Innate Immunity and deficiencies

Question 1

Describe phagocytosis

Answer 1

1. Pathogen taken into phagosome
2. Phagosome fuses with Lysosome. Oxidative (NADPH complex)/ non oxidative killing (Lysozyme + Lactoferrin).
3. Depleted neutrophil glycogen- cell death + pus formation

Question 2

Which receptors are expressed by natural killer cells?

Answer 2

Inhibitory receptors for self HLA
Activating receptors for Heparin sulphate proteogylcans

Question 3

Other than bacteria, what do NK cells kill

Answer 3

Altered self- Malignant/ virus infected

Question 4

Which proteins are found in the classical complement pathway?

Answer 4

C1
C2
C4

Question 5

Which proteins are found in the mannose binding lectin complement pathway?

Answer 5

C4
C2

Question 6

What activates the alternative complement pathway?

Answer 6

Bacterial cell wall component e.g. lipopolysaccharide

Question 7

Which complement activation pathway is dependent on the acquired immune response?

Answer 7

Classical

Question 8

On which complement protein do all pathways converge? What is the consequence of this?

Answer 8

C3
If defect/ deficiency all pathways affected

Question 9

What does activation of C3 result in?

Answer 9

Final common pathway C5-9
formation of Membrane attack complex

Question 10

What is the function of the membrane attack complex?

Answer 10

Opsonises pathogen
Activates immune cells
Activates more complement

Question 11

What is the consequence of defects or deficiency in phagocytosis?

Answer 11

Recurrent deep bacterial infections: S. aureus
+ Enteric bacteria
Recurrent fungal infections: Candida albicans + Aspergillus spp.

Question 12

Give 3 causes of failure of production of neutrophils

Answer 12

Reticular dysgenesis
Kostmann syndrome
Cyclic neutropenia

Question 13

4 features of Reticular dysgenesis

Answer 13

Pancytopenia
No differentiation of stem cells
No granulocytes, no myeloid/ lymphoid cells
Most severe SCID

Question 14

3 features of Kostmann syndrome

Answer 14

Severe congenital neutropenia
AR mutation in HAX1
Can’t produce neutrophils

Question 15

3 features of Cyclic neutropenia

Answer 15

Episodic neutropenia every 4-6w
AD mutation in neutrophil elastase
Neutrophil count fluctuates ~monthly

Question 16

What are the 4 failures causing defects/ deficiency of phagocytes?

Answer 16

Failure of production
Failure of trafficking
Failure of killing
Failure of signalling

Question 17

What causes failure of trafficking to site of infection?

Answer 17

Leukocyte adhesion deficiency:
CD18 deficiency

Question 18

Describe the pathophysiology of leukocyte adhesion deficiency

Answer 18

CD18 should form dimer with CD11 that binds ICAM-1 on endothelial cells to allow transmigration
Absence means neutrophils can’t leave bloodstream

Question 19

Give 3 characteristics of leukocyte adhesion deficiency

Answer 19

Very high neutrophil count
Absence of pus
Delayed umbilical cord sloughing

Question 20

What causes neutrophil failure of killing?

Answer 20

Chronic granulomatous disease

Question 21

Why do granulomas form in chronic granulomatous disease?

Answer 21

Neutrophils die quicker as use glycogen + lysozyme stores faster
Phagocytes fuse forming granuloma

Question 22

What causes chronic granulomatous disease?

Answer 22

NADPH oxidase deficiency
Thus no respiratory burst
Impaired killing of intracellular pathogens

Question 23

What causes excessive inflammation in chronic granulomatous disease?

Answer 23

Persistent neutrophil/ macrophage accumulation
Failure to degrade antigens

Question 24

Give 2 clinical signs of chronic granulomatous disease

Answer 24

Hepatosplenomegaly
Lymphadenopathy

Question 25

Which bacteria are patients with chronic granulomatous disease particularly susceptible to?

Answer 25

Catalase +ve PLACESS Pseudomonas Listeria Aspergillus Candida E.coli Staph aureus Serratia

Question 26

Which tests can be used to diagnose chronic granulomatous disease?

Answer 26

Nitroblue tetrazolium (NBT): yellow to blue if oxidative killing. CGD -ve. Dihydrorhodamine (DHR) flow cytometry: fluorescent if oxidative killing. CGD -ve.

Question 27

What causes a failure of signalling as a defect of phagocytosis?

Answer 27

IL12-IFN gamma pathway defect Defect in cytokines or receptors

Question 28

What is the pathophysiology of IL12-IFN gamma pathway defect?

Answer 28

Defect in signalling between macrophages + T cells Can't activate T cells Granulomas can't be formed

Question 29

What are patients with IL12-IFN gamma pathway defect susceptible to?

Answer 29

Mycobacteria (TB + Atypical) BCG Salmonella

Question 30

What is classical NK deficiency?

Answer 30

Absent NK cells, not differentiating from stem cells GATA4 or MCM4 mutations

Question 31

What is functional NK deficiency?

Answer 31

Abnormal function- too little/ too much (AI)

Question 32

What are those with NK cell deficiencies especially vulnerable to?

Answer 32

Herpes virus: HSV, VZV, EBV, CMV Papilomavirus: HPV

Question 33

Which infections are those with complement deficiency particularly susceptible to?

Answer 33

Neisseria meningitides Haemophilus influenzae Streptococcus pneumonia

Question 34

What can cause complement deficiency?

Answer 34

Primary: body not making Secondary: Liver failure, AI disease using up complement e.g. SLE

Question 35

What results from deficiency early in the classical complement pathway?

Answer 35

Not clearing apoptotic/ necrotic cells- increases self-antigens esp. nuclear, promotes AI Not clearing immune complexes- deposition in skin, joints, kidneys + inflammation

Question 36

Which deficiency in the classical complement pathway is most common? What disease is this associated with?

Answer 36

C2 SLE

Question 37

What can cause a secondary deficiency in the classical complement pathway?

Answer 37

Active lupus Due to persistent production of complexes + consequent depletion of complement Low C3 + C4

Question 38

What can cause secondary C3 deficiency?

Answer 38

Nephritic factors; autoantibodies against C3 convertase Cause constant activation + thus depletion of C3

Question 39

Which diseases may secondary C3 deficiency be seen in?

Answer 39

Glomerulonephritis: blood in urine Lipodystrophy: abnormal fat distribution e.g. Lipomas

Question 40

Describe management of phagocyte deficiencies

Answer 40

Infection prophylaxis Abx: Septrin PO/IV Anti-fungals: Itraconazole Definitive therapy: HSCT: ‘Replaces’ defective population.

Question 41

What treatment is given in chronic granulomatous disease?

Answer 41

Interferon gamma therapy

Question 42

What investigations are used to diagnose complement deficiencies?

Answer 42

CH50 AP50

Question 43

Describe the management of complement deficiencies

Answer 43

Vaccination Prophylactic abx Screen family