Deficiencies of Innate Immunity

Question 1

Causes of secondary immune deficiencies

Answer 1

• Physiological (neonates, pregnancy, old age)
• Infection
• Drugs
• Malnutrition
• Malignancy

Question 2

Diseases affecting mobilisation of phagocytes

Answer 2

Reticular dysgenesis - affects neutrophil production

Kostmann syndrome/Cyclic Neutropenia - affect neutrophil maturation

Leukocyte adhesion deficiencies - affect migration to infection site

Question 3

Reticular Dysgenesis

Answer 3

• Severe form of SCID
• Stem cells cannot differentiate along myeloid or lymphoid lineages, so there are no neutrophils, monocytes/macrophages, lymphocytes or platelets
• Fatal in early life unless corrected with BMT

In autosomal recessive severe SCID, there is mutation in mitochondrial energy metabolism enzyme AK2

Question 4

Kostmann Syndrome

Answer 4

• Autosomal Recessive
• Mutation in HAX1 means neutrophils cannot mature
• There is severe congenital neutropenia

Question 5

Cyclic neutropenia

Answer 5

• Autosomal dominant

- Mutation in neutrophil elastase (ELA-2) results in episodic neutropenia every 4-6 weeks

Question 6

Leukocyte Adhesion Deficiencies

Answer 6

• Deficiency of CD18, which forms part of the adhesion molecule LFA-1. (LFA-1 normally binds to ICAM on affected endothelial cells)
• Neutrophils are mobilised to the bloodstream, but cannot express LFA-1 and therefore cannot exit the bloodstream
• There are high neutrophil counts with absence of pus formation
• DELAYED UMBILICAL CORD SEPARATION

Question 7

Chronic Granulomatous Disease - pathophysiology

Answer 7

• Deficiency in one component of NADPH complex means there is absent respiratory burst
• Cannot generate oxygen free radicals
• Impaired killing of intracellular pathogens
• Excessive inflammation due to persistent activation of neutrophils and macrophages, these collect to form granulomas

Question 8

Chronic Granulomatous Disease - Presentation

Answer 8

• Lymphadenopathy
• Hepatosplenomegaly
• Susceptibility to bacterial infections, especially catalase +ve (PLACESS)

Pseudomonas
Listeria
Aspergillosis 
Candida
E. coli
Staph aureus
Serratia

Question 9

Testing for Chronic Granulomatous Disease

Answer 9

Testing for the presence of H2O2.
First activate neutrophils with a stimulus e.g. Salonella.

NBT (Nitroblue Tetrazolium test) becomes yellow to blue in the presence of H202.

Dihydroamine flow cytometry (DHR) used oxidised rhodamine which fluoresces in the presence of H2O2.

Question 10

Cytokine deficiencies

Answer 10

Deficiencies in IL-12, IFN-y, IL-12R and IFN-yR
This disrupts the cytokine cycle between macrophages and T-cells.

1. Infected macrophages released IL-12
2. IL-12 acts on T-cells, and stimulated them to produce IFN-y
3. IFN-y acts on macrophages and T-cells to stimulate production of free radicals and TNF
4. This stimulates oxidative killing pathways

Deficiency results in:

• Susceptibility to infection from mycobacterium and Salmonella
• Inability to form granulomas

Management of cytokine deficiencies:

• Aggressive management of infection
• Prophylactic antibiotics e.g. Septrin
• Prophylactic anti-fungals e.g. itraconazole
• Definitive therapy - HSCT

Question 11

Management of chronic granulomatous disease

Answer 11

Definitive management is IFN-y (boosts macrophage function)

Question 12

NK cell deficiency

Answer 12

• Can be classical (absence of NK cells in peripheral blood) or functional (poor NK cell function)
• Patients are susceptible to viral infections, particularly Human Herpes virus infections and HPV

Management:

• Prophylactic aciclovir
• IFN-y to stimulate cytokines
• Definitive treatment - HSCT

Question 13

Complement deficiency - alternative pathway

Answer 13

Deficiency in Factor B/I/P leads to inability to mobilise complement rapidly in response to bacterial infections

Recurrent infections with encapsulated bacteria (NHS)

Question 14

Complement deficiency - Classical pathway

Answer 14

DEFICIENCY IN C1/2/4

• Classical pathway promoted phagocytosis-mediated clearance of dead cells
• When immune complexes fail to activate the classical pathway, these cells are not cleared and the nuclear load is released
• Therefore there is an increased load of self-antigens which can promote auto-immunity
• The immune complexes deposit in skin, joints and kidneys causing local inflammation

Question 15

Complement deficiency - MBL pathway

Answer 15

Does not lead to immunodeficiency!
Deficiency in MBL is present in 30% people
But where there is another cause of immune impairment, there can be increased risk of infection

Question 16

Why does complement deficiency reduce immunity against encapsulated bacteria?

Answer 16

Defence against encapsulated bacteria involves antibody-mediated and complement-mediated processes

Question 17

Link between classical pathway deficiency and SLE

Answer 17

Almost all patients with C2 deficiency have SLE

C1q deficiency tends to present with SLE at a young age

Question 18

Secondary complement deficiency - causes

Answer 18

SLE patients:

• Constant production of immune complexes in SLE patients means that complement factors become depleted
• There is functional complement deficiency
• C3 and C4 falls (C4 falls more)

Nephritic factors:

• Nephritic factors are autoantibodies which stabilise C3 convertases, so C3 is activated and consumed
• Can occur with glomerulonephritis or partial lipodystrophy

Question 19

Investigating complement deficiencies

Answer 19

CH50 - measures C1, C2, C4, C3, C5-9

AH50 - measures Factor D, Factor B, Properidin, C3, C5-9

Question 20

Management of complement deficiencies

Answer 20

• Vaccination against encapsulated organisms (Pneumovax, Meningovax and Hib)
• Prophylactic penicillin
• Aggressive management of infections
• If there is C7 or C9 infection, screen family members