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Evolution of the immune system in humans from infancy to old age

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Evolution of the immune system in humans from infancy to old age

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This article reviews the development of the immune response through neonatal, infant and adult life, including pregnancy, ending with the decline in old age. A picture emerges of a child born with an immature, innate and adaptive immune system, which matures and acquires memory as he or she grows. It then goes into decline in old age. These changes are considered alongside the risks of different types of infection, autoimmune disease and malignancy.
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Cite this article: Simon AK, Hollander GA,
McMichael A. 2015 Evolution of the immune
system in humans from infancy to old age.
Proc. R. Soc. B 282: 20143085.
http://dx.doi.org/10.1098/rspb.2014.3085
Received: 20 January 2015
Accepted: 1 May 2015
Subject Areas:
health and disease and epidemiology,
immunology, microbiology
Keywords:
adaptive immunity, innate immunity,
infections
Author for correspondence:
Andrew McMichael
e-mail: andrew.mcmichael@ndm.ox.ac.uk
One contribution to the special feature
‘Evolution and genetics in medicine’ Guest
edited by Roy Anderson and Brian Spratt.
Invited to commemorate 350 years
of scientific publishing at the Royal
Society.
Evolution of the immune system in
humans from infancy to old age
A. Katharina Simon1, Georg A. Hollander2and Andrew McMichael3
1
Nuffield Department of Medicine, Weatherall Institute of Molecular Medicine, and
2
Department of Paediatrics,
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
3
Nuffield Department of Medicine Research Building, University of Oxford, Old Road Campus, Oxford OX3 7FZ, UK
AKS, 0000-0002-4077-7995
This article reviews the development of the immune response through neo-
natal, infant and adult life, including pregnancy, ending with the decline in
old age. A picture emerges of a child born with an immature, innate and adap-
tive immune system, which matures and acquires memory as he or she grows.
It then goes into decline inold age. These changes are considered alongside the
risks of different types of infection, autoimmune disease and malignancy.
1. Introduction
And one man in his time plays many parts,
His acts being seven ages.
William Shakespeare
1
More than 1600 genes are involved in innate and adaptive immune responses [1].
These genes are of great importance for sustaining life in a hostile environment. Yet
the immune system is relatively immature at birth and has to evolve during a life of
exposure to multiple foreign challenges through childhood, viayoung and mature
adulthood (including pregnancy), to the decline of old age (figure 1).
2. Ontogeny of the immune system in early life
At first the infant,
Mewling and puking in the nurse’s arms.
In utero, the fetal environment demands that the immune system remains tolerant
to maternal alloantigens. After birth, the sudden enormous exposure to environ-
mental antigens, many of them derived from intestinal commensal bacteria, calls
for a rapid change to make distinct immune responses appropriate for early life.
(a) The innate immune system
The innate immune system provides an early first line of defence against invading
pathogens. The cells involved are neutrophils, monocytes, macrophages and den-
dritic cells, which all interact with the adaptive immune system. These cells
develop and mature during fetal life, but at different times, and the function of
all components of innate immunity is weak in newborns compared with later life.
Mature neutrophils are present at the end of the first trimester and steeply
increase in number, stimulated by granulocyte-colony-stimulating factor, shortly
before birth. Their number then returns to a stable level within days, but they
show weak bactericidal functions, poor responses to inflammatory stimuli,
reducedadhesion to endothelial cells anddiminished chemotaxis [3]. These deficits
are more striking in preterm infants, which also have lower serum IgG and comp-
lement. Consequently, the newborn, and especially premature infants, have
impaired neutrophil functions [4], putting the child at risk of bacterial infections.
In preterm and newborn infants, classical monocytes and macrophages are
also immature. They have reduced TLR4 expression [5] with impaired innate
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signalling pathways [6– 8], resulting in diminished cytokine
responses compared with adults. Consequently, there is poor
tissue repair, impaired phagocytosis of potential pathogens
and poor secretion of bioactive molecules. However, while
there is a reduced frequency of pulmonary macrophages in pre-
mature and term infants, adult levels of these cells are reached
within days after birth [9].
Compared with blood from children or adults, cord blood
contains fewer myeloid-type dendritic cells (mDC). They
express lower cell surface levels of HLA class II, CD80 and
CD86 than adult mDC [10]. They secrete low concentrations
of IL-12p70 in response to activating innate stimuli [11]. Thus
priming of Th1 and CD8 T-cell responses is diminished com-
pared with adults, correlating with an increased susceptibility
to infections caused by viruses, Mycobacterium tuberculosis and
Salmonella spp.In contrast, newborn mDC stimulated via
TLR4 secrete adult-like concentrations of pro-inflammatory
cytokines [12] that promote Th17 immune responses.
Plasmacytoid dendritic cells (pDC) release high concen-
trations of type I interferon (IFN) in response to TLR7 and
TLR9 stimulation in adults. However, newborn pDC are severely
limited in secreting interferon a/bupon exposure to different
viruses, despite expressing levels of TLR7 and TLR9 that are
similar to adults [13]. Consequently, innate immune responses
to viruses such as respiratory syncytial virus, herpes simplex
virus and cytomegalovirus are poor compared with later in life.
Natural killer (NK) cells in adults restrain viral replication
and dissemination before adaptive immunity is established
[14]. They are regulated by inhibitory receptors that recognize
HLA-A, B, C and E, and therefore contribute to self-tolerance.
In early gestation, NK cells are hypo-responsive to target cells
lacking major histocompatibility complex (MHC) class I mol-
ecules (such as trophoblast [15]) and are highly susceptible
to immune suppression by transforming growth factor-b
(TGF-b). NK cytolytic function increases during gestation but is
still only half of adult level at birth. Neonatal NK cells are less
responsive to activation by IL-2 and IL-15, and produce limited
IFN-gconcentrations. However, the cells’ threshold for activation
is lower, which provides some anti-viral protection [15].
The three independent pathways that activate the comp-
lement system are critical to host defence and inflammation.
Complement components facilitate opsonization, are chemo-
attractants for innate cells, mediate cell lysis and influence anti-
body production. Newborn serum concentrations of almost all
circulating components are 10–80% lower than in adults [16],
with diminished biological activity. Complement levels
increase after birth,with some serum factors reaching adult con-
centration within a month (e.g. Factor B), but others evolve
more slowly [16]. Because infants have low immunoglobulin
concentrations, complement effector functions depend on the
alternative and lectin-binding activation pathways, triggered
by polysaccharides and endotoxins.
110 20 30 40 50 60 70 80 90
110 20 30 40 50 60 70 80 90
1
3
5
7
9
11
13
15
seasonal
influenza
pandemic
influenza
influenza
deaths per 1000 persons
y
ears
strength of the response
Th1
Treg
B and innate
maternal
antibodies pregnancy
Th2
(a)
(b)
(c)
Figure 1. (a) The seven ages of woman. (b) Schematic graph of excess deaths from seasonal or pandemic influenza over the lifetime of an individual represented as
number of deaths per 1000 persons (adapted from [2]). Note that while pregnancy increases the risk of severe influenza, in severe pandemics such as 1918/1919
there were also excess deaths in previously healthy young adults who were not pregnant. (c) Schematic graph of the different arms of the immune response to
influenza over the lifetime of an individual.
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Overall, the innate immune system is muted at birth, a
price probably paid by the fetus not only to tolerate non-
shared maternal antigens but also to ignore the considerable
amount of stress and remodelling that takes place during
development. This makes the newborn, and particularly
the premature baby, relatively susceptible to bacterial and
viral infections.
