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


Abstract and Figures

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.
Received: 20 January 2015
Accepted: 1 May 2015
Subject Areas:
health and disease and epidemiology,
immunology, microbiology
adaptive immunity, innate immunity,
Author for correspondence:
Andrew McMichael
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
Evolution of the immune system in
humans from infancy to old age
A. Katharina Simon1, Georg A. Hollander2and Andrew McMichael3
Nuffield Department of Medicine, Weatherall Institute of Molecular Medicine, and
Department of Paediatrics,
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
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
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
&2015 The Authors Published by the Royal Society under the terms of the Creative Commons Attribution
License, which permits unrestricted use, provided the original
author and source are credited.
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
deaths per 1000 persons
strength of the response
B and innate
antibodies pregnancy
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. Proc. R. Soc. B 282: 20143085
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
and CD8
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
T cells respond
strongly to alloantigens, they tend to develop towards Foxp3
regulatory T cells (T
) through the influence of
TGF-b[19], and thus actively promote self-tolerance. Peri-
pheral T
represent around 3% of total CD4
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
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 Proc. R. Soc. B 282: 20143085
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
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
within the CD45RA negative CD4 T cells. During
childhood, T
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
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 Proc. R. Soc. B 282: 20143085
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
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 Proc. R. Soc. B 282: 20143085
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
kers is altered and the CD4
to CD8
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
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
), 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
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
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
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. Proc. R. Soc. B 282: 20143085
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.
All epigraphs in this paper are from William Shakespeare’s As you
like it, act 2, scene 7.
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... The presence of these cells in milk makes it possible to effectively fight infections caused by various types of pathogens. The cells of the immune system present in the mother's milk not only provide active immunity to the infant by producing bioactive ingredients but also modify the microenvironment of the newborn's digestive tract [23,24]. A newborn's immune system matures gradually. ...
... Critical early protection against many of the infectious diseases that the mother has previously experienced is provided by passive IgG antibodies delivered by the placenta and breast milk. On the other hand, milk contains all the cells of the immune system that are actively involved in the immune response [24]. ...
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Background: Grossly bloody colostrum is defined as the presence of brownish or bloody-colored colostrum. The frequency is determined to be 0.1% of all births, and no predisposing factor for its occurrence was determined. The purpose of this study was to find factors that increase the probability of the syndrome and the possible influence of the presence of erythrocytes (red blood cells—RBCs) in breast milk on the symptoms of maternal milk intolerance in newborns. Methods: Here, 2 mL of colostrum was collected from 137 participants on postpartum days 1–3, separately from each breast, and transferred to the laboratory. For microscopic analysis, 0.5 mL of colostrum was centrifuged and then stained using the May–Grünwald–Giemsa method. Using an Olympus BX 43 light microscope at 400× total magnification, samples were visually assessed for the presence of RBCs. Additionally, the participants completed a questionnaire regarding their health status, observation of feeding tolerance of the newborn, observed milk color and other factors. Results: The number of RBCs in the yellow or white colostrum samples ranged from 8 to 1000 RBCs/mL and was found in 24.8% of cases. Regardless of the number of RBCs, the color of the milk was white (28.5%) or yellow (66.4%). Only one participant (0.7%) presented classical bloody-stained colostrum with visible bloody-milk colorization. We did not observe the influence of any analyzed factor as the reason for the increased number of RBCs in the colostrum. Conclusions: The presence of RBCs in breast milk did not cause milk intolerance among newborns and was independent of the analyzed factors. Mothers should be supported, and in view of the overall composition of breast milk, especially the content of immune cells in colostrum, even a temporary interruption in breast milk feeding in the case of grossly bloody colostrum is not recommended.
... A rational explanation is a decreased inflammatory response as a result of a less developed immune system in pediatric patients compared to adults. 19 Nevertheless, in the present study, an enhancement in CRP was detected in more than 50% of evaluated cases, which was the same as some results obtained in adult patients (61%). 3 In another study, it was mentioned that pediatric cases of lower ages tend to have a higher incidence of viral infections, and viral exposures may strengthen the immune system when confronted with COVID-19. ...
