Women who have unprotected sexual intercourse with the same man
for
> 1 year (and to a much lesser extent men with the same female
partner)
generate a significant peripheral alloimmune response against
their partner's
leucocytes compared with third-party leucocytes : this
"immunisation" probably
arises via repeated exposure to HLA antigens expressed on
leucocytes and
epithelial cells in semen and female genital secretions
Immunosuppressive
effects
of human seminal plasma
prostaglandins of the E series (PGE
and 19-hydroxy PGE) predominate and raise intracellular cAMP in
leukocytes.
By this mechanism they suppress lymphocyte proliferation, NK
cell
activity and are likely to modify cytokine release from APCs. In
this way,
acquired and innate responses (including immune surveillance) in
the reproductive
tract will be curtailed, at least temporarily, after
intercourse.
inhibitors of complement : a unique reservoirs of CD59
/ MIRL
is found on the prostasomes.
The prostasomes also inhibit lymphocyte proliferation and the
activity
of phagocytic cells.
TGF-b
may inhibit primed responses to antigen, and FcgRs
which might bind inflammatory agents. Human species is less
fertile to
allow TGF-b
in semen to immunodepress woman's immune system inducing
tolerance to the
future xenograft.
The presence of HLA molecules on the surface of the seminal
cells and spermatozoa has been a matter of controversy, and several
techniques have been used to address this issue [3, 4]. The
expression of these molecules on sperm cells may play a role in the
fertilization process [5]. In infertile women, a significantly
higher incidence of circulating anti-HLA antibodies was found [6],
and the existence of mechanisms inhibiting the fertilization of
MHCcompatible gametes have been postulated in tunicates [7] and
mammals [8]. Indeed, HLA heterozygosity is favored in certain human
populations [9], and an excess of HLA antigen sharing has been found
in couples with repetitive abortions [10]. Recent work from our
group clearly showed the expression of HLA class I and class II
molecules on purified sperm cells [11]. The expression seemed
diploid, followed a cyclic pattern, and apparently showed an inverse
correlation with inhibin concentration [11], inducing cyclic
expression
3. Arnaiz-Villena A, Festenstein H. HLA genotyping by using
spermatozoa:evidence for haploid gene expression. Lancet 1976;
II:707–709.
4. Bishara A, Oksensberg JR, Frankel G, Margalioth EI, Persitz
E, Nelken D, Friedmann A, Brautban C. Human leukocyte antigens
(HLA) class I and class II on sperm cells studied at the
serological, cellular and genomics levels. Am J Reprod Immunol
Microbiol 1987; 13:97–103.
5. Mori T, Wu GM, Mori E, Shindo Y, Mori N, Fukuda A, Mori T.
Expression of class II major histocompatibility complex antigen
on mouse sperm and its role in fertilization. Am J Reprod
Immunol 1990; 24:9–14.
6. Schaller J, Glander HJ, Ladusch M, Westhoff U, Grosse-Wilde
H. Lack of HLA-molecules on human spermatozoa and seminal
plasma. Andrologia 1993; 25:77–81.
7. Scofield VL, Schlumpberger JM, West LA, Weissman I.
Protochordate allorecognition is controlled by a MHC-like gene
system. Nature 1982; 295:499–502.
8. Yamazaki K, Boyse EA, Mike V, Thaler HT, Mathieson BJ,
Abott J, Boyse J, Zayas ZA, Thomas L. Control of mating
preferences in mice by genes in the major histocompatibility
complex. J Exp Med 1976; 144:1324–1335.
9. Degos L. La re´partition anthropologique des genes
HLA et dynamique des populations. In: Dausset J (ed.), HLA 1982.
Complexe Majeur d’Histocompatibilite´ de l’homme. Paris:
Flammarion; 1981: 131–159.
10. Caudle MR, Rote NS, Scolt JR, De Witt C, Barney MF.
Histocompatibility in couples with recurrent spontaneous
abortion and normal fertility. Fertil Steril 1983; 39:793–798.
