Basic Immunology Flashcards
Define the innate and adaptive immune systems, and what the main components of each are.
Innate = Rapid, non specific reactions. Involves macrophages, neutrophils, NK cells, and complement proteins
Adaptive = Antigen specific reactions that can recognise pathogenic organisms both in initial reaction and in subsequent contact. Involves T and B cells, antibodies.
What are the humoral components of the innate and adaptive immune systems
Innate = Complement
Adaptive = Antibodies
Define a phagocyte, and what are the 2 main basic types of phagocyte
Phagocyte = Anything that ingests infectious agents and cellular debris
1) The monocyte/Macrophage lineage
2) Granulocytes = Which can be further divided into neutrophils, Mast cells, basophils, and eosinophils
What is the difference between monocytes and macrophages
These are both basically the same. They are both one of the types of phagocyte
Monocyte = Short lived cells that circulate in blood for a few hours then migrate into tissues and turn in mature macrophages
How do macrophages work
Remember these are the long lived tissue macrophages.
They have receptors for Fc region of IgG
They bind to organisms via these Fc receptors if =
1) pathogen is coated with Ab
2) Or if bacteria has been opsonised by complement
Macrophages can then phagocytose and process pathogen. Can then present peptides to T cells and therefore trigger adaptive arm of immune system
What are dendritic cells, and what is their role?
These are a type of additional phagocytic cell derived from monocytes.
Sole function = Capture, process and present antigens to T cells. They are also called antigen-presenting cells
What is the most common immune cell in the blood? And what %
Neutrophils = 50-70% of all immune cells.
How do neutrophils work?
Remember these are granulocytes, which makes up the second type of phagocytes.
Neutrophils = Activated through Fc or complement receptors. Can phagocytose or release granules that are cytotoxic
What are mast cells, and what role do they play. Where are they located?
They are located in skin, mucosal surfaces, and around blood vessels
They are also phagocytic, and express Fc receptors for IgE.
Activation = Causes release of wide range of molecules including histamine, heparin, PGs, cytokines, and chemokines.
Outcome = These can all cause and control inflammation in sorrounding tissues
How about basophils. What cell are they similar to?
These are phenotypically similar to mast cells.
Also have receptors for IgE
How about Eosinophils? Where do they reside and what is there function
Location = Resp and gut subepithelia
Function = Attach to surface of parasites such as schistosomes. They attach then degranulate that damage the parasite membrane.
Describe what NK cells are, and what part of the immune system they are in
System = They are sort of a bridge between the innate and adaptive arms
NK cells = They are large granular lymphocytes that are a morphologically unique population.
Functino = They have cytotoxic activity against a wide range of tumour cells and virally infected cells.
What are the 2 receptors that NK cells use? and what are they for?
1) CD16 receptors = Attach to specific antibodies on tumour cells or on virally infected cells. This is therefore an antibody-dependant cell-mediated toxicity
2) KIR Killer cell immunoglobulin-like receptors = Heterogenous group. Contains both activating and inhibitory receptors that bind with MHC class 1 molecules on target cells.
Healthy cells that express MHC class 1 are protected from NK cell lysis. But tumour cells cause a downregulation of MHC class 1 = So NK cells can attack.
What are the three consequences of activation of the complement system?
1) lysis of microorganisms = Including enveloped viruses and infected cells (by damaging the plasma membrane)
2) Opsonisation = Coating of all foreign particles with complement protein fragments. Then phagocytes have receptors for these = So can phagocytose it all up (via their Fc receptors)
3) Triggering the complement cascade Forming a bridge between innate and adaptive responses.
REMEMBER complement = The humoral component of the innate immune system
Briefly describe complement protein nomenclature
They are called C1-C9. And they are activated in a cascade so that a small initial stimulus can activate and cause a large effect
Minor fragments = Have the suffix a like C3a. These diffuse from the site of activation and can initiate a local inflammatory response by binding to receptors
Major fragments = Have the suffix b like C3b. These bind to target cell membrane
What are the 3 pathways that complement can be activated by. And what does the activation of all three pathways start with?
