Primary Autoimmunity in INNATE immunity

Question 1

What is autoimmunity?

Answer 1

Congenital or acquired state where the immune response has
i) missing components
ii) non-functioning components
iii) incorrectly functioning components
which increases susceptibility to infection.

Question 2

What are the three types of Inheritance

Answer 2

1) Autosomal dominant
2) Autosomal recessive
3) X-linked

Question 3

Autosomal dominant

Answer 3

1 normal functioning allele and one defective allele where the defective allele dominates.

There is a 50%chance of having an affected child

Question 4

Autosomal recessive

Answer 4

This is least common. There is a defective allele from both parents.

There is 1/4 chance of an affected child, 50% chance of being a carrier.

Question 5

X-linked

Answer 5

Most common. There is a defect in the X chromosome. Males inherit this X gene from carrier mothers.

Question 6

What is Leukocyte adhesion deficiency (LAD) 1, 2, 3?

Answer 6

Autosomal recessive
The deficiency of leukocytes to bind to membranes.
LAD type 1: CD18 deficiency resulting in no tethering to endothelium

LAD2 type 2: Fucose transport/ CD15 deficiency results in no rolling

LAD type 3: Kindlin 3 deficiency results in no migration through endothelium

Rac 2 deficiency is autosomal dominant

Question 7

What are the symptoms/consequences of LAD?

Answer 7

-Inability to recruit neutrophils to site of infection
-delayed umbilical cord detachment
-omphalitis: inflammation of the umbilical cord when it detaches (unusual)
-Bacterial infection (no puss) which they cannot deal with no any level.
-Poor wound healing
-Death
Treatment: bone marrow transplantation

Question 8

What is hyper IgE ?(Autosomal dominant)

Answer 8

Problem with signalling pathway

Question 9

Why do we know more about these conditions?

Answer 9

There is about 270 conditions we know; this is due to change in molecular genetics and identification of incorrect proteins.

Question 10

What is Sialyl lewis X molecule (LAD2)

Answer 10

Molecule involved in neutrophil rolling; Sialyl lewis on neutrophil binds to E-selectin on endothial cells for weak adhesion for rolling along surface.

LAD type 2 means no rolling, no recruitment to site of infection.

Question 11

What is CD18 (LAD1)

Answer 11

It is part of the LFA-1 molecule on neutrophil surface.

Therefore, there is rolling but there is no tight binding of neutrophil LFA-1 to endothial surface ICAM in LAD 1

Question 12

What is Kindlin 3?

Answer 12

An intracellular molecule that enables signal for neutrophil to move through/between endothial layer.

Therefore LAD 3 there is no signalling within cell, no completion of tight binding and so no neutrophils to site of infection.

Question 13

What is the cause of Chronic granulomaous disease (CGD)?

Answer 13

A X linked or autosomal recessive disease caused most commonly by an X linked gene called gp91phox (in 70%)

although an X linked male disease for males, an affected mother can be carrier and affected; she will make some normal neutrophils, and some with abnormal gene; more abnormal gene neurophils selected then mother will show symptoms

Rare recessive genes like p21, as well as rare autosomal dominant gene Rac2 which also cause disease

Question 14

What is Chronic granulomatous disease (CGD)

Answer 14

Deficiency in one of the proteins that makes up the NADPH oxidase that causes the superoxide production for degradation of particular types of CATALYASE POSITIVE BACTERIA.

Question 15

How are granulomas formed? How does this compare to CGD?

Answer 15

mycobacteria triggers protective reaction; it surrounds/blocks the mycobacterium like TB with T cells.
In CGD it is not mycobacterium but inability to destroy common bacterias. Neutrophils phagocytose bacteriums but cannot destroy it.

Question 16

What are granulomas?

Answer 16

A central infected phagocyte population (forming the dead zone) surrounded by T cells trying to wall of uncontrolled bacterium.

This will decrease functions of healthy tissues/organs

Question 17

What are the symptoms/consequences of CGD?

Answer 17

1 )Recurrent infections wih CATALASE positive bacteria: causing pneumonia, abscesses of skin and infection of lymph nodes.

2) Lung disease
3) Inflammatory bowel disease
4) Granulomas in lungs and livers.

Treatment: Stem cell transplant from bone marrow

Question 18

What affect does CGD have on the immune system?

Answer 18

immune cells are over activated; there is a large pathogen burden causing signals bu no ability to clear infection.

Question 19

What is the test for CGD?

