Immuno: Primary Immune Deficiencies 2 Flashcards
Name a defect in stem cells that causes SCID and name the gene that is mutated.
Reticular dysgenesis - adenylate kinase 2 (AK2)
NOTE: this is a mitochondrial energy metabolism enzyme
What is the most common type of SCID?
X-linked SCID
Which mutation is responsible for X-linked SCID?
- 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
Describe the typical cell counts you would expect to see in X-linked SCID.
- Very low T cells
- Very low NK cells
- Normal or increased B cells
- Low immunoglobulin
Describe the pathophysiology of ADA deficiency.
- ADA - adenosine deaminase
- This is an enzyme required by lymphocytes for cell metabolism
- ADA deficiency leads to failure of maturation along any lineage
Describe the typical cell counts you would expect to see in ADA deficiency.
- Very low T cells
- Very low B cells
- Very low NK cells
Describe the clinical phenotype of SCID.
- 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
What are the two mechanisms by which CD8+ T cells kill cells?
Perforin and granzyme
Fas ligand
Which cellular insults are CD8+ T cells particularly important in protecting against?
- Viral infections
- Tumour
Outline the immunoregulatory functions of CD4+ T cells.
- Provide help to mount a full B cell response
- Provide help for some CD8+ T cell responses
In which group of syndromes does the thymus gland fail to develop properly.
- 22q11.2 deletion syndromes (e.g. Di George syndrome)
- This is characterised by failure of development of the pharyngeal pouch
What are the main clinical features of 22q11.2 deletion syndromes?
- 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
What are the immunological consequences of an underdeveloped thymus gland?
- 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
What condition is caused by a deficiency of MHC Class II? Briefly outline its pathophysiology.
- 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
Which defect leads to Bare lymphocyte syndrome?
Defects in the regulatory proteins involved in expression of class II genes:
- Regulatory factor X
- Class II transactivator
Describe the typical cell counts that you would expect to see in Bare Lymphocyte syndrome type 2.
- 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
Outline the clinical phenotype of bare lymphocyte syndrome.
- Unwell by 3 months of age
- Infections of all types
- Failure to thrive
- Family history of early death
What are the common clinical features of T lymphocyte deficiencies?
- 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
List some investigations that may be used for suspected T cell deficiencies.
- Total white cell count and differentials
- Lymphocyte subsets
- Immunoglobulins
- Functional tests of T cell activation and proliferation
- HIV test
How are lymphocyte counts different in children compared to adults?
Higher in children compared to adults
Describe the 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 2
-
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
Outline some management approaches for immunodeficiency involving T cells.
- 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)
Describe the stereotypical presentation in the following lymphocyte deficiencies.
- X-linked SCID
- IFN-gamma receptor deficiency
- 22q11.2 deletion syndrome
- Bare lymphocyte syndrome type 2
- 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 Mycobacterium 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.
What determines the class of immunoglobulin?
Heavy chain