Background: There are a few studies on the laboratory and clinical results of COVID-19 in pediatric patients. Objectives: The aim of the present study was to evaluate the laboratory and clinical findings of children who were hospitalized due to infection with COVID-19. Methods: This case-series study was conducted from May 1, 2020 to July 30, 2022 and evaluated hospitalized patients up to the age of 18 years old who were admitted with the diagnosis of COVID-19 infection in the endemic period of SARS-CoV-2 at Imam Ali hospital in Karaj. The required data were collected from medical records, including medical history, demographic information, SARS-CoV-2 symptoms, physical examination, laboratory test results, comorbidities, severity the of disease, and mortality rate. After obtaining the data, SPSS-26 was used to perform statistical analysis. Results: This study included 96 confirmed COVID-19 cases (42 females and 54 males), and the mean age of patients was 7.2 years. COVID-19 comorbidities were positive in 22 cases (22.9%), and diabetes was the most common comorbidity, which was detected in 13 cases (13.5%). Twelve (12.5%) cases of COVID-19 exhibited critical severity, and the mortality rate was 5.2%. The four most frequent clinical symptoms were found to be fever, cough, dyspnea, and vomiting, which were noted in 82 (85.4%), 52 (54.2%), 29 (30.2%), and 29 (30.2%) cases, respectively. In addition, respiratory distress and cyanosis were observed in 20 (20.8%) and 6 (6.3%) patients, respectively. Moreover, 18 (18.8%) cases had allergies, and skin allergies were the most prevalent, followed by allergic rhinitis and exercise-induced cough. Conclusion: This case series survey addressed the laboratory and clinical features of pediatric SARS-CoV-2 patients. Despite the relatively small number of samples, the findings could provide a useful report of the clinical manifestations and paraclinical findings of COVID-19 in children.
... These changes impact organ functions, tissue structures, as well as cellular interactions 1 . Regarding the immune system, alterations can be noted in the memory T and B-cell compartments, and they are influenced by previous infections, vaccinations, microbiome, food-derived and inhaled antigens, in a biological phenomenon known as immunobiography 2,3 . ...
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Immunobiography describes the life-long effects of exogenous or endogenous stimuli on remodeling of immune cell biology, including the development of memory T and B-cells. The present study aimed at investigating the rhythms of changes in phenotypic features of memory T and B-cells along childhood and adolescence. A descriptive-observational investigation was conducted including 812 healthy volunteers, clustered into six consecutive age groups (9Mths–1Yr; 2Yrs; 3–4Yrs; 5–7Yrs; 8–10Yrs; 11–18Yrs). Immunophenotypic analysis of memory T-cell (CD4⁺ and CD8⁺) and B-cell subsets were performed by flow cytometry. The results pointed out that memory-related biomarkers of T and B-cells displayed a bimodal profile along healthy childhood and adolescence, regardless of sex. The first stage of changes occurs around 2Yrs, with predominance of naive cells, while the second and more prominent wave occurs around the age 8–10Yrs, with the prevalence of memory phenotypes. The neighborhood connectivity profile analysis demonstrated that the number of correlations reaches a peak at 11–18Yrs and lower values along the childhood. Males presented higher and conserved number of correlations when compared to females. Altogether, our results provide new insights into immunobiography and a better understanding of interactions among the cellular subsets studied here during childhood and adolescence.
... GO overrepresentation analysis was then performed on the genes contained in each quadrant of the plot ( Figure 3D). Risk genes (quadrant I) were enriched in terms related to immune response (as expected, since upregulation of the immune system at old age can induce chronic inflammation with increased mortality) [31]. On the other hand protective genes (quadrant III) were found to be highly enriched in extracellular matrix organization (e.g. ...
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The killifish Nothobranchius furzeri is the shortest-lived vertebrate model organism and is characterized by laboratory strains differing in lifespan by more than a factor of two. The genetic architecture underlying this difference is complex and the pathways responsive remain elusive. We performed an analysis in N. furzeri of public transcritomic datasets comprehensive of four different tissues and one embryonic stage in two strains: the shorter-lived GRZ and the longer-lived MZM0410. Remarkably, the two strains differ in their transcriptome profile already at the embryonic stage. The short-lived strain GRZ shows an anticipated aging profile consistently in all tissues investigated, with differences in expression of aging-related genes detected already at sexual maturity. In addition, analysis of a longitudinal dataset revealed that genes whose expression is prognostic of longer lifespan at the individual level are also differentially expressed between strains at an early adult age, suggesting antagonistic pleiotropism.
