Primary Immunodeficiencies

Question 1

name the 4 main components of the immune system and their immune mechanism

Answer 1

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

Question 2

what are 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

main causes of primary immunodeficiencies in europe

Answer 3

predominately antibody disorders
predominantely T cell disorders
phagocyte disorders
other well defined PIDs
complement deficiencies
auto-immune and immune dysregulation syndromes
auto-inflammatory syndromes
unclassified

Question 4

what are secondary immunodeficiences

Answer 4

• 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.
• Most well-known examples are HIV infection and patients treated for malignancies.
• Much more common than primary immunodeficiencies.

Question 5

causes of secondary immunodeficiencies: environmental

Answer 5

malnutrition
trauma
burns

Question 6

causes of secondary immunodeficiencies: disease

Answer 6

infection
diabetes
renal failure
asplenia
malignancies (leukaemia, lymphoma)

Question 7

causes of secondary immunodeficiencies: iatrogenic

Answer 7

surgery
splenectomy
drugs (immunosuppressive, antirheumatic, antiepileptic)

Question 8

3 categories of primary immunodeficiencies

Answer 8

antibodies deficiencies
cellular immunodeficiencies
innate immune disorders

Question 9

primary immunodeficiencies: antibody deficiency

Answer 9

characterised by a deficiency of one or more (sub)classes of antibodies e.g. IgG, IgA, IgM, IgG2 due to defective B cells
or
absence of mature B cells

Question 10

primary immunodeficiencies: cellular immunodeficinces

Answer 10

characterised by impaired T cell funciton or the absence of normal t cells

Question 11

primary immunodeficiencies: innate immune disorders

Answer 11

defects in phagocyte function
complement deficiencies
absence or polymorphisms in pathogen recognition receptors

Question 12

infections in primary immunodeficiencies: antibody deficiencies

Answer 12

recurrent bacterial infections of the upper and/or lower RT

s. pneumoniae, H. influenzae

Question 13

infections in primary immunodeficiencies: cellular immunodeficiencies

Answer 13

unisal or opportunistic infections often combined with failure to thrive
pneumocystic jirovecii, CMV pneumonia

Question 14

infections in primary immunodeficiencies: innate immune disorders

Answer 14

defects in phagocyte function:
s. aureus  (sepsis, skin lesions, abscesses internal organs)
aspergillus infections (lung, bones, brain)

complement deficiencies
n. miningitidis

Question 15

consequences of neutrophil defects

Answer 15

• Absence of neutrophils > congenital neutropenia
• Adhesion > leucocyte adhesion defect
• Recognition and Phagocytosis > deficiencies of PRR
• Intracellular Killing > chronic granulomatous disease

Question 16

describe hereditary angioedema

Answer 16

• C1-inhibitor deficiency (autosomal dominant)
• Recurrent episodes of painless, non-pitting, non-pruritic, non erythematous swellings
• Subcutaneous tissues, intestines, oropharynx
•
Acute emergency management of:
•
Pharyngeal/laryngeal obstruction
•
Acute abdominal pain
•
C1-inhibitor infusion OR fresh frozen plasma
•
(steroids, antihistamines ineffective)

Question 17

disorders of adaptive immunity: B cells

Answer 17

• 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 18

disorders of adaptive immunity: T cells

Answer 18

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

Question 19

describe with a diagram b cell maturation and defects

Answer 19

see notes

Question 20

what is 22q11 deletion syndrome aka

Answer 20

diGeorge

Question 21

what is 22q11 deletion syndrome

Answer 21

•
Hemizygous 22q11.2 deletion
•
Most common microdeletion syndrome
•
de novomutations (10% deletion identified in a parent)
•
Highly variable expression
•
1:4000 (Down syndrome 1:1200)
•
UK/Ireland: 10,000-15,000 affected
•
2ndmost common cause of developmental delay and major congenital heart disease (after DS)

Question 22

clinical presentation of 22q11 deletion syndrome

Answer 22

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

Question 23

physical appearance in 22q11 deletion syndrome

Answer 23

• Short forehead
• Hooded eyelids with upslanting palpebral fissures
• Malar flatness
• Bulbous nasal tip with hypoplastic alea nasi
• Protuberant ears

Question 24

immune deficiency in 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 | fatal < 2

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

infections in: adaptive CD4 def

Answer 28

pneumocystitis spp ``` ophthalmic pneumocystosis pneumocystitis pneumonia hepatosplenic infiltrates renal pneumocystosis bone marrow infiltrates ```

Question 29

infections in: innate neutrophil disorders

Answer 29

aspergillus spp ``` cerebral aspergillosis kerattis sinusitis allergic and invasive pulmonary aspergillosis aspergilloma invasive aspergillosis osteomyelitis cutaneous aspergillosis ```

Question 30

infections in: systemic innate (phagocytic disorders)/mucosal addaptice (IL-17 response)

Answer 30

candida spp ``` cerebral abscess endopthalmitis thrush oesphagitis endocarditis candidemia hepatic abscess urinary candidiasis vilvovaginal candidiasis osteomyelitis cutaneous candidiasis onychomycosis ```

Question 31

infections in: adaptive CD4 def cryptococcus spp

Answer 31

``` meningitis cerebral abscess endophthalmitis pulmonary infiltrates endocardititis crpytococcemia renal abscess subcut abscess ```

Question 32

invasive fungal infections in PID

Answer 32

* Presenting symptom of primary immunodeficiency * In children with neutropenia due to leukaemia and/or chemotherapy * Invasive candidiasis in premature neonates due to immature (but physiological) immune system * In children admitted to PICU and treated with broad spectrum antibiotics and/or abdominal surgery

Question 33

management of PID

Answer 33

``` • Symptomatic treatment = prevention of infections • Causative • Immunoglobulin substitution • Gene therapy (ADA-SCID) • Stem cell transplant (CGD) • Thymus transplant (diGeorge) • Genetic counselling & prenatal diagnosis ```