Immunodeficiency

Question 1

The main physiological function of the immune system is to protect from infection.

What does it need to do in order to be able to do this?

Answer 1

• Recognise pathogens
• mount an immune response which requires cell-to-cell communication
• clear the pathogen
• self-regulation

Question 2

What may clearing tha pathogen require?

Why is self-regulation important?

Answer 2

Clearing the pathogen may require adaptive responses to the changing pathogen

Self-regulation is important to minimise host damage

Question 3

What are the characteristics of innate immunity?

Answer 3

• General - it is NOT antigen-specific, but can recognise broad classes
• rapid speed of onset
• does not alter on repeated exposure (same response happens each time)
• no memory

Question 4

What are the characteristics of adaptive immunity?

Answer 4

• Antigen specific
• slower response, but it is more potent due to antibody production
• subsequent exposure leads to a more effective response
• memory

Question 5

Complete the diagram showing the innate and adaptive immune responses

Answer 5

Question 6

What is meant by immunodeficiency?

Answer 6

Clinical situations where the immune system is not effective enough to protect the body against infection

Question 7

What are the 2 different types of immunodeficiency?

Answer 7

Primary:

• there is an inherent defect within the immune system
• this is usually genetic

Secondary:

• the immune system is affected due to external causes

Question 8

What are the secondary causes of immunodeficiency?

Answer 8

1. Breakdown in physical barriers - e.g. cystic fibrosis
2. Protein loss
3. Malignancy
4. Drugs
5. Infection

Question 9

How can cystic fibrosis act as a secondary cause of immunodeficiency?

Answer 9

Mucus mounts up as it cannot be cleared

pathogens will collect within this mucus, and are more likely to cause infection

Question 10

How can protein loss and malignancy act as a secondary cause of immunodeficiency?

Answer 10

Protein loss:

• burns
• protein loosing enteropathy
• malnutrition
• this can lead to the loss of immunoglobulins

Malignancy:

• in blood cancers, the clones of the cells expand in the immune system and take up space
• e.g. Lymphoproliferative disease, myeloma

Question 11

Which drugs and infections act as secondary causes of immunodeficiency?

Answer 11

Drugs:

• steroids
• DMARDS
• Rituximab
• anti-convultants
• myelosuppressive drugs that knock out the bone marrow

Infection:

• HIV
• TB

Question 12

What are the 2 main types of phagocytes?

What is their role?

Answer 12

Neutrophils are short-lived

macrophages are long-lived and found in tissues

they ingest bacteria and fungi and then destroy them

Question 13

What is a pathogen recognition receptor?

Answer 13

PRRs recognise conserved pathogen associated molecular patterns (PAMPs)

These are unique to each pathogen

They tend to be repeated sequences, such as lipopolysaccharides on bacteria

Phagocytes use PRRs to detect pathogens and ingest them

Question 14

What are the 3 main toll like receptors?

Answer 14

Toll like receptors are a type of PRR

• TLR4 recognises lipopolysaccharide
• TLR5 recognises flagellin (found on some bacteria)
• TLR3 recognises viral RNA within the nucleus

Question 15

What happens if there is a defect in TLR3?

Answer 15

Without TLR3, the cell does not recognise viruses

This leads to recurrent HSV encephalitis (herpes simplex virus)

Question 16

What happens when the toll like receptor binds to the molecule that it recognises?

Answer 16

It leads to a cascade of events involving various intracellular molecules

this leads to the production of inflammatory cytokines

MyD88 and IRAK4 are involved in this cascade

Question 17

If a patient had IRAK4 or MyD88 deficiency, what would the clinical presentation be like?

Answer 17

• Recurrent bacterial infection - especially streptococcus and staphylococcus

This includes pneumonia, meningitis, arthritis

• poor inflammatory response
• susceptibility to infection decreases with age

Question 18

What is meant by a “poor inflammatory response” in IRAK4 deficiency?

Answer 18

The patient will NOT have raised CRP and they will have normal levels of lymphocytes and neutrophils

This is because cytokines are not being released, so the patient feels okay

Question 19

What is the treatment for IRAK4 of MyD88 deficiency?

Answer 19

1. Prophylactic antibiotics
2. IV immunoglobulin if severe

Question 20

What is the role of the phagolysosome?

How is the NADPH complex involved?

Answer 20

The NADPH complex is formed of several proteins, including gp91^phox

This is encoded by the X chromosome

NADPH releases an electron, which combines with superoxide to produce hypochlorous acid

This is a bleach that will kill the pathogen

Question 21

How does chronic granulomatous disease present?

Answer 21

• Recurrent abscesses - in the lung, liver, bone, skin and gut
• inflamed lymph nodes
• infection with unusual organisms - staphylococcus, klebsiella, serretia, aspergillus

Question 22

What would you see in a clinical presentation of a patient with chronic granulomatous disease?

Answer 22

• History of recurrent skin abscesses
• maybe previous pneumoia
• normal immunoglobulins, lymphocytes and neutrophil count
• it is an X-linked recessive disease, so may be family history

Question 23

What is the background behind chronic granulomatous disease?

Answer 23

There is a mutation in gp91^phox, meaning the NADPH complex does not work

This means that no hypochlorous acid is produced within the phagolysosome

Neutrophils can’t kill bacteria, but they can take them up

Question 24

What is the treatment for chronic granulomatous disease?

Answer 24

• Haemopoeitic stem cell transplant
• antibiotics

Question 25

How can you test to see if someone has chronic granulomatous disease? What does the test rely on?

Answer 25

Test the function of macrophages by measuring **dihydrorhodamine reduction** using flow cytometry This test relies on **_REDUCTION_** DHR in the blood is reduced by the e- released from NADPH, causing activation of the neutrophil by PMA

Question 26

What visual test can be used for chronic granulomatous disease?

