Primary immune deficiencies

Question 1

AR mutation in mitochondrial enzyme AK2

Failure to produce myeloid or lymphoid cells

Answer 1

Reticular dysgenesis (type of SCID)

Reticular dysgenesis is caused by a mutation in AK2 that is a mitochondrial energy enzyme. It is the most severe form of SCID, preventing HSCs in the BM from maturing to either lymphocytes or myeloid cells

Question 2

AR mutation in HAX1

Failure of neutrophils to mature

Answer 2

Kostmann’s

Kostmann’s is a mutation in HAX1 (Hax of neutrophils) which prevents neutrophil maturation only.

Question 3

AD mutation in ELA2
Cyclical neutropenia (every 3w for 6d)

Answer 3

Cyclical neutropenia

Cyclical neutropenia is a mutation in ELA2 which results in a dip in neutrophil maturation every few weeks

Question 4

Deficiency of CD18 adhesion molecule (binds ICAM-1 on epithelial cells)
Neutrophilia, no pus formation

Answer 4

Leukocyte adhesion deficiency

In Leukocyte adhesion deficiency, there is a mutation in the CD18 adhesion molecule (think ‘eighteen (hating) to join’). This prevents it from binding to ICAM-1 on epithelial cells and migrating into tissues.

Question 5

Failure of oxidative killing (NADPH oxidase deficiency)
Chronic inflammation forms lots of granulomas
Catalase +ve organisms (PLACESS)
NBT + DHR tests negative

Answer 5

Chronic granulomatous disease
(‘Can’t get ‘em destroyed)

(NBT + DHR tests indicate whether oxidative killing has occurred - NBT should change from yellow to blue, NHR oxidised to fluorescent rhodamine - negative in CGD as lack of oxidative killing)

PLACESS organisms - catalase positive - Pseudomonas, Listeria, Aspergillus, Candida, E coli, SA, Serratia (they are really hard to kill and need oxidative killing to get them)

Question 6

Chronic Mycobacteria / Salmonella infection

Lack of granuloma formation

Answer 6

IL12-IFN-gamma network deficiency

(Normally intracellular organisms like mycobacteria / salmonella infect macrophages + stimulate IL12 production - this then induces IFN-gamma production by T cells to form granulomas)

Question 7

What are PLACESS organisms and in what immunodeficiency do they predominate?

Answer 7

Catalase positive organisms - Pseudomonas, Listeria, Aspergillus, Candida, E coli, S aureus, Serratia
More likely in CGD

Question 8

What are the innate primary immunodeficiencies?

Answer 8

Reticular dysgenesis
Kostmann's syndrome
Cyclic neutropenia
Leukocyte adhesion deficiency
CGD
IFN-gamma deficiency

Question 9

Mutation in reticular dysgenesis

Answer 9

AR in AK2

Question 10

Mutation in Kostmann’s

Answer 10

HAX1

Question 11

Mutation in cyclical neutropenia

Answer 11

ELA2

Question 12

What is the definitive treatment for phagocyte deficiencies?

Answer 12

Stem cell transplant

IFN-gamma

Question 13

What are the two types of NK cell deficiency?

Answer 13

• Classical (absence)

- Functional (abnormal function)

Question 14

Absent NK cells in blood
GATA2 and MCM4 mutations
Severe chicken pox + CMV infections

Answer 14

Classic NK cell deficiency (absence)

Question 15

NK cells in blood that do not function

FCHR3A mutation

Answer 15

Functional NK cell deficiency (abnormal function)

Question 16

Describe the complement pathway

Answer 16

• Classical (C1, C2, C4) - antigen-antibody complex triggered
• MBL (C2, C4) - mannose-binding lectin carbohydrate (MBL) on microbe triggers
• Alternate (B, D, H, properidin) - bacterial cell wall triggers

Result in formation of C3, C5-C9 then join to form MAC complex. MAC complex is pro-inflammatory - pt. for lysis of encapsulated bacteria