1) Classic pathway
2) Alternative pathway
3) Lectin pathway
Central to all three pathways = Cleavage of C3 (the most abundant complement protein), followed by activation of the lytic sequence.
But the three pathways differ in how it is initiated
Describe the classic complement pathway
Initiation = Binding of Ab to antigen. Ab has to be either IgG or IgM bound to surface of pathogen.
This antibody-antigen complex causes a conformational change in the Fc portion of the antibody which exposes a binding site for C1q (the first complement protein)
Classic pathway = Therefore means complement is activated through adaptive immunity, because Abs are used here. Therefore can only be activated in situation where immune system already knows the pathogen.
Describe the alternative complement pathway
Initiation = Binding of C3b to hydroxyl and amine groups on surface of pathogens which includes many gram -ve and +ve bacteria.
This pathway is inefficient = As requires high conc of various components
Innate = Alternative pathway does not require Ab. It is activated through innate immune system
Describe the lectin complement pathway
Initiation = Binding of lectin to glycoproteins or carbs on surface of pathogens, which again includes many gram -ve and +ve bacteria.
Lectin is more efficient then alternative pathway
Innate immune system = Again no Abs required, so initiation through innate immune system
What do all three of the complement pathways eventually lead to?
They all lead to activation of the final lytic sequence = After C3b. There is activation of C5,6,7,8,9 sequentially.
This eventually forms the membrane attack complex = Binds to membrane forming a transmembrane channel which allows salt/water through causing lysis of the target cell.
What is the main limitation of the innate immune system?
Very good first line of defence against bacteria, years, parasites.
But it cannot attack viruses or other intracellular organisms well. Relies on adaptive immune system for this
Briefly describe the role of B cells in the adaptive immune system
They have Abs on their cell surface = These bind to antigens, then antigen is internalised, degraded, and complexed with MHC class 2, then returned to cell surface
Peptide-MHC complex = Can then be presented to antigen specific T cells, which secrete cytokines, and induce clonal B cell proliferation and differentiation into Ab producing plasma cells.
What are the similarities between all 5 classes of Ab, and what differs them
All = Are made up of 2 identical light chains, and 2 identical heavy chains.
But they differ = In size, charge, carbohydrate content, and amino acid sequence
What heavy chains are present in each of the 5 Abs?
IgM = Mu heavy chain IgG = Gamma heavy chain IgA = Alpha heavy chain IgE = Epsilon heavy chain IgD = Delta heavy chain
Which Abs are able to activate the complement pathway. And which one and why is the most potent activator of complement.
Remember this is the classical complement pathway only = Therefore it is only IgM and IgG because these are the ones that are involved in adaptive immune system mainly
IgM = More potent activator, since it has 5 complement binding sites (pentamer)
Which Abs are present on membrane of mature B cells
IgM = Because these are used in actviation of Ab production on B cells
IgD = Also. As far as we are aware this is all IgD does = Acts as transmembrane antigen receptor for mature B cells. Has no effect function.
Which Ab is present in mucosal secretions
IgA
Which Ab induces mast cell degranulation?
IgE
Which Ab is able to cross the placenta?
Only IgG
Which Abs are able to bind to phagocyte Fc receptors?
Remember the Fc receptors can bind to Abs in order to phagocytose pathogens that are covered in Abs.
IgG = Defo can bind to Fc receptor ?IgM = We think this can also bind.
What are the 2 main regions of the Ab, what are they called and what is their function?
Each end of the Ab has a light chain and heavy chain on each side. Meaning that one end will be comprised of both 1 light chain, and 1 heavy chain. (look at pic on p297)
Fab = Antigen-binding region. At this end there is the amino-terminal domains of the heavy and light chains. This is also known as the variable region because it changes for every antigen.
Fc = Constant region = This is the carboxy-terminal domains of the heavy and light chains. The Fc region determines which effector function will be activated.
Note that all Ab types are bifunctional = They are able to bind to antigens, but also the Fc region has an effector function. THE ONLY EXCEPTION is IgD.
