Lecture 20; Immune privilige Flashcards
What is special about sperm production?
It is an immunologically privileged site.
- Semeniferous tubulus
- Blood testis barrier
- Tight junctions between sertoli cells
When is the blood/testis barrier broken?
- Broken when barrier is damaged
- Testicular Trauma
- Infection
- Vasectomy
What happens when the blood testis barrier is broken?
Production of antisperm antibodies
What are the mechanisms of antisperm antibodies?
- Agglutination
- Transport in female tract
- Fertilisation
Whats a potential application of ASA?
Contraception
Are oocytes immunologically protected?
No, there is no blood ovaries barrier.
Oocytes become arrested in meiosis prior to ovulation.
Therefore instances of autoimmunity can occur
What is an example of autoimmunity against oocytes?
Premature Ovarian failure
Define POF;
Menopause <40
1% women
- Follicles cannot mature
- Immunity to the primordial follicles leads to total loss
What are the possible causes of POF?
Antigenic Targets
Idiopathic
Diseases in other organs i.e addinsons
What are the potential antigenic targets in POF?
- Steroid Hormone Metabolising Enzymes
P450 side chain cleavage (cholesterol to pregnenolone)
17a hydroxylase (progesterones – androgens)
3b hydroxysteroid dehydrogenase (pregnenolone to progesterone)
Whats an animal model for POF (1)?
- Neonatal thymectomy 2–5 days post birth
– Causes autoimmune disease including POF in some strains of mice e.g. balb/C
Whats an animal model for POF (2)?
- Immunisation with ovarian antigens
– e.g. ZP3
Describe the relationship between the fetus and mum immunologically using grafts as an anology;
- The fetus is a semi-allograft
- Fetus is a complete allograft with donor oocytes/surrogates
- Why isn’t it rejected by mum?
Why isnt the fetus rejected?
Syncytiotrophoblast! the cloak of invisibility
Why is Syncytiotrophoblast invisible?
It expresses no HLA molecules
Protects the fetus/placenta from maternal immune system
What happens if the syncytiotrophoblast is breached?
Breaches could lead to a maternal response e.g. villitis
Is it really invisible?
Syncytiotrophoblast does express minor histocompatibility antigens
What other fetal related structure invades mum?
Fetal trophoblast invade deeply into the maternal tissue in the uterus
• Fetal trophoblasts invade the maternal
decidua
• The decidua is full of leucocytes
Describe the leucocytes of the decidua;
Leucocytes in decidua • 70% NK-like cells • 20% macrophages • 10% T cells • Almost no B cells
Describe Nk cells;
- 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
Describe uterine dendritic like cells
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
What is required for uNK cells to kill?
- Only kill if IL-2 supplied
* IL-2 strikingly absent from implantation site
What HLA do trophoblast express?
Invasive trophoblasts (EVTs) Do not express HLA-A or HLA-B Do express HLA-G & HLA-E Do express HLA-C
What HLA molecules are thought to play a role in reproduction?
HLA-C has an emerging role in reproductive success
Specific role of HLA-G in reproduction
Describe HLG
– 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
What HLA’s do NK cells express?
1) C-type lectin CD94/NKG2A
2) ILT Immunoglobulin like transcripts
3) KIRs killer cell Ig-like receptors
Descibre C-type lectin CD94/NKG2A;
- 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
Describe ILT Immunoglobulin like transcripts;
Low levels of ILT-2 are expressed by uNK
Describe KIRs killer cell Ig-like receptors;
- 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
Describe KIRs and HLA-C haplotypes;
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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
Describe KIRs and HLA-C haplotypes;
– 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
