Immuno 2: Primary Immuno Defficiency

Question 1

Which Primary immunodeficiency disease is autosomal recessive and prevents stem cells from differentiating along myeloid or lymphoid cell Lines ?

Answer 1

Reticular dysgenesis

• causes recessive severe SCID

Question 2

Which primary immunodeficiency disease is characterised by failure of development of neutrophils ?

Answer 2

Kostmann syndrome

-Causes autosomal recessive congenital neutropenia

Question 3

Which primary immunodeficiency disease is characterised by cycles of reduced neutrophils (e.g every month) ?

Answer 3

Cyclical neutropenia

Question 4

Which two Cluster of differentiation (CD) markers make up LFA-1 ?

Answer 4

CD11a

CD18

Question 5

What is the endothelial cell receptor for LFA-1 that regulates Neutrophil adhesion/transmigration ?

Answer 5

ICAM-1

Question 6

In which primary immunodeficiency disease do you get a defect in Neutrophil adhesion/transmigration across endothelial cells ?

V high neutrophil count and no pus formation

Answer 6

Leukocyte adhesion deficiency (LAD)

-CD18 deficiency causes LFA-1 defect which stops it binding to ICAM-1

Question 7

In which Primary immunodeficiency disease do you have a failure of oxidative killing mechanisms causing excessive inflammation and granulomas ?

Answer 7

Chronic Granulomatous disease

Also get lymphadenopathy and hepatosplenomegaly

Question 8

Which 2 tests can be used to diagnose Chronic Granulomatous disease ?

Answer 8

Nitroblue tetrazolium test (NBT)

DIhydrorhodamine flow cytometry test

Question 9

Which 2 cytokines are important in activation signalling between macrophages and T cells ?

Answer 9

IL12

IFN gamma

Question 10

Deficiency of either IL12 or IFN gamma causes an increase of infections with …….

Answer 10

Atypical mycobacterium infections

Question 11

What is the treatment for Chronic Granulomatous disease ?

Answer 11

Interferon Gamma therapy

Question 12

What is the definitive treatment of primary immunodeficiency diseases ?

Answer 12

Haematopoietic stem cell transplant

Question 13

Which infections are people with Natural killer cell deficiency particularly at risk of ?

Answer 13

Herpes Virus infections

Question 14

Where are complement proteins produced ?

Answer 14

The liver

Question 15

What type of infection are people with complement deficiency prone to

Answer 15

Encapsulated Bacteria

Question 16

Give 3 examples of encapsulated bacteria ?

Answer 16

Neisseria Meningitides
Haemophilus Influenza
Streptococcus Pneumoniae

Question 17

How can complement deficiency lead to increased Immune complex deposition ?

Answer 17

Without complement phagocytes aren’t activated so necrotic cells aren’t cleared. This causes a lot of self antigens such as dsDNA to float around. This can trigger an auto-immune response. The antibodies bind to the antigens causing complex formation which deposits in skin and joints etc. Normaly complement stimulates clearance of immune complexes by Erythrocytes which does happen in the case of Complement deficiency.

Question 18

Which disease is really common in patients with C2 deficiency ?

Answer 18

SLE

• with severe skin disease

Question 19

What are nephritic factors ?

Answer 19

Auto-antibodies against C3

Question 20

Which complement molecule becomes deficient when there are nephritic factors present ?

Answer 20

C3

Question 21

List 2 diseases that are associated with acquired C3 deficiency (e.g due to nephritic factors)?

Answer 21

Glomerulonephritis (membranoproliferative)
Partial lipodystrophy (abnormal fat distribution)

Question 22

What is the functional test for the classical complement pathway ?

Answer 22

CH50

Question 23

What is the functional test for the Alternate complement pathway ?

Answer 23

AP50

Question 24

what are the 3 groups of immunodeficiencies

Answer 24

primary (inherited) - rare
secondary (acquired)
physiological (expected) - neonates, elderly, pregnancy

Question 25

when do we suspect immunodeficiency

Answer 25

two major or one major+ recurrent minor infections in one year 
unusual organisms 
unusual sites
unresponsive to treatment 
chronic infections 
early structural damage

Question 26

list the main types of phagocyte deficiency

Answer 26

failure to produce neutrophils
defect of phagocyte migration
failure of oxidative killing mechanisms

Question 27

describe conditions that result in failure to produce neutrophils

Answer 27

reticular dysgenesis - autosomal recessive severe SCID, no lymphoid or myeloid cells
kostmann syndrome - autosomal recesisve severe congenital neutropaenia
cyclic neutropaenia - autosomal dominant episodic neutropaenia, every 4-6 weeks

