Immunology - Primary immune deficiencies parts 1 & 2

Question 1

Recall 3 infections that can cause immunodeficiency

Answer 1

HIV
Measles virus
Mycobacterial infection

Question 2

Recall 3 diseases of neutrophil deficiency. Give their modes of inheritance

Answer 2

Reticular dysgenesis - recessive
Kostmann syndrome - recessive
Cyclic neutropenia - dominant

Question 3

What is the cause of Leukocyte adhesion deficiency?

Answer 3

CD18 deficiency - failure to express this ligand means they cannot exit the bloodstream

Question 4

What will be the most obvious abnormal result on the blood count in leukocyte adhesion deficiency?

Answer 4

Very high neutrophils (they cannot exit the bloodstream)

Question 5

What is chronic granulomatous disease?

Answer 5

A failure of phagocytic oxidative killing mechanisms

Question 6

Recall 2 tests that are useful in the investigation of chronic granulomatous disease

Answer 6

1. Nitroblue tetrazolium (NBT) test (change from yellow to blue when contact w h202)
   - stays negative (yellow in CGD)
2. Dihydrohodamine flow (DHR) cytometry test (negative = fluorescent)

Question 7

Which innate immunodeficiency is characterised by severe chickenpox and disseminated CMV infection?

Answer 7

Classic Natural Killer cell deficiency

Question 8

Which innate immunodeficiency is characterised by recurrent infections with hepatosplenomegaly and abnormal dihydroRHODAMINE test (does not fluoresce)?

Answer 8

Chronic granulomatous disease

Question 9

Which innate immunodeficiency is characterised by recurrent infections with no neutrophils on FBC?

Answer 9

Kostmann syndrome

Question 10

Which innate immunodeficiency is characterised by infection with atypical mycobacterium, and a normal FBC?

Answer 10

IFN gamma receptor deficiency

Question 11

Which innate immunodeficiency is characterised by recurrent infections with high neutrophil count on FBC but no abscess formation?

Answer 11

Leukocyte adhesion deficiency

Question 12

With which innate immunity deficiency is meningococcal septicaemia associated?

Answer 12

Deficiency of complement C7

Question 13

With which innate immunodeficiency is membranoproliferative nephritis and abnormal fat distribution associated?

Answer 13

C3 deficiency with presence of a nephritic factor

Question 14

What mutation is causative of X-linked SCID?

Answer 14

Common gamma chain on chromosome X q13.1
so unable to respond to cytokines

Question 15

Describe the phenotype of X-linked SCID in terms of T, B and NK cell numbers

Answer 15

T cells: very low or absent

B cells: Normal or increased B cells, but LOW Ig

NK cells: very low or absent

Question 16

How does adenosine deaminase deficiency affect the immune system?

Answer 16

This enzyme is necessary for cell metabolism in lymphocytes.

When it is deficient, there is early arrest of T and NK cell development and NO production of B cells.
unable to respond to cytokines

Question 17

Describe the phenotype of Adenosine deaminase deficiency in terms of T, B and NK cell numbers

Answer 17

All very low or absent
key diff between x scid

Question 18

what happens in first 3 months with SCID and ADA

Answer 18

neonate is protected from these conditions due to IgG for maternal placental supply and IgG from breast milks (not as good as former)

Question 19

What is the gene mutation implicated in DiGeorge syndrome?

Answer 19

22q11.2 deletion

Question 20

How does DiGeorge syndrome affect B and T cell levels?

Answer 20

Normal B cells
Reduce T cells

Question 21

What is bare lymphocyte syndrome type 2?

Answer 21

Absent expression of MHC class II causing severe deficiency of CD4+ T helper cells --\> results in low IgG OR IgA 
B cells & CD8 number are normal

Question 22

What inherited immunodeficiency might cause a profound deficiency of CD4+ T cells specifically?

Answer 22

Bare lymphcoyte syndrome type 2

Question 23

What is Kostmann syndrome?

Answer 23

Failure of neutrophils to mature - causes a congenital neutropenia

Question 24

What is cyclic neutropaenia?

Answer 24

Autosomal dominant episodic neutropenia every 3 weeks

Question 25

What are the features of chronic granulomatous disease?

Answer 25

Absent respiratory burst, leading to: - Excessive inflammation - Granuloma formation - Lymphadenopathy - Hepatosplenomegaly

Question 26

What immunodeficiency are recurrent skin and mouth infections most likely to be indicative of?

Answer 26

Phagocyte deficiency

Question 27

Which phagocyte deficiency has absent neutrophils and normal leukocyte adhesion molecules?

Answer 27

Kostmann syndrome

Question 28

Which phagocyte deficiency has absent CD18 and increased neutrophils?

Answer 28

Leukocyte adhesion deficiency (LAD) they lack LFA-1

Question 29

Which phagocyte deficiency has normal neutrophil levels and leukocyte adhesion markers, an abormal NBT/DHR test and pus is produced?

