Lecture 20; Immune privilige

Question 1

What is special about sperm production?

Answer 1

It is an immunologically privileged site.

• Semeniferous tubulus
• Blood testis barrier
• Tight junctions between sertoli cells

Question 2

When is the blood/testis barrier broken?

Answer 2

• Broken when barrier is damaged
  
  • Testicular Trauma
  • Infection
  • Vasectomy

Question 3

What happens when the blood testis barrier is broken?

Answer 3

Production of antisperm antibodies

Question 4

What are the mechanisms of antisperm antibodies?

Answer 4

1. Agglutination
2. Transport in female tract
3. Fertilisation

Question 5

Whats a potential application of ASA?

Answer 5

Contraception

Question 6

Are oocytes immunologically protected?

Answer 6

No, there is no blood ovaries barrier.

Oocytes become arrested in meiosis prior to ovulation.

Therefore instances of autoimmunity can occur

Question 7

What is an example of autoimmunity against oocytes?

Answer 7

Premature Ovarian failure

Question 8

Define POF;

Answer 8

Menopause <40
1% women

1. Follicles cannot mature
2. Immunity to the primordial follicles leads to total loss

Question 9

What are the possible causes of POF?

Answer 9

Antigenic Targets
Idiopathic
Diseases in other organs i.e addinsons

Question 10

What are the potential antigenic targets in POF?

Answer 10

• Steroid Hormone Metabolising Enzymes

P450 side chain cleavage (cholesterol to pregnenolone)
17a hydroxylase (progesterones – androgens)
3b hydroxysteroid dehydrogenase (pregnenolone to progesterone)

Question 11

Whats an animal model for POF (1)?

Answer 11

1. Neonatal thymectomy 2–5 days post birth

– Causes autoimmune disease including POF in some strains of mice e.g. balb/C

Question 12

Whats an animal model for POF (2)?

Answer 12

2. Immunisation with ovarian antigens

– e.g. ZP3

Question 13

Describe the relationship between the fetus and mum immunologically using grafts as an anology;

Answer 13

• The fetus is a semi-allograft
• Fetus is a complete allograft with donor oocytes/surrogates
• Why isn’t it rejected by mum?

Question 14

Why isnt the fetus rejected?

Answer 14

Syncytiotrophoblast! the cloak of invisibility

Question 15

Why is Syncytiotrophoblast invisible?

Answer 15

It expresses no HLA molecules

Protects the fetus/placenta from maternal immune system

Question 16

What happens if the syncytiotrophoblast is breached?

Answer 16

Breaches could lead to a maternal response e.g. villitis

Question 17

Is it really invisible?

Answer 17

Syncytiotrophoblast does express minor histocompatibility antigens

Question 18

What other fetal related structure invades mum?

Answer 18

Fetal trophoblast invade deeply into the maternal tissue in the uterus

• Fetal trophoblasts invade the maternal
decidua
• The decidua is full of leucocytes

Question 19

Describe the leucocytes of the decidua;

Answer 19

Leucocytes in decidua
• 70% NK-like cells
• 20% macrophages
• 10% T cells
• Almost no B cells

Question 20

Describe Nk cells;

Answer 20

• Non-MHC restricted lymphocytes
• Comprise ~3% of Peripheral blood lymphocytes
• Kill by releasing cytotoxic products e.g. Granzyme & porforins
• Antibody-dependent cell-mediated cytotoxicity (ADCC)
• Target HLA/MHC-ve cells
  e. g. Tumours & virally infected cells - trophoblasts

Question 21

Describe uterine dendritic like cells

Answer 21

Peripheral blood NK cells are CD16+
(Responsible for ADCC by NK cells)
uNK cells CD16-, CD56bright
Origin is not clear in humans
Appear in decidua during menstrual cycle Large numbers during 1st half of pregnancy

In contact with trophoblast

Question 22

What is required for uNK cells to kill?

Answer 22

• Only kill if IL-2 supplied

* IL-2 strikingly absent from implantation site

Question 23

What HLA do trophoblast express?

Answer 23

Invasive trophoblasts (EVTs) Do not express HLA-A or HLA-B
Do express HLA-G & HLA-E Do express HLA-C

Question 24

What HLA molecules are thought to play a role in reproduction?

Answer 24

HLA-C has an emerging role in reproductive success

Specific role of HLA-G in reproduction

Question 25

Describe HLG

Answer 25

– Very limited/(no) functional polymorphism
– Expressed almost exclusively by EVTs
– Structurally different to classical Class I
proteins
– 6 isoforms, only HLA-G1 expressed at cell surface
– May interact with inhibitory receptors on NK cells to prevent cytolysis of invasive trophoblast

Question 26

What HLA’s do NK cells express?

Answer 26

1) C-type lectin CD94/NKG2A
2) ILT Immunoglobulin like transcripts
3) KIRs killer cell Ig-like receptors

Question 27

Descibre C-type lectin CD94/NKG2A;

Answer 27

• Not expressed peripheral blood NK cells,
  Is expressed by uterine NK cells
• Ligand HLA-E
• HLA-E preferentially presents peptides derived from the leader sequences of other HLA molecules, particularly HLA-G

Question 28

Describe ILT Immunoglobulin like transcripts;

Answer 28

Low levels of ILT-2 are expressed by uNK

Question 29

Describe KIRs killer cell Ig-like receptors;

Answer 29

• Inhibitory/stimulating receptors recognising HLA- C
• Expressed by a higher proportion of uNK cells than PBLs from the same woman
• Activating receptors that induce cytokine secretion but not cytotoxicity KIR2/DS1
• uNK cells produce many cytokines including LIF, GM-CSF, CSF, TNF

Question 30

Describe KIRs and HLA-C haplotypes;

Answer 30

–
•
–
–
•
HLA-C is highly polymorphic and expressed by EVTs
Essentailly HLA-c alleles can be divided into two haplotypes C1 and C2
KIRs are also polymorphic.
In essence women may have two KIR haplotypes KIRA or KIRB

Question 31

Describe KIRs and HLA-C haplotypes;

Answer 31

– Women homozygous for the KIR A haplotype have an increased risk of pregnancy disorders when the fetus has a (paternal) HLA-C C2 haplotype
– this gives strongly inhibitory signals to uterine NK cells.
– HLA-C2 haplotypes + KIR2DS1 is protective