Question 28

describe conditions that result in defects of phagocytes migration

Answer 28

leukocyte adhesion deficiency - caused by deficiency of CD18
CD18 and CD11 make up LFA-1
LFA-1 binds to ICAM-1 on endothelial cells and regulates neutrophil adhesion and transmigration
If you have no CD18, neutrophils cannot enter tissues
these patients have a high neutrophil count, no pus formation

Question 29

describe conditions that result in failure of oxidative killing mechanisms

Answer 29

chronic granulomatous disease

• absent respiratory burst - deficiency of a component of NADPH oxidase
• excessive inflammation
• granuloma formation
• lymphadenopathy and hepatosplenomegaly

Question 30

list different cytokine deficiencies

Answer 30

IL-12, IL-12 R, IFN a and IFN y deficiency
macrophages produce IL-12 - stimulated T cells - T cells make IFN - y - IFN y acts on macrophages and causes production of TNF - a and free radicals (by activating NADPH oxidase)
most of these patients present with atypical mycobacterial infections

Question 31

how is chronic granulomatous disease investigated

Answer 31

nitroblue tetrazolium (NBT) - changed from yellow to blue 
dihydrorhodamine (DHR) - becomes fluorescent 

looks at ability of neutrophils to generate oxidative stress

Question 32

list common infections seen in phagocyte deficiencies

Answer 32

Bacterial - S aureus, enteric bacteria
Fungal - candida albicans, aspergillus fumigatus/ flavus
Mycobacterium infections - mycobacterium tb, atypical mycobacteria

Question 33

how do we treat phagocyte deficiencies

Answer 33

infection prophylaxis:
- antibiotics eg septrin 
- antifungals eg itraconazole 
definitive therapy:
- haematopoietic SC transplantation 
- specific treatments for granulomatous disease eg IFNy therapy

Question 34

list NK cell deficiencies

Answer 34

classical NK deficiencies - no NK cells in peripheral blood

functional NK deficiency - present but function abnormal

Question 35

what infections do people with NK deficiencies develop

Answer 35

herpes simplex 
VZV
EBV 
CMV 
HPV

Question 36

what is the treatment for NK deficiencies

Answer 36

prophylactoc antiviral drugs (aciclovir, ganciclovir)
cytokines - IFNy to stimulate NK function
haematopoietic SC transplantation (if severe)

Question 37

list innate immune cell deficiencies

Answer 37

kostmann syndrome- recurrent infections with no neutrophils on FBC
leukocyte adhesion deficiency - high neutrophil count, no abscess formation
chronic granulomatous disease - infection with atypical mycobacterium, normal FBC
IFN y receptor deficiency - recurrent infections with hepatosplenomegaly and abnormal DHR test ( x flouresce)
classical NK deficiency - severe chicken pox, disseminated CMV infection

Question 38

what does complement deficiency increase the risk of

Answer 38

encapsulated bacterial infections (NHS)
neisseia meningitidis
haemopholus influenzae
streptococcus pneumoniae

Question 39

what disorder is associated with deficiencies of early classical complement pathway components

Answer 39

SLE
complement deficiency leads to ineffective clearance of apoptotic/3necrotic cells - increases load of self antigens
these promote autoimmunity and the formation of immune complexes
complement deficiency therefore results in deposition of immune complexes which stimulate local inflammation of the skin, joints, kidneys

(C2 = most common deficiency) - almost all patients with C2 deficiency have SLE

Question 40

describe acquired complement deficiencies

Answer 40

Active lupus - causes persistent production of immune complexes - consumption of complement components - deficiency
Nephritic factors - AA directed against components of complement pw - result in C3 activation and consumption - glomerulonephritis, associations with partial lipodystrophy

Question 41

how can we investigate the complement pw

Answer 41

C3 and C4 routinely measured

C1 inhibitro = decreased in hereditary angio-oedema

Question 42

what are functional complement tests

Answer 42

CH50 - test of classical pw (C1,2,4,3,5-9)

AP50 - test of alternative pw (B,D,properidin, C3, C5-9)

Question 43

how can we manage complement deficiencies

Answer 43

vaccination esp against polysaccharide encapsulated bacteria (meningovax, pneumocax)
prophylactic antibiotics
treat infections aggressively
screen family members

Question 44

list common complement deficiency sterotypes

Answer 44

C1q def - severe childhood onset SLE with normal C3 /C4 levels
C3 def + nephritic factor - membranoproliferative nephritis + abnormal fat dist.
C7 def - meningococcous meningitis
MBL deficiency - recurrent infections when neutropenic following chemo