Answer 29

Chronic granulomatous disease

Question 30

Which phagocyte deficiency has normal neutrophil levels and leukocyte adhesion markers, a normal NBT/DHR test but no pus is produced?

Answer 30

Cytokine deficiency (IL12/IFN gamma pathway)

Question 31

Describe the classical pathway of complement activation

Answer 31

Antibody-antigen complex antibody + C1, then C2, C4 to C3

Question 32

Describe the mannose binding lectin pathway of complement activation

Answer 32

MBL, C2,C4 to C3 Activation of complement by the direct binding of MBL to microbial cell surface carbohydrates

Question 33

Describe the alternate pathway of complement activation

Answer 33

Involves bacterial cell wall PAMP (LPS, teichoic acid) to C3

Question 34

complement deficiency increases chance of which bacterial infections

Answer 34

NHS Neisseria meningitides Haemophilus influennzae Streptococcus pneumoniae

Question 35

What does classical complement pathway deficiency increase susceptibility to?

Answer 35

classic = C1,C2,C4 deficiency SLE/automimmunity

Question 36

Susceptibility to encapsulated bacteria may be indicative of what type of immunodeficiency?

Answer 36

Complement deficiency

Question 37

How does SLE affect complement?

Answer 37

Persistent production of immune complexes --\> activation of classical pathway --\> low levels of C3 and C4 (functional complement deficiency)

Question 38

What are the standard tests in suspected complement deficiency?

Answer 38

C3 levels C4 levels CH50 - classical AP50 + properdin and factors B & D - alternate

Question 39

What does CH50 measure?

Answer 39

Classical complement pathway

Question 40

What does AP50 measure?

Answer 40

Alternative complement pathway

Question 41

Which complement function test would be abnormal in C1q deficiency?

Answer 41

CH50

Question 42

Which tests would be abornmal in C9 deficiency?

Answer 42

CH50 and AP50

Question 43

Which complement deficiency is most associated with developmental SLE?

Answer 43

C1q deficiency

Question 44

In which complement pathway is properdin found?

Answer 44

Alternative alternative also involves factors B, P (above), D regulated by factors H, I

Question 45

Which complement deficiency is most associated with meningococcal disease?

Answer 45

C7 deficiency

Question 46

How do phagocytes detect pathogens at the site of infection?

Answer 46

Expression of genetically-coded receptors such as toll-like receptors, which detect PAMPs - Pathogen-associated molecular pattern

Question 47

What type of B cells produce IgM?

Answer 47

Pro B cells

Question 48

What is the most severe form of SCID?

Answer 48

Reticular dysgenesis

Question 49

What is the most common form of SCID?

Answer 49

X-linked SCID

Question 50

Why are SCID babies initially protected?

Answer 50

IgG of mother

Question 51

Why does Di George syndrome produce immunodeficiency?

Answer 51

failure of thyme development

Question 52

What test can be used to see lymphocyte subsets in a blood sample?

Answer 52

FACS (flow cytometry)

Question 53

What is Bruton's X-linked hypogammaglobulinaemia? what gene is affected and what's the treatment?

Answer 53

Abnormality in B cell tyrosine kinase (BTK) gene: Pre B cells don't mature so no circulating Ig after around 3 months Only affects boys treat w IVIG

Question 54

What is the inheritance pattern of hyper IgM syndrome?

Answer 54

X linked

Question 55

What is X linked recessive hyper IgM syndrome?

Answer 55

mutation in CD40 ligand gene which is expressed by activated T cells When there is a defect in CD40, this leads to defective T-cell interaction with B cells

Question 56

In which disease is CD40 not expressed on activated T cells?

Answer 56

Hyper IgM syndrome

Question 57

Which syndrome is characterised by elevated IgM and undetectable IgA, IgE and IgG?

Answer 57

Hyper IgM syndrome

Question 58

Which disease is marked by reduction in IgG with low either IgA/IgM

Answer 58

Common variable immune deficiency

Question 59

What are 2 features of common variable immune deficiency?

Answer 59

Recurrent bacterial infections atypical SLE

Question 60

What % of Selective IgA deficiency patients are symptomatic, and what are these symptoms?

Answer 60

1/3 Recurrent GI and resp infections - mucosal surfaces IgA deficiency is the most common inherited immunodeficiency,

Question 61

How are B cell deficiencies managed?

Answer 61

Lifelong immunoglobulin replacement

Question 62

Recall the levels of T, B and NK cells in ADA deficiency

Answer 62

All very low or absent

Question 63

What mutation causes reticular dysgenesis?

Answer 63

Adenylate kinase 2 (AKA2) - a mitochondrial energy enzyme

Question 64

What mutation causes kostmann syndrome?