How many subclasses of IgG are there, and which ones are more active in 1) crossing placenta 2) activating complement 3) binding to Fc receptors on phagocytes
There are 4 subclasses of IgG
1) IgG 1, 3, 4 = Cross placenta and therefore protect foetus
2) IgG 1, 3 = Activate complement the most
3) IgG1, 3 = Are good at opsonisation, so can bind well to Fc receptors on phagocytes for phagocytosis
NOTE = 134, then 13, then 13.
What is the name of the receptor on T cells, and what are the two main groups of this receptor, as well ass where they are expressed?
T cell receptor = TCR
1) Alpha/beta TCRs = Expressed on more then 95% of circulating T cells
2) Gamma/Delta TCRs = Rarely expressed on blood T cells. But are present on T cells in mucosal surfaces such as small intestine, pregnant uterus, as well as in the liver
Describe how alpha/beta T cells are formed
Alpha/beta T cells (remember this is one of the 2 groups) are generated in bone marrow.
They undergo TCR gene rearrangement in the thymus. And the immature T cells (thymocytes) that recognise self MHC mosulces are selected. The cells that do not undergo apoptosis
Thymocytes then migrate deeper into the cortex = Here they increase expression of TCR, and cell surface molecules, CD3, CD4, and CD8
TCRs that recognise self with high affinity are also deleted here = This process is known as negative selection
Then T cells = Either go on to express either only CD4 or CD8
Descibre the difference between CD4 and CD8 cells
CD4 = T helper cells. These are MHC class 2 restricted
CD8 = Cytotoxic T cells which are MCH class 1 restricted
Describe how gamma/delta T cells are generated
These are also made in the bone marrow.
But these differ from the alpha/beta ones.
Gamma/delta = They have neither CD4 or CD8, and are MHC unretricted
Describe how CD4 T cells (helper cells) interact with APCs/
The CD4 on the T helper cells binds to the MHC class 2 molecules on the APC that has the antigen on it.
Activation = Following this activation the naive CD4 cell produces IL-2 and either turns into Th1 or Th2 depending on what signals it gets after activation.
Describe the 2 subset of CD4 T cells and how they differ
They can be categorised as either Th1 or Th2 based on the pattern of cytokines they release
1) Th1 cells = Produce IFN-y and IL-2. These cytokines activate macrophages and CD8 T cells, therefore promoting cell-mediated immunity. More useful for intracellular pathogens like intracellular bacteria and viruses.
2) Th2 cells = Produce IL-4 and IL-5. These cytokines stimulate B cells to produce antibodies. Therefore promoting humoral/anti-body mediated immunity
After CD4 T cell activation wit APC, what determines whether it becomes Th1 or TH2
1) Th1 = IFN-y and IL-12 cause Th1
2) Th2 = IL-4 promotes Th2
Besides Th1 and Th2, there are 3 other th types of CD4 T cell. What are these and what are there roles
1) Th3 cells = produce high amounts of TGF-beta (transforming growth factor beta)
2) Th0 cells = Express both Th1 and Th2 cytokines
3) Tr1 cells = Secrete IL-10 and little or no IL-2 or IL-4. Which overall leads to immune supression
Describe what the CD8 receptor does, and what it does for CD8 positive T cells
CD8 receptor = This works as a cell adhesion molecule. CD8 binds to MHC class 1 on the target cell or on the APC
So it if is binding to a target cell = It is to kill it.
Describe how CD8 T cells can also be subdivided
Just like CD4, CD8 T cells can also be driven towards 1 of 2 types.
Tc1 = Cytotoxic phenotype. Also driven by IL-12 and IFN-y like in TH1 cells.
Tc2 = Driven to this phenotype by IL-4 (same as Th2 also)
Both these phenotypes remain cytolytic in function
What are the 4 main types of cytokine
1) Interferons
2) Interleukins
3) Chemokines
4) Growth factors
Describe the role of interferons broadly
They are mainly involved in stopping viral infections
They are produced early in viral infection and are pivotal in stopping spread of virus until adaptive immunity has a chance to develop
Name 3 interferons, and their source
1) IFN-a = Produced in leucocytes
2) IFN-b = Produced in fibroblasts
3) IFN-y = Product of activated Th1 cells and NK cells.