(b) The adaptive immune system
T cells develop in the thymus, which is largest at birth and
during the first years of life. Mature single CD4
þ
and CD8
þ
positive T cells are first detected in the thymus at week 15
and abundant in the periphery well before birth [17,18]. How-
ever, neonatal T cells differ significantly from adult cells,
reflecting the fetal life, where exposure to foreign antigens is lar-
gely restricted to non-inherited maternal alloantigens. The
function of early-life T cells is different from adult T cells.
For example, though fetal naive CD4
þ
T cells respond
strongly to alloantigens, they tend to develop towards Foxp3
þ
CD25
þ
regulatory T cells (T
reg
) through the influence of
TGF-b[19], and thus actively promote self-tolerance. Peri-
pheral T
reg
represent around 3% of total CD4
þ
T cells at birth
[20] and these cells persist for an extended period of time [21],
giving the early-life immune response an anti-inflammatory
profile [22].
Foreign antigen activation of late fetal or neonatal T cells
results in a response skewed towards Th2 immunity [23],
which is reinforced by neonatal dendritic cells and epigenetic
features [24,25]. Very early-life adaptive T-cell immunity is thus
characterized by tolerogeneic reactivity, reduced allo-antigen
recognition and poor responses to foreign antigens.
In the newborn, in addition to conventional T cells that
recognize peptide antigens in the context of classical MHC
molecules, there are populations of gd T-cell receptor (TCR)-
positive and innate-like ab TCR-positive T cells. These include
functionally competent iNKT cells that rapidly produce IFN,
mucosal-associated invariant T (MAIT) cells [26] and the
newly described interleukin-8 (CXCL8)-secreting naive T cells
that bridge innate and adaptive immunity [27]. MAIT cells
develop in the thymus, but their maturation can take place in
fetal mucosal tissues before microbial colonization. The
CXCL8-producing T cells produce important effector functions
in human newborns as they have the potential to activate
antimicrobial neutrophils and gd T cells. They appear to be par-
ticularly active at the mucosal barriers of premature and term
infants, though their frequency decreases with age. In contrast
to adult blood, wherethe repertoire ofgd TCR is restricted, neo-
natal blood gd T cells display a variety of receptor chain
combinations that change with gestation [27]. gd T cells can pro-
duce significant amounts of IFN-g, after brief polyclonal
stimulation, compensating for the immaturity of the more
classical Th1-type T-cell response to neonatal infections [28,29].
Two types of B cell arise via distinct developmental
pathways [30]. B1 cells spontaneously secrete low-affinity
IgM with a limited range of antigen specificities (includ-
ing common bacterial polysaccharides), have fewer somatic
mutations and serve as a first line of defence [31]. B1 cells secrete
IL-10 and TGF-b, and thus promote a Th2 response. At birth, B1
cells comprise 40% of peripheralblood B cells and this frequency
remains high for a few months [32]. Conventional B cells (desig-
nated B2 cells) originate from a multi-linage CD34
þ
common
lymphoid progenitor and generate a broad repertoire of
immunoglobulin specificities due to their expression of terminal
deoxynucleotidyl transferase, which enhances diversity in
V-D-J immunoglobulin gene segment joining. B cells are
typically present in secondary lymphoid organs and in the
bone marrow, where they contribute to the humoral response
of the adaptive immune system.
Most antibody responses, including those to bacterial pro-
teins, bacterial polysaccharides and to polysaccharide– protein
conjugate vaccines, are dependent on T-cell help. They rely
on interactions between the TCR and the engagement of co-
receptors including CD28 and CD40 ligand on Th2 or follicular
T helper cells with their corresponding binding partners
HLA-peptide, CD80/86 and CD40 on antigen-specific B cells.
However, neonatal B cells express low levels of these co-
receptors, limiting their capacity to respond [33]. Furthermore,
low levels of the receptor for complement C3d fragment (CD21)
impede responses to polysaccharide– complement complexes
[34]. Together, these features contribute to blunted humoral
immune responses with incomplete immunoglobulin class
switching [35], although memory B cells are generated [36].
B cells from neonates and infants aged less than 2 months
show decreased somatic hypermutation compared with
adults, limiting affinity maturation of antibodies [37]. Finally,
there is a failure of early-life bone marrow stromal cells to sup-
port long-term plasmablast survival and differentiation to
plasma cells, so that any IgG antibodies elicited rapidly decline
after immunization, unlike in older children and adults [38].
Hence, the efficiency of the adaptive immune system to respond
to T-cell-dependent antigens early is markedly impaired in neo-
nates compared with older children and adults. This
physiological behaviour is particularly relevant to vaccination
programmes. Together with the impaired innate immunity,
the weak Th1 and antibody responses amply explain why neo-
natal mortality can be high under conditions of increased
pathogen exposure.
3. From childhood to adulthood
Then, the whining schoolboy with his satchel
And shining morning face, creeping like snail
Unwillingly to school.
The young human child, even as the innate and adaptive
immune systems start to mature, is at risk from many patho-
genic viruses, bacteria, fungi and parasites. Nevertheless, he
or she has a good chance of survival in developed countries.
Before there was good nutrition, hygiene and comprehensive
vaccination, there was a high mortality in infants and young
children. In 1900, the UK infant mortality rate was 140 per
1000, falling to 7 per 1000 by 2000 [39]. This reduction in mor-
tality was proportionally greater in infants and children
compared with other age groups [40]. Better prevention and
control of infections accounts for most of this fall. However, in
many countries, infant mortality rates remain above 50 per
1000, giving some indication of the evolutionary pressure that
must have selected a working protective immune system. Fur-
thermore, such pressure has selected the extreme genetic
polymorphism in the MHC, which through peptide presen-
tation to T cells and NK cells is a key regulator of almost all
immune responses.
The immune system gradually matures during infancy.
Critical early protection against many infectious diseases
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previously experienced by the mother is given by the passive IgG
antibody transferred from the mother transplacentally and in
milk. Once that fades away, young children become more vulner-
able to infections, though by then better armed with the maturing
innate and adaptive immune systems. The risks are now much
reduced by vaccinations, which stimulate protective immune
responses in the maturing immune system. Nevertheless, chil-
dren may still acquire viral, bacterial and parasitic infections
that have to be fought off and controlled by immune responses.
Besides promoting recovery, such antigen stimulation results in
immunological memory [41,42]. Thus, over time, protection pro-
vided by the immune response increases, and young adults
suffer fewer infections. This accumulation of immunological
memory is an evolving feature of the adaptive immune response.
The memory persists into old age [41] but then may fade.
Besides frank infections and vaccinations, the newborn is
exposed to other antigens. He or she comes from a relatively
sterile environment in utero and is then rapidly exposed to
multiple microbes [43]. The first major exposure to bacteria
is during passage through the birth canal, and then as soon
as he/she makes oral, skin and respiratory contact with the
exterior. From then on, exposure to microorganisms is con-
tinuous. Many of the bacteria that colonize the gut and
other mucosal sites are essential for healthy life, including
digestion of food and acquisition of vital nutrients. They
also impact on the development of the immune system [44].
Approximately 20% of all lymphocytes reside in the
gut [45], exposed to many possible foreign immunogens.
