Immunology has generally been divided into
two classes of cellular response: the innate and the adaptive responses. The
adaptive response has the ability to confer specific protection against
pathogens and prevent re-infection due to T/B cell memory, this is the basic theory
underlying vaccination. The innate response has previously been thought of as a
non-specific, rapid response to infection that cannot protect against
re-infection. Evidence in nature disagrees with this general theory as we see
both insects and plants being able to respond in a more effective manner when
confronted with re-infection of a pathogen even though these organisms lack an
adaptive immune system (Rodrigues et al., 2010) (Spoel and Dong, 2012). Other evidence from humans has existed for at least a century when we
consider vaccinations such as the BCG vaccine conferring non-specific protection
to recipients resulting in a generalised reduction in mortality (Aaby et al., 2011) from various potential pathogen that likely has nothing to do with Mycobacterium tuberculosis protection.
Mechanisms for this process, termed: “innate immune memory” have recently begun
to be studied, with epigenetic changes of innate immune cells, particularly monocytes,
proving the richest in terms of mechanistic evidence. It appears that metabolic
changes in the cell are also highly linked to cytokine production and phagocytic
activity, two of the key features conferring effective protection against
re-infection. Along with a more effective response to secondary infection which
is known as “training”, the opposite effect has also been observed (Saeed et al., 2014). “Tolerance” has been
observed in macrophages after initial exposure to a stimulus such as
Lipopolysaccharide (LPS) which is believed to occur similarly, as a result of
epigenetic modification resulting in a less inflammatory macrophage phenotype.
The consequences of innate immune memory in monocytes can therefore be
generally divided into two categories: training and tolerance. In this review I
will discuss some of the historical evidence for innate immune memory, its
effects on monocyte and macrophage functionality, the mechanisms believed to be
underlying innate immune memory in monocytes and how it can potentially be used
in a medical setting.


Vaccines and Historical
evidence of innate immune memory

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The live attenuated Bacillus
Calmette-Guérin (BCG) vaccine is one of the most commonly used vaccinations in
the world with over 100 million children receiving the vaccine in 2004 (World
Health Organisation, 2004). BCG is currently the best option for conferring
immunity against Tuberculosis yet its efficacy at promoting an effective immune
response during reinfection with Mycobacterium
tuberculosis is highly variable with successful protection from TB fluctuating
hugely between regions (WHO, 2004). Like other live attenuated vaccines, BCG
has been associated with non-specific effects (NSEs) that are not immediately
related to the vaccine’s intended function and are not well understood.
Examples of such NSEs derived from in
vivo infant BCG vaccination include a general reduction of mortality due to
a reduction in neonatal sepsis, respiratory infection and fever (Aaby et al., 2011). A recent study (Kleinnijenhuis et al., 2012)
demonstrated the NSEs of BCG vaccination by measuring cytokine production in
human monocytes post BCG vaccination. After initial vaccination with BCG, blood
samples were drawn from human volunteers and exposed to various pathogens
including mycobacterium tuberculosis. Significant increases in monocyte-derived pro inflammatory cytokines such as
IFN-?, IL-1? and TNF-? were
observed in mycobactierum challenged
samples as well as monocytes exposed to S.
aureus and C. albicans relative
to blood samples taken pre-BCG vaccination, proving the non-specific effects of
the vaccine once more. An increase in the production of these cytokines would
increase the relative magnitude of the body’s immune response when confronted
with infection and may explain the reduction in neonatal morality observed.
Elevated cytokine production was still observed after 3 months showing the
longevity of BCG NSEs. While the more effective immune response observed due to
BCG training has sometimes been linked to T cell mediated immunity (Parra et al., 2013), experimental evidence has
shown that the heightened immune response observed is independent of T or B
cell help by using severe combined immunodeficiency (SCID) mice, lacking T and
B cells. Upon injection with lethal dosage of C. Albicans, survival in mice with prior BCG vaccination proved to
be greatly increased (Kleinnijenhuis et al., 2012). Combining
the longevity and T/B cell independence of these results we can see strong
evidence that an entirely innate immune system is indeed capable of having
innate immune memory, forming the basis of the topic “innate immune memory”. The
BCG vaccine is a useful example due to its ubiquitous use since the 1920’s
however it is important to note that other live attenuated vaccines have shown
indications of similar NSEs, such as the measles vaccine (Aaby et al., 2010). Considering the lack of
adaptive immune systems in organisms such as Plants and invertebrates, the
adaptation of innate immune memory seems logical in order to increase an
organism’s lifespan and therefore increase its reproductive success. The
non-specific nature of this response leads to difficulty in harnessing it for
clinical applications, however instead of trying to cure a certain illness or
disease perhaps innate immune memory can be harnessed to treat general

The effects of innate immune memory on Monocyte/Macrophage

entering the cell and discussing molecular mechanisms of innate immune memory,
it is worth exploring recent experimental evidence of innate immune memory in
monocytes and some of the characteristics of trained, tolerant and normal
monocytes as well as the conditions leading to innate immune memory. (Bekkering et al., 2016) conducted a study investigating the ability of
three inflammatory stimuli that are common in literature: ?-glucan
(a key component of fungal cell walls), oxidised low-density-lipoprotein
(Ox-LDL) and BCG vaccine, to induce innate immune memory. The study measured
parameters such as: pro and anti-inflammatory cytokine release, cellular
morphology, lactate production (an indirect measure of glucose consumption and
therefore glycolytic flux) and production of reactive oxygen species (ROS)
production all when cells were re-stimulated with a pathogen after a training
period. Increased glycolytic flux is a hallmark of trained immunity and will be
discussed later in more detail in terms of overall cellular metabolism. This
study showed how monocytes are altered as a result of innate immune memory but
also how differing stimuli induce a different cell phenotype and how altering
the conditions of training alters the function of the macrophage phenotype. For
example: all three stimuli resulted in increased 


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