Immuno: Primary Immune Deficiencies 2

Question 1

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

Answer 1

Reticular dysgenesis - adenylate kinase 2 (AK2)

NOTE: this is a mitochondrial energy metabolism enzyme

Question 2

What is the most common type of SCID?

Answer 2

X-linked SCID

Question 3

Which mutation is responsible for X-linked SCID?

Answer 3

• Mutation in common gamma chain on Xq13.1
• This is a component of many cytokine receptors leading to an inability to respond to cytokines, causing arrest in T and NK cell development and the production of immature B cells

Question 4

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

Answer 4

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

Question 5

Describe the pathophysiology of ADA deficiency.

Answer 5

• ADA - adenosine deaminase
• This is an enzyme required by lymphocytes for cell metabolism
• ADA deficiency leads to failure of maturation along any lineage

Question 6

Describe the typical cell counts you would expect to see in ADA deficiency.

Answer 6

• Very low T cells
• Very low B cells
• Very low NK cells

Question 7

Describe the clinical phenotype of SCID.

Answer 7

• Unwell by 3 months age (once protection by maternal IgG dissapates)
• Infections of all types
• Failure to thrive
• Persistant diarrhoea
• Unusual skin disease (colonisation of infant’s empty bone marrow by maternal lymphocytes can cause a graft-versus-host disease-like condition)
• Family history of early death

Question 8

What are the two mechanisms by which CD8+ T cells kill cells?

Answer 8

Perforin and granzyme

Fas ligand

Question 9

Which cellular insults are CD8+ T cells particularly important in protecting against?

Answer 9

• Viral infections
• Tumour

Question 10

Outline the immunoregulatory functions of CD4+ T cells.

Answer 10

• Provide help to mount a full B cell response
• Provide help for some CD8+ T cell responses

Question 11

In which group of syndromes does the thymus gland fail to develop properly.

Answer 11

• 22q11.2 deletion syndromes (e.g. Di George syndrome)
• This is characterised by failure of development of the pharyngeal pouch

Question 12

What are the main clinical features of 22q11.2 deletion syndromes?

Answer 12

• Facial abnormalities (high forehead, low set ears, cleft palate, small mouth and jaw)
• Underdeveloped parathyroid gland (resulting in hypocalcaemia)
• Oesophageal atresia
• Underdeveloped thymus
• Complex congenital heart disease

Question 13

What are the immunological consequences of an underdeveloped thymus gland?

Answer 13

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

Question 14

What condition is caused by a deficiency of MHC Class II? Briefly outline its pathophysiology.

Answer 14

• Bare lymphocyte syndrome (BLS) type 2
• Deficiency of MHC Class II means that CD4+ T cells cannot be selected in the thymus leading to CD4+ T cell deficiency

Question 15

Which defect leads to Bare lymphocyte syndrome?

Answer 15

Defects in the regulatory proteins involved in expression of class II genes:

• Regulatory factor X
• Class II transactivator

Question 16

Describe the typical cell counts that you would expect to see in Bare Lymphocyte syndrome type 2.

Answer 16

• Normal CD8+
• Very low CD4+
• Normal B cell count
• Low IgG

NOTE: BLS Type 1 is a similar condition caused by failure of expression of HLA Class I

Question 17

Outline the clinical phenotype of bare lymphocyte syndrome.

Answer 17

• Unwell by 3 months of age
• Infections of all types
• Failure to thrive
• Family history of early death

Question 18

What are the common clinical features of T lymphocyte deficiencies?

Answer 18

• Viral infections (e.g. CMV)
• Fungal infections (e.g. PCP)
• Some bacterial infections (e.g. TB, salmonella)
• Early malignancy

NOTE: disorders of T cell effector function include defects in cytokine production, cytokine receptors and T-B cell communication

Question 19

List some investigations that may be used for suspected T cell deficiencies.

Answer 19

• Total white cell count and differentials
• Lymphocyte subsets
• Immunoglobulins
• Functional tests of T cell activation and proliferation
• HIV test

Question 20

How are lymphocyte counts different in children compared to adults?

Answer 20

Higher in children compared to adults

Question 21

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

1. SCID
2. Di George
3. BLS Type 2

Answer 21

1. SCID
   
   • CD4 low
   • CD8 low
   • B cells normal/low
   • IgM normal/low
   • IgG low
2. Di George
   
   • CD4 low
   • CD8 low
   • B cells normal
   • IgM normal
   • IgG normal/low
3. BLS Type 2
   
   • CD4 low
   • CD8 normal
   • B cells normal
   • IgM normal
   • IgG low

Question 22

Outline some management approaches for immunodeficiency involving T cells.

Answer 22

• Aggressive prophylaxis/treatment of infection
• Haematopoietic stem cell transplantation
• Enzyme replacement therapy (e.g. PEG-ADA for ADA deficiency)
• Gene therapy
• Thymic transplantation (in Di George syndrome)

Question 23

Describe the stereotypical presentation in the following lymphocyte deficiencies.

1. X-linked SCID
2. IFN-gamma receptor deficiency
3. 22q11.2 deletion syndrome
4. Bare lymphocyte syndrome type 2

Answer 23

1. 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
2. IFN-gamma receptor deficiency: young adult with chronic infection with Mycobacterium marinum
3. 22q11.2 deletion syndrome: recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG
4. 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 24

What determines the class of immunoglobulin?

