Week 8 Flashcards
(37 cards)
What is immunity?
Protection from disease, especially infectious diseases
What are markers of ‘self’?
At the heart of the immune response is the ability to distinguish between self and nonself
Every body cell carries distinctive molecules that distinguish it as ‘self’
Normally the body’s defences do not attack tissues that carry a self marker; rather immune cells coexist peaceably with other body cells in a state known as self-tolerance
What are markers of ‘non-self’?
Bacterium or virus express molecules that are non-self which are capable of triggering an immune response
Human beings are genetically diverse, so markers on tissue if transplanted into another individual will be seen as ‘non-self’ and get rejected
What is the major histocompatibility complex?
The main immunological barrier to allotransplantation
Early experimental work on allotransplantation in mice identified a very clear distinction between individuals due to the expression of the genes located on a particular region.
This was termed the major histocompatibility complex (MHC)
This region exists in all vertebrates and is highly polymorphic, so that in outbred populations 2 individuals will almost certainly differ at this region unless they are monozygotic
What is the molecular base of the MHC?
Cluster of genes on the short arm of human chromosome 6
Encoding a set of polymorphic (many different forms) membrane glycoproteins called MHC molecules
Their function is in the presentation of short peptide antigens to T cells.
What class of MHC molecules do CD8 T cells recognise?
Class I
What class of MHC molecules do CD4 T cells recognise?
Class II
What is Anergy?
A state of immune unresponsiveness
Induced when TCR is stimulated, in the absence of a ‘second signal’ from an APC.
Where do the genetic regions of your MHC come from?
Inherit one from mother and one from father
What is graft rejection in transplantation?
Skin graft to syngeneic recipient
- Graft tolerated
Skin graft to allogeneic recipient
Graft rejected rapidly
Skin graft to minor H antigen incompatible recipient
Graft rejected slowly
Why isnt the foetus rejected?
Rejection involved direct and indirect recognition of MHC
Paternal alloantigens - MHC class I alleles that are co-dominantly expressed
By definition, the fetus is comprised of proteins from both maternal and paternal genes.
MHC call I genes are co-expressed, so both maternal and paternally derived molecules are present on the cell surface
The paternal genes are of course foreign to the mother (unless they are are of the same MHC haplotype which only occurs in inbred animals)
So you have a situation where there is non-self antigens expressed
What are the antigens on the foetus?
Major histocompatibility complex (MHC) genes
- Used to differentiate between self and non-self
- MHC class I YES
- MHC class II NO
–> Not induced with IFNg
- Minor histocompatibility genes
- H-Y antigens in male conceptuses
- Analogous to a transplant BUT mostly not destroyed
–> The foetal allograft (medawar 1950s)
–> Semi allogeneic more accurate
Can the foetus be viewed as ‘foreign’?
Foetus genetic material
Paternal and maternal origins
Encodes for foreign (paternal) antigens seen by immune system as ‘non-self’
Non-self normally rejected by the immune system?
What are key compartments that may influence immunity during pregnancy?
Uterus
Foeto-placental unit
Hormones and growth factors
How is the immune system modulated?
- Specific: Directed against paternal alloantigen
- Non-specific: General “dampening” of the immune system
What are some examples of immune modulation in pregnancy?
- Foetal evasion
- Defence mechanisms
- Shift in environment
i. Cytokines
ii. Tregs
What is foetal evasion?
Control antigen expression
- Regulated (reduced) expression of polymorphic MHC class I at the foetal-maternal interface (placenta)
- No MHC class II (basal or inducible)
Very few trophoblast specific antigens
What might the foetus do to the non-self MHC molecules on the cell surface?
During infections, an infected cell will present foreign peptides with self MHC class I
In transplants and pregnancy, there is a non-self MHC on the cell surface
This non-self MHC looks a lot like self with a foreign peptide.
Our T cells are quite good at recognizing foreign MHC molecules. Transplant rejection reactions are quite vigorous between unmatched individuals.
So to reduce the possibility of this reaction, one survival strategy by the fetus is to not present these molecules on the cell surface.
Remember that MHC class I genes are highly polymorphic
What do we know about MHC class I expression?
Human trophoblast express HLA-C (polymorphic), -E, -F, -G (non-polymorphic)
HLA-G only expressed by trophoblast and protects foetus from destruction by NK cells
HLA-C actovates T cells but also Tregs
What does the lack of MHC class I on the cell surface do?
Leaves the door open to killilng by NK cells.
Therefore, in humans, there is expression of a special MHCclass I molecule called HLA-G.
It is not polymorphic, therefore it is the same between individuals and is selcted for as self in the thymus.
It is only expressed at the fetal maternal interface and is believed to protect fetal cells from destruction by maternal NK cells.
What are the defence mechanisms used by trophoblasts?
Trophoblast derived products that modulate the local environment to protect themselves from killing
Foetal production of Idoleamine-2,3-dioxygenase (IDO)
- Depletes amino acid tryptophan
- Inhibits T cells proliferation
Trophoblast cells express FasL (CD95L) that binds to Fas (CD95) expressing activated T cells
- Gld mice (lack functional CD95) have increased numbers of T cells at maternal-foetal interface and increased foetal loss
Starves T cells of tryptophan which is required for activity
IDO activity in the human placenta is high
Downregulates the maternal T cell activity
What are the defence mechanisms proapoptotic molecules?
Human syncytiotrophoblast cells secrete exosomes
- 30-100nm microvesicles act as a carrier of proteins, lipids, microRNAs, that modulate immune cell function
What happens in the shift in immune environment?
Turn the tide: shift towards ‘suppressive’ immune responses
Includes changes in both peripheral and local responses
Best example is cytokines
You have heard about what we call the TH1/TH2 paradigm eseveral times including today.
You should know by now what the primary TH1 cytokine is_ and the primary type 2_
Th1 promotes effective cell killing and is useful in clearing intracellular infections.
Consequently, it has been found to be detrimental to the pregnanct state.
In several species, we find that Th2 cytokines present at higher concetrations at the fetal maternal interphace and sometimes throughout the whole body.
Elevated TH1 has been associated with pregnancy loss in both humans and mice.
What do we know about CD4+ cytokines?
Th1: Associated with cell mediated immunity… pro-inflammatory
Th2: Associated with humoral immunity… less inflammatory
Immunosuppressive cytokines: IL-10, TGFß associated with immune suppression
