Immuno 4: Primary Immune Deficiencies 2

Question 1

What is the most common form of SCID ?

What mutation + how does this lead to the diease?

Answer 1

X-linked SCID

Mutation in common gamma chain on Xq13.1:

• gamma chain = important component of Cytokine receptors
• Mutation leads -> inability to respond to cytokines -> causing arrest in T and NK cell development + arrest in production of immature B cells

Question 2

Describe the typical cell counts you would expect to see in X-linked SCID.

Answer 2

Very low T cells
Very low NK cells
Normal or increased B cells
Low immunoglobulin

No IgA or IgG because CD4+ Th cells needed for Isotype switching.

Question 3

Pathophys of ADA deficiency?

Typical cell counts?

Answer 3

Adenosine deaminase enzyme (ADA) is deficient which causes failure of lymphocyte maturation

Low T, NK and B cells

Question 4

Why are infants with SCID protected in the first 3 months ?

Answer 4

maternal IgG is still present in the infants circulation and provides immunity

Question 5

What is the function of CD4+ T cells in the immune response ?

What are they important in protecting against?

MoA of killing by these cells?

Answer 5

• activates B cells
• activates CD8+ cytotoxic T cells

Viral infections + Tumours

Injection of perforin + granzyme
Fas ligand

Question 6

Which genetic syndrome causes the thymus to be underdeveloped and therefore a reduced number of T cells in children?

Answer 6

DiGeorge syndrome

T cell numbers recover with age

Question 7

List the main pathologies of DiGeorge syndrome ?

Developmental defect where?

immunological consequences?

Answer 7

CATCH 22

Cardiac abnormalities ( Tetralogy of fallot)
Abnormal facies (low set ears, high forehead)
Thymic aplasia (Reduced T cells)
Cleft palate
Hypocalcaemia (hypoparathyroidism)

22nd chromosome mutation 22q11

(There is developmental defect in the pharyngeal pouch)

Immunological consequences?

• Normal B cell count
• Low T cell count
• Homeostatic proliferation with age (T cell numbers increase with age)
• Immune function is mildly impaired and tends to improve with age

Question 8

What syndrome causes a profound deficiency in CD4+ T cells but normal numbers of CD8+ T cells ? How?

Answer 8

Bare Lymphocyte syndrome -Type 2 (BLS type 2)

Absent expression of MHC class II molecules. (Means that T cells cant undergo affinity selection in the thymus to become CD4+)

Question 9

Why do you get a reduction/absence in IgG and IgA immunoglobulins with CD4+ T cell defficiency (e.g in BLS type2) ?

Answer 9

The CD4+ T helper cells are involved in B cell Isotope switching so you have IgM B cells but cant switch to IgG/ IgA in the germinal centres.

Question 10

What is the definitive treatment of SCID and BLS type 2 ?

Answer 10

Haematopoeitic stem cell transplant

Question 11

How do you treat ADA SCID ?

Answer 11

Enzyme replacement therapy

Question 12

Which bacterial infection are patients with an IFN gamma deficiency particularly susceptible to ?

Answer 12

Recurrent Mycobacterium Marinum infections (atypical mycobacterium)

Question 13

22q 11.2 deletion syndrome is also known as ???

Answer 13

DiGeorge syndrome

Defect in the development of the pharyngeal pouch

Question 14

Is the IgM B cell response T cell dependent ?

Answer 14

No

Question 15

How do CD4+ T cells help B cells undergo B cell differentiation (isotype switching)?

Answer 15

CD40 ligand is expressed on CD4+ Th cells and this acts on CD40 receptors on B cells causing isotope switching.

Question 16

Which part of an Antibody identifies pathogens/toxins ?

Answer 16

Fab (fragment antigen-binding) region

Question 17

Which part of an antibody interacts with Complement/phagocytes/NK cells ?

Answer 17

Fc (ragment crystallizable) region

Question 18

Bruton’s X linked agammaglobulinaemia pathophysiology?

Answer 18

An abnormal B cell tyrosine kinase (BTK) gene

Prevents the maturation of B cells at that point at which they emerge from the bone marrow

This results in the absence of mature B cells and, hence, an absence of antibodies

Question 19

Which X-linked syndrome is associated with failure of B cell maturation and isotype switching causing an elevated serum IgM but no IgG/IgA? How does it do this?

Answer 19

Hyper IgM syndrome

Mutation in CD40 ligand on T cells which means CD4+ T helper cells cant help B cells to undergo Maturation in germinal centres

Question 20

Which immune deficiency disease is associated with poor response to immunisation, with low IgG/ IgA / IgM ?

What are they at risk of?

Answer 20

Common variable immune deficiency

Not much known but it is a defect in production of Immunoglobulins

They get a lot of inflammatory and auto-immune diseases

Question 21

Which immunodeficiency disease is associated with recurrent respiratory tract infections, low IgA levels and normal levels of all other immunoglobulins ?

Answer 21

IgA deficiency

Question 22

Which genetic mutation is associated with Wiskott-Aldrich syndrome ?

Answer 22

WASp gene

Question 23

Which mutation is associated with Bare lymphocyte syndrome type 2 ?

Answer 23

MHC class II

Question 24

Which mutation is associated with SCID ?

Answer 24

IL-2 receptor

Question 25

Which mutation is associated with Bruton’s X-Linked Agammaglobulinaemia ?

