Primary Immunodeficiency I Flashcards Preview

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Flashcards in Primary Immunodeficiency I Deck (24)
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1
Q

What is immunodeficiency?

A

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.
2
Q

What are the different kinds of immunodeficiency inheritance?

A

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).

3
Q

What are the odds of having an infected child with an autosomal dominant condition?

A

One parent affected, one not affected.

50% chance of infected child.

4
Q

What are the odds of having an infected child with an autosomal recessive condition?

A

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.

5
Q

What are the odds of having an infected child with an X linked condition?

A

Father not affected, mother is a carrier.

1 male and 1 female not affected, 1 affected male, 1 carrier female.

6
Q

What can happen to phagocytes in PID in innate immunity? What are two conditions that are caused by this?

A

Genetic defects of phagocyte number, function, or both.
270 described immunodeficiency conditions with known genes.
2 conditions- LAD, CGD.

7
Q

What are neutrophils (PMN)?

A

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.

8
Q

What is leukocyte adhesion deficiency (LAD)?

A

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.

9
Q

How is neutrophil recruitment affected in each type of LAD?

A

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.

10
Q

What are the consequences of LAD?

A

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.

11
Q

What is chronic granulomatous disease?

A

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.

12
Q

What causes CGD?

A

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.

13
Q

What does NADPH do?

How is a granuloma caused?

A

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.

14
Q

How does a granuloma affect organs and tissues?

A

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.

15
Q

How can you test for CGD?

A

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.

16
Q

What are the consequences of CGD?

A

Recurrent infections with catalase positive bacteria leading to pneumonia, abscesses of skin and infection of lymphnodes.

Lung disease with aspergillus.

Inflammatory bowel disease.

Granulomas- failure to clear phagocytosed bacteria.

Stem cell (bone marrow) transplant advised- recovery rates are much better now, gene therapy has been tried with limited success- no selective pressure.

17
Q

Describe TLR deficiencies and some conditions caused by them.

A

Deficiencies in different TLR receptors or signalling molecules lead to particular pathogen susceptibilities.

Herpes simplex encephalitis -deficiency in TLR3 (AD), TRIF (AD), UNC93B(AR), uniquely susceptible to Herpes simplex encephalitis on primary infection.

IRAK4 (AR)/MyD88 (AR)- susceptibility to pyogenic (bacteria that cause fever) infections that improves with age.

A lot of redundancy in systems.
Don’t need them for your entire life.
AD- autosomal dominant, AR- autosomal recessive.

18
Q

Describe some toll like receptors and what they detect.

What is the main targets for these receptors?

A

On the cell membrane:
Diacyl lipopetides- TLR-6, TLR-2.

Triacyl lipopeptides- TLR-1, TLR-2.

Flagellin- TLR-5.

LPS- TLR-4, MD-2.

In the endosome:
dsRNA- TLR-3.

ssRNA- TLR-7.

CpGDNA- TLR-9.

Main target for most of them in NFkB.
TLR-3 is most interested in viral infections.

19
Q

Describe herpes simplex type 1.

A

Ds DNA virus typically associated with infection of oral mucosa or conjunctiva. Ds RNA is generated during its replication.

After initial infection virus is transported via sensory neurons to trigeminal nerves and ganglia where it establishes a latent infection.

Rarely it causes HSE- defects along the TLR3 signalling pathway are associated with increased susceptibility.

No susceptibility to other viruses. TLR3 unique in CNS to protect from HSV-1. Deficiency of STAT-1 can also cause HSV-1 susceptibility.

Ds RNA is pathogen pattern for TLR3. Only comes into play when virus is replicating. Can’t signal after dsRNA recognition, don’t make IFN, which protects you from the infection.

Very specific to HSV-1. Same susceptibility to other viruses as other children.

20
Q

What are the consequences of HSE?

A

High fever and right sided seizures.

Recurrent herpes simplex encephalitis.

Necrosis of brain hemispheres- can cause death or paralysis.

Can be fatal or lead to disability due to paralysis.

No other susceptibilities.

HSV infection can be successfully treated with acyclovir.

21
Q

Describe IRAK4/MyD88 deficiency.

A

Interleukin 1 receptor associated kinase 4 deficiency.

IL-1 receptors and TLR (except TLR3) share a common signal transduction pathway leading to NFkB activation.

This leads to production of pro-inflammatory cytokines (IL-6 and TNF-a).

Functioning IRAK4 or MyD88 is critical to the ability to make responses to TLR ligands.

22
Q

What happens to children with the IRAK4/MyD88 deficiency?

A

Children with deficiency don’t get fever, systemic effects of pro-inflammatory cytokines. Have overwhelming bacterial infections but don’t get sick.
Can get deep seated bacterial infections.
Don’t upregulate C-reactive protein (this is main things that can be tested for infection).
Don’t make complement components or other things that help fight infections.

(TLR-3 doesn’t use IRAK4/MyD88 proteins).

23
Q

Describe the main cytokines secreted by macrophages and dendritic cells, and what they do.

A

IL-1:
Main producer- macrophages, keratinocytes.
Acts upon- lymphocytes, liver.
Effect- lymphocytes- enhances responses, liver- induces acute-phase protein secretion.

IL-6:
Main producer- macrophages, dendritic cells.
Acts upon- lymphocytes, liver.
Effect- lymphocytes- enhances responses, liver- induces acute-phase protein secretion.

CXCL8 (IL-8):
Main producer- macrophages, dendritic cells.
Acts upon- phagocytes.
Effect- chemoattractant for neutrophils.

IL-12:
Main producer- macrophages, dendritic cells.
Acts upon- naive T cells.
Effect- diverts immune response to Th1, pro-inflammatory, cytokine secretion.

TNF-a:
Main producer- macrophages, dendritic cells.
Acts upon- vascular endothelium.
Effect- induces changes in vascular endothelium (expression of cell adhesion molecules (E and P selectin), changes in cell-cell junctions with increased fluid loss, local blood clotting).

24
Q

What are the consequences of IRAK4/MyD88?

A

Severe recurrent invasive infection with pyogenic bacteria- 40% die by 8 yo.

Unusually weak febrile response.

Their susceptibility to recurrent invasive infections resolves with age to that of normal population by the age of 14yo.

Lifelong susceptibility to bacterial infections (not invasive).

Early days only 49 patients identified IRAK4, 22 for MyD88.

Don’t make what you would expect them to make in such a bacterial infection.

If they get to adolescence, parts of immune response can cover infections (good antibody responses) and you can react to infections vaguely normally.

Particularly pyogenic bacteria (lifelong susceptibility).

Present with lung damage later on.

All patients are in teens and 20s just now.

Not worth doing bone marrow transplants- chances of survival, and disease don’t weigh up.