Answer 64

HCLS1-associated protein X-1 (HAX-1)

Question 65

What mutation causes cyclic neutropaenia?

Answer 65

Neutrophil elastase (ELA-2)

Question 66

What can be used to treat chronic granulomatous disease?

Answer 66

Interferon gamma (as this stimulates macrophages)

Question 67

What are the symptoms of DiGeorge syndrome?

Answer 67

CATCH 22 Cardiac abnormalities (especially ToF) Abnormal facies (low set ears) Thymic aplasia Cleft palate Hypoalcaemia/hypoPTHism Chromosome 22

Question 68

Recall some clinical signs of bare lymphocyte syndrome type 2

Answer 68

Hepatomegaly and jaundice May be associated with sclerosing cholangitis

Question 69

What is the inheritance pattern of Wiskott-Aldrich Syndrome?

Answer 69

X linked recessive

Question 70

What mutation causes Wiskott-Aldrich Syndrome?

Answer 70

WASP gene mutation (actin cytoskeleton rearrangement which is needed to stabilise T cell-APC interaction)

Question 71

Which immunodeficiency might cause a low IgM with raised IgA and IgE?

Answer 71

Wiskott-Aldrich Syndrome

Question 72

What comborbidity does Wiskott-Aldrich Syndrome put you at risk of?

Answer 72

Malignant lymphoma

Question 73

What is the prevelance of selective IgA deficiency?

Answer 73

1:600

Question 74

Recall 3 clinical features of hyper IgM syndrome

Answer 74

Pneumocystis jiroveci infection Autoimmune disease Malignancy

Question 75

At what age does common variable immune deficiency present?

Answer 75

Adulthood

Question 76

Which mutation is most likely to be the cause of CVID?

Answer 76

MHC class III - causing aberrant class switching

Question 77

defiance of NK cells causes what type if infection

Answer 77

viral - HHV (HSV 1/2, VZV, EBV, CMV) HPV

Question 78

classic presentation of leucocyte adhesion deficiency

Answer 78

delayed umbilical cord separation

Question 79

chronic granulomatous disease is a failure of what mechanisms? what enzyme is affected

Answer 79

failure of oxidative killing part of NADPH oxidase is missing

Question 80

2 types of NK cell deficiency

Answer 80

``` classic = absence of NK in PB functional = NK present but abnormal function ```

Question 81

what genes in classic and functional NK deficiency

Answer 81

``` classic = GATA2 or MCM4 functional = FCGR3A ```

Question 82

which pathways of complement activation are not dependent on acquired immune response

Answer 82

MBL alternative

Question 83

C3 nephritic factors are associated w what 2 conditions

Answer 83

glomerulonephritis (membrandoprofilerative) lipodystrophy

Question 84

management of complement deficiency

Answer 84

vaccination (pneumovax, Hib, meningovax) prophylactic ABx screen family

Question 85

management fo B cell deficiency

Answer 85

prophylaxis IVIG

Question 86

outline 5 B cell maturation defect disorders

Answer 86

1. Bruton X linked agammaglobulinaemia - failure of B cell maturation 2. Selective IgA def - failure of IgA production 3. CVID - failure of IgG production 4. SCID - failure of lymphocyte precursor 5. X linked hyper IgM - failure of T cell costimulation

Question 87

how do you detect DiGeorge?

Answer 87

FISH cytogenetic analysis Fluorescence in situ hybridization

Question 88

inheritance of DiGeorge

Answer 88

dominant

Question 89

what are the primary lymphoid organs

Answer 89

BM - T & B cell derivation, B cell mature thymus - T cell mature, most active in foetal and neonates

Question 90

outline 4 T cell deficiency disorders

Answer 90

1. DiGeorge - failure of thymic develop 2. Bare lymphocyte syndrome - failure to express HLA molecules 3. SCID (X linked & ADA) - failure of lymphocyte precursors 4. IFNg receptor deficiency, IF12 receptor def - failure of signalling/cytokine production

Question 91

4 treatment options for T cell immunodeficiency

Answer 91

HSCT - replace abnormal population in SCID, abnormal cells in care lymphocyte enzyme replacement - PEG ADA enzyme for SCID gene therapy thymus transplant in DiGeorge

Question 92

give a feature of RD

Answer 92

sensorineural deafness

Question 93

what's the treatment of rd a scid

Answer 93

hsct

Question 94

treatment of cyclic neutropaenia

Answer 94

Granulocyte Colony Stimulating Factor.

Question 95

where are IgA antibodies found in the body

Answer 95

mucosal surfaces breast milk

Question 96

what type of cell does the respiratory burst/oxidative killing?

Answer 96

neutrophils the neutrophils in CGD lack NADPH oxidase

Question 97

CD20 is a marker of what cells

Answer 97

mature B cells | (not plasma cells or immature)