... This severity is postulated to be a consequence of an excessive and dysregulated immune response (Weatherhead et al., 2020). The diminished capacity for cytokine production observed in older patients (Weiskopf et al., 2009;Simon et al., 2015) may serve to mitigate the cytokine storm characteristic of severe COVID-19 outcomes. It is noteworthy that in our study, the mean age of patients admitted to the ICU was 55 years (95% CI [51.5; 58.4]), younger than those not requiring ICU care, who had a mean age of 60 years (95% CI [56.7; 63.7]). ...
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Background: The objective of this study was to investigate the impact of COVID-19 vaccination on mortality, intensive care unit (ICU) admissions, and organ protection in hospitalized COVID-19 patients. Methods: This retrospective, single-center cohort study included hospitalized COVID-19 patients with confirmed vaccination status and chest imaging data from July 2021 to February 2022. Outcomes such as mortality, ICU admission, and organ damage were evaluated using clinical data, chest CT scans, and laboratory parameters. Our study used logistic regression and advanced statistical methods, including LASSO regression to analyze differences in hospitalized COVID-19 patients based on vaccination status, adjusting for significant demographic parameters and confounding variables, with a focus on ICU admissions and mortality. Results: The study encompassed 167 patients (69% male, mean age 58 years, 95% CI [55; 60], 42% fully vaccinated) for data analysis. After adjusting for confounding factors, vaccinated hospitalized COVID-19 patients exhibited a significantly reduced relative risk for mortality (RR: 0.46, 95% CI [0.13; 0.99]) and ICU admissions (RR: 0.59, 95% CI [0.28; 0.89]) compared to their non-vaccinated counterparts. Additionally, vaccinated COVID-19 patients demonstrated significantly fewer pulmonary lesions (Cohen’s d: -0.38, 95% CI [-0.74; -0.02]), reduced instances of COVID-19-induced coagulopathy (RR: 0.26, 95% CI [0.00; 0.88]), and lower AST (Cohen’s d: -0.40, 95% CI [-0.69; -0.12]) and ALT levels (Cohen’s d: -0.45, 95% CI [-0.73; -0.17]). The number needed to treat to prevent one ICU admission among hospitalized COVID-19 patients was found to be as low as four. The protective effect of COVID-19 vaccination seems to amplify with the severity of the disease. The vaccination's protective effect was particularly pronounced in preventing ICU admissions among middle-aged patients (around 55 years old) (RR: 0.64, 95% CI [0.32; 0.99]). Type 2 diabetes emerged as a significant risk factor for increased mortality (OR: 3.02, 95% CI [1.24; 7.34]) and ICU admission (OR: 3.09, 95% CI [1.33; 7.57]). Conclusions: COVID-19 vaccination may mitigate the risk of mortality, severe disease progression, and damage to the pulmonary, liver, and coagulation systems in hospitalized COVID-19 patients, particularly among middle-aged patients around 55 years old.
... For instance, in February 2022, cases of norovirus were 48% higher than expected in educational settings, 5 resulting in a warning to the public about the health threat. 5 Children are particularly susceptible to infections because their immune systems are developing, 6 they are often in close contact with other children, and although they can adhere to hygiene practices, 7 they are at risk of infections. 2 8 9 Preventing ill children from mixing with others is essential in mitigating the spread of infection. 10 11 The UK Government has issued guidance on how long a child should not attend school for when they show symptoms of an infectious illness. 2 A systematic review indicates that a large proportion of symptomatic children may be attending school (known as 'school-based presenteeism'). ...
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Objectives To prevent the spread of infectious disease, children are typically asked not to attend school, clubs or other activities, or socialise with others while they have specific symptoms. Despite this, many children continue to participate in these activities while symptomatic. Design and setting We commissioned a national cross-sectional survey with data collected between 19 November and 18 December 2021. Participants Eligible parents (n=941) were between 18 and 75 years of age, lived in the UK and had at least one child aged between 4 and 17 years. Parents were recruited from a pre-existing pool of potential respondents who had already expressed an interest in receiving market research surveys. Outcome measures Parents were asked whether their children had exhibited either recent vomiting, diarrhoea, high temperature/fever, a new continuous cough, a loss or change to their sense of taste or smell in the absence of a negative (PCR) COVID-19 test (‘stay-at-home symptoms’) since September 2021 and whether they attended school, engaged in other activities outside the home or socialised with members of another household while symptomatic (‘non-adherent’). We also measured parent’s demographics and attitudes about illness. Results One-third (33%, n=84/251, 95% CI: 28% to 39%) of children were ‘non-adherent’ in that they had attended activities outside the home or socialised when they had stay-at-home symptoms. Children were significantly more likely to be non-adherent when parents were aged 45 and younger; they allowed their children to make their own decisions about school attendance; they agreed that their child should go to school if they took over-the-counter medication; or they believed that children should go to school if they have mild symptoms of illness. Conclusion To reduce the risk of spreading disease, parents and teenagers need guidance to help them make informed decisions about engaging in activities and socialising with others while unwell.