Gut immune cells monitor the boundary with a potentially
dangerous source of infections. Gut bacteria influence the
development of Th17 cells [46], T
reg
cells [47] and memory
T cells [48–50]. At birth, nearly all T cells carry the CD45RA
glycoprotein, typical of naive T cells, which have never
encountered foreign antigen. There are also relatively abun-
dant T
regs
within the CD45RA negative CD4 T cells. During
childhood, T
reg
cell numbers decline, and memory Th1,
Th17 and Th2 cells gradually increase to equal the number of
naive T cells [51]. Although some of these memory T cells
could have been stimulated by infections with specific patho-
gens and by vaccinations, many may be primed by the
microbiome, not only in the gut but also in the respiratory
tract and skin. These primed memory T cells may respond to
subsequent infections through cross-reactions [48,52,53]. For
example, adults who have never been exposed to HIV-1 have
memory T cells in their repertoire that react with HIV peptides
presented at the cell surface by HLA proteins; these T cells are
likely to be reawakened should HIV infection occur [48,50],
similarly to other microbes [52]. The cross-reactivity arises
from the discrete short (8 15 amino acids) peptides (epitopes)
which fit into peptide-binding grooves on the HLA class I or
II molecules at the cell surface and are then recognized by T
cells. Within the microbiome sequences, there are numerous
perfect and near-perfect matches to known virus peptide
epitopes, such as those from HIV-1 [48,50]. These could easily
be responsible for generating the memory T cells specific for
pathogen epitopes the person has never encountered.
Segmented filamentous bacteria in the gut are necessary
for the development of Th17 cells [47] and Clostridium spp.
induce colonic T
reg
cells [54,55]. Germ-free mice have
immunological defects, including fewer Peyers patches, smal-
ler lymphoid follicles and abnormal germinal centres in the
small intestine lymphoid tissue [56]. This immuno-deficiency
can be corrected in a few days by adding a single mouse with
normal gut flora to a cage of germ-free animals [56,57]. Thus
animal data support the notion that the microbiome shapes
the development of both memory T and B cells.
Similar events occur for B cells. The carbohydrate antigens
of the ABO blood groups cross-react with gut bacterialantigens
and stimulate IgM antibody responses. Antibodies to the gp41
protein of HIV-1 may be derived from B cells whose antibody
receptors cross-react with a protein in Escherichia coli [58].
As the child grows, the immune repertoire is also shaped by
intercurrent infections and vaccinations [59]. Pathogenic infec-
tions can be documented by symptomatic illnesses suffered
by the child or adult, but for many viruses, such as influenza,
infection may be subclinical, but still sufficient to stimulate or
boost immune responses [60]. Generally, the protection offered
by the immuneresponse, both by antibodies and T cells, is very
potent. Most childhood infections happen only once and then
protection is lifelong.
The maintenance of long-term B-cell memory is remark-
able given that IgG immunoglobulin has a half-life in vivo
of around 25 days [61]. The antibody-producing plasma
cells that develop during an immune response migrate to
the bone marrow, where they are very long lived. In addition,
there may be continuous regeneration of memory B cells in
contact with persisting antigen and helper T cells. Particulate
antigens persist for years in lymph nodes, held by follicular
dendritic cells [62]. Antigen persistence and cross-reactive
antigens probably help to keep these B cells alive, dividing
occasionally and secreting antibodies.
It is remarkable that a mother can transfer sufficient
antibody to protect her infant when she was infected 20–30
years previously. The transmission of protective antibody pro-
tection from a mother to her child is hugely important,
especially in environments where 15% or more infants and chil-
dren die of infection. Paradoxically, a mother who avoided a
dangerous childhood infection, through herd immunity, may
actuallyput her child at risk by being unable to transfer specific
protective antibodies.
There are a large number of asymptomatic chronic infec-
tions, mostly viral, that provoke immune responses. Examples
are cytomegalo virus (CMV), Epstein– Barr virus (EBV) and
Mycobacterium tubercolosis (Mtb), but the full list is long and
expanding [63]. EBV, CMV and Mtb provoke very strong CD4
and CD8 T-cell responses in humans. The CMV-specific
CD8 T-cell response can result in oligoclonal T-cell expansions
reaching more than 10% of circulating CD8 T cells. These
T cells are important because they control the virus
and their depletion, for instance by immunosuppressive
therapy, can activate the infection (e.g. Mtb,EBV,CMV),with
devastating consequences.
The evolution of antibody responses in B lymphocytes has
been reviewed elsewhere in detail [64]. In brief, naive B cells
with antibody receptors specific for the immunogen bind anti-
gen in the germinal centre of lymph nodes and receive a partial
signal. The bound antigen is internalized and digested in lyso-
somes. A few resulting peptides bind to the HLA class II
molecules of that cell and are then presented on the cell surface
where T follicular helper cells with appropriate T-cell receptors
respond and deliver further signals, including IL-21, to the B
cell. These signals trigger B-cell division, class switching of
the antibody genes and somatic hypermutation. B cells that
express mutated antibody that binds immunogen with higher
affinity are then favoured. Selection for better binding
antibodies continues over months, ultimately resulting in
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high-affinity antibody coming from highly mutated germ line
genes. High-affinity antibodies are more effective at neutraliz-
ing or opsonizing invading microbes and their pathogenic
products.
The somatic hypermutation process does not occur in T cells,
even though they have antibody-like T-cell receptor genes,
because there is no advantage in having a high-affinity T-cell
receptor. The T-cell receptor binding to the peptide–HLA com-
plex on an antigen presenting cells has low affinity. It is enhanced
by several co-receptor– ligand pairs that are not antigen-specific,
giving the T cell the signal to divide and function.
As a result of an immune challenge, the responding T and B
cells may expand transiently to very high numbers [65], some-
times more than 10% of all circulating T cells, but these decline
rapidly as a result of activation-induced cell death and from
attrition over a longer time period. Thus as the pathogen is con-
trolled and disappears, some memory T and B cells persist for a
long time in numbers that far exceed the number of naive and
‘naive-memory’ T cells that were there before infection.
As the individual gets older, he or she develops an expand-
ing repertoire comprising memory T and B cells triggered by
previous infections and vaccinations, but also a naive-memory
repertoire shaped by exposure to the microbiome, food antigens
and inhaled antigens. Given the great complexity of the T- and
B-cell repertoires and a large stochastic element in choosing
which cells will respond to a given stimulus, and somatic
mutations in B cells, the precise composition will differ in each
individual, even in monozygotic twins [66]. Add to this con-
siderable genetic variability in how individuals respond,
determined by the highly polymorphic HLA genes [67] and
by the genes of innate immunity, and it is not surprising that
the immune responses of any single adult vary considerably.
(a) Pregnancy
It is beyond the scope of this review to explore the immunology
of pregnancy in detail (reviewed in [68,69]). However, success-
ful reproduction is of central evolutionary importance and there
are immunological issues. How the newborn retains mechan-
isms by which the fetus minimizes its immune responses to
the mother has been discussed above. A bigger puzzle is how
the mother tolerates a semi-allogeneic graft without rejecting
it and without the immunosuppression necessary to accept an
organ transplant [70]. There are features at the trophoblast
maternal interface at the site of initial implantation and in the
placenta that subvert the normal graft rejection immune
response. These include expression only of non-polymorphic
non-classical HLA antigens on the trophoblast [71], local
immune suppression mediated by infiltrating NK cells [72],
monocytes and T regulatory cells [69,73], and inhibition of
T-cell activation by tryptophan catabolism [74]. Around the
time of implantation, a local inflammatory response sets up
the stable placental site [68]. There is evidence that the mother
changes the balance of her T-cell responses to Th2 rather than
Th1 [68]. Thus pregnant women can show remissions of auto-
immune disease [75], and are more susceptible to severe
complications of influenza [76] and some other infections.