Question 17

Classical complement pathway

Answer 17

Antigen-antibody complex trigger

C1, C2, C4

Question 18

MBL pathway

Answer 18

MBL - microbe carbohydrate trigger

C2, C4

Question 19

Alternate pathway

Answer 19

Bacterial cell wall trigger

Factors B, D, H, Properidin

Question 20

Encapsulated bacteria

Answer 20

Some Killers Have Pretty Nice Capsules

S pneumoniae, Klebsiella, H influenzae, Pseudomonas, Neisseria, Cryptococcus

Question 21

Recurrent childhood pyogenic infections

Answer 21

MBL / alternative pathway deficiency

Question 22

Failure to clear complexes
Lack of C1, C2, C4
Severe childhood onset SLE
CH50 reduced

Answer 22

Primary classical pathway deficiency

(Classical pathway involves the formation of antigen-antibody complexes that need to be cleared, therefore a deficiency will cause accumulation. CH50 is a measure of classical pathway function. Classical pathway involves C1, C2 and C4 and therefore deficiency in any of these will result in classical pathway deficiency. SLE occurs because there is accumulation of the complexes that deposit in organs / vessels)

Question 23

Recurrent meningitis infections

Answer 23

Primary common pathway deficiency (C5-C9)

(This is not really specific for the common pathway (can happen with any complement deficiency but the common pathway is integral to all pathways hence important)

Question 24

Glomerulonephritis with presence of nephritic factor

Loss of adipose tissue

Answer 24

Common pathway deficiency (C3)

(In glomerulonephritis, nephritic factor is produced which attack C3 by stabilising C3 convertase enzyme - basically just think of nephritic factor being produced which destroys C3. This also causes partial lipodystrophy, in which there is a failure to maintain adipose tissue

Question 25

Reduced C3 and C4

Answer 25

SLE (secondary complement deficiency) In SLE there is formation of lots of antigen-antibody complexes which need to be cleared, Just remember that this particularly uses up C3 and C4

Question 26

What are the two main causes of secondary complement deficiency?

Answer 26

- Active SLE: Persistent immune complex formation uses up classical / common (pt. C2) to clear complexes - Membranoproliferative GN: nephritic factors pt. attack C3

Question 27

What is true about SLE in complement deficiency?

Answer 27

SLE can both cause complement deficiency (secondary) AND result from complement deficiency (primary classical) - failure to clear complexes

Question 28

Mutation of common gamma chain of IL2 receptor

Answer 28

X-linked SCID

Question 29

When do adaptive immune deficiencies tend to appear?

Answer 29

3m - before this age maternal IgG crosses placenta / enters breast milk and protects

Question 30

X-linked WASp gene Lymphoma, thrombocytopenia, eczema Easy bruising, nose bleeds, GI bleeds Low IgM, raised IgA and IgE (not sure why)

Answer 30

Wiskott-Aldrich syndrome

Question 31

Most severe form of SCID AK2 mutation (mitochondrial metabolism) Unable to differentiate from BMSCs

Answer 31

Reticular dysgenesis

Question 32

Low T cells, lots of non-functioning B cells Failure to thrive, unwell by 3 months IL-2R gamma chain mutation

Answer 32

X-linked SCID (In X-linked SCID (the most COMMON type of SCID) there is a mutation in the gamma chain of IL2 receptor (think X has two lines). Just remember that there are low T cells as they stop being produced with the absent receptor) + the B cells accumulate because they can't be activated by the T cells. Babies become unwell by 3 months because they lose mothers IgG)

Question 33

What are the 3 main types of T cell immunodeficiency?

Answer 33

DiGeorge Syndrome Bare Lymphocyte syndrome 1 Bare Lymphocyte syndrome 2

Question 34

Describe the process of T lymphocyte production | Describe the 3 step process of B cell activation by T lymphocytes

Answer 34

HSCs in BM exported as pre-T cells to thymus - selection by central tolerance (does it bind HLA?) - differentiation to CD4 (binds best to MHC II) or CD8 (binds best to MHC I) B cells are activated by CD4 (Th2) T cells 1. CD40-CD40L 2. Th2 TCR - MHC II 3. IL4 release Once activated B cells will undergo class switching- before class switching they just produce IgM but after class switching they can produce IgAGE and more IgM

Question 35

Absent / hypoplastic thymus Low T cells, Normal B cells, normal IgM, decreased IgG/IgA CATCH-22