11. Martin-Villa JM, Luque I, Martinez Quiles N, Corell A,
Regueiro JR, Timon M, Arnaiz-Villena A. Diploid expression of
human leukocyte antigen class I and class II molecules on
spermatozoa and their cyclic inverse correlation with inhibin
concentration. Biol Reprod 1996; 55: 620–629
Human sperm
express CD46
/
membrane cofactor protein (MCP)
on the inner acrosomal membrane (IAM) as a hypoglycosylated form
that is
not observed in other tissues. Sperm-specific abnormalities in MCP
have
been associated with infertility in humans. Antibodies to the first
complement
control protein (CCP) repeat of MCP inhibit both binding and
penetration
of human sperm to zona pellucida more efficiently than Abs to CCPs
2-4,
which block complement regulatory activity.
Pregnancy
: immunological inertia : specific depression of immunity
in a mother
toward the histocompatibility antigens of a fetus, or in a fetus
toward
those of the mother; it does not include immunologic
tolerance.
couples with very similar genetic backup have reduced fertility
: this
may be due to lack of induction of protective anti-trophoblast
antibodies
and hence attack by NK cells. The same mechanism is involved in
chorial
tumours.
asymmetric
IgG antibodies
(AAb)
during pregnancy are found in serum and bound to placenta with
specific
activity to paternal antigens, suggest a protective role of AAb
during
pregnancyRef.
The in vitro increase of protective asymmetric IgG synthesis in
response
to Th2-cytokines support the hypothesis that a local
Th2-switch
is beneficial for pregnancy outcomeRef.
during pregnancy uterus and placenta are Th2-polarized
environments with high levels of IgE, irrespective of maternal
atopy
the number of naturally occurring regulatory
T
cells (CD4+CD25+)
(suppressing the proliferation of alloreactive cells in a MLR)
in the lymph
nodes and spleen of pregnant mice is markedly increased compared
with non-pregnant
control mice, even when mice are mater with syngeneic males,
indicating
that the presence of fetal alloantigen is not required to
drive expansion,
despite their regulatory function is only required when the
fetus expresses
alloantigen, which is inevitable under non-experimental
circumstances.
The presence of these regulatory populations might explain the
observed
remission of some autoimmune
disease
and enhanced maternal tolerance to some paternal grafts during
pregnancyref
trophoblast cells
express
CD178 / FasL
(up-regulated by CRH
secreted by embryoblasts and womb cells)
high levels of indoleamine
2,3-dioxygenase
(IDO),
which catabolyzes Trp : because Trp is an essential amino
acid, its depletion
will impair protein synthesis in mother's T lymphocytes.
suppression of MHC class II molecule expression in
trophoblasts is secondary
to dominant negative trans-acting factors that
suppress class
II transactivator (CIITA)
transcription : a trophoblast-derived noncoding RNA
(TncRNA) suppresses
CIITA promoter IIIref
and IVref
activity with a mechanism that does not involve methylation of
the promoter
pregnancy loss associated with an inflammatory response :
ligation
of the immune co-stimulatory molecule CD40
in pregnant mice leads to decreased progesterone
synthesis and embryo resorption. The mechanism involves TNF-a
production by NK cell
in response to the inflammatory environment produced by CD40
ligation on
DCs. Increased levels of TNF then upregulate expression of the
STAT5 inhibitors
SOCS1
and SOCS3
in the ovaries, which in turn inhibit prolactin-receptor
signallingref
the cytokine receptor family type 2 (CRF2) comprises receptors
for important
immunomediators like interferons and IL-10.
CRF2-soluble 1 (CRF2-s1)
represents the first exclusively soluble receptor in this group,
expressed
neither in resting nor in stimulated leucocyte populations : the
CRF2-s1
gene covers about 28 kb and is located on chromosome 6 in close
proximity
to the CRF2 members IFNR1 and IL-20R1. It comprises 7 exons and
generates
2 different mRNA splice variants, CRF2-s1-long and CRF2-s1-short,
which encode proteins of 263 and 231 amino acids, respectively.