This immune modulation, necessary for the well-being of the
fetus, can occasionally be harmful to the mother.
(b) Malignancy and autoimmunity
The primary role of the immune system is probably to protect
against infections. Other roles such as destruction of mutated
cells may be very important, though more so in old age after
reproduction. Many tumours turn off T cells specific for
tumour antigens by binding to ‘check-point’ receptors such
as PD-1 or CTLA4, and new treatments that block these
receptor– ligand interactions have great therapeutic potential
[77,78]. However, the side effects of such therapy and of the
passive transfer of anti-cancer T cells include autoimmune
reactions, suggesting a balance between anti-self-immune
reactions preventing cancer and causing autoimmunity [79].
In adult life, the balance usually works, but one-third of
Western humans develop cancer, usually later in life, while
5–10% develop clinical autoimmune disease, so the balance
is finely set and may shift over time. The fading immune
system in old age (see below) may ameliorate autoimmunity
but at the expense of increased cancer risk.
Microorganisms cause about a quarter of all cancers (e.g.
EBV, hepatitis B and C viruses, human papilloma virus and
Helicobacter pylori). Specific T-cell responses normally hold
these microbes in check. However, if immunity is impaired
through ageing (see below), immunosuppressive therapy or
certain infections, particularly HIV-1, these cancers emerge [80].
Therefore, having developed a fully effective immune
response in early childhood, this matures as memory
accumulates and maintains the health of the individual
during critical periods of life, including child bearing. It not
only protects against potentially lethal infections but also
controls a number of persisting infections, some of which
have the potential to cause cancer. It can also deal with
mutant cells that have potential for becoming malignant. It
can be over-reactive and cause autoimmune disease or
allergy, a price paid for the overall benefit.
4. Immune decline with age
Last scene of all,
That ends this strange eventful history,
Is second childishness and mere oblivion,
Sans teeth, sans eyes, sans taste, sans everything.
As age advances, the immune system undergoes profound
remodelling and decline, with major impact on health and
survival [81,82]. This immune senescence predisposes older
adults to a higher risk of acute viral and bacterial infections.
Moreover, the mortality rates of these infections are three
times higher among elderly patients compared with younger
adult patients [83]. Infectious diseases are still the fourth most
common cause of death among the elderly in the developed
world. Furthermore, aberrant immune responses in the aged
can exacerbate inflammation, possibly contributing to other
scourges of old age: cancer, cardiovascular disease, stroke,
Alzheimer’s disease and dementia [84].
During a regular influenza season, about 90% of the
excess deaths occur in people aged over 65. Furthermore,
poor immune responses account for diminished efficacy of
vaccines [82,85]. Immune senescence also results in reactiva-
tion of latent viruses, such as varicella-zoster virus, causing
shingles and chronic neuralgia.
Deterioration of the immune system with age may compro-
mise the homeostatic equilibrium between microbiota and host.
Thus reduced bacterial diversity in the gut has been correlated
with Clostridium difficile-associated diarrhoea, a major compli-
cation for the elderly in hospitals [86]. Moreover, deviations
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from the intestinal microbiota profile, which was established
in youth, are associated with inflammatory bowel disease
[87]. The increase with age in pro-inflammatory pathobionts
and the decrease in immune-modulatory species may promote
and sustain inflammatory disorders [86].
At the same time, the ageing immune system fails to main-
tain full tolerance to self-antigens, with an increased incidence
of autoimmune diseases. [88]. This is probably due to lympho-
paenia occurring with age, leading to excess homeostatic
lymphocyte proliferation [89], as well as a decrease in regulat-
ory T-cell function and decreased clearance of apoptotic cells
by macrophages [81].
Cancer is most frequent in older people; the median age for
cancer diagnosis in industrialized countries is approaching
70 years of age. The main reason is obviously the accumulation
of cellular and genetic damage throughout life; however, given
the role of the immune response in controlling cancers, reduced
immune functions in the elderly must contribute to the higher
risk [90]. This immune impairment is in apparent contradiction
to the increase in autoimmunity as anti-tumour responses can
be directed against self; however, the general decline of the
immune system probably prevails and tumours are no longer
rejected as efficiently. Moreover, the increased inflammation
found with age facilitates cancer emergence.
The increased morbidity due to the decline of the immune
system is a directconsequence of dysregulated adaptive immunity
in the elderly. The low number of naive T cells versus T cells [41,42]
is a consequence of the reduced thymic output from the involuted
thymus. As a consequence of this age-induced lymphopaenia,
T cells proliferate andincrease the ‘virtual memory’ compartment
[91], but at the same time, the ability to establish immunological
memory in response to de novo antigens is reduced, compromis-
ing vaccinations. Functions such as cytokine production by CD4
andCD8Tcellsareimpaired,theexpressionofkeysurfacemar-
kers is altered and the CD4
þ
to CD8
þ
T-cell ratio is inverted
[81]. The expanded T-cell responses that keep latent viruses such
as EBV and CMV under control reduces space for CD8
þ
T cells
specific for other potentially lethal viruses [92], exacerbated by
the reduced thymic naive T-cell output.
While peripheral B-cell numbers do not decline with age,
the composition of this compartment changes. Similar to T
cells, naive B cells are replaced by antigen-experienced
memory cells, some of which are ‘exhausted’ (CD19
þ
IgD
2
CD27
2
), and they display decreased affinity maturation and
isotype switching [81].
In general, the changes in the T- and B-cell compartments
hamper the adequate immune response to new acute and
latent viral infections and vaccinations.
The innate immune response also declines with age. There
are changes in innate cell numbers, with skewing of haemato-
poiesis towards the myeloid lineages [93,94]. The senescent
neutrophil is less functional with decreased phagocytic ability
and superoxide production partly due to decreased Fc
g
recep-
tor expression [95]. Similarly, ageing macrophages have a
decreased respiratory burst. Together with DCs, they display
reduced phagocytic function and HLA II expression [81]. The
immunological ‘silent’ removal of apoptotic and increasing
numbers of senescent cells is therefore compromised, and
may contribute to the pro-inflammatory phenotype. Indeed,
when senescent cells were removed from aged mice artificially,
the animals lived longer and were healthier [96].
Possibly the most critical change in the ageing innate
immune system is the increase in pro-inflammatory cytokines
IL-1b, IL-6, IL-18 and TNFa[97]. The resulting low-grade
inflammation probably contributes to atherosclerosis, demen-
tia and cancer, inextricably linking inflammation and ageing
of other tissues [84,98].
The cellular and molecular basis of immune senescence is
still not well understood. Three phenotypes characterize
senescent cells: telomere attrition accompanying each round
of proliferation, leading to arrested cell division or ‘replicative
senescence’; increased mitochondrial load/dysfunction and
reactive oxygen species; and senescence-associated secretory
phenotype (SASP), defined as the secretion of pro-inflamma-
tory cytokines, chemokines and proteases by senescent cells
[99]. While most of the data have been obtained in fibroblasts,
senescent immune cells probably show similar features.
These features impact on mitotically active cells by depletion
or arrested division (e.g. haematopoietic stem cells—HSCs or
T cells), and on post-mitotic immune cells by causing cellular
dysfunction (e.g. neutrophils).