Full text link: The adverse effects of climate change on human health are unfolding in real time. Environmental fragmentation is amplifying spillover of viruses from wildlife to humans. Increasing temperatures are expanding mosquito and tick habitats, introducing vector-borne viruses into immunologically susceptible populations. More frequent flooding is spreading water-borne viral pathogens, while prolonged droughts reduce regional capacity to prevent and respond to disease outbreaks with adequate water, sanitation, and hygiene resources. Worsening air quality and altered transmission seasons due to an increasingly volatile climate may exacerbate the impacts of respiratory viruses. Furthermore, both extreme weather events and long-term climate variation are causing the destruction of health systems and large-scale migrations, reshaping health care delivery in the face of an evolving global burden of viral disease. Because of their immunological immaturity, differences in physiology (e.g., size), dependence on caregivers, and behavioral traits, children are particularly vulnerable to climate change. This investigation into the unique pediatric viral threats posed by an increasingly inhospitable world elucidates potential avenues of targeted programming and uncovers future research questions to effect equitable, actionable change. Impact A review of the effects of climate change on viral threats to pediatric health, including zoonotic, vector-borne, water-borne, and respiratory viruses, as well as distal threats related to climate-induced migration and health systems. A unique focus on viruses offers a more in-depth look at the effect of climate change on vector competence, viral particle survival, co-morbidities, and host behavior. An examination of children as a particularly vulnerable population provokes programming tailored to their unique set of vulnerabilities and encourages reflection on equitable climate adaptation frameworks. Full text link:
This study aimed to investigate parasitic infection in captive sun bears (Helarctos malayanus) in Malaysia from December 2018 to May 2019. We collected 58 fecal samples from sun bears housed in the National Zoo, Taiping Zoo & Night Safari, Lok Kawi Wildlife Park, and Bornean Sun Bear Conservation Centre. We analyzed the samples using modified fecal flotation techniques. We found 4 species of helminths (Ancylostoma spp., Baylisascaris spp., Trichuris spp., and Strongyloides spp.) and 1 species of protozoa (Eimeria spp.) in captive sun bears. The general prevalence of infection was 55.2%, with 48.3% prevalence of helminth infections and 34.5% protozoic infections. Juvenile males (69.2%) and juvenile females (61.5%) had the highest prevalence of parasitic infection. For nematodes, Baylisascaris spp. and Ancylostoma spp. had ≥50% prevalence rate in captive bears. For protozoa, the prevalence rate was <50%. We also found a high intensity of infection for Ancylostoma spp. in captive sun bears with a mean of 258.24 ± 0.62 eggs per gram (EPG), and the lowest intensity was recorded for Strongyloides spp. with 34.37 ± 1.17 EPG. Generally, the parasites we found were common in other species of bears and other mammals. This study revealed presence of parasites that could affect the well-being of sun bears in captivity. Therefore, we suggest that fecal screening be done regularly at 3-month intervals, and that it is essential to reduce the degree of parasitic infection in captive animals.
Immune escape is a prerequisite for tumor growth. We previously described a decline in intratumor activated cytotoxic T cells and T cell receptor (TCR) clonotype diversity in invasive breast carcinomas compared to ductal carcinoma in situ (DCIS), implying a central role of decreasing T cell responses in tumor progression. To determine potential associations between peripheral immunity and breast tumor progression, here, we assessed the peripheral blood TCR clonotype of 485 breast cancer patients diagnosed with either DCIS or de novo stage IV disease at younger (<45) or older (≥45) age. TCR clonotype diversity was significantly lower in older compared to younger breast cancer patients regardless of tumor stage at diagnosis. In the younger age group, TCR-α clonotype diversity was lower in patients diagnosed with de novo stage IV breast cancer compared to those diagnosed with DCIS. In the older age group, DCIS patients with higher TCR-α clonotype diversity were more likely to have a recurrence compared to those with lower diversity. Whole blood transcriptome profiles were distinct depending on the TCR-α Chao1 diversity score. There were more CD8 ⁺ T cells and a more active immune environment in DCIS tumors of young patients with higher peripheral blood TCR-α Chao1 diversity than in those with lower diversity. These results provide insights into the role that host immunity plays in breast cancer development across different age groups.