A comparison
of predicted protein structures led to the postulation that each
receptor
variants binds a different ligand. CRF2-s1-long is only
expressed in placenta,
whereas CRF2-s1-short is additionally expressed in human mammary
gland
and, at a lower level, in skin, spleen, thymus and stomachref.
CD56+
NK cells
are closely related to decidua irrespective of its eutopic or
ectopic location
rather than to the implantation site. This suggests that the
recruitment
and/or increase of uterine NK cells into the uterus is not
dependent on
the physical presence of an implanting embryo but instead is
controlled
hormonallyref.
immunosuppressive glycoproteins in pregnancy : the
immunosuppressive
activity of pregnancy sera can be destroyed by treatment with
periodate
which oxidises protein-linked oligosaccharidesref
glycodelin-A
(GdA)
/ progestagen-associated endometrial protein (PAEP / PEP) /
placental
protein 14 / pregnancy-associated endometrial a2-globulin
/ a uterine protein is a
human glycoprotein
that belongs to the lipocalin
superfamily, found in amniotic fluid that has potent
contraceptive and
immunosuppressive activities. During the menstrual cycle, GdA
is not expressed
in the proliferative endometrium during the fertile
periovulatory phase
but increases substantially in response to progesterone
and relaxin exposure from the fourth postovulatory day
(peri-implantation
phase), peaking around the 12th day (last week of the luteal
phase). Changes
in local and/or circulating glycodelin concentrations have
been observed
in women with reproductive disorders. After implantation of
the embryo,
GdA synthesis is induced to very high levels (4 to 10% of
total protein).
GdA is also secreted into the amniotic fluid in concentrations
sufficient
to manifest immunosuppressive effects in vitro. The
human embryo/fetus
is thus surrounded by and bathed in a glycoprotein with potent
immunosuppressive
activities. The structure of GdA was determined by a
combination of LC-ES-MS,
FAB-MS, exoglycosidase digestion, and linkage analysis. GdA
has 2 occupied
sites for N-linked glycosylation, which carry substantially
different ensembles
of oligosaccharides. Among these are complex-type biantennary
structures
whose antennae are composed of fucosylated or sialylated
LacDiNAc (GalNAxb1-4GlcNAc)
sequences, which are rare in other human glycoproteins.
Oligosaccharides
with at least one fucosylated LacDiNAc sequence have been
previously shown
to be potent inhibitors of selectin-mediated adhesions. It is
thus possible
that GdA may manifest some of its immunosuppressive effects by
blocking
selectin-mediated events. Immunological and molecular
biological analyses
have suggested that GdA is expressed in tissues other than the
endometrium.
Furthermore, a glycoprotein that cross-reacted with antibodies
to GdA was
detected in human seminal plasma over 15 years ago. The role
of this seminal
plasma form of glycodelin (GdS) remains unknown, but
the expression
of
a potential contraceptive glycoprotein in the seminal plasma
of the human
male did not make physiological sense. Comparative
structure-function studies
of GdA and GdS have helped to address this anomaly by
revealing that GdS
is glycosylated quite differently from GdA. None of the
LacDiNAc structure
in GdA is present in GdS, and the latter carrier abundant,
highly fucosylated
antigenic determinants, which are absent in GdA. The chemical
modification
of glycodelins has resulted in compounds with antiviral
activity. Depending
on glycosylation, glycodelin appears in various isoforms. In
the uterus,
glycodelin-A is the major progesterone-regulated glycoprotein
secreted
into uterine luminal cavity by secretory/decidualized
endometrial glands.
The other tissues expressing glycodelin include fallopian
tubes, ovary,
breast, seminal vesicle, bone marrow, and eccrine glands.
Glycodelin-A
potently and dose-dependently inhibits human sperm-egg
binding, whereas
differently glycosylated glycodelin-S from seminal plasma has
no such effect.
Absence of contraceptive glycodelin-A in the uterus during
periovulatory
midcycle is consistent with an open "fertile window."
Glycodelin induced
by local or systemic administration of progestogens may
potentially reduce
the fertilizing capacity of sperm in any phase of the
menstrual cycle.
