Immunodeficiencies

Question 1

4 main components of the immune defence system

Answer 1

B-cells and antibodies (humoral, specific immunity)
T-cells (cellular, specific immunity)
Phagocytes (innate immunity)
Complement system (innate immunity)

Question 2

Primary immunodeficiencies

Answer 2

Group of > 300 rare, chronic disorders in which part of the body’s immune system is missing or functions improperly
Caused by single genetic defects
May affect a single part of the immune system or more components of the immune system

Question 3

Secondary Immunodeficiencies

Answer 3

Components of the immune system itself are all present and functional.
Acquired diseases affecting the immune system and/or treatments negatively influencing the immune system.
Caused by environmental/iatrogenic insults.

Question 4

Antibody Deficiencies

Answer 4

Characterized by a deficiency of one of more (sub)classes of antibodies (e.g. IgG, IgA, IgM, IgG2) due to defective B-cell function. There is an absence of mature B cells

Question 5

Cellular Immunodeficiencies

Answer 5

Characterised by impaired T-cell function or the absence of normal T-cells

Question 6

Innate Immune Disorders

Answer 6

Defects in phagocyte function

Complement deficiencies

Absence or polymorphisms in Pathogen Recognition Receptors

Question 7

Presentation of antibody deficiencies

Answer 7

Recurrent bacterial infection of the upper and lower respiratory tract

S.pneumoniae, H.influenza

Question 8

Cellular Immunodeficiencies presentation

Answer 8

Unusual or opportunistic infections often combined with failure to thrive

Pneumocystic Jirovecii, CMV (pneumonia)

Question 9

Defects in phagocyte function presentation

Answer 9

Pneumonia, osteomyelitis, skin infections, liver abscesses, suppurating lymph nodes.

Question 10

Features of infection of primary immunodeficiencies

Answer 10

Severe
Persistant
Unusual
Recurrent 
Runs in the family

Question 11

10 warning signs of primary immune deficiency

Answer 11

1. Four or more new ear infection within 1 year for children, two or more for adults
2. Two or more serious sinus infections
3. Two or more bouts of pneumonia
4. Chronic diarrhoea with weight loss and failure to grow normally
5. Recurrent viral infections
6. Persistent thrush or fungal infectiion
7. Recurrent deep skin or organ abscesses
8. Need for IV antibiotics to clear infections
9. Two or more deep seated infection
10. A family history of primary immune deficiency

Question 12

Neutrophil Defects

Answer 12

Absence of neutrophils - congenital neutropenia

Adhesion - leucocyte adhesion defect

Recognition and phagocytosis - deficiencies of RR

Intracellular killing - chronic granulomatous disease

Question 13

Complement cascade disorders

Answer 13

Bacterial infections will be the consequence

Nisseria meningiditis infection are at increased risk

Severe meningococcal sepsis

Question 14

Hereditary Angioedema

Answer 14

An autosomal dominant disorder characterised by recurrent attacks of painless, non-pitting, non-pruritic, non-erythematous swellings in subcutaneous tissues, intestinal walls, larynx and oropharynx. It results due to deficiency of one of the major control proteins preventing inappropriate activation of the classical complement pathway (C-1 inhibitor)

Question 15

Management of Hereditary Angioedema

Answer 15

Acute emergency management of:
Pharyngeal/laryngeal obstruction
Acute abdominal pain

C1-inhibitor infusion OR fresh frozen plasma
(steroids, antihistamines ineffective)

Question 16

Pneumocystis infections

Answer 16

Adaptive CD4 defeciency

Question 17

Aspergillus Infection

Answer 17

Innate Neutrophil disorders

Question 18

Candida Infection

Answer 18

Systemic - innate disorders

Mucosal - adaptive (IL-17 response)

Question 19

Cryptococcus infection

Answer 19

Adaptive CD4 deficiency

Question 20

Disorders of B-cell immunity

Answer 20

Absence of mature B-cells due to maturation stop in the bone marrow (BTK mutation)
Absence of immunoglobulin production
Absence of specific immunoglobulins and/or subclasses
IgG, IgA, IgM, IgG1, IgG2, IgG3, IgG4
Absence of functional antibodies (upon immunisations)

Question 21

Disorders of T cell immunity

Answer 21

Isolated T-cell subset deficiencies (CD3, CD4, CD8)
Combined deficiencies (severe combined immunodeficiency)
Syndromal immunodeficiencies

Question 22

22q11 deletion syndrome

Answer 22

Hemizygous 22q11.2 deletion

1:4000

Question 23

Clinical presentation of 22q11 deletion syndrome

Answer 23

Congenital cardiac anomalies
Palatal defects (affecting feeding and speech)
Characteristic facial features
Immunodeficiency –Thymus a-/hypo-plasia
Hypocalcaemia
Developmental disabilities
Learning disabilities
Behavioral problems
Psychiatric illness
Structural abnormalities (renal, eye, dental, skeletal, brain,  GI-tract)
Haematological & AI disorders

Question 24

Immune system disorders 22q11 deletion syndrome

Answer 24

Recurrent RTI’s during infancy
low T-cell numbers (+ qualitative defects)
low IgA and IgM
reduced antibody responses

Autoimmune phenomena (30%)
anaemia/thrombocytopenia
juvenile chronic arthritis (JIA; low IgA)
Raynaud’s
thyroid disease

