldeyer’s ring, or exposed to acid in the stomach before being sampled by the
dendritic cells in small bowel (Schulz and Pabst 2013). The array of mechanisms
used by the airways to disarm the inhaled pathogens is impressive. Bacterial cell wall
LPS, acting via TLR4 induces release of nasal mucosa-derived exosomes containing
inducible nitric oxide synthase. These exosomes transfer the enzyme to
neighbouring epithelial cells which then increases release of nitric oxide (Nocera
et al. 2019). Bacterial attachment also leads to release of cathelicidin (also known as
18 Darwinian Medicine: We Evolved to Require Continuing Contact with the. . .
339