W10 - Primary immunodeficiency part 1

Question 1

Immunodeficiencies are classified into 3 types - name them.

Answer 1

1. Primary (inherited)
2. Secondary (acquired)
3. Physiological

Question 2

Give 3 examples of physiological immunodeficiency

Answer 2

1. Neonates
2. Older age
3. Pregnant

Question 3

Give 3 laboratory tests to order when suspecting primary immunodeficiency

Answer 3

1. FBC - WBC + lymphocyte subsets, special tests for white cell migration/function
2. Immunoglobulins - IgM, IgG, IgA, specific Igs and response to vaccination
3. Complement - complement function, individual components

Question 4

What are the two broad categories of primary immunodeficiency?

Answer 4

• Deficiencies in the INNATE immune system
• Deficiencies in the adaptive immune system

Question 5

Name the 4 types of phagocyte deficiency

Answer 5

1. Failure to produce neutrophils:
   - Reticular dysgenesis
   - Kostmann syndrome
   - Cyclic neutropenia
2. Defect of phagocyte migration:
   - Leukocyte adhesion deficiency
3. Failure of oxidative killing mechanisms:
   - Chronic granulomatous disease
4. Cytokine deficiency:
   - IL12, IL12-R, IFN-gamma, IGN-g-R deficiency

Question 6

Inheritance mode of reticular dysgenesis?
- what is the underlying problem?

Answer 6

Autosomal recessive SEVERE SCID
- failure of HSCs to differentiate along myeloid and lymphoid lineage

Question 7

Inheritance mode of Kostmann syndrome?
- what is the underlying problem?

Answer 7

Autosomal recessive severe congenital neutropenia
- specific failure of neutrophil maturation

Question 8

Inheritance mode of Cyclic neutropenia?
- what is the underlying problem?

Answer 8

Autosomal dominant
- episodic neutropenia every 4-6 weeks

Question 9

What is the underlying problem in leukocyte adhesion deficiency?

Answer 9

neutrophils do not express CD18, which is needed to bind to ICAM-1 on endothelial cells for transmigration = HIGH NEUTROPHIL COUNTS in blood, absence of pus formation

Question 10

What is the underlying problem in Chronic Granulomatous Disease?

Answer 10

Failed oxidative killing due to deficiency in a component of NADPH oxidase => impaired killing => persistent neutrophils/macrophages accumulation =>

1. granuloma formation
2. lymphadenopathy
3. hepatosplenomegaly

Question 11

What are 2 investigations you could use to test for chronic granulomatous disease? Explain the results

Answer 11

1. Nitroblue tetrazolium (NBT) test
   - activate neutrophils => stimulate respiratory burst => production of hydrogen peroxide => NBT dye changes from yellow to blue
2. Dihydrorhodamine (DHR) flow cytometry test
   - as above => DHR is oxidised to rhodamine which is GREEN fluorescent

Question 12

What is the underlying problem in cytokine deficiency?

Answer 12

IL-12 - IFN-g are an important network in control of mycobacteria infection. therefore here, there is lack of stimulation to activate macrophages, and patients present with atypical mycobacteria infections

Question 13

What are the 2 typical presentations in phagocyte deficiencies?

Answer 13

• b/c they are needed for our “initial” immunity against pathogens, they present with:
  1. recurrent infections = skin/mouth:
• bacterial => staph aureus, enteric
• fungal => candida, aspergillus

2. Mycobacterial infections => TB, atypical mycobacteria

Question 14

Complete the table

Answer 14

Question 16

Describe immediate treatment of phagocyte deficiencies

Answer 16

1. Infection prophylaxis
   - Abx: e.g., Septrin (Trimethoprim / Sulfamethoxazole)
   - Anti-fungals: e.g., Itrazonacole
2. Oral/IV abx as needed

Question 17

Describe definitive therapy for phagocyte deficiency

Answer 17

1. Haematopoietic stem cell transplantation
   - replace defective population
2. Specific treatment for CGD = Interferon gamma therapy

Question 18

What are the 2 classes of NK cell deficiencies - explain the difference

Answer 18

1. Classical NK deficiency = absence of NK cells within peripheral blood
2. Functional NK deficiency = NK cells present but function is ABNORMAL

Question 19

How do NK cell deficiencies typically present?

