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.
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.
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