Name 5 main functions of IFN-y
Remember this is the main interferon that is produced by Th1 cells and NK cells
1) Antiviral effects (the main thing for interferons)
2) Increasing MHC class 1 and 2 expression
3) Activating macrophages and NK cells (important as they stop initial viral spread)
4) Promote cytotoxic susceptibility of target cells (lets them kill viral infected cells)
5) Polarising TH0 cells to become Th1 phenotype (this makes more IFN-y, and this is cell mediated immunity, so best for killing viruses.
The main interleukens are IL1,2,4,10,12. List the cells that make these, and broadly their biological function. FOR IL-1
Source cell = Macrophages and monocytes
Biological function = Pro inflammatory effects
The main interleukens are IL1,2,4,10,12. List the cells that make these, and broadly their biological function. FOR IL-2
Source cell = T cells, including Th1 cells. (remember this is one of the things along with IFN-Y made by TH1 cells for cellular immunity)
Biological function = Growth factor for T cells by stimulating proliferation and growth of T cells.
Also increases cytolytic activity of NK cells
(All these things increase cell mediated immunity which is all Th1)
The main interleukens are IL1,2,4,10,12. List the cells that make these, and broadly their biological function. FOR IL-4
Source cell = Th2 cells = Remember this is made by Th2 cells after differentiation
Biological function = Promotes proliferation and differentiation of B cells (Th2 is humoral immunity). Also upregulates B cell HLA class 2 expression
The main interleukens are IL1,2,4,10,12. List the cells that make these, and broadly their biological function. FOR IL-10
Source cell = T and B cells. Monocytes and mast cells
Biological function = Potent anti-inflammatory effects
Inhibits IFN-y and IL-2 production by TH1 cells.
Regulates growth and differentiation of B cells
Enhances expression of HLA class 2
The main interleukens are IL1,2,4,10,12. List the cells that make these, and broadly their biological function. FOR IL-12
Source cell = Macrophages, dendritic cells, and B cells
Biological function = Enhances cytolyic activity of CD8 T cells and NK cells
Also encourages TH1 type immunity by inducing secretion of IFN-y, IL-2, and TNF-a
(This is one of the cytokines that causes CD4 cells to go for Th1 immunity).
There are 2 main pro-inflammatory cytokines. What are these, and where are they produced, and what is the trigger for their production?
1) IL-1 = produced by macrophages and B cells. Works to activate lymphocytes (T , B and NK cells).
Also increases expression of adhesion molecules on endothelial cells (more rolling)
2) TNF-a = has the same effects as IL-1 above, but is primarily produced by macrophages and activated T cells
Triggers for production of both the above = Oxidative stress, or by endotoxins like bacterial lipopolysaccharide
What are the roles of chemokines,
Important for cell migration, activation, and chemotaxis.
They diffuse from site of production = Tissue leucocytes or endothelium. And work as a conc gradient.
What is the main chemokine receptors for Th1 and Th2 cells
Th1 = CCR5
Th2 = CCR3 and CCR4
Name the 2 main growth factor cytokines, and their role
1) Granulocyte-macrophage colony stimulating factor (GM-CSF) = Released by macrophages, T cells, fibroblasts.
These induce development of non-lymphoid cells like granulocytes. They therefore also activate macrophages and eosinophils
2) TGF-b = Modulates immune response by inhibiting T and B cells. ALso suppresses macophages and NK cells.
What is the difference betwen MHC and HLA, and what is the chromosome that encodes it?
MHC is the protein it self = T cells cannot respond to antigens unless on an MHC
HLA = This is the gene that encodes the human MHC
Chromosome = Found on 6p21.3
What are the 2 types of MHC class 2, how do they differ and where are they expressed
1) Classic MHC class 1 molecules = HLA-A, HLA-B, HLA-C These are the highly polymorphic ones that are present on most nucleated cells
2) Non classic MHC class 1 molecules = HLA-E, HLA-F, HLA-G These have limited polymorphism and limited tissue expression HLA-E and HLA-F = On a variety of adult and foetal tissues HLA-G = Only on extravillous cytotrophoblast tissue of the palcenta.