Answer 19

NK cells typically help eliminate virally-infected cells and malignant cells. Therefore:

1) Viral infections:
- Herpes virus infections:

Herpes simplix virus I and II

Varicella Zoster virus

EBV

CMV

• Papillomavirus infection
  2) Malignancy
• Papillomavirus-associated cancers

Question 20

How do we treat (3) NK deficiencies?

Answer 20

1. Prophylactic antiviral drugs (acyclovir)
2. Cytokine i.e. IFN-a to stimulate NK cytotoxic function
3. HSCT in severe phenotypes
   - essentially, no good trial data available

Question 21

recurrent infections with high neutrophil count on FBC but no abscess formation. what is the cause?

Answer 21

leukocyte adhesion deficiency

Question 22

child with recurrent infections with hepatosplenomegaly and abnormal dihydrohodamine test (does not fluoresce). what disease is it?

Answer 22

chronic granulomatous disease

Question 23

Recurrent infections with no neutrophils on FBC - what is the diagnosis?

Answer 23

Kostmann syndrome

Question 24

Infection with atypical mycobacterium, normal FBC - what is the diagnosis?

A) Kostmann syndrome

B) Leukocyte adhesion deficiency

C) Chronic granulomatous disease

D) IFN-gamma receptor deficiency

Answer 24

D) IFN-gamma receptor deficiency

Question 25

Severe chicken pox, disseminated CMV infection - what immunodeficiency is it?

Answer 25

Classical NK cell deficiency

Question 26

What pathogens does one become susceptible to with complement deficiency?

Answer 26

NHS = 3 encapsulated bacteria: 1. Neisseria meningitides (esp with properidin and C5-9 deficiency) 2. Haemophilus influenzae 3. Streptococcus pneumoniae

Question 27

For classical pathway deficiency, explain: A) which factors may be deficient B) underlying issues C) any associated diseases

Answer 27

A) C2, C1q B) failure of phagocytosis of dead cells = increased nuclear debris B) failure to clear immune complexes = immune complex deposition in blood vessels C) SLE C) increase susceptiblity to encapsulted bacterial infections (NHS)

Question 28

For MBL deficiency, explain: A) which factors may be deficient B) underlying issues C) any associated diseases

Answer 28

A) MBL B) nil - usually is **_not_** associated with immunodeficiency C) None

Question 29

Explain how complement deficiency and SLE could effect each other in 2 opposite directions

Answer 29

**1. Complement deficiency first** Deficiency of early component of complement (usually **C1q and C2**) =\> you dont phagocytose your dead cells and you get a lot of nuclear debris you put yourself at danger of making abs to those molecules, such as ANA, anti-dsDNA = SLE **2. Active SLE first** active lupus causes persistent production of immune complexes and consequent consumption of complement (**C3** and C4) =\> functional complement deficiency

Question 30

Describe C3 nephritic factors

Answer 30

nephritic factors are auto-abs directed against components of the complement pathway nephritic factors stabilise C3 convertase =\> **_C3 activation + consumption_**

Question 31

What is C3 nephritic factors associated with (2 things)

Answer 31

* glomerulonephritis * partial lipodystrophy (lose fat from their upper bodies, and not their lower bodies)

Question 32

Complete the chart

Answer 32

Question 33

What investigations (3) can be undertaken if we suspect complement pathway deficency?

Answer 33

1. C3, C4 routinely measured - other component not routinely checked but can be checked if suspected deficiency 2. CH50 = classical pathway test 3. AP50 = alternative pathway test

Question 35

Describe management (4) of patients with complement deficiencies

Answer 35

1. Vaccination - Meningovax - Pneumovax - HIB vaccines 2. Prophylactic abx 3. Treat infections aggresively 4. Screening of family members

Question 36

meningococcus meningitis with family history of sibling dying of same condition aged 6. no features of SLE, no proteinuria, normal fat distribution. which deficiency do they have? * C1q deficiency * C3 deficency with presence of a nephritic factor * C7 deficiency * MBL deficiency

Answer 36

C7 deficiency - complement deficiency in properidin and C5-9 deficiency increases susceptilibility to Neisseria meningitides (As part of 3 encapsulated bacteria group, NHS)

Question 37

9 year old girl with severe SLE And normal C3 and C4. Which is the most likely complement deficiency? * C1q deficiency * C3 deficiency with presence of a nephritic factor * C7 deficiency * MBL deficiency

Answer 37

C1q deficiency