Glycodelin also has immunosuppressive activity. Its high
concentration
at the fetomaternal interface may contribute to protection of
the embryonic
semiallograft. Besides being an epithelial differentiation
marker, glycodelin
appears to play a role in glandular morphogenesis, as
transfection of glycodelin
cDNA into a glycodelin-negative breast cancer cells resulted
in formation
of gland-like structures, restricted proliferation, and
induction of other
epithelial markersref.
Tamm-Horsfall
glycoprotein
(THP) / uromucoid is a GPI-anchored protein
exposed
at the surface of Henle's loop and distal nephron cells and
cleaved to
represent the major glycoprotein present in human urine
(THP-related proteins
are also found in the superficial layers of the oral mucosa) :
it acts
as a defence factor against urinary tract infections by
inhibiting the
binding of S- and P-fimbriated Escherichia
coli
to renal epithelial cells and interacts with the S2 subunit
within the
pertussis
toxin (PTX)
B oligomer inhibiting cytoadherence. It is an
immunosuppressive molecule
whose ability to inhibit T cell proliferation is increased
13-fold during
pregnancy. Pregnancy-associated THP is called uromodulin.
Tamm-Horsfall
protein acts on nucleation and inhibit crystal aggregation,
while uromodulin
promotes aggregation of calcium oxalate crystals. Mass
spectrometric strategies
have recently uncovered pregnancy-associated changes in the O-glycosylation
of
THP, which could account for the enhanced immunomodulatory
effects of
uromodulin. THP from nonpregnant females and males expresses
primarily
core 1-type O oligosaccharides terminated with either sialic
acid or fucose
but not the sialyl Lex epitope. In contrast, the O-oligosaccharide
linked
to uromodulin include unusual core 2-type oligosaccharides
terminated
with up to 3 sialyl Lex sequences.
early pregnancy
factor (EPF)
is a protein with growth regulatory and immunosuppressive
properties secreted
into the maternal serum 12-16 hours after fertilization
(detected by the
rosette inhibition assay (RIA)) and also found in cervical
mucusref
of pregnant women. It is an extracellular form of chaperonin
10
(Cpn10) / HSPE1, a molecular chaperone and a
co-chaperone for Hsp60
in the protein folding process, found in the mitochondrial
matrix and several
extramitochondrial compartments (including zymogen granules in
pancreatic
acinar cells, growth hormone granules in anterior pituitary,
secretory
granules in PP pancreatic islet cells and mature red blood
cells which
lack mitochondriaref)
Chlamydia
trachomatis heat shock protein 10 (Chsp10) is associated
with chronic
genital tract infection with C. trachomatis,
homologous to human
chaperonin 10 (Cpn10) and early pregnancy factor (EPF),
infertility was
associated with the presence of anti-Chsp10 and anti-EPF
antibodies. The
HLA class II haplotype DR8 DQ4 is associated with the presence
of anti-Chsp10
antibodies but not of anti-EPF antibodiesref.
Colostrum (see also physiology
of mammary gland).
100
mL / day are produced for < 10 days after delivery. thin,
yellow,
milky fluid secreted by the mammary gland before or after
parturition.
It contains up to 20% protein, predominant among which are
immunoglobulins,
representing the antibodies found in maternal blood. It contains
more minerals
and less fat and carbohydrate than does milk. It also contains many
colostrum
corpuscles and usually will coagulate on boiling due to a large
amount
of lactalbumin.
colostrum gravidarum : the colostrum secreted before
parturition,
and especially that secreted during the first few days following
delivery
colostrum puerperarum : the colostrum secreted after
labor.
