Innate Immunity and deficiencies Flashcards
Describe phagocytosis
- Pathogen taken into phagosome
- Phagosome fuses with Lysosome. Oxidative (NADPH complex)/ non oxidative killing (Lysozyme + Lactoferrin).
- Depleted neutrophil glycogen- cell death + pus formation
Which receptors are expressed by natural killer cells?
Inhibitory receptors for self HLA
Activating receptors for Heparin sulphate proteogylcans
Other than bacteria, what do NK cells kill
Altered self- Malignant/ virus infected
Which proteins are found in the classical complement pathway?
C1
C2
C4
Which proteins are found in the mannose binding lectin complement pathway?
C4
C2
What activates the alternative complement pathway?
Bacterial cell wall component e.g. lipopolysaccharide
Which complement activation pathway is dependent on the acquired immune response?
Classical
On which complement protein do all pathways converge? What is the consequence of this?
C3
If defect/ deficiency all pathways affected
What does activation of C3 result in?
Final common pathway C5-9
formation of Membrane attack complex
What is the function of the membrane attack complex?
Opsonises pathogen
Activates immune cells
Activates more complement
What is the consequence of defects or deficiency in phagocytosis?
Recurrent deep bacterial infections: S. aureus
+ Enteric bacteria
Recurrent fungal infections: Candida albicans + Aspergillus spp.
Give 3 causes of failure of production of neutrophils
Reticular dysgenesis
Kostmann syndrome
Cyclic neutropenia
4 features of Reticular dysgenesis
Pancytopenia
No differentiation of stem cells
No granulocytes, no myeloid/ lymphoid cells
Most severe SCID
3 features of Kostmann syndrome
Severe congenital neutropenia
AR mutation in HAX1
Can’t produce neutrophils
3 features of Cyclic neutropenia
Episodic neutropenia every 4-6w
AD mutation in neutrophil elastase
Neutrophil count fluctuates ~monthly
What are the 4 failures causing defects/ deficiency of phagocytes?
Failure of production
Failure of trafficking
Failure of killing
Failure of signalling
What causes failure of trafficking to site of infection?
Leukocyte adhesion deficiency:
CD18 deficiency
Describe the pathophysiology of leukocyte adhesion deficiency
CD18 should form dimer with CD11 that binds ICAM-1 on endothelial cells to allow transmigration
Absence means neutrophils can’t leave bloodstream
Give 3 characteristics of leukocyte adhesion deficiency
Very high neutrophil count
Absence of pus
Delayed umbilical cord sloughing
What causes neutrophil failure of killing?
Chronic granulomatous disease
Why do granulomas form in chronic granulomatous disease?
Neutrophils die quicker as use glycogen + lysozyme stores faster
Phagocytes fuse forming granuloma
What causes chronic granulomatous disease?
NADPH oxidase deficiency
Thus no respiratory burst
Impaired killing of intracellular pathogens
What causes excessive inflammation in chronic granulomatous disease?
Persistent neutrophil/ macrophage accumulation
Failure to degrade antigens
Give 2 clinical signs of chronic granulomatous disease
Hepatosplenomegaly
Lymphadenopathy
Which bacteria are patients with chronic granulomatous disease particularly susceptible to?
Catalase +ve PLACESS
Pseudomonas
Listeria
Aspergillus
Candida
E.coli
Staph aureus
Serratia
Which tests can be used to diagnose chronic granulomatous disease?
Nitroblue tetrazolium (NBT): yellow to blue if oxidative killing. CGD -ve.
Dihydrorhodamine (DHR) flow cytometry: fluorescent if oxidative killing. CGD -ve.
What causes a failure of signalling as a defect of phagocytosis?
IL12-IFN gamma pathway defect
Defect in cytokines or receptors
What is the pathophysiology of IL12-IFN gamma pathway defect?
Defect in signalling between macrophages + T cells
Can’t activate T cells
Granulomas can’t be formed
What are patients with IL12-IFN gamma pathway defect susceptible to?
Mycobacteria (TB + Atypical)
BCG
Salmonella
What is classical NK deficiency?
Absent NK cells, not differentiating from stem cells
GATA4 or MCM4 mutations
What is functional NK deficiency?
Abnormal function- too little/ too much (AI)
What are those with NK cell deficiencies especially vulnerable to?
Herpes virus: HSV, VZV, EBV, CMV
Papilomavirus: HPV
Which infections are those with complement deficiency particularly susceptible to?
Neisseria meningitides
Haemophilus influenzae
Streptococcus pneumonia
What can cause complement deficiency?
Primary: body not making
Secondary: Liver failure, AI disease using up complement e.g. SLE
What results from deficiency early in the classical complement pathway?
Not clearing apoptotic/ necrotic cells- increases self-antigens esp. nuclear, promotes AI
Not clearing immune complexes- deposition in skin, joints, kidneys + inflammation
Which deficiency in the classical complement pathway is most common? What disease is this associated with?
C2
SLE
What can cause a secondary deficiency in the classical complement pathway?
Active lupus
Due to persistent production of complexes + consequent depletion of complement
Low C3 + C4
What can cause secondary C3 deficiency?
Nephritic factors; autoantibodies against C3 convertase
Cause constant activation + thus depletion of C3
Which diseases may secondary C3 deficiency be seen in?
Glomerulonephritis: blood in urine
Lipodystrophy: abnormal fat distribution e.g. Lipomas
Describe management of phagocyte deficiencies
Infection prophylaxis
Abx: Septrin PO/IV
Anti-fungals: Itraconazole
Definitive therapy:
HSCT: ‘Replaces’ defective population.
What treatment is given in chronic granulomatous disease?
Interferon gamma therapy
What investigations are used to diagnose complement deficiencies?
CH50
AP50
Describe the management of complement deficiencies
Vaccination
Prophylactic abx
Screen family
