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MIIM30003 - Medical & Applied Immunology > Lecture 28 - Reproductive Immunology > Flashcards

Lecture 28 - Reproductive Immunology Flashcards

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USMLE® Step 1 flashcards
1
Q

Why can pregnancy pose an immunological problem?

A
  • Foetus carries maternal and paternal HLA molecules
  • Paternal HLA molecules expressed by the foetus can act as alloantigens for the mother
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2
Q

Describe the changes to autoimmunity during pregnancy

What is the implication of this?

A

Clinical course of autoimmune disease changes:

  • Rheumatoid arthritis improves
  • SLE gets worse
  • TH1 → TH2
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3
Q

What is the blastocyst?

A
  • 128 cell stage
  • Consists of:
    • ​Trophoblast
      • ​Cell forming the outer lining of the blastocyst
      • Syncitiotrophoblast (outer layer)
      • **Cytotrophoblast **(inner layer)
    • Inner cell mass
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4
Q

What is ST and CT?

A

ST:

  • Syncitiotrophoblast
  • Outer layer of trophoblast

CT:

  • Cytotrophoblast
  • Inner layer of trophoblast
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5
Q

Describe the development of the placenta

A
  1. ST makes contacts with the endometrium epithelium
  2. ST proliferates and invades into the endometrium
  3. Formation of lacunae
  4. Lacunae fill with maternal blood
  5. CT proliferate and invade down into the decidua, surrounded by ST cells
  6. Formation of chorionic villi
  7. Development of spiral arteries
    • ​Important for nutrient transport
    • (Experimental data indicates that cytokines from NK cells in placenta is important for this process)
  8. Formation of EVT cells within the Decidua
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6
Q

Describe how the foetus is in contact with the maternal immune system

A

Two main points of contact:

  1. **ST - **Syncitiotrophoblast
    • ​​Bathed in maternal blood
  2. EVT - extravillous trophoblast cells
    • ​​Contact maternal cells in the decidua
    • “Contact the embryoblast”
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7
Q

Describe transport from maternal to foetal blood

A
  • Maternal blood bathes ST, which form the chorionic villi
  • On the other side, there is foetal blood
  • There is transport of nutrients across the chorionic villi
  • Foetal FcR expressed on chorionic villi
    • ​Binds and transports IgG into the foetus
    • Important for generation of some immunity
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8
Q

How does the ST avoid destruction by the maternal immune system?

A
  • Lack HLA molecules
    • ​Prevents recognition by maternal alloreactive T cells
  • Elevated levels of complement control proteins
    • ​Reduces impact of Ab binding ST cells
      • CD46
      • CD55
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9
Q

How does EVT avoid destruction by the maternal immune system?

A
  • Altered HLA expression
    • ​Lack HLA-A & HLA-B molecules
      • (​Major molecules involved in CD8 T cell activation)
    • Express
      • HLA-C
      • Nonclassical HLA-E and HLA-G
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10
Q

Describe the important features of HLA-C

A
  • HLA class I
  • Polymorphic
  • Lower expression than HLA-A and HLA-B
  • Two groups, as defined by Residue 80
    • ​Group 1
    • Group 2
  • KIR ligand
    • ​KIR2DL1
    • KIR2DL2/3
    • Both are inhibitory receptors on NK cells
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11
Q

Describe the role of HLA-E interacting with NK cells

A

‘Catch all’ presentation of HLA class I to NK cells through NKG2A (inhibitory receptor)

  • HLA-E presents conserved peptides from HLA-A,B,C
    • When HLA-A,B,C are expressed, some peptides are transported into the ER and loaded onto HLA-E
    • HLA-E then trafficked to the surface of the cell
    • NK cell NKG2A recognises HLA-E:peptide complex
    • Inhibition of NK cells
  • Effectively, NK cell is ‘seeing’ all of HLA-A,B,C
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12
Q

Describe the important features of HLA-E

A
  • Nonclassical HLA class I
  • Monomorphic
    • ​Extremely limited peptide repertoire
    • Two alleles, which differ by one residue
  • Lower cell surface expression than HLA-A,B,C
  • Optimised for presentation of conserved peptide from other HLA-I molecules
    • Ligand for CD94-NKG2A
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13
Q