Colostrum collected within 24-48 hours post birth contains :
leukocytes
neutrophils and macrophages (90%)
colostrum corpuscles / Donné's bodies or
corpuscles : large
rounded bodies in colostrum, containing droplets of fat and
sometimes a
nucleus; they apparently are phagocytic cells of the mammary
gland, present
for the first two weeks after parturition
lymphocytes (10% : 10,000 / mL
; 20% are T lymphocytes, with a CD4/CD8 ratio similar
to that in
blood). Because newborns have low gastric acidity and peptic
enzyme secretion,
lymphocytes survive the gastrointestinal tract and traverse
the mucosal
wall
memory T lymphocytes (mature in infants at 2 years of
age)
carbohydrates (72.0 ± 2.5 g / L) attract &
bind to pathogens
preventing them from attaching or entering the mucous membrane
lactose (5.5-6.0 g / dL) : in lactating mammary tissues
alternate
transcription initiation site of UDP-Gal:betaGlcNAc
b1,4-
galactosyltransferase gene allows encoding a
shorter transcript
whose product is posttranslationally cleaved and forms a
heterodimer with
a-lactalbumin
to catalyze UDP-galactose + D-glucose
<=> UDP +
lactose, hence acting as lactose synthase. Lactose
concentratrion
is 50% higher than in cow milk, allowing a better calcium
absorption, higher
fast calorie availability, and overgrowth of Lactobacillus
bifidus
in intestinal flora
oligosaccharides (1.0-1.5g / dL)
glycoconjugates
mucins
glycolipids
proteins (10.5 ± 2.0 g / L ) : neither maternal
diet nor
body composition affects milk protein level. Most proteins in
human milk
are heavily glycosylated and are therefore resistant to
proteolysis both
after ingestion by the infant and after short-term storage (4-24
hours)
at low to moderate ambient temperatures (15-25 °C). Human
milk proteins
are more easily digested than casein from cow milk.
hormones (concentration higher in milk than in plasma :
they are
hyperglycosylated within the mammary gland to protect these
bioactive components
during passage through the GI tract)
Epo
: a significant proportion of milk-borne Epo resists
proteolytic degradation.
Epo
receptors (EpoR)
have been found on gastric mucosa and intestinal mucosa, and
in mesenteric
vessel endothelium. Evidence to date shows that intact Epo
reaches these
local organs, as well as distal organs. After feeding Epo,
local gastrointestinal
physiological effects are seen in suckling rats. In humans
and rats, short-term
feeding of high-dose Epo increases reticulocytes, but it is
unclear whether
sustained treatment increases red cell mass.
insulin
: 21.5 ± 5 mg / L (2.6 ± 0.3 mg / L in milk)
IGF-1
: 10.9 ± 5.3 mg / L (7.1-19.1 mg / L in milk)
cytokines (concentration higher in milk than in plasma
: they are
hyperglycosylated within the mammary gland to protect these
bioactive components
during passage through the GI tract)
digestive enzymes compensate for immature pancreatic
function and
are remarkably stable for years in milk stored at low
temperature (-20
- -70 °C); activity is unchanged after storage for 24
hours at 38 °C.
salivary amylase (AMY1A,
AMY1B,
and AMY1C)
isozyme (amylase activity in the duodenum of the
newborn is only 0.2-0.5%
of the adult level. At the time of starch supplementation
(after 4-6 months
of exclusive breast-feeding), the infant is still
deficient in endogenously
produced amylase from salivary glands and pancreas, and it
does not reach
adequate levels until 2 years after birth.)
protease inhibitors might protect the mammary gland
from local proteolysis
and might prevent the proteolytic breakdown of milk proteins
which have
to reach the infant intact (eg, immunoglobulins, digestive
enzymes)
lysozyme
(more abundant than in bovine milk; present at higher
concentrations during
prolonged lactation than during the early stages; infants
produce it only
at ~ 1-2 years)
caseins (a,
b,
and k)
have been shown to prevent the attachment of Helicobacter
pylori
to human gastric mucosa. Further it is broke down to produces
b-casomorphins,
opioid agonists which lower response to pain and elevate mood
in the nursing
mother or the newborn
transfer factors : ribonucleopeptides responsible for
the adoptive
immune transfer of antigen-specific cell mediated immunity
IgA is produced by mammary gland B lymphocytes, which
originate at maternal
sites of high environmental pathogen exposure (eg, the small
intestine
or respiratory tract), and therefore protects the infant
against pathogens
present in the immediate environment. Infants produce SIgAs
only at ~ 4-12
months of age.