What is the role of MHC class 1
Their role is to present all sorts of antigens that are found within the cell = Including intracellular viruses and endogenous antigens.
They present these to CD8 cells which can then kill cell
Describe MHC class 2 proteins, including where they are found, and what their role is
MHC class 2 = High polymorphic as well, including HLA-DR, HLA-DQ, HLA-DP as examples
Expression = Found on APCs including monocytes, macrophages, B cells, and dendritic cells.
These work to express antigens from outside the cell (exogenous antigens) to CD4 cells. Unlike MHC class 1 which presents endogenous antigens within the cell.
What is MHC class 3
This region contains a large number of genes
Including Complement C2 and C4 factors
Heat shock proteins
And TFN-a
Define autograft, isograft, allograft, xenograft
Allograft = From one site of body to another site on the same person. Like skin
Isograft = Between genetically identical individuals, like monozygotic twins
Allograft = Between different genetic people. Like a transplant
Xenograft = Different species, like pig heart valves
Describe what occurs in allorecognition in transplanted organs
The donors APCs can present donor MHC molecules to recipient naive T cells.
This will cause an alloresponse
Note = Even minor histocompatibility antigens can be targets of rejection even when MHC between donor and recipient are identicle.
Most important example = Histocompatibility antigen H-Y, encoded by Y chromosome and hence only expressed on male cells.
Describe briefy what occurs in graft versus host disease. How can it be avoided.
This is when the donor graft actually attacks host such as in bone marrow transplantation
Immune competent donor T cells reside in graft = They recognise recipient MHC and/or minor histocompatibility antigens and treat as foreign and attack.
Avoided = By carefully matching donor and recipient and removal of all T cells from graft with immunosupression.
What are the 3 main types of rejection
Hyperacute
Acute
Chronic
When does hyperacute rejection occur, and what happens
Time = Within minutes to hours
When natrually occuring recipient antibodies attack antigens on donor cells. Often ABO mismatch or when patient has already been sensitised to that donor MHC before (eg prev transplant)
Ab binding = Causes cascade with complement activation (classic pathway), vascular leakage, activation of coagulation process, increased expression of adhesion molecules, rapid destruction of graft
When does hyperacute rejection occur, and what happens
Time = Days to weeks
Donor Leucocytes (known as passenger leucoytes) migrate out of graft and initate a primary immune response.
The activated recipient T cells then migrate into organ and kill it with delayed type 4 sensitivity, as well as generation of Tc cells
When does hyperacute rejection occur, and what happens
Time = Months to years
Less udnerstood. But you get occlusion of blood vessels, macrophage infiltration, and sm proliferation which causes blockage of blood vessels causing ischaemia of graft
When matching HLA for transplant, which one is more important to match?
More important to match HLA class 2 = A single class 2 mismatch is equivalent to 3 or 4 class 1 mismatch.
Name 5 groups of immunosupressive drugs used in transplant, and their function
Azathioprine = Inhibition of nucleic acid synthesis in all mitotic cells
Corticosteroids = General anti inflammatory effects
Ciclosporin A and tacrolimus (CI inhibitors) = Blockage of T cell activation
Sirolimus (NOT a CI inhibitor, acts on mTOR to inhibit IL2 and other cytokines) = Inhibition of T cell proliferation
Anti CTLA4 Abs = Promotion of unresponsiveness in alloreactive T cells.
Describe the 5 types of hypersensitivity
1) Type 1 = Mediated by antigens (allergens). Bind and cross link with IgE that are bound to Fc recepeotrs on mast cells or blood basophils. Causes activation and degranulation.