Compare HLA expression in normal cells and EVT cells

A

Normal cells express:

  • ​HLA-A
  • HLA-B
  • HLA-C

EVT cells express:

  • HLA-C
  • HLA-E
  • HLA-G
  • Don’t express:
    • ​HLA-A
    • HLA-B
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14
Q

Describe the important features of HLA-G

A
  • Limited polymorphism
    • ​Constrained peptide repertoire
    • Less constrained than HLA-E
  • Non-classical HLA class I
  • High level of expression in EVT, whereas normally not expressed
  • Not KIR ligand
    • Textbook wrong
    • May bind unusual KIR
  • Ligand for LILRB1/2
    • ​Leukocyte immunoglobulin like receptors
  • Two predominant isoforms
    • Soluble form
    • Membrane bound form
    • Generated by alternate exon splicing
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15
Q

Is HLA-C immunogenic in pregnancy?

Give reasons

A

No, does not lead to an influx of T cells

  1. Elevated Tregs
    • ​At maternal-foetal interface
    • Normal levels systemically in mother
  2. Expression of Indolamine-2,3 dioxygenase
    • Depletes tryptophan
    • Absence of tryptophan and presence of the metabolites results in the generation of a local suppressive environment
      • ​Supression of T and NK cells
  3. Expression of FasL on EVT cells
    • Ligates Fas (expressed on activated T cells)
    • Triggers apoptosis
  4. Tolerogenic (MHC II+) DCs and Macrophages
    • Present in placenta
    • Could potentially present alloantigens to T cells
    • ? expansion of CD4/8+ Tregs
  5. HLA-G
    • ​Expressed by EVT
    • High affinity ligand for LILR​ on myelomonocytic cells
    • LILR activation results in induction of ‘tolerogenic DCs’ (?)
      • No mechanism has been confirmed
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16
Q

What is the role of IDO in pregnancy?

A

IDO: indolamine dioxygenase

  • Catabolises tryptophan
  • Expressed by **EVT **and DCs in the placenta
  • Function:
    • ​Inhibits T cell and NK cell function
    • Results in a local suppressive environment in the placenta
17
Q

What is LILR?

What is the role in pregnancy?

A

Leukocyte immunoglobulin-like receptor

  • Expressed by myelomonocytic cells
    • ​DCs
    • Monocytes
    • Macrophages
  • Structure:
    • Extracellular Ig-like domains
    • Intracellular ITIMs
  • Types
    • LILRB1
    • LILRB2
    • LILRB3
  • Ligands
    • HLA class I

​Role in pregnancy:

  • EVT cells express HLA-G (a ligand for LILR)
  • Interacts with LILR on myelomonocytic cells
  • ? Results in tolerogenic DCs
    • ​The mechanism has not been confirmed
    • Not enough evidence yet
18
Q

Describe the features of the NK cells found in the placenta

Which molecules do they express?

What is the role of these NK cells?

A
  • Special population of NK cells = uNK cells
    • ​CD56hi CD16-
    • ‘Regulatory NK cells’
    • Resemble a minor population in peripheral blood
  • These cells represent **70% **of leukocytes at the implantation site
  • Express high levels of CD94-NKG2A
    • ​Binds HLA-E on EVT
  • Express KIR2DL4
    • Binds ?? HLA-G on EVT

Function

  • Produce soluble factors/cytokines
    • ​May be involved in remodelling the placenta:
    • Development of spiral arteries
      • VEGF
      • PIGF (placental growth factor)
      • TNF
      • IL-1Bβ
      • IFN-γ
      • IL-8
19
Q

What does CD94-NKG2A bind?

A

HLA-E

20
Q

What binds KIR2DL4?

A

HLA-G

21
Q

Describe the importance of blood supply in reproduction

What can go wrong?

A

Reproductive success relies on adequate vascularisation

Vascularisation is regulated by trophoblast invasion

  • Balance:
    • _​_Too much invasion
      • ​Compromises the mother
      • → haemorrhage
      • → placenta percreta
    • Too little invasion
      • Limitation of blood supply to the foetus
      • → pre-eclampsia
      • → recurrent spontaneous miscarriage
22
Q

What are KIRs?