Answer 24

Heavy chain

Question 25

What determines the effector function of immunoglobulin?

Answer 25

Constant region of the heavy chain

Question 26

Briefly outline the functions of antibodies.

Answer 26

* Identification of pathogens and toxins (particularly against extracellular pathogens) * Interacts with other components of the immune response (e.g. complement, phagocytes, NK cells) * Important in defence against bacteria

Question 27

Outline the pathophysiology of Bruton's X-linked hypogammaglobulinaemia.

Answer 27

* Prevents the maturation of B cells at that point at which they emerge from the bone marrow * Caused by an abnormal B cell tyrosine kinase (BTK) gene * This results in the absence of mature B cells and, hence, an absence of antibodies

Question 28

Outline the clinical phenotype of Bruton's X-linked hypogammaglobulinaemia.

Answer 28

* Boys present in the first few years of life * Recurrent bacterial infections (e.g. otitis media, pneumonia) * Viral, fungal and parasitic infections * Failure to thrive

Question 29

Outline the pathophysiology of X-linked hyper IgM syndrome.

Answer 29

* Blocks the maturation of IgM B cells through germinal centres into B cells that produce other classes of immunoglobulin (i.e. prevents germinal centre reactions) * Caused by a mutation in the CD40 ligand gene * This is technically a T cell problem, however, it means that CD4+ T helper cells cannot provide help to B cells so they cannot undergo germinal centre reactions NOTE: CD40 ligand is encoded on Xq26

Question 30

Describe the typical biochemical results you would expect to see in X-linked hyper IgM syndrome.

Answer 30

* Normal B cells * Normal T cells * No germinal centre reactions * High IgM * Absent IgG, IgA and IgE (failure of isotype switching)

Question 31

Outline the clinical phenotype of X-linked hyper IgM syndrome.

Answer 31

* Boys present in the first few years of life * Recurrent infections (mainly bacterial) * Subtle abnormality in T cell function (predisposes to PCP, autoimmunity and malignancy) * Failure to thrive

Question 32

What is common variable immunodeficiency and what are the main features?

Answer 32

A group of disorders caused by some form of failure of differentiation of B lymphocytes. Defined by: * Marked reduction in IgG, IgA and IgE * Poor/absent response to immunisation * Absence of other defined immunodeficiency

Question 33

Outline the clinical phenotype of common variable immunodeficiency.

Answer 33

* May present in adults or children * Recurrent bacterial infection (often severe) * Pulmonary disease (e.g. interstitial lung disease) * GI disease (e.g. IBD-like disease) * Autoimmune disease (e.g. AIHA) * Malignancy (e.g. NHL)

Question 34

What is the prevalence of selective IgA deficiency?

Answer 34

1 in 600

Question 35

What are the clinical features of antibody deficiency?

Answer 35

* Bacterial infections (e.g. *Staphylococcus)* * Toxins (e.g tetanus) * Some viral infections (e.g. enterovirus)

Question 36

List some investigations that may be used for suspected B cell deficiencies.

Answer 36

* Total white cell count and differential * Lymphocyte subsets * Serum immunoglobulins and protein electrophoresis * Functional tests of B cell function (e.g. measure IgG antibody against a specificpathogen (e.g. *S. pneumoniae*, if this is low, vaccinate using a killed vaccine and check levels again in 6-8 weeks) NOTE: IgG prodution is a surrogate marker for CD4+ T helper cell function

Question 37

Which peak repesents immunoglobulin in protein electrophoresis?

Answer 37

Gamma peak NOTE: albumin produces a large peak

Question 38

Outline the typical levels of CD4, CD8, B cell, IgM, IgG and IgA you would expect to see in: 1. SCID 2. Bruton's X-linked Hypogammaglobulinaemia 3. X-linked Hyper IgM syndrome 4. Selective IgA deficiency 5. Combined variable immunodeficiency

Answer 38

1. **SCID** * CD4 low * CD8 low * B cell low * IgM low * IgG low * IgA low 2. **Bruton's X-linked Hypogammaglobulinaemia** * CD4 normal * CD8 normal * B cell low * IgM low * IgG low * IgA low 3. **X-linked Hyper IgM syndrome** * CD4 normal * CD8 normal * B cell normal * IgM high * IgG low * IgA low 4. **Selective IgA deficiency** * CD4 normal * CD8 normal * B cell normal * IgM normal * IgG normal * IgA low 5. Combined variable immunodeficiency * CD4 normal * CD8 normal * B cell normal * IgM normal * IgG low * IgA low

Question 39

Outline the management approaches to immunodeficiency involving B cells.

Answer 39

* Aggresive prophylaxis/treatment of infection * Immunoglobulin replacement * Immunisation (only if the patient is able to produce antibodies)

Question 40

Describe a stereotypical presentation of the following diseases: 1. Common variable immunodeficiency 2. X-linked hyper IgM syndrome 3. Bruton's X-linked hypogammaglobulinaemia 4. IgA deficiency

Answer 40

1. **Common variable immunodeficiency:** adult with bronchiectasis, recurrent sinusitis and development of atypical SLE 2. **X-linked hyper IgM syndrome:** recurrent bacterial infections as a child, episode of PCP, high IgM, absent IgA and IgG 3. **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 4. **IgA deficiency:** recurrent respiratory tract infections, absent IgA, normal IgM and IgG