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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.
During infection, CD8 + T cells initially expand then contract, leaving a small memory pool providing long lasting immunity. While it has been described that CD8 + T cell memory formation becomes defective in old age, the cellular mechanism is largely unknown. Autophagy is a major cellular lysosomal degradation pathway of bulk material, and levels are known to fall with age. In this study, we describe a novel role for autophagy in CD8 + T cell memory formation. Mice lacking the autophagy gene Atg7 in T cells failed to establish CD8 + T cell memory to influenza and MCMV infection. Interestingly, autophagy levels were diminished in CD8 + T cells from aged mice. We could rejuvenate CD8 + T cell responses in elderly mice in an autophagy dependent manner using the compound spermidine. This study reveals a cell intrinsic explanation for poor CD8 + T cell memory in the elderly and potentially offers novel immune modulators to improve aged immunity.
Although we might shudder at the thought of billions of bacteria living in our lower intestine, we are colonized by these passengers shortly after birth. However, the relationship is mostly of mutual benefit, and they shape our immune system throughout life. Here, we describe our developing understanding of the far-reaching effects that the commensal flora have on mucosal and systemic immunity and their relevance to the effects of hygiene on human disease.
AIM: To develop a cancer vaccine of dendritic cells derived from human cord blood CD34+ cells and to investigate its cytotoxicity on human hepatocarcinoma cells in vitro and in sever combined immunodeficiency (SCID) mice. METHODS: Lymphocytes from cord blood or peripheral blood were primed by DCs, which were derived from cord blood and pulsed with whole tumor cell lysates. Nonradiative neutral red uptake assay was adopted to detect the cytotoxicity of primed lymphocytes on human hepatocarcinoma cell line BEL-7402 in vitro. The anti-tumor effect of primed lymphocytes in vivo was detected in SCID mice, including therapeutic effect and vaccination effect. RESULTS: The cytotoxicity of DC vaccine primed lymphocytes from cord blood or peripheral blood on human hepatoc-arcinoma cell line BEL-7402 was significantly higher than that of unprimed lymphocytes in vitro (44.09% vs 14.69%, 47.92% vs 19.44%, P 0.05). The tumor growth rate and tumor size were smaller in SCID mice treated or vaccinated with primed lymphocytes than those with unprimed lymphocytes. SCID mice vaccinated with primed lymphocytes had a lower tumor incidence (80% vs 100%, P<0.05) and delayed tumor latent period compared with mice vaccinated with unprimed lymphocytes (11 d vs 7 d, P<0.01). CONCLUSION: Vaccine of cord blood derived-DCs has an inhibitory activity on growth of human hepatocarcinoma cells in vitro and in SCID mice. The results also implicate the potential role of cord blood derived-DC vaccine in clinical tumor immunotherapy.
In spite of their precipitous encounter with the environment, newborn infants cannot readily mount T helper type 1 (TH1) cell antibacterial and antiviral responses. Instead, they show skewing toward TH2 responses, which, together with immunoregulatory functions, are thought to limit the potential for inflammatory damage, while simultaneously permitting intestinal colonization by commensals. However, these collective capabilities account for relatively few T cells. Here we demonstrate that a major T cell effector function in human newborns is interleukin-8 (CXCL8) production, which has the potential to activate antimicrobial neutrophils and γδ T cells. CXCL8 production was provoked by antigen receptor engagement of T cells that are distinct from those few cells producing TH1, TH2 and TH17 cytokines, was co-stimulated by Toll-like receptor signaling, and was readily apparent in preterm babies, particularly those experiencing neonatal infections and severe pathology. By contrast, CXCL8-producing T cells were rare in adults, and no equivalent function was evident in neonatal mice. CXCL8 production counters the widely held view that T lymphocytes in very early life are intrinsically anti-inflammatory, with implications for immune monitoring, immune interventions (including vaccination) and immunopathologies. It also emphasizes qualitative distinctions between infants' and adults' immune systems.