Includes severe anaphylactic reactions, as well as atopic diseases like asthma and hay fever
2) Type 2 = mediated by IgG or IgM. They react with Fc receptors on a range of effector cells including platelets, neutrophils and cause activation of complement system to damage target cells
Examples = Transfusion reactions and haemolytic disease of newborne
3) Type 3 = Failure of phagocytes to clear immune complexes. These immune complexes then cause immune inflammatory response via complement activation and histamine and proinflammatory cytokine release. Most of the tissue damage stems from release of lysosomal enzymes by granulocytes as they attempt to phagocytose complexes back.
Examples = RA, SLE.
4) type 4 = Delayed hypersensivity which is cell mediated. Caused by antigen specific T cells.
5) Type 5 = Something like when Abs cause stimulation of receptor like Grave’s disease and myasthenia gravis
What are the 3 subtypes of type 4 hypersensitivity
1) Contact hypersensitivity = Point of contact with allergen like nickel.
2) Tuberculin type hypersensitivity = Induced by soluble antigens from organisms like Mycobaterium tuberulosis or mycobacterium leprae. Causes localised inflamm response
3) Granulomatous hypersensivitiy = Develops over 21-28 days. Persistence of the antigen causes chronic stimulation of T cells and release of cytokines. This causes epithelioid cell granulomas to form. Such as in TB, leprosy and Corhn’s disease.
What are the 2 interfaces where mum and foetus interact?
1) When tips of chorionic villi invade into decidua in early stages of pregnancy. Later it also invades spiral arteries to supply maternal blood to intervillous space. This tissue-tissue interface is important in the first trimester of pregnancy
2) Between the surface of the chorionic villi (syncytiotrophoblasts) and the maternal blood, where exchange occurs. This means this is a tissue-blood interface and is more important in 2nd and 3rd trimester
- This second interface actually extends throughout mums blood = As there is shedding of cellular syncytiotrophoblast debris, DNA, and mRNA. Also there are haemorrhages of foetal blood across placenta. Thus foetal RBCs and leucocytes can be found in maternal circulation as early as first trimester.
What maternal immune cells are present in interface 1; between invasive cytotrophoblasts and maternal immune cells in decidua
About 40% of maternal cells in the decidua are bone marrow derived.
Include = T cells 10%, Macrophages 20%, dendritic cells 2%. And other ells
Basically no B ells.
LARGEST population of cells by far = The decidual NK cell 70%
Describe the decidual NK cells that are found in interface 1. What role do the decidual NK cells play
These are by far the largest proportion of maternal immune cells in the decidua, and differ from normal NK cells.
Stain = They stain bright for CD56 (adhesion molecule), but are negative for CD16 (Fc receptor found on all other NK cells).
Phenotype = Differs from normal NK cells also. Instead of being cytotoxic, activated decidual NK cells produce cytokines/chemokines and angiogenic factors that facilitate trophoblast invasion.
Describe the contact that occurs in interface 2 = Between syncytiotrophoblasts and maternal immune cells in blood
Remember this is a tissue:blood interface
The syncytiotrophoblasts = Act as epithelium that covers the surface of placenta.
It therefore functions like an endothelium - Because it lines the placental side of the intervillous space through which maternal blood flows.
It is therefore in full contact with a range of maternal blood cells.
Describe how the expression of MHC antigens is different in cytotrophoblasts in interface 1
They express MHC class 1
But do not express HLA-A or HLA-B. But they do express HLA-C. Remember these are the main highly polymorphic ones, so lack of these reduces rejection
They do however express non-polymorphic non-classical MHC class 1 antigens = Including HLA-E and HLA-G
They do not express MHC class2
Describe how expression of MHC antigens is different in the syncytiotrophoblasts in interface 2
Syncytiotrophoblasts in interface 2 = Completely negative for Class 1 MHC. Making is almost unique in human body, with exception for RBCs
These are therefore very unlkely to stimulate maternal immune system
They also do not express MHC class 2.
What are the three HLA present on extravillous cytotrophoblasts (interface 1)
HLA-C = Major one
HLA-E and HLA-G = Minor ones
Describe the 7 different forms of HLA-G
Remember HLA-G = One of the minor ones.