Attrition of telomeres is a protective mechanism against
cancer, as each round of proliferation is likely to introduce
mutations [100]. Only epithelial lymphocytes and stem cells
including haemopoietic (HSCs) express the telomere-lengthen-
ing enzyme telomerase in the adult [101], requiring a careful
balance against the risk of cancer. Both memory T cells and
HSCs characteristically divide rarely, to minimize telomere
attrition, but reliably either in response to infection (memory
lymphocytes) or for tissue renewal (stem cells) throughout the
entire lifespan. End-stage senescent CD27
2
CD28
2
Tcells
have the shortest telomeres and show decreased proliferation
after activation, but nevertheless exhibit potent effector func-
tions. These cells accumulate in old age and in patients with
autoimmune diseases and chronic viral infections [102]. The
second characteristic of aged cells is increased mitochondrial
dysfunction and ensuing oxidative damage to proteins and
DNA. DC function in aged micecan be restored through admin-
istration of anti-oxidants [103]. Oxidative stress causes DNA
breaks and may be the cause of telomere attrition, which links
the first two causes of ageing. The accumulation of oxidative
damage could be due to a decline in lysosomal and autophagy
function [104]. Autophagy, degrading bulk cytoplasmic material
by delivering it to the lysosomes, falls with age, including in
human CD8
þ
T cells [105]. Mice without autophagy in their
haematopoietic system display a prematurely aged haemato-
poietic system [106]. Failing memory T cells’ responses to flu
vaccination observed in the elderly can be restored with an
autophagy-inducing compound [107]. A third more recent
addition to these fundamental changes of aged cells is the acqui-
sition of the SASP, contributing to increased pro-inflammatory
cytokine secretion and low-grade inflammation [99].
5. Evolution of the human immune system
As a long-lived species, humans have evolved mechanisms of
innate immunity and immunological memory to survive recur-
rent infections.However,over the lifetime of an individual, these
immune mechanisms change, first to adapt to the change from
fetus to infant, and then to mature and expand during growth,
subtly changing in pregnancy and finally decreasing in senes-
cence. The output of naive lymphoid cells and the ability to
form new immunological memory becomes increasingly less
important as the older individual will have encountered and
established a memory bank to many pathogens over its lifetime.
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There is a possibility that the myeloid bias and the increased
secretion of pro-inflammatory cytokines during ageing are
essential for improved phagocytosis of an increasing number
of senescent cells, raising the question of whether the changes
in the ageing immune system might serve a purpose.
The immune system has been primarily moulded by evol-
ution to respond efficiently to acute infections in young
people, to adapt to pregnancy and to transmit protection to
infants, and is adapted to cope with many chronic infections
lasting for decades. Apart from fighting viruses, bacteria,
fungi and parasites, the immune system also assumes other
roles such as tissue repair, wound healing, elimination of dead
and cancer cells, and formation of the healthy gut micro-
biota. Assuming an absence of a major selective pressure on
humans beyond reproductive age, we may have to pay for gen-
etic traits selected to ensure early-life fitness by the later
development of immunological phenotypes such as chronic
inflammation. Massive ageing and advanced longevity are
very recent phenomena occurringin an optimized environment.
As proposed by Hayflick [108], ageing may be an artefact of
civilization, and hence changes in the ageing immune system
might just be a consequence of evolutionary unpredicted anti-
genic exposure over the lifetime of an individual.
In some aspects, the immune system of the aged organism
resembles that of the newborn, with reduced antimicrobial
activity by neutrophils and macrophages, reduced antigen pres-
entation by DCs and decreased NK killing, and somewhat
compromised adaptive lymphocyte responses. Both the very
young and old immune systems are therefore similarlycompro-
mised in coping with a typical viral infection such as influenza,
whereas the young (non-pregnant) adult organism seems to be
perfectlyequipped for this challenge (figure 1). The evolution of
the immune system within an individual possibly reflects the
central role of the young adult in the survival of the species
for its procreative potential.
Competing interests. We declare we have no competing interests.
Funding. A.K.S. was funded by a Wellcome Trust New Investigator
Award and G.A.H. by Wellcome Trust Strategic Awards.
Acknowledgements. We acknowledge Andrew Allen for preparation of
the figure.
Endnote
1
All epigraphs in this paper are from William Shakespeare’s As you
like it, act 2, scene 7.
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... As we age, we accumulate protections necessary to live in, and with the microbial world (including our own microbiome), but also necessary to deal with the challenges of our environment and bad habits (e.g. smog, smoking and over-eating) [1][2][3][4][5][6][7][8]. Like a computer, some components are immediately functional, like the innate components, but other components must learn the programs and details necessary to function, the antigen-specific component. ...
... The inflammaging and immunosenescence of the immune system also contributes to the aging of the rest of the body [1]. The aged system is less capable of performing its basic functions, including surveillance for tumors and other aberrant cells, clearance of these and apoptotic cells, production of cytokines to support epithelial maintenance (e.g. ...
Article
The components of the immune system develop in utero and like a computer, some components are immediately functional (the innate components) but other components must learn the programs and details necessary to function (antigen adaptive components). Like other systems, including military and municipal, the innate and antigen specific components develop into an immune system that helps maintain and surveil the other body processes and systems for aberrations, provide surveillance and protection of the mucoepithelial borders and protection from microbial invasion. Inability, excesses, or errors in these processes cause disease. Aging of the immune system brings immunosenescence, inflammaging, more errors, and decreased surveillance which increases risk for new infections (e.g. COVID-19, influenza), recurrence of latent infections, cancer and autoimmune and inflammatory diseases. With greater understanding of the surveillance, effector and regulatory deficits upon aging, better therapies can be developed.
... Introduction regulated [26]) immune system in infants and a senescing one in older adults [25]. This hypothesis rests on the assumption that infection-induced mortality is essentially due to impaired resistance, defined as the capacity to limit pathogen multiplication [27]. ...
... Changes in immune functioning across ages point towards older adults being more likely to suffer from both types of damage compared to younger age classes. Indeed, depletion of naïve T cells, reduced responsiveness of B cells, or impaired phagocytic activity are among the many functional changes associated with aging which can account for reduction in host resistance (impaired capacity to limit pathogen proliferation) [24,25]. Concomitantly, older adults also experience major changes in their capacity to repair damaged tissues. ...
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Host age is often evoked as an intrinsic factor aggravating the outcome of host-pathogen interactions. However, the shape of the relationship between age and infection-induced mortality might differ among pathogens, with specific clinical and ecological traits making some pathogens more likely to exert higher mortality in older hosts. Here, we used a large dataset on age-specific case fatality rate (CFR) of 28 human infectious diseases to investigate i) whether age is consistently associated to increased CFR, ii) whether pathogen characteristics might explain higher CFR in older adults. We found that, for most of the infectious diseases considered here, CFR slightly decreased during the first years of life and then steeply increased in older adults. Pathogens inducing diseases with long-lasting symptoms had the steepest increase of age-dependent CFR. Similarly, bacterial diseases and emerging viruses were associated with increasing mortality risk in the oldest age classes. On the contrary, we did not find evidence suggesting that systemic infections have steeper slopes between CFR and age; similarly, the relationship between age and CFR did not differ according to the pathogen transmission mode. Overall, our analysis shows that age is a key trait affecting infection-induced mortality rate in humans, and that the extent of the aggravating effect on older adults depends on some key traits, such as the duration of illness.
