Primary Immunodeficiency I Flashcards
What is immunodeficiency?
A congenital (secondary) or acquired (primary) state where the immune response has:
- Missing components.
- Non functioning components.
- Incorrectly functioning components.
This leads to a deficiency in the function of the immune response and therefore increases susceptibility to infection.
The nature of the infections gives a strong clue to the arm of the immune response that is deficient:
- Opportunistic infections seen in HIV include Candida, Mtb, Herpes viruses, Pneumocystis jiroveci and M avium.
- These infection are ALL normally controlled by robust T cell mediated immune response. Problems with T cells- absent ones or ones that don’t function.
What are the different kinds of immunodeficiency inheritance?
Autosomal dominant- 1 normal functioning allele and one defective allele. The defective allele dominates the function of the normal product e.g. ALPS, hyper IgE, C1inhibitor.
Autosomal recessive- defective allele from both parents, both parents are carriers e.g. RAG1/2.
X linked- Recessive defect on the X chromosome. Males inherit defective gene from their mothers who are carriers e.g. XLA, WAS, XLP, Xhyper IgM, NEMO, Properdin.
(What is the likelihood of parents being carriers? What is the likelihood of children being affected?
ALPS- functional trimer- one or two of three doesn’t work, so entire complex won’t work.
X linked is most common.
Males will inherit disease from carrier mother (who has two X chromosomes) if defective X is inherited, as they only have one X chromosome).
What are the odds of having an infected child with an autosomal dominant condition?
One parent affected, one not affected.
50% chance of infected child.
What are the odds of having an infected child with an autosomal recessive condition?
Both parents are carriers. Neither parent has disease- need two affected alleles to have disease.
1 in 4 chance affected, 50% chance of carrier.
This is least common.
What are the odds of having an infected child with an X linked condition?
Father not affected, mother is a carrier.
1 male and 1 female not affected, 1 affected male, 1 carrier female.
What can happen to phagocytes in PID in innate immunity? What are two conditions that are caused by this?
Genetic defects of phagocyte number, function, or both.
270 described immunodeficiency conditions with known genes.
2 conditions- LAD, CGD.
What are neutrophils (PMN)?
Characteristic cell of acute inflammation.
Most abundant white blood cell in circulation.
Bone marrow derived.
Myeloid lineage.
Short lived: 1-3 days.
Very rapid turnover.
Rapidly mobilised from marrow.
Die in tissues.
Azurophilic granules in neutrophils- greeny colour- why pus is green sometimes.
What is leukocyte adhesion deficiency (LAD)?
Inheritance is autosomal recessive.
LAD type 1- CD18 deficiency resulting in no tethering to endothelium (200 cases).
LAD type 2-deficiency of fucose transport Sialyl lewis X- lectin interaction for neutrophil rolling. (CD15 deficiency)- no rolling (30 cases).
LAD Type 3 Kindlin 3 deficiency- signalling problem leading to failure to migrate through endothelium (5 cases- all in Turkey and Israel).
(Rac 2 deficiency - L selectin expression autosomal dominant). Two families described in the world (from Turkey).
Affects ability of leukocytes to bind to membranes.
Very rare conditions.
Recessive conditions more likely where close family members have children- small gene pool.
All 3 cause the same kind of deficiency although genetics that cause them are different.
How is neutrophil recruitment affected in each type of LAD?
LAD-2: Neutrophils can’t get to rolling adhesion stage.
LAD-1: Rolling adhesion happens, but tight binding and tethering doesn’t.
LAD-3: no completion of tight binding. Lack of signal to go through endothelium.
All of them mean that neutrophils can’t be recruited to the site of infection so infection can’t be cleared.
What are the consequences of LAD?
Normally occurs within two months of birth.
have abcesses that don’t clear up.
Inability to recruit neutrophils to site of infection.
Delayed umbilical cord detachment.
Omphalitis-inflammation of the umbilical cord.
Overwhelming bacterial infections with no pus. Can’t deal with any kind of bacterial infection.
Poor wound healing.
Death without bone marrow transplantion.
What is chronic granulomatous disease?
Inheritance X linked and autosomal recessive.
Most common gp91phox- this is gene that is affected (X linked) 70% of cases- most sufferers will be male.
Mothers are carriers and may be affected. May be affected-clones of stem cells. Will produce some neutrophils that are normal and some that are abnormal. If more abnormal ones made, mother will show signs of condition.
Autosomal recessive p21, p47, p67, p40 .
Autosomal dominant Rac2.
What causes CGD?
Deficiency in one of the proteins that make the functioning NADPH oxidase in the lysosome.
Usually, neutrophils takes up microbes by phagocytosis and microbes are killed intracellularly. Oxidative burst happens in phagolysosome.
This doesn’t happen in CGD.
What does NADPH do?
How is a granuloma caused?
NADPH produces superoxidase to destroy certain bacteria.
Inability to destroy common bacteria that causes granuloma- have phagocytosed, but can’t destroy it (no ability to superoxidase). Body tries to protect body by causing granuloma.
Unusual to do this for common bacteria that are usually easily broken down.
How does a granuloma affect organs and tissues?
A lot of granuloma in functioning organs/tissues- will greatly affect organ function- granuloma is cytokine producing junk that is taking away proper organ function.
These can’t be cleared in CGD.
How can you test for CGD?
Measure ability of neutrophils to reduce chemical, known as DHR.
Load up cells with DHR- activate everything with mitogen- if reduced, makes rhodamine which fluoresces red.
Healthy- DHL reduced- all neutrophils are red.
Disease- can’t reduce DHL- no difference from resting neutrophils.
Can see whether person has a functioning respiratory burst.