Answer 25

BTK gene

Question 26

Which lymphocytes respond to foreign HLA-DR types ?

Answer 26

CD4+ T cells

Question 27

Which lymphocytes respond to foreign HLA-B types ?

Answer 27

CD8+ T cells

Question 28

Patient presents with recurrent nose bleeds, easy bruising and blood in the stool.

Blood tests reveal a thrombocytopenia, elevated IgA and IgE and reduced IgM levels.

Most likely diagnosis ?

Answer 28

Wiskott-Aldrich syndrome

Question 29

Patient presents with jaundice and hepatomegaly. His bloods show a low CD4+ T cell level but normal CD8+ level.

Most likely Diagnosis?

Answer 29

Bare lymphocyte syndrome Type 2

Question 30

Young girl presents with recurrent skin infections with a normal neutrophil count and a NTB test remains colourless

Most likely diagnosis ?

Answer 30

Chronic granulomatous disease.

Caused by a deficiency in NADPH which causes absence of the respiratory burst.

Question 31

Typical levels of CD4, CD8, B cells, IgM and IgG that you would expect to see in the following diseases:

SCID
Di George
BLS Type II

Answer 31

SCID: 
CD4 low 
CD8 low 
B cells normal/low 
IgM normal/low 
IgG low 

Di George:
CD4 low 
CD8 low 
B cells normal 
IgM normal 
IgG normal/low 

BLS Type 2:
CD4 low 
CD8 normal 
B cells normal 
IgM normal 
IgG low

Question 32

Describe the stereotypical presentation in the following lymphocyte deficiencies:

X-linked SCID
IFN-gamma receptor deficiency
Di George Syndrome
BLS Type II

Answer 32

X-linked SCID: severe recurrent infections from 3 months of age, CD4 and CD8 are absent, B cells present, Ig low, normal facial features and echocardiogram

IFN-gamma receptor deficiency: young adult with chronic infection with Mycobaterium marinum

22q11.2 deletion syndrome: recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG

Bare Lymphocyte Syndrome Type 2: 6-month old baby with two recent serious bacterial infections. T cell present but only CD8. IgM present but IgG is low

Question 33

Outline the typical levels of CD4, CD8, B cell, IgM, IgG and IgA you would expect to see in:

SCID

• Bruton’s X-linked Hypogammaglobulinaemia
• X-linked Hyper IgM Syndrome
• Selective IgA deficiency
• Combined variable immunodeficiency

Answer 33

SCID: 
CD4 low 
CD8 low 
B cell low 
IgM low 
IgG low 
IgA low 

Bruton’s X-linked Hypogammaglobulinaemia:
CD4 normal 
CD8 normal 
B cell low 
IgM low 
IgG low 
IgA low 

X-linked Hyper IgM Syndrome:
CD4 normal 
CD8 normal 
B cell normal 
IgM high 
IgG low 
IgA low 

Selective IgA deficiency:
CD4 normal 
CD8 normal 
B cell normal 
IgM normal 
IgG normal 
IgA low 

Combined variable immunodeficiency :
CD4 normal 
CD8 normal 
B cell normal 
IgM normal 
IgG low 
IgA low

Question 34

Describe a stereotypical presentation of the following diseases:

Common variable immunodeficiency
X-linked Hyper IgM syndrome
Bruton’s X-linked hypogammaglobulinaemia
IgA deficiency

Answer 34

Common variable immunodeficiency: adult with bronchiectasis, recurrent sinusitis and development of atypical SLE

X-linked hyper IgM syndrome: recurrent bacterial infections as a child, episode of PCP, high IgM, absent IgA and IgG

Bruton’s X-linked hypogammaglobulinaemia: 1-year old boy. Recurrent bacterial infections, CD4 and CD8 cells present, B cells absent, absent IgG, IgA and IgM

IgA deficiency: recurrent respiratory tract infections, absent IgA, normal IgM and IgG

Question 35

Which peak represents immunoglobulin in protein electrophoresis?

Answer 35

Gamma peak

NOTE: albumin produces a large peak

Question 36

What are the clinical features of antibody deficiency?

Answer 36

Bacterial infections (e.g. Staphylococcus)

Toxins (e.g. tetanus)

Some viral infections (e.g. enterovirus)

Question 37

Summary of T Lymphocyte problems + examples?

Answer 37

Failure of lymphocyte precursors (X-linked SCID)

Failure of thymic development (DiGeorge)

Failure of HLA molecule expression (BLS)

Failure of signalling , cytokine production and effector function (IFN-gamme / receptor deficiency, IL12 or receptor deficiency)

Question 38

Summary of B Lymphocyte problems + examples?

Answer 38

Failure of lymphocyte precursors (SCID)

Failure of B cell maturation (Bruton’s X-linked agammaglobulinaemia)

Failure of T cell co-stimulation (X-linked Hyper IgM syndrome)

Failure of production of IgG antibodies (Common variable immune deficiency, Selective antibody deficiency)

Failure of IgA production (Selective IgA deficiency)

Question 39

Name a defect in stem cells that causes SCID and name the gene that is mutated.

Answer 39

Reticular dysgenesis – adenylate kinase 2 (AK2) - this causes the most severe form of SCID

NOTE: this is a mitochondrial energy metabolism enzyme