Answer 26

**Nitro blue tetrazolium dye reduction** in this test, healthy neutrophils should turn purple in colour

Question 27

What is meant by "complement"? What are their roles?

Answer 27

Non-immunoglobulin proteins, that are important in the immune system for: 1. Cell lysis 2. Control of inflammation 3. Stimulation of phagocytosis

Question 28

How can you test complement function?

Answer 28

Complement should lose foreign cells if the foreign cells are covered in antibody this will trigger the classical complement cascade patients serum is placed on sheep erythrocytes, and it should lyse them

Question 29

What are the 2 types of complement deficiency and how do they tend to present?

Answer 29

**C2, C4 deficiency:** * presents as SLE, infections and myositis **C5 - C9 deficiency:** * these form the membrane attack complex * presents with **repeated episodes of _BACTERIAL MENINGITIS_** * particularly with infection with *Neisseria meningitis*

Question 30

How does the adaptive immune system work?

Answer 30

The antigen binds to the B cell (antigen-presenting cell) The B cell presents the antigen to the helper T cell via MHCII The T cell stimulates the B cell to proliferate and differentiate The plasma cells are stimulated to produce antibodies

Question 31

What are the roles of T helper cells (CD4)? In which disease are they compromised?

Answer 31

they produce cytokines that effect B cells and the recruitment of other immune cells In HIV, there is a low CD4 count

Question 32

What is the role of the plasma cell?

Answer 32

They stay in the blood for a long period of time and produce the same antibody

Question 33

Complete the table showing the roles of antibodies binding to antigens

Answer 33

Question 34

What causes X-linked agammaglobulinaemia?

Answer 34

**_NO antibodies are produced_** This is due to a defect in **Bruton's tyrosine kinase (BTK)** this is needed for B cell signalling and B cell maturation B cell maturation is not completed in the bone marrow so no antibodies are produced

Question 35

What are the typical presentations of X-linked agammaglobulinaemia?

Answer 35

Patients present young (before age 5) Previous hospital admissions with pneumonia and recurrent chest infections Relatives may have passed away young from bronchiectasis (scarring of the lungs that builds up with each infection)

Question 36

What would the bloods look like in someone with X-linked agammaglobulinaemia?

Answer 36

* No B cells but normal T cells * No IgG, IgA or IgM * CT shows bronchial thickening

Question 37

How does the defect in BTK affect B cell production?

Answer 37

The defect means that B cells are not present in the periphery Plasma cells are not produced, so there are no antibodies

Question 38

What are 4 other B cell defects?

Answer 38

* CVID * IgA deficiency * X linked hyper IgM syndrome * transient hypogammaglobulinaemia of infancy

Question 39

What are patients with IgA deficiency more prone to?

Answer 39

They have no IgA antibodies Most patients are fine, some have recurrent infections They are more prone to autoimmune diseases

Question 40

What is meant by transient hypogammaglobulinaemia of infancy?

Answer 40

A patient has no antibodies when they are a baby, but acquires them when they get older A baby does not start making antibodies until around 4-5 months of age (they initially have antibodies from their mother)

Question 41

What are the consequences of a B cell defect? What is the treatment?

Answer 41

* Loss of antibody secretion * usually leads to recurrent bacterial infection with pyogenic organisms * treat with antibiotics and then **IV IgG for life**

Question 42

What is a more common reason to have an antibody deficiency?

Answer 42

Secondary antibody deficiency due to drugs often caused by immunosuppressants such as: 1. Methotrexate 2. Infliximab 3. Rituximab

Question 43

What would the bloods look like in a patient with secondary antibody deficiency due to drugs?

Answer 43

* Slightly low B and T cells * low IgG and IgA

Question 44

Why does someone acquire a secondary antibody deficiency due to drugs?

Answer 44

Drugs (such as Rituximab) target the **CD20** molecule on the surface of B cells This prevents the B cell from functioning, differentiating and producing antibodies

Question 45

What are the main mechanisms of antibody deficiency treatment?

Answer 45

* Antibiotics * immunoglobulin G replacement

Question 46

How would chickenpox vary in a healthy child and a child with SCID?

Answer 46

**Healthy:** * mild disease with typical vesicles **SCID:** * fulminant disease with haemorrhagic lesions * may have pneumonitis and/or meningitis

Question 48

What would the blood results look like in a young child presenting with **severe combined immunodeficiency (SCID)**?

Answer 48

* Normal levels of IgG (as this comes from the mother for the first 6 months of life) * no IgA * reduced IgM * lymphocyte markers show absent/reduced T cells and NK cells but present B cells

Question 49

Why are defects in T cells usually more severe than defects in B cells?

Answer 49

B cells also need T cell help Even if there are B cells, they will not function

Question 50

WHat are the symptoms of a T cell defect (SCID or DOCK8 deficiency)?

Answer 50

* Recurrent infection with opportunistic pathogens * These are infections that a healthy person wouldn't usually contract * e.g. Candida (fungi) or pneumocystis (protozoa)

Question 51

what are the treatments for SCID?

Answer 51

* Antibiotics, antivirals and antifungals * asepsis * haemopoietic stem cell transplant is the only cure (i.e. bone marrow transplant)

Question 52

What are the causes of SCID?

Answer 52

**Defect/absence of a critical T cell molecule:** * T cell receptor, common gamma chain * if any of the chains are missing, the TCR will not function **Loss of communication:** * deficiency of MHCII means there is no communication between B and T cells **Metabolic:** * adenosine deaminase deficiency * leads to a build up of metabolites that are toxic to lymphocytes