A
  • Killer-cell Ig-like receptors
  • Present on NK cells
  • Bind HLA molecules
  • Structure:
    • ​Domains:
      • ​2D
      • 3D
    • Tails:
      • ​Short
        • ​No ITIMs
      • Long
        • ​Contain ITIMs
23
Q

Outline the different KIR haplotypes

A

NK cells can have one of two haplotypes

The key difference between the haplotypes if the number of activating genes

Type A

  • Only one activating gene
  • NK cells form individuals with A haplotype are more inhibited

Type B

  • Multiple activating genes
  • NK cells from individuals with B haplotype are more easily activated

Thus, an individual can either be:

  • AA
  • AB
  • BA
  • BB
24
Q

Compare the molecules for which the following are ligands:

  • HLA-C
  • HLA-E
  • HLA-G
A
  • HLA-C:
    • ​KIR2DL1
    • KIR2DL2/3
  • HLA-E:
    • ​CD94-NKG2A
  • HLA-G:
    • LILRB1/2
    • ​? KIR2DL4
25
Q

Compare location of expression of the following:

  • HLA-C
  • HLA-E
  • HLA-G
A
  • HLA-C
    • Constitutive
    • Lower expression than HLA-A/B
  • HLA-E
    • Constitutive
    • Lower expression than HLA-A/B/C
  • HLA-G
    • Predominantly expressed in the foetus
    • Some evidence showing expression in tumours etc.
26
Q

What is the mechanism for generation of tolerogenic DCs in the placenta?

A
  1. HLA-G expressed by EVT
  2. HLA-G ligates LILR on DCs
  3. LILR has ITIMs, and is thus an inhibitory receptor
  4. Through some unknown mechanism, the DC gains a ‘tolerogenic’ phenotype
27
Q

Compare NK cell function across the different KIR haplotypes

A
  • AA haplotype
    • ​NK cells are more inhibited
    • As they only express one type of activating KIR
    • High risk of pre-eclampsia if foetus carries **HLA-C2 allele **(ligand for inhibitory KIR)
  • AB & BA haplotype
    • ​Low number of activating KIR
  • BB haplotype
    • ​NK cells express high levels and various activating KIR molecules
28
Q

What is the hypothesis for pre-eclampsia?

A

Associated with high levels of inhibited NK cells

  • NK cells in the placenta play an important role by releasing cytokines
  • These cytokines are thought to be involved in the remodelling of the placenta and formation of spiral arteries
  • If NK cells are too inhibited, such as in mothers with the AA KIR haplotype, this development doesn’t occur
  • Pre-eclampsia results

NB the precise mechanism has yet to be fully proven

29
Q

When does pre-eclampsia generally occur?

A

Often occurs early in the third trimester

30
Q

Describe how levels of HLA expression in pregnancy can play a role in reproductive disorders

A

During pregnancy, the level of HLA-C2 can be altered, thus the NK cells ‘see’ a different level of ligand.

  • Mother normally expresses HLA-C2 at a certain level
    • NK cells threshold for activation is set by level of maternal expression
  • Foetus carries an extra copy of HLA-C2 from father
  • There is now higher levels of expression of HLA-C2
  • NK cells become more inhibited
    • ​Cannot carry out their function in releasing cytokines that drive remodelling of the placenta / formation of the spiral arteries
  • Increased risk of:
    • Pre-eclampsia
    • Foetal growth restriction
    • Recurrent miscarriage
31
Q

For which molecules is HLA-C2 a ligand?

A
  • KIR2DL1
    • Inhibitory
    • Only in KIR-A haplotypes
    • Assoiated with increased risk of pregnancy disorders
  • KIR2DS1
    • Activating
    • Only in KIR-B haplotypes
    • Associated with decreased risk of pregnancy disorders
32
Q

Where does IDO come from at the maternal-foetal interface?

A
  • Secreted by:
    • ST
    • EVT
33
Q

What factors prevent uNK cells from killing EVT?

A
  • HLA-E and HLA-G expression
  • These molecules ligate inhibitory receptors on the uNK cell
    • HLA-E – NKG2A
    • HLA-G – KIR2DL4 (?)

MIIM30003 - Medical & Applied Immunology (30 decks)

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