Expressed cytotrophoblasts in interface 1
Has 4 different membrane bound forms = HLA-G1,G2,G3,G4
And 3 soluble forms = HLA-G5,G6,G7
This means that HLA G can mediate effects both locally with membrane form, and systemically via soluble forms.
Why does HLA-G not cause that many issues for immune rejection in pregnancy
Remember this is one of the minor ones of HLA that does not show much polymorphism
This ensures that paternal and maternal HLA-G will be almost identical. So unlikley to cause an alloreactive maternal T cell response in pregnancy
HLA-G on the extravillous cytotrophoblasts can bind to T cells and NK cells (maternal ones). What effect does each of these have and what are the names of the receptors it binds to
HLA-G binds with T cells = Causes apoptosis of the CD8 cell via Fas and Fas ligant. This supresses proliferation of CD4 T cells and Tc cells.
HLA-G binding with NK cells = Binds to the KIRs receptors on NK cells. This is KIR2DL4. This causes the production of a number of immunoregulatory molecules, including;
Cytokines
Chemokines
Angiogenic factors.
These all work to promote and regulate trophoblast invasion
What is the role of HLA-E on cytotrophoblasts, what receptors does it bind to
A bit like HLA-G, this is also a minor HLA.
Meaning that it is bascially monomorphic and doesnt cause much problems with immune rejection
Role = Inhibition of NK cell mediated killing of trophoblasts
Receptor = Binds to the CD94/HKG2A receptor on decidual NK cells
What is the role of HLA-C on cytotrophoblasts, and what is the receptor it binds to
Remember HLA-C is one of the major ones that is very polymorphic.
But, like HLA-G, HLA-C does not seem to itneract with T cells much, but more with NK cells
And this interaction = Beleived to be beneficial by stimulating beneficial cytokines, chemokines, and aniogenic factors
Receptor = Binds to KIR2D on decidual NK cells
How come the mother makes anti-feotus antibodies during pregnancy? When we’ve just spent all that time explaining that HLA dont do anything on the cytotrophoblasts?
Mum can make Abs against the foetal cells that end up circulating around in maternal blood.
Foetal cells = Will contain HLA-A,HLA-B, and HLA-C
Therefore can make Abs against these
What % of first and subsequent pregnancies does mum make Abs
In first pregnancy = 15% chance of making Abs against HLA-A,B,C
Subsequent pregnancies = 60% of subsequent pregnancies from same father
How come the maternal Abs that mum makes against foetal HLA-A,B,C do not harm the foetus?
These Abs = are actually fitlered out by the placenta.
They are transported across syncytotrophoblasts (interface 2) and then will bind to paternal HLA antigens expressed on the macrophaages and endothelium of the chorionic villus.
This will form immune complexes and then cleared by macrophages.
Therefore no harmful Abs enter foetal circulation
Describe the pathophysiology and process of Rhesus D disease in first and subequent pregnancies
First pregnancy = Baby needs to be Rh+ve, and mum Rh-ve. In first pregnancy during labour the seperation of placenta means foetal RBCs enter mothers circulation and sesnitises her, and means that Rh-specific memory B cells are made post partum.
This means generally first pregnancy is unaffected
Future pregnancies = Results in formation of IgG anti-RhD Abs which can cross placenta and cause damage to foetal red blood cells.
Consequences for foetus = Range from mild to severe anaemia, impaired platelet function, dysfunction of the liver and spleen.
What is haemolytic disease of the newborn
This can be due to multiple causes = including RhD incompatibility
But this is now a rare cause
What is the treatment for Rh Disease
We give RhD prophylaxis
Where we give Anti-RhD antibodies to RhD negative mothers immediately after delivery of RhD positive babies.
These Abs will bind to foetal erythrocytes and destroy them before mums immune system can be sensitised by them.
Why is there less cell mediated immunity in pregnancy
Remember normally = CD4 cells can either become th1 or th2 depending on what cytokines are present
During pregnancy = Placenta produces more Th2 promoting cytokines icluding IL-4 and IL-10, as well as progesterone which inhibits Th1.
What is the clinical evidence that there is a shift towards more Th2 immunity in pregnancy?
