DR.

MICHELLE BUELA APR 14, 2021

TOPIC OUTLINE -serves as a protection against maternal

I. Introduction adversity
II. The Fertilization Process Following ovulation → corpus luteum (CL) is formed
III. Biomarkers → secretes progesterone (trophic effect on the
IV. Suppression of Maternal Immunity endometrium)
V. Role of cellular components during Pregnancy
VI. Reproductive Immune Failure
VII. Anti-phospholipid Antibody Syndrome
VIII. Treatment III. Biomarkers

LEGEND 1. Platelet-Activating Factor

Must Know Book Doctor’s Lec Lecturio
I. Introduction
Establishment and maintenance of pregnancy
- represents a challenge for the maternal immune
system
- has to defend against pathogens and tolerate
paternal alloantigens expressed in fetal tissues
Implantation of embryo into the uterine walls
- initiates a series of pathways
1. suppress the maternal immune system
2. modulate the local immune reactions that take
place in the uterus
Certain tissues present at the maternal-fetal interface
- responsible for the systemic as well as local
immunosuppression during pregnancy
Human leukocyte antigen (HLA) molecules
- presented to the maternal system
- responses to which play a role in establishing and
maintaining pregnancy
II. The Fertilization Process
sperm penetrates the egg at fertilization → ‘invisible’
to the maternal immune system → foreign antigens
are expressed → fertilized egg rapidly becomes
surrounded by the zona pellucida
➢ Embryonic cell proliferation
- lasts approximately 3 days while the embryo
travels within the fallopian tube
➢ Development of the zona pellucida
- acetylated phosphoglyceride expressed
by the embryo
- mostly local within the fallopian tube
- aids in the transfer of the embryo into the
uterus
2. Early Pregnancy Factor
- identified as chaperonin 10
- shown to influence immune effects
mediating the suppressive effect by
binding T cells, NK cells, and monocytes
3. HLA-G
- expressed by the trophoblast
- may protect the embryo against NK cell-
mediated lysis
- pregnancy can also occur in its absence
- When present, higher pregnancy rate
4. Preimplantation Factor
- modulates the maternal immune system
towards tolerance prior to implantation
- primes the endometrium for implantation
IV. Suppression of Maternal Immunity
➢ Anatomic Barrier
1. Placenta
- connects embryo and uterine wall
- selectively permeable
- allows entrance of nutrients and
facilitates exit of metabolic wastes
- secretes progesterone in large quantities
→ leads to overall maternal
immunosuppression
2. Chorion
- outermost membrane that surrounds the
embryo and fetus

Arevalo, Jaranilla, Loreno, Jazareno, Luciano, Raro, Cuajao, Madera, Malaiba, Chito, Marco,
Mausisa, Najito, Picones, Villones, Carillo, Utod, Galvez, Tan
 DR. MICHELLE BUELA APR 14, 2021

- outer layer of trophoblast cells and an • Secretes pro-inflammatory cytokines

inner mesoderm layer • Should be decreased in pregnancy
3. Decidua Uterine NK Cells
- forms the maternal component of the • 70% of decidual leukocytes
placenta • Non-destructive
• Regulate uterine stromal cells decidualization
and vascular development
• Modulate trophoblast invasion and vascular
remodeling
• Promote uterine spiral artery remodelling
o Nonpregnant women → spiral artery is
coiled
o Pregnant women → spiral artery is
straightened
• Promote immune tolerance

V. Role of Cellular Components during

Pregnancy
Roles of B-Cells in Pregnancy
• Production of asymmetric antibody (blocking
antibody)
o Asymmetric due to absence of one heavy
chain
o Blocking due to blockade of inflammatory
response
o Present in placenta Macrophage in Pregnancy
o Bind paternal antigen → NO TRIGGER OF • Pro-angiogenic factors
CLASSICAL IMMUNE RESPONSE →NO • Vascular remodeling
INFLAMMATION (for recognition of paternal • Good utero-placental circulation
antigens only) • Feto-maternal immune tolerance
o Specific for paternal antigen Regulatory T-cells
o Low in patients with recurrent pregnancy loss • blocks cytotoxic T cells (CD8+) during
• Production of autoantibodies implantation
o i.e Antiphospholipid antibodies • Suppress
o Causes infertility o NK cell activity
o Spontaneous abortion o dendritic cell activity
o Pre-eclampsia o B cell activity
o Pro-coagulant effect
o Fetal growth restrictions
Peripheral Blood NK Lymphocytes
• 10-15% of peripheral blood lymphocytes
• Kills tumor, virus-infected cells
• Embryotoxic

Arevalo, Jaranilla, Loreno, Jazareno, Luciano, Raro, Cuajao, Madera, Malaiba, Chito, Marco,
Mausisa, Najito, Picones, Villones, Carillo, Utod, Galvez, Tan
 DR. MICHELLE BUELA APR 14, 2021

Immune Reaction during Pregnancy • Increased production of pro-inflammatory NK

cells in peripheral blood → embryotoxic

VII. Anti-phospholipid Antibody Syndrome

Revised Sapporo Criteria for the Diagnosis of
Obstetric Anti-phospholipid Antibody Syndrome
(OAPS)