Answer 35

Di George syndrome (T cells leave the BM and go to the thymus for maturation. When there is an absent thymus they cannot mature fully so there are low T cells and they cannot activate B cells to class switch and produce IgAGE)

Question 36

CATCH-22

Answer 36

``` Cardiac abnormalities Atresia of oesophagus Thymic aplasia Cleft palate Hypocalcaemia 22q11 ```

Question 37

Absence of HLA II / I expression in thymus Low CD4 / CD8 production Chronic mild diarrhoea, sclerosing cholangitis, hepatomegaly, jaundice

Answer 37

BLS 1 / 2 (In BLS HLA is not expressed in the thymus for T cell maturation so they do not express MHC (type depends on HLA absence). There are lots of GI complications - think 'bare bum' as they are constantly on the toilet with diarrhoea)

Question 38

What are the 4 main types of B lymphocyte deficiency?

Answer 38

Bruton's X-linked hypogammaglobulinaemia Hyper IgM Common variable (CVID) Selective IgA

Question 39

What is class switching?

Answer 39

``` B cells initially only produce IgM Once class switching has occurred they produce more IgG, IgA, IgE and more IgM ```

Question 40

Recurrent GI and respiratory tract infections | Anaphylaxis in blood transfusion

Answer 40

Selective IgA deficiency (IgA = mucosal immunity; anaphylaxis can occur in blood transfusions because IgA is seen as a foreign substance and there is a sudden increase in donor IgA - the body is not used to it and anaphylaxis will occur)

Question 41

Why can anaphylaxis occur when blood transfusion is given in IgA deficiency?

Answer 41

Sudden increase in donor IgA - body is not used to presence of IgA

Question 42

Mutation of MHC III Bronchiectasis, recurrent sinusitis + atypical SLE Predisposition to NHL Poor immunisation response

Answer 42

CVID (Common variable immune deficiency) (There is a mutation in MHC III - the mechanism is not understood, but seems to prevent B cell maturation + class switching. Look for respiratory tract signs)

Question 43

What are the two main categories of B cell deficiency?

Answer 43

``` Affect BM - all B cells and Ig low = SCID, Bruton's Affect class switching - B cells and IgM usually high, other Igs (AGE) low = Hyper IgM, selective IgA, CVID ```

Question 44

BLS1 vs. BLS2

Answer 44

``` BLS1 = Reduced MHC class I expression = Reduced CD8+ BLS2 = Reduced MHC class II expression = Reduced CD4+ (CD4+ activate B cells so also reduced IgAGE) ```

Question 45

BTK gene mutation Recurrent bacterial infections + FTT Low B cells and Ig Boys (X-linked)

Answer 45

Bruton's (Bruton's is selective lack of B cell maturation in the BM. B cells are important for bacterial infection fighting. Think of B cells as starts with B)

Question 46

CD40-L mutation = B cells without CD40L Normal T and B cells Lots of IgM, no IgAGE P jiroveci infection

Answer 46

``` Hyper IgM (One of the 3 steps of B cell activation requires CD40-CD40L interaction. Therefore there is no class switching so only IgM is produced (think of as M has 4 lines)) ```

Question 47

Low Ig | Renal symptoms, swelling

Answer 47

Nephrotic syndrome

Question 48

3w Hx of diarrhoea Recurrent chest infections since first episode Tired + feverish

Answer 48

Protein losing enteropathy

Question 49

Encapsulated bacteria infection | Dactylitis

Answer 49

Sickle cell anaemia | Hyposplenism

Question 50

T cell vs. B cell deficiencies

Answer 50

T cell: Viral infections (e.g. CMV), Intracellular bacteria infections, Fungal infections B cell: Bacterial infections (e.g. Staph, Strep), Toxins (Tetanus, Diphtheria)

Question 51

What are AP50 and CH50 measures of?

Answer 51

AP50 is a measure of alternate pathway function CH50 is a measure of classical pathway function If both AP50 and CH50 are reduced

Question 52

SERPING1 gene mutation | Hereditary angioedema

Answer 52

Hereditary condition due to mutation in SERPING1 gene | Leads to hereditary angioedema