lipids (39.0 ± 4.0 g / L) : higher concentrations
of oleic
acid and essential fatty acids than in cow milk
phospholipid and cholesterol (the lipids that
constitute
the milk fat globule membrane) content are higher in colostrum
and transitional
milk than in mature breast milk
Ascherson's membrane : the covering of casein
enclosing the milk
globules
triglycerides : digestion in the stomach and intestine
produces
FFAs and monoglycerides that have been shown to have
antiviral, antiprotozoan,
and possibly also antibacterial activity
long chain polyunsaturated fatty acids (LC-PUFA) are
higher in preterm
and transitional milk and remain high for the first 6 months
in women who
deliver preterm. In term milk, on the other hand, LC-PUFA
declines throughout
the first 6 to 12 months of lactation. The endogenous
synthesis of fatty
acids (FA) declines with parity, most notably after 10 births,
but FAs
(C6-C16) rise with a high-carbohydrate
diet. Palmitic
acid (C16) content of breast milk increases in a
low-calorie
diet. The period of colostrum lasts less than 10 days, but
during this
short time the higher lipid levels are beneficial in such
processes as
neonatal cell membrane production needed for growth, brain
development,
and bile salt synthesis. These fatty acids are stored in the
fetus only
in the last trimester of pregnancy; therefore, preterm infants
are born
with low reserves of LC-PUFA, and their best source for these
essential
fatty acids is human milk. LC-PUFA levels normally decrease in
breast milk
during lactation, but in women who have delivered infants
before term,
the levels remain constant in preterm milk for at least 6
months. the mechanism
for endogenous synthesis of fatty acids (ie, mainly medium
chain fatty
acids) seems to become exhausted in women of very high parity;
that infants
who receive milk with low fat content (ie, less than 3.0
g / dL when
the norm is 3.5 to 4.5 g / dL) tend to nurse more frequently
and for longer
time periods, thereby causing an increase in milk volume; and
that there
is a strong positive relationship between weight gain during
pregnancy
and milk fat content.
fluoride
(concentration in milk seem to be independent of maternal
nutrition) :
16 ± 5 mg / L.
Supplemental fluoride
if the water supply in the area has levels < 0.3 ppm
iodine
(avidly accumulated by the mammary gland) : 100 ± 40
mg
/ L
iron
(concentration in milk seem to be independent of maternal
nutrition) :
300 ± 100 mg / L. No need
iron supplements
during the first 6 months of life, also due to increased
bioavailability
due to co-presence of lactoferrin
Natural and caesarean births can leave substantial wounds in mothers
:
lactation speeds wound healing and lowers stress in rats. After a
mother
gives birth, her prolactin
and oxytocin
levels increase : prolactin boosts the number of circulating immune
cells,
which may speed repair, and oxytocin, which prompts lactation,
lowers the
levels of stress hormones.
It appears that BF may have a protective effect on childhood
cancer,
both the duration of BF as well as the quantity of milk ingested
is probably
critical to the beneficial immunological effects of BF against
childhood
cancer if anyref.
Cow milk : the rate of IgG1 accumulation decreased
rapidly
after calving; this decrease corresponded to a return to normal
serum levels
of this immunoglobulin. Selective accumulation of IgA > IgM
> IgG1
was maintained throughout lactation, but IgG2 showed no
selective
accumulation beyond 5 days postpartum. In serum, IgA and IgM
levels were
elevated at parturition and showed a significant decrease
postpartum. Increases
in serum IgA levels 60 days postpartum corresponded to a rise in
lacteal
concentration. The concentration of all immunoglobulins increased
during
late lactation, coincident with a major reduction in milk yield.
Six strains
of mastitis-causing organisms were cultured during the period of
the experiment;
however, none resulted in clinical mastitis or showed an effect on
immunoglobulin
secretionref.
and 19-hydroxy PGE) predominate and raise intracellular cAMP in
leukocytes.
By this mechanism they suppress lymphocyte proliferation, NK
cell