VI. Reproductive Immune Failure

Category I
• Absence of blocking antibodies
• Blocking antibodies → necessary for fetus to be
tolerated
• Absence would lead to pregnancy loss Note: OAPS is diagnosed if one clinical and one laboratory
Category II criteria are met on 2 separate occasions, 12 weeks apart.
• Anti-phospholipid antibody
• Leads to pro-inflammatory and pro-coagulant Algorithm for testing OAPS:
activity
Category III
• Autoimmunity
• E.g. Hyperthyroidism/Hypothyroidism, DM, SLE
Category IV
• Anti-sperm antibodies
• NO SUCCESSFUL PREGNANCY
• The only way is through IVF
Category V
• Active Natural killer cells

Arevalo, Jaranilla, Loreno, Jazareno, Luciano, Raro, Cuajao, Madera, Malaiba, Chito, Marco,
Mausisa, Najito, Picones, Villones, Carillo, Utod, Galvez, Tan
 DR. MICHELLE BUELA APR 14, 2021

Note: If the patient clinically presents with OAPS, but
negative in the initial testing of LAC, ACA, and Anti-β2-GP1,
he/she can still be treated for OAPS.
Other Anti-phospholipid Antibodies:
1. IgG cardiolipin
2. IgG Phosphatidylethanolamine
3. IgG Phosphatidylinositol
4. IgG Phosphatidic acid
5. IgG Phosphatidylglycerol
6. IgG Phosphatidylserine
Non-Criteria APAS:
Note: Non-criteria OAPS is considered present if the patient
has:
a. A combination of non-criteria clinical manifestations
with international consensus laboratory criteria; or
b. International consensus clinical criteria with a non-
criteria laboratory manifestation.
VIII. Treatment
1. ASPIRIN
- Improve blood flow in the uterine vessels
via inhibition of thromboxane A2
- Can also stimulate IL-3 → essential factor
for implantation and placental growth
2. HEPARIN
- Suppresses NK cell cytotoxicity
- Prevents aPL-induced trophoblast
inflammation and inhibition of aPL-
triggered trophoblast cell death
- Prevents leukocyte adhesion
- Blocks IFN-y
- Inhibits complement activation and
promotion of growth factors
- Abrogates apoptosis of primary first
trimester villous trophoblast in response
to treatment w/ proinflammatory cytokines
IFN-y and TNF-α
- Attenuates anti-β2-GPI antibody-mediated
cell death and inflammatory response at
high concentrations
- Upregulates soluble fms-like tyrosine
kinase receptor-1 secretion independently
of aPL by LMWH
IMPORTANT: 44% live birth rate upon treatment
with Aspirin alone. Higher live birth rate when
aspirin is used in combination with heparin (80%).
3. STEROIDS
- Given especially if APAS is not controlled
- Decreases macrophages, promotes TH2
response, and decreases TH17
4. IVIg
- Expands and activates regulatory T cells
- Decreases IL-12, co-stimulatory
molecules, and antigen presentation by
MHC II
- Increases inhibitory FcRII
- Can be given in any inflammatory or
autoimmune conditions
- Other functions:
a. Neutralization of pathogens, microbial
toxins and superantigens
b. Recruitment of pathogens into
lymphoid organs
c. Balance the cytokine network
d. Opsonization and phagocytosis
e. Blocking cellular receptors for
pathogens
f. Antibody- dependent cellular
cytotoxicity
g. Modulation of T-cell function and
antibody production
5. INTRALIPID
- Soy-based compound (eg. EPA, DHA)
- Suppresses the NK cell activity
IMPORTANT: It has been shown that in
suppression of NK cells, IVIg almost equals
that of intralipid

Arevalo, Jaranilla, Loreno, Jazareno, Luciano, Raro, Cuajao, Madera, Malaiba, Chito, Marco,
Mausisa, Najito, Picones, Villones, Carillo, Utod, Galvez, Tan
 DR. MICHELLE BUELA APR 14, 2021

Summary TRANSERS’ SPACE

- 3 essential elements are required for pregnancy
to succeed:
a. Viable embryo
b. Immune tolerance
c. Viable receptive uterus
- Immune recognition occurs even prior to
implantation
- Roles of the different immune cells in the
tolerance of pregnancy
- Different immune mechanism may be involved
in the failure of pregnancy
REFERENCES
• Burmester, G. R., Pezzutto, A., Ulrichs, T., &
Aicher, A. (2003). Color atlas of immunology
(Vol. 18). NY: Thieme.
END OF TRANSCRIPTION

REVIEW QUESTIONS
1. This modulates the maternal immune system
towards tolerance prior to implantation
2. T or F. Pregnancy can still occur in absence of
HLA-G
3. Regulatory T-cells suppress all of the following
except
A. NK cell activity
B. dendritic cell activity
C. B cell activity
D. Macrophage activity
4.Treatment for category I reproductive immune
failure
A. IVIg
B. Aspirin + Heparin
C. IVF
D. Lymphocyte Immunotherapy
5. T or F. According to the Revised Sapporo Criteria
for OAPS, having either one clinical criterion or one
laboratory criterion on one occasion is diagnostic of
the disease.
Answers: 1.Pre-implantation factor 2. True , 3. D 4. D 5. False.

Arevalo, Jaranilla, Loreno, Jazareno, Luciano, Raro, Cuajao, Madera, Malaiba, Chito, Marco,
Mausisa, Najito, Picones, Villones, Carillo, Utod, Galvez, Tan