... While biofilms appear on tank surfaces, they do not appear to negatively affect the health of adult scallops, but it is assured that scallops encounter biofilm debris and planktonic cells released from mature tank biofilms, and that scallops ingest this material during normal feeding. Even though adult scallops do not seem to be negatively affected, scallop larvae might have a different response to these biofilms as juvenile animals typically have a different microbial community and immune system capabilities than adults, e.g., (Blyton et al., 2022;Knoop et al., 2020;Simon et al., 2015). It is possible, but unconfirmed, that the diverse community which associates with adult scallops may offer some protective effects, emphasizing the need for characterization of scallop microbes. ...
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Animals have trillions of microorganisms living in or on many body sites, these communities of microorganisms are called microbiomes. Microbiomes are typically host-specific, and a lot of information about the host can be determined from investigating them. Microbiome research has many real-world applications, and this thesis utilizes the One Health perspective, which acknowledges the connection of humans, animals, and environments, and emphasizes the need for collaborative, interdisciplinary research. The first interdisciplinary project is an investigation into the bacteria in wild and cultured Atlantic deep-sea scallop, Placopecten magellanicus larvae. Adults in hatcheries can be induced to spawn, but the last two weeks of the larval maturation phase are plagued by massive animal death. The reasons for this are unknown, but research into other scallop and aquaculture species point to loss from bacterial infections and altered functionality of host- associated microbial communities. This pilot study used 16S rDNA sequencing to identify bacterial communities in wild larvae, cultured larvae, and tank biofilms. Tank biofilms were also cultured for the presence of common aquatic pathogenic Vibrio species of bacteria using selective media. We assessed the similarities between bacteria associated with these three sample types, to determine the role of environmental microbes in establishing a microbial community in scallop larvae. These results, along with future work, will be able to inform the hatcheries on methods that will hopefully increase the larval survival in these facilities. The second chapter of the thesis reviews Cryptosporidium species of protozoa. Cryptosporidium spp. are apicomplexan parasites responsible for cryptosporidiosis, the leading cause of diarrheal-related death in young children and neonatal calves (Bos taurus). Cryptosporidium parvum is the most common zoonotic species that infects livestock and humans, but dozens of species have been identified. The detection of oocysts has historically relied on microscopy and molecular identification, but these can be hampered by the difficulty of processing the sample substrate or a lack of species or strain resolution. Further, Cryptosporidium is difficult to maintain in culture for in-depth study. Because of its ubiquity in the environment, range of host species, and ease of transmission, eradication of the disease in livestock is unlikely. Consequently, understanding the modes of transmission, risk of infection, treatments, and research methods is essential to understanding the ecology of the protozoa to prevent outbreaks. The goal of this research is to emphasize the importance of exploring the relationships between animals, humans, and the environment, and microbes, host, and environment, as well as the need for collaboration to accomplish these types of interdisciplinary research projects. The scallop study focuses on connecting microbes to the host and the environment, and without collaborations from the scallop industry, we would not be able to apply our research to real-world problems. The Cryptosporidium review emphasizes the lack of research and knowledge to be able to minimize risk of outbreaks, and collaboration with farmers and other agriculture workers is needed to do this research as well as to implement disease prevention strategies.
... IL-10-ko mice are usually around 6-8 weeks old as well, however for this study they happened to be available at 5 weeks of age. Younger animals have a more variable gut microbial community and immune system than older animals [187][188][189], ...
Article
Inflammatory Bowel Diseases (IBD) are chronic, reoccurring, and debilitating conditions characterized by inflammation in the gastrointestinal tract, some of which can lead to more systemic complications and can include autoimmune dysfunction, a change in the taxonomic and functional structure of microbial communities in the gut, and complicated burdens in a person’s daily life. Like many diseases based in chronic inflammation, research on IBD has pointed towards a multifactorial origin involving factors of the host’s lifestyle, immune system, associated microbial communities, and environmental conditions. Too often, research focuses on just one aspect of IBD or uses one model with a narrow scope, that may result in unanticipated microbial changes, or that are not representative of genetic factors. This is reflected in the absence of genetic models in biochemical-centric research focused on the role of broccoli-metabolite sulforaphane (SFN) in preventing and treating IBD. To be an accurate reflection of IBD, research studies should expand their scope, for example by addressing the concepts of biogeographic specificity of both nutrient absorption and microbial community dynamics, or by using multiple research tools to better mimic the multiple presentations of IBD. To date, no previous SFN or broccoli diet studies have used the IL-10-ko mouse model. With our study, we sought to cover this research gap by, first, proofing broccoli dietary measures in IL-10-ko mice that have a Crohn’s disease-like presentation of inflammation. We fed IL-10-ko mice either a broccoli diet or a control diet, initiated inflammation, and assessed that inflammation using bodyweight gain, a disease activity index score, and immunohistology. All three of the parameters measured showed a consistent and marked reduction of inflammation in mice that were fed a broccoli diet. To assess the performance of this study, we also compared the bodyweight results of our novel IL-10-ko model to the results of an established dextran sulfate sodium (DSS) model of IBD. As expected, the broccoli diet prevented inflammation in the DSS model when compared to control diet fed mice. Excitingly, the IL-10 model had a much more pronounced effect on bodyweight gain, suggesting IL-10-ko mice may be an excellent environment for studying broccoli diet and SFN interactions with gut microbes.
... It might be due to the different production mechanisms of IgG and IgM antibodies, so the same type of anti-PD1/PDL1 AAbs were significantly correlated, while there was no significant correlation between different types of antibodies. The immune system degenerates with age, resulting in a reduced ability of patient's immune response and production of fewer AAbs (Simon et al. 2015). This might be the reason why anti-PD1/PDL1 AAbs were related risk factors for LC in different age stratification in this study. ...
Article
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Antibodies targeting programmed cell death-1 (PD1) and its ligand (PDL1) have transformed current cancer therapy while little is known about the expression of anti-PD1/PDL1 autoantibodies between lung cancer (LC) patients and normal controls (NC). The expression level of anti-PD1/PDL1 IgG and IgM was detected in plasma of 325 LC and 324 NC by indirect enzyme-linked immune sorbent assay (ELISA). Western blot and indirect immunofluorescence (IIF) were used to verify the ELISA results. The association analysis was used to evaluate the odds ratio (OR) of LC. The expression of anti-PD1/PDL1 IgG in LC samples was significantly higher than NC (P < 0.001 and P < 0.05, respectively). The positive rate of anti-PD1/PDL1 IgG in LC was significantly higher than NC and significant difference was also shown in LC samples of different clinical characteristics, such as clinical stage, nodules diameter, lymph node metastasis and distant metastasis (P < 0.001). Moreover, PD1/PDL1 expression in tissues showed no significant relation with that in plasma (P > 0.05). Anti-PD1/PDL1 IgG were the risk factors related to LC (OR (95% CI): 22.433 (5.426–92.745) and 5.051 (1.316–19.386)), while anti-PD1/PDL1 IgM were the risk factors for LC with ≤ 60 years (OR (95% CI): 6.122 (1.365–27.455) and 7.664 (1.715–34.251)) and anti-PD1 IgM was also the risk factor for male LC cases(OR (95% CI): 6.948 (1.076–44.868)). Plasma anti-PD1/PDL1 IgG and IgM might serve as potential biomarkers and risk predictors for LC.