Question 25

Complete DiGeorge Anomaly

Answer 25

DiGeorge + thymus aplasia

Question 26

Atypical complete DiGeorge anomaly

Answer 26

Oligoclonal T-cells, rash, lymphadenopathy | T-cells can reject transplant

Question 27

Typical complete DiGeorge anomaly

Answer 27

Very low T-cell numbers, no rash | May develop into ‘atypical’ phenotype

Question 28

Management of PID

Answer 28

Immunoglobulin substitution Gene therapy (ADA-SCID) Stem cell transplant (CGD) Thymus transplant (diGeorge) Antibiotic prophylaxis Antiviral prophylaxis Antifungal prophylaxis

Question 29

Chronic Granulomatous Disease

Answer 29

Inherited X-linked or autosomal recessive disorder in which gene defects lead to dysfunction or absence of cytochrome b558 enzyme which is involved in the generation of neutrophil and macrophage superoxide and oxygen radicals. Intracellular killing is usually severely impaired. Fatal unless treated aggressively.

Question 30

Leucocyte Adhesion Deficiency

Answer 30

Autosomal recessive disorder in which neutrophils fail to express adhesion molecule (CD11.CD18) which is required for neutrophils to adhere to vascular endothelium and thereby exit the blood into tissues. They can still produce normal blood polymorph leucocytosis in response to an infective stimulus. Bone marrow transplantation is useful treatment.

Question 31

Myeloperoxidase Deficiency

Answer 31

An autosomal recessive disorder which causes mild impairment of phagocyte oxidative burst. This is mild and frequently asymptomatic.

Question 32

Bacterial infections found in phagocytic disorders

Answer 32

Staphylococci, E.coli, salmonella, pseudomonas, serratia, nocardia Aspergillus fungi

Question 33

Physiological functions of complement

Answer 33

1) chemotaxis of phagocytes to sites of inflammation (C3a, C5a) 2) opsonisation (C3b, C4b) 3) lysis of micro-organisms (C5b-9 complex) 4) maintenance of solubility of Ag / Ab (C3b, C4b, C2)

Question 34

Clinical features of C1,4,2,3 deficiencies

Answer 34

Immune complex disease | Infection

Question 35

Clinical features of c3 or alternate pathway component deficiencies

Answer 35

Recurrent staph infection Recurrent strep/Haemophilus infection Recurrent meningococcal infection

Question 36

C5,6,7,8,9 deficiency presentation

Answer 36

Recurrent neisserial infection

Question 37

Type 1 hereditary angioedema

Answer 37

Decreased level of C1-hibitors

Question 38

Type 2 Hereditary Angioedema

Answer 38

Normal levels of C1-inhibitor but the molecule is functionally defective.

Question 39

Working classification of primary defects of adaptive immunity

Answer 39

1) Severe Combined Immune Deficiency (SCID) 2) Predominantly antibody deficiencies 3) Predominantly T cell deficiencies 4) Other (usually combined T & B) deficiencies

Question 40

Severe Combined Immune Deficiency

Answer 40

Severe dysfunction or defective development of T and B cells. Occur due to defects in pluripotent stem cells, lymphoid stem cells or T & B cells themselves

Question 41

Clinical features of severe combined immune deficiency

Answer 41

``` 1:60,000 live births (conservative estimate) clues - usually well for first 3 months of life persistent superficial candida diarrhoea and failure to thrive chronic bronchiolitis interstitial pneumonitis overwhelming bacterial sepsis ```

Question 42

Treatment of severe combined immune deficiency

Answer 42

Intensive supportive therapy with nutritional support, prophylactic and therapeutic antibiotics, anti-fungal and anti-viral therapy as required and immunoglobulin replacement therapy. Bone marrow transplant

Question 43

IgA deficiency

Answer 43

1:700 of population Recurrent sinus and respiratory tract infections, GI disease, allergic symptoms and autoimmune disease. due to deletion or mutation of the IgA gene. Sometimes occurs secondary to use of particular drugs such as phenytoin, penicillamine, gold or sulphasalazine.

Question 44

IgG deficiency

Answer 44

low levels of all four IgG subclasses have been described. The only important well defined, clinical entity however is an association between IgG2 deficiency and recurrent respiratory tract infections.

Question 45

Specific antibody deficiency

Answer 45

a specific, isolated inability to make antibodies against pneumococcal surface polysaccharide. Generally associated with mild infections of middle ear, sinusus and respiratory tract. All other immune effector defences (including other antibodies) are normal.

Question 46

X-linked agammaglobinaemia

Answer 46

male infants, symptoms start at age 3-6 months, patients fail to make immunoglobulins of any class because of defective B cell maturation with mature B cells and plasma cells being absent from blood, bone marrow and tissues. Due to mutation of a single gene (Btk) which is essential for B cell maturation. T cell immunity normal. Presents with bacterial infections but these patients are also susceptible to Echovirus infection

Question 47

Common variable Immune deficiency

Answer 47

symptom onset at any age but especially 3rd/4th decades. Low IgG & IgA with normal IgM. Infectious complications dominate but non-infectious complications are also common. Numerous genetic defects predispose to development of CVID and as a result the clinical presentations tend to be fairly heterogeneous. 20-30% of cases also have variable T cell deficiencies (and are therefore combined rather than simple antibody deficiencies).