Immuno: Primary Immune Deficiencies Pt.3

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
• IL-2 Receptor deficient
• 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
• Low monocytes
• Normal or increased B cells (but non-functional due to lack of T cells)
• Low immunoglobulin (B cells need signalling from T cells to produce immunoglobulins)

Question 5

Describe the pathophysiology of ADA deficiency.

Answer 5

Form of SCID

• 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 as thymus continues to develop)
• 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