... растного снижения функции и продуктивности иммунной системы [7,9]. Следует отметить, что данный результат не соответствует некоторым исследованиям, в которых была обнаружена обратная тенденция, заключающаяся в увеличении количества ТК в тимусе с возрастом [8]. ...
Article
Full-text available
Most mechanisms of ageing are believed to be more or less associated with inflammation. With age, a unique form of chronic inflammation develops which is termed as inflamm-ageing. The mechanisms of this process are still not fully clear due to the lack of reliable assessment criteria. Immune system is among those involved in accelerating age-related changes in the body. It also directly participates in the process of inflammation. In its pathogenesis, the reaction of mast cells may be of great importance. The role of mast cells in tissue remodeling deserves special attention, since the latter event is among the main features associated with ageing. Hence, the inflamm-ageing is considered a sufficient indicator of ageing, and the mast cells could provide biomarkers of this process. In order to test the proposed hypothesis, the present study was conducted to determine age-related morpho-functional changes in mast cell populations in various organs in rats. Some morpho-functional parameters of mast cells (number, synthetic and functional activity, degree of maturation) in different animal organs were evaluated in male Wistar rats of different ages (4 months and 2 years). We have found the age-dependent changes upon examination of thymus, adrenal glands, and skin, i.e., a decrease in the number of mast cells and their synthetic capacity, along with significantly increased functional activity. In the stomach, small and large intestines, at the constant number of mast cells, we revealed a decrease in their synthetic ability, and increased functional activity. These changes were accompanied by enlargement of blood vessels in the studied organs. Liver is the only organ which did not exhibit any changes in mast cell populations with age. The detected changes in mast cell populations may play an important role in formation of inflamm-ageing events, which accompany the ageing processes, because these cells are an integral component of inflammatory response. The progression of inflamm-ageing leads to accumulation of cytokines and pro-inflammatory mediators in tissues, which, in turn, activate the mast cells. At the same time, increased degranulation of mastocytes may promote the process of inflamm-ageing. The oberved mutual influence of mast cells and inflamm-ageing makes it possible to consider mastocytes as potential candidates for searching the biomarkers in inflamm-ageing.
... In turn, other IMC populations showed modulation in older adults (e.g. eosinophils, immature neutrophils, CD62L + FceRI -cMos and CD36 + Slan + ncMos), potentially as a result of a skewing of hematopoiesis towards myeloid vs. lymphoid lineages, decrease in the function of neutrophil, monocytes and DCs and possibly also low-grade inflammation also known as "inflamm-aging" (88,89). ...
Article
Full-text available
Innate myeloid cell (IMC) populations form an essential part of innate immunity. Flow cytometric (FCM) monitoring of IMCs in peripheral blood (PB) has great clinical potential for disease monitoring due to their role in maintenance of tissue homeostasis and ability to sense micro-environmental changes, such as inflammatory processes and tissue damage. However, the lack of standardized and validated approaches has hampered broad clinical implementation. For accurate identification and separation of IMC populations, 62 antibodies against 44 different proteins were evaluated. In multiple rounds of EuroFlow-based design-testing-evaluation-redesign, finally 16 antibodies were selected for their non-redundancy and separation power. Accordingly, two antibody combinations were designed for fast, sensitive, and reproducible FCM monitoring of IMC populations in PB in clinical settings (11-color; 13 antibodies) and translational research (14-color; 16 antibodies). Performance of pre-analytical and analytical variables among different instruments, together with optimized post-analytical data analysis and reference values were assessed. Overall, 265 blood samples were used for design and validation of the antibody combinations and in vitro functional assays, as well as for assessing the impact of sample preparation procedures and conditions. The two (11- and 14-color) antibody combinations allowed for robust and sensitive detection of 19 and 23 IMC populations, respectively. Highly reproducible identification and enumeration of IMC populations was achieved, independently of anticoagulant, type of FCM instrument and center, particularly when database/software-guided automated ( vs. manual “expert-based”) gating was used. Whereas no significant changes were observed in identification of IMC populations for up to 24h delayed sample processing, a significant impact was observed in their absolute counts after >12h delay. Therefore, accurate identification and quantitation of IMC populations requires sample processing on the same day. Significantly different counts were observed in PB for multiple IMC populations according to age and sex. Consequently, PB samples from 116 healthy donors (8-69 years) were used for collecting age and sex related reference values for all IMC populations. In summary, the two antibody combinations and FCM approach allow for rapid, standardized, automated and reproducible identification of 19 and 23 IMC populations in PB, suited for monitoring of innate immune responses in clinical and translational research settings.
Article
Background Despite widespread use of pneumococcal conjugate vaccines (PCVs) in children, morbidity and mortality caused by pneumococcal disease (PD) remain high. In addition, many children do not complete their PCV course on schedule. V114 is a 15-valent PCV that contains two epidemiologically important serotypes, 22F and 33F, in addition to the 13 serotypes present in PCV13, the licensed 13-valent PCV. Methods This phase III descriptive study evaluated safety and immunogenicity of catch-up vaccination with V114 or PCV13 in healthy children 7 months–17 years of age who were either pneumococcal vaccine-naïve or previously immunized with lower valency PCVs (NCT03885934). Overall, 606 healthy children were randomized to receive V114 (n = 303) or PCV13 (n = 303) via age-appropriate catch-up vaccination schedules in three age cohorts (7–11 months, 12–23 months, or 2–17 years). Results Similar proportions of children 7–11 months and 2–17 years of age reported adverse events (AEs) in the V114 and PCV13 groups. A numerically greater proportion of children 12–23 months of age reported AEs in the V114 group (79.0%) than the PCV13 group (59.4%). The proportions of children who reported serious AEs varied between different age cohorts but were generally comparable between vaccination groups. No vaccine-related serious AEs were reported, and no deaths occurred. At 30 days after the last PCV dose, serotype-specific immunoglobulin G geometric mean concentrations were comparable between vaccination groups for the 13 shared serotypes and higher in the V114 group for 22F and 33F. Conclusions Catch-up vaccination with V114 in healthy individuals 7 months–17 years of age was generally well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, regardless of prior pneumococcal vaccination. These results support V114 catch-up vaccination in children with incomplete or no PCV immunization per the recommended schedule.
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Evaporative cooling is an energy efficient form of air conditioning in dry climates that functions by pulling hot, dry outdoor air across a wet evaporative pad. While evaporative coolers can help save energy, they also have the potential to influence human health. Studies have shown residential evaporative coolers may pull outdoor air pollutants into the home or contribute to elevated levels of indoor bioaerosols that may be harmful to health. There is also evidence that evaporative coolers can enable a diverse microbial environment that may confer early‐life immunological protection against the development of allergies and asthma or exacerbate these same hypersensitivities. This review summarizes the current knowledge of bioaerosol and microbiological studies associated with evaporative coolers, focusing on harmful and potentially helpful outcomes from their use. We evaluate the effects of evaporative coolers on indoor bacterial endotoxins, fungal β‐(1 → 3)‐D‐glucans, dust mite antigens, residential microbial communities, and Legionella pneumophila. To our knowledge, this is the first review to summarize and evaluate studies on the influence that evaporative coolers have on the bioaerosol and microbiological profile of homes. This brings to light a gap in the literature on evaporative coolers, which is the lack of data on health effects associated with their use.