1) Temporary remission in RA (th1 mediated) in pregnancy
2) Exacerbation of diseases caused by intracellular pathogens = Herpes/malaria. Because Th1 is cell mediated immunity
3) Worsening of SLE, as this is Th2 mediated, in pregnancy
Why can deficits in immune systems lead to implantation failure, miscarriage and pre-eclampsia
Remember from before, immune mechanisms are important for trophoblast invasion.
The binding of HLA-C,G,E to decidual NK cells promote this trophoblast invasion
Therefore issues in immune systems can increase risk of implantation failure, miscarraige, and pre-eclampsia
Remember there are 3 main HLAs that are present on cytotrophoblasts (interphase 1). How can the lack or difference in the presence of these HLAs cause poor foetal outcomes.
HLA-G = The more expresison that there is of this, the better. More soluble HLA-G means more likely to implant.
HLA-G expression has also shown to be reduced in recurrent abortion and pre-eclampsia
HLA-C = There is 2 major subtypes HLA-C1 (activates NK cells) and HLA-C2 (inhibits NK cells). There are also 2 types of KIR receptor on NK cells, KIR-A (inhibit NK cells) and KIR-B (activates NK cells
HLA-C1 + KIR-B = good pregnancy where decidual NK cells can produce benefial cytokines, chemokines, and angiogenic factors
HLA-C2 + KIR-A = more common in pre-eclampsia and recurrent miscarriage
HLA-E expression = Not know how this effects
How can the balance of Th1 and Th2 in pregnancy cause negative outcomes
Normally = Pregnancy is more Th2 biased, because placenta produces IL-4 and IL-10
But if it is not like this = Can get an exagerated inflammatory response which can lead to endothelial dysfunction in the mother
This can be the cause of maternal syndrome = HTN, Proteinuria, oedema, DIC. You also get higher rates of recurrent miscarriage and pre-eclampsia
In these pregnancies = You tend to see higher levels of IFN-y which promtoes Th1.
What are the 3 antiphospholipid Abs, and how and why are they related to miscarriage rates
Abs = lupus anticoagulant, anti-cardiolipin, anti beta2glycoprotein
Lupus anticoagulant = Inhibits coagulation by inhibiting prothrombin to thrombin. Therefore less of this means more clotting
Anti cardiolipin Abs = develop against certain phospholipid/cell membrane components. Found in 15% of women with a miscarriage. The syncytiotrophoblats have some membrane components that can be attacked by these Abs and cause defect placentation.
How can the antiphospholipid Abs directly affect the foetus (besides causing miscarriage)
These Abs can be transferred across the placenta into foetus
Can cause = Transient autoimmune thryoiditis, myastheania gravis, and autoimmune thrombocytopaenia
What are the three forms of immunotherapy that have been tested in order to reduce implantation failure, recurrent miscarriage, and pre-eclampsia associated with the immune system?
1) Paternal and third party leucocyte immunisation
2) IvIg
3) Treatment with Abs against TNFa
Describe how paternal and third party leucocyte immunisation works
Based on idea that the negative outcomes are due to exposure of maternal immune system to paternal antigens during implantation, and early pregnancy fails to trigger the neccessary useful inflammatory response.
In renal transplant = Give pretransplant blood transfusion actually increases allograft survival
So in pregnancy = Argued that can give paternal or third party leukocyte injection. And this will stimulate appropriate immune response during early pregnancy so it can be a sucess.
This is controversial, and little evidence so far
Describe how IVIG works to promote successful pregnancy
IVIG is produced from pooled human plasma obtained from multiple donors and used as immunomodulator in many diseases.
Thought process = It contains Abs that are beneficial to pregnancy survival by downregulating B and NK cell function.
Again data is conflicting.
Describe how treatment with Abs against TNFa helps in pregnancy
Remember that TNFa is associated with Th1 system, prodcuced by Th1 cells after they are made.
And pregnancy is Th2 biased
So thought that anti-TNFa will help reduce implantation failure, and miscarriage rates.
Recent cochrane review = Showed immunotherapy shows no significant benefit over placebo for improving live birth rate.
