Immuno

Question 1

Fetus growth and develop depends on fetomaternal tolerance.
How is it initiated?
What is the result?

Answer 1

1) Presentation of the paternal-fetal Ag from semen by seminal plasma factors
2) Maternal DCs process Ag, & present to T cells in the draining LNs.
3) Ag-specific Treg cells proliferate–>peripheral tolerance
towards fetal Ag allowing implantation
4) Treg maintained through pregnancy=tolerogenic anti- inflammatory state or hyporesponsiveness towards paternal Ag until late gestation (birth)

Question 2

TQ

How are activities of NK cells regulated in pregnancy?

Answer 2

1) Inhibited by PIBF via blockage of degranulation and perforin release
2) sHLA-G (HLA-IB type) on trophoblast decr NK lytic activity (sHLA-G ligand for NK cell inhibitory receptor)
3) IDO»kynurenines»
decr activating NK receptors»apoptosis

Question 3

• Prevents T-cell med rejection of fetus by starving cells of tryptophan in the placenta»
• Inactivation/death of activated T cells

-Produces immunosupp kynurenines (metab of tryptophan) which causes cell cycle arrest and induce CD4–>Treg

-Activates Treg cells to create immune privilege and blocks inflammatory signals that usually stimulate effector T-cell responses.

-note: Inhibits the growth of viruses, bacteria, and parasites via tryptophan depletion (essential aa)

Answer 3

Indoleamine2,3,-
Dioxydase (IDO)

Note: Infections»
Activate T cells»
Interferons (IFNs)»
Produce IDO

Question 4

What is the MOA of local immunosuppression in preg by Regeneration and Tolerance Factor?

notes:
-Progesterone»trophoblasts production of RTF
-RTF (also called TJ6) is a cell-surface protein identified in trophoblasts of
early placentas (7-9 weeks)

Answer 4

RTF is cleaved to yield sRTF»
Up-regulates IL-10 (T-reg) & interferes w/ IL-2 signaling (decr T cell growth)
-RTF shifts the balance towards a Th2 T-cell response

Question 5

What is the MOA of local immunosuppression in preg by Progesterone Induced Blocking Factor?

Progesterone induces in trophoblasts production of PIBF.

Answer 5

• PIBF promotes Th2 response (IL-3, IL-4, IL-5, IL-10) and inhibits Th1 (IFNs, TNF-a, and IL-2)
• In B cells, PIBF induces production of non-cytotoxic Abs which do not fix complement
• Women with multiple miscarriages (< 3 months) have low production of PIBF.

Question 6

How is local regulation of complement maintained in the placenta?

Answer 6

Placenta uses complement regulatory proteins to block MAC:
-Membrane cofactor protein (MCP): cofactor for factor 1-mediated inactivation of C3b/C4b

-Decay accelerating factor (DAF):
prevents the assembly of the C3bBb complex

note:
- In B cells, PIBF induces production of non-cytotoxic Abs which do NOT fix complement

Question 7

What is the role of immuno-regulatory cytokines in abortive prevention?

Answer 7

• Abortion in animals: LPS injection–> excess of Th1 cytokines TNF-α and IFN-γ
• Abortion-prone mice have low uterine TH2 cytokines (IL-3, IL-4, IL-10).
• Need TH2!!!
• The TH2 milieu should be established BEFORE maternal allorecognition

Question 8

MOA of antisperm antibodies (ASA) in immuno-infertility in women?

Men:

• If sertoli cell tight junctions (blood-testis barrier) damaged ASAs can be produced.
• ASAs binding to sperm occurs after ejaculation.

Answer 8

• APCs in the female genital tract=Mφ and DCs (Langerhans cells)
• concurrent infection…sperm cells can become “innocent bystanders”.
• Women who experience either clinical or ‘silent’ pelvic inflammatory disease have a high incidence of ASAs.
• Sperm Abs in men and women are a mixture of several polyclonal Abs.

Question 9

What are the therapeutic approaches for treatment of immuno-infertility?

Answer 9

• Immunosuppressive therapies
• Assisted reproductive technologies
• Laboratory techniques

Question 10

T/F
A predominant Th1-type of response is associated with a tendency to spontaneous
abortion

Answer 10

TRUE

complement-dependent Th1

Question 11

• The outer layers of the placenta (trophoblasts) NEVER express class I and II MHC antigens»
• No class I MHC expression on the inner trophoblasts exposed to maternal blood

Result?

Answer 11

-No attack by maternal cytotoxic T lymphocytes.

Question 12

What are some general functions of HLA-G?

hint: blunts APC fx

Answer 12

Placental immunosuppression!

• APOPTOSIS of NK cells
• CD4+ T cells–>Treg cells.
• Apoptosis CD8+ T cells (Fas-FasL pathway).
• Mφ: immuno-suppressed
• Suppresses activation of B cells.
• DC: induces tolerance.

Question 13

Role of Treg cells in pregnancy?

Answer 13

Suppress Th1-mediated maternal attack of the fetus

Deficiency in Treg cell numbers and/or suppressive function are associated with infertility, recurrent spontaneous abortion and preeclampsia in women.

Question 14

What cytokines are involved in Treg production?

Answer 14

• CCL4=recruitment
• IL-10 + TGF-B»IDO=Treg prolif
• TGFB, PGE2, GM-CSF, IL-4, IL-10, G-CSF=tolerance

Question 15

• synthetic steroid indicated for the medical termination of intrauterine pregnancy through 49 days of pregnancy.
• RU 486 – blocks progesterone receptors and prevents PIBF production.
• RU 486-induced abortion is linked with a surge in TNF-α production (Th1)
• RU 486-induced abortion can be thought of as an immuno-endocrine event

Answer 15

Mifepristone

Question 16

• Abortions before 3 months are secondary to a defect in what?
• After 3 months?

Answer 16

• Defect in active maternal tolerance of the fetus.
• Strong Th1 response (IFN-gamma and TNF-alpha)…infection, or failure of ovary to produce progesterone–>incr Th1 response)

Question 17

What is the role of immuno-regulatory cytokines in implantation?

Answer 17

• TH2 state at the time of implantation the uterus
• GM-CSF cytokines in the seminal fluid prepare uterus
• Coital clean up–>inflammatory (IL-1, IFN-γ, and TNF-α)
• Cytokine response downregulated 3.5 days post-coitum
• Cytokines incr adhesion molecules on pre-implantation blastocyst and in the uterus»facilitate embryo adhesion, attachment and invasion.
• Cytokines–>embryonic production of enzymes such as matrix metalloproteases for penetration of the stroma