Answer 19

DHR reduction assay: In lab, we measure the ability of neutrophils in blood to reduce a chemical called DHR (dihydrodarhodamine)

• load up neutrophils from control and patient
• activate with chemical PMA that hits a signalling pathway
• if positive for CGD they are not able to reduce DHR, there is no respiratory burst so no second peak from resting neutrophil peak.
• flow cytometer used to measure fluorescence

Question 20

What are TLR deficiencies?

Answer 20

Deficiencies in different Toll like receptors or signalling molecules which mean patient is susceptible to pathogen

Question 21

Name two TLR deficiencies?

Answer 21

1) Herpes simplex encephalitis

2) IRAK4

Question 22

What is Herpes simplex encephalitis (TLR Deficiency) ?

Answer 22

A deficiency in TLR3 (AD), and signalling molecules in TLR3 pathway: TRIF (AD) , AR. This means on the first exposer to herpes simplex there is a dangerous response. However it is only this virus that they have a problem with.

Question 23

What is IRAK4 (TLR Deficiency) ?

Answer 23

where patients are susceptible to pyogenic infections .

Question 24

What is a pyogenic infection?

Answer 24

bacteria that cause fever

Question 25

Summarise the TLR on the membrane and on the endosome that signal downstream.

Answer 25

On membrane:

• TLR6/2: receive diacyl lipopeptides
• TLR1/2: receive triacyl lipopeptides
• TLR 5: receives flagellin
• TLR 4 receives LPS

On endosome:

• TLR 3: receives ds RNA (involved in viral infection)
• TLR7: receives ssRNA
• TLR9: receives CpGDNA

Question 26

Describe Herpes simplex virus.

Answer 26

Double stranded virus associated with infection of oral mucosa or the eye.

Replication makes dsRNA which is the pathogen pattern recognised by TLR3.

Virus infects, and is transported via sensory neurones to the trigeminal nerves and ganglia where it starts a LATENT infection

Question 27

How does the virus Herepes simplex response differ in TLR deficiency?

Answer 27

When TLR3 is lacking, patients get encephalitis; they cannot signal after virus dsRNA is received by receptor. and therefore doesnt make Type 1 IFN, the main factor to resolve this virus.

Other infections are manageable as TLR 7 and TLR 9 can cover other receptors.

Question 28

How does STAT1 deficiency influence the susceptibility to Herpes?

Answer 28

STAT1 is part of the common pathway for type 1 IFN production.

Question 29

What are the symptoms of HSE? (TLR def.)

Answer 29

1) High fever
2) recurrent herpes simplex encephalitis due to latency and uncontrolled response
3) death, paralysis

Treatment: infection treated with acyclovir

Question 30

Describe IRAK4 Deficiency

Answer 30

A deficiency in Interleukin 1 receptor kinase4 (IRAK4) which is a common signalling molecule in the pathway from TLR1, 7, 8, 9 recognition to to NFkB activation which is meant to produce proinflammatory cytokines (IL6, TNF-alpha)

Another signalling molecule called MyD88 may also be deficient causing same disease.

Question 31

What does IL6 and TNF-alpha cytokines do?

Answer 31

IL6-activates lymphocytes, and increases antibody production. It also induces acute phase response in liver

TNF-a: activates endothelium and increases vascular permeability so more IgG, complement can arrive. It also drains fluid to lymph nodes.

Deficient patients although they have infection, dont feel sick as they lack the sytemic influence of immune response.

Question 32

What organs do IL6, and TNF-a influence?

Answer 32

Liver: accute phase response causing opsonization
bone marrow: neutrophil migration causing phagocytosis
hypothalamus: increases body temperature which decrease viral infection/replication.
fat and muscles: protein/energy mobilisation increases temperature.
DC cells: TNF-a stimulates migration of DC to lymph node to start adaptive immune response.

Question 33

What else is unusal about IRAK4 deficient children?

Answer 33

They do no upregulate their C-reacive protein which is a opsonin which activates complement.

They don’t upreguate complement components like manose binding lectin which activates MB-lectin pathway.

Question 34

What are the symptoms/consequences of IRAK4 Deficiency?

Answer 34

1) Recurrent invasive infection with pyogenic bacteria
2) weak febrile response; they don’t produce correct response.
3) in adulthood recurrance of same bacterial infections but dealt with like a average patient
4) lifelong susceptibility to bacterial infections that are not invasive even in adulthood which damage lungs but is not fatal.

Question 35

What does IRAK deficiency show about TLR?

Answer 35

TLR are only vital in childhood. In adulthood, other parts of immune response such as antibodies that covers patient from infections.