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Background and aim Experimental studies show that short-term exposure to air pollution may alter cytokine concentrations. There is, however, a lack of epidemiological studies evaluating the association between long-term air pollution exposure and inflammation-related proteins in young children. Our objective was to examine whether air pollution exposure is associated with inflammation-related proteins during the first 2 years of life. Methods In a pooled analysis of two birth cohorts from Stockholm County (n = 158), plasma levels of 92 systemic inflammation-related proteins were measured by Olink Proseek Multiplex Inflammation panel at 6 months, 1 year and 2 years of age. Time-weighted average exposure to particles with an aerodynamic diameter of <10 μm (PM10), <2.5 μm (PM2.5), and nitrogen dioxide (NO2) at residential addresses from birth and onwards was estimated via validated dispersion models. Stratified by sex, longitudinal cross-referenced mixed effect models were applied to estimate the overall effect of preceding air pollution exposure on combined protein levels, “inflammatory proteome” over the first 2 years of life, followed by cross-sectional protein-specific bootstrapped quantile regression analysis. Results We identified significant longitudinal associations of inflammatory proteome during the first 2 years of life with preceding PM2.5 exposure, while consistent associations with PM10 and NO2 across ages were only observed among girls. Subsequent protein-specific analyses revealed significant associations of PM10 exposure with an increase in IFN-gamma and IL-12 B in boys, and a decrease in IL-8 in girls at different percentiles of proteins levels, at age 6 months. Several inflammation-related proteins were also significantly associated with preceding PM10, PM2.5 and NO2 exposures, at ages 1 and 2 years, in a sex-specific manner. Conclusions Ambient air pollution exposure influences inflammation-related protein levels already during early childhood. Our results also suggest age- and sex-specific differences in the impact of air pollution on children's inflammatory profiles.
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Most of the polymorphic amino acids of the class I histocompatibility antigen, HLA-A2, are clustered on top of the molecule in a large groove identified as the recognition site for processed foreign antigens. Many residues critical for T-cell recognition of HLA are located in this site, in positions allowing them to serve as ligands to processed antigens. These findings have implications for how the products of the major histocompatibility complex (MHC) recognize foreign antigens.
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Analyses of the relationships between different viruses and viral proteins have focused on homologies between linear amino acid sequences, but cross-reactivities at the level of T cell recognition may not be dependent on a conserved linear sequence of several amino acids. The CTL response to Pichinde virus (PV) and vaccinia virus (VV) in C57BL/6 mice previously immunized with lymphocytic choriomeningitis virus (LCMV) included the reactivation of memory cytotoxic T lymphocyte (CTL) specific to LCMV. Limiting dilution assays (LDA) demonstrated that at least part of this reactivation of memory cells in LCMV-immune mice related to cross-reactivity at the clonal level, even though acute infections with these viruses in nonimmune mice elicited CTL responses that did not cross-react in conventional bulk CTL assays. Precursor CTL (pCTL) to LCMV were generated in splenic leukocytes from LCMV-immune mice acutely infected with PV or VV when stimulated in vitro with only the second virus but not with uninfected peritoneal exudate cells (PECs). Cytotoxicity mediated by LCMV-specific CTL clones activated by PV infection was greatly inhibited by anti-CD8 antibody, suggesting that these memory CTL clones recognizing LCMV-infected targets were of low affinity. LCMV-immune splenocytes stimulated in vitro with PV or VV demonstrated a low but significant precursor frequency (p/f) to the heterologous viruses, and splenocytes from PV- or VV-immune mice when stimulated in vitro against LCMV generated a low but significant p/f to LCMV. Short-term CTL clones cross-reactive between LCMV and PV were derived from splenic leukocytes from LCMV-immune mice acutely infected with PV. To distinguish whether the cross-reactivity was directed against a viral peptide or a virus-induced endogenous cellular neoantigen, we demonstrated that a pCTL frequency to PV about 1/4-1/7 that of the frequency to LCMV could be generated from LCMV-immune splenic leukocytes stimulated with the immunodominant LCMV NP peptide. A partially homologous PV peptide generated from the equivalent site to the LCMV NP peptide did not sensitize targets to lysis by either LCMV- or PV-specific CTLs, suggesting that the cross-reactivity in killing was not due to evolutionarily conserved equivalent sequences. Experiments also indicated that prior immunity to one virus could modulate future primary immune responses to a second virus. Elevated pCTL frequencies to PV were seen after acute PV infection of LCMV-immune mice, and elevated pCTL frequencies to LCMV were seen after acute LCMV infection of PV- and VV-immune mice.(ABSTRACT TRUNCATED AT 400 WORDS)
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Monoclonal antibodies derived from blood plasma cells of acute HIV-1-infected individuals are predominantly targeted to the HIV Env gp41 and cross-reactive with commensal bacteria. To understand this phenomenon, we examined anti-HIV responses in ileum B cells using recombinant antibody technology and probed their relationship to commensal bacteria. The dominant ileum B cell response was to Env gp41. Remarkably, a majority (82%) of the ileum anti-gp41 antibodies cross-reacted with commensal bacteria, and of those, 43% showed non-HIV-1 antigen poly-reactivity. Pyrosequencing revealed shared HIV-1 antibody clonal lineages between ileum and blood. Mutated immunoglobulin G antibodies cross-reactive with both Env gp41 and microbiota could also be isolated from the ileum of HIV-1 uninfected individuals. Thus, the gp41 commensal bacterial antigen cross-reactive antibodies originate in the intestine, and the gp41 Env response in HIV-1 infection can be derived from a preinfection memory B cell pool triggered by commensal bacteria that cross-react with Env.
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Granulocytes, monocytes, macrophages, and dendritic cells (DCs) represent a subgroup of leukocytes, collectively called myeloid cells. During the embryonic development of mammalians, myelopoiesis occurs in a stepwise fashion that begins in the yolk sac and ends up in the bone marrow (BM). During this process, these early monocyte progenitors colonize various organs such as the brain, liver, skin, and lungs and differentiate into resident macrophages that will self-maintain throughout life. DCs are constantly replenished from BM precursors but can also arise from monocytes in inflammatory conditions. In this review, we summarize the different types of myeloid cells and discuss new insights into their early origin and development in mice and humans from fetal to adult life. We specifically focus on the function of monocytes, macrophages, and DCs at these different developmental stages and on the intrinsic and environmental influences that may drive these adaptations.
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The preexisting HIV-1-specific T cell repertoire must influence both the immunodominance of T cells after infection and immunogenicity of vaccines. We directly compared two methods for measuring the preexisting CD4(+) T cell repertoire in healthy HIV-1-negative volunteers, the HLA-peptide tetramer enrichment and T cell library technique, and show high concordance (r = 0.989). Using the library technique, we examined whether naive, central memory, and/or effector memory CD4(+) T cells specific for overlapping peptides spanning the entire HIV-1 proteome were detectable in 10 HLA diverse, HIV-1-unexposed, seronegative donors. HIV-1-specific cells were detected in all donors at a mean of 55 cells/million naive cells and 38.9 and 34.1 cells/million in central and effector memory subsets. Remarkably, peptide mapping showed most epitopes recognized by naive (88%) and memory (56%) CD4(+) T cells had been previously reported in natural HIV-1 infection. Furthermore, 83% of epitopes identified in preexisting memory subsets shared epitope length matches (8-12 amino acids) with human microbiome proteins, suggestive of a possible cross-reactive mechanism. These results underline the power of a proteome-wide analysis of peptide recognition by human T cells for the identification of dominant antigens and provide a baseline for optimizing HIV-1-specific helper cell responses by vaccination.
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