Immuno: Primary Immune Deficiencies 2 Flashcards
(42 cards)
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
45% of all SCID
Which mutation is responsible for X-linked SCID?
- Mutation in common gamma chain on Xq13.1 –> impairs IL2 function
- 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 toxin buildup –> 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
Types of SCID
X-linked SCID
ADA deficiency
Reticular dysgenesis
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 (cytoxic granule release)
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?
Congenital cardiac disease
Abnormal facial features - high forehead, low set ears, cleft palate, small mouth and jaw
Thymus hypoplasia
Cleft palate
Hypocalcemia (due to underdeveloped parathyroid)
CATCH 22
immune function improves with age
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
Di George syndrome
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
- Low IgG and IgA –> as no class switching occurs as CD4 cells are necessary for this
Normal CD8 and B cells
Which defect leads to Bare lymphocyte syndrome?
Defects in the regulatory proteins involved in expression of MHC 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, IgA
NOTE: BLS Type 1 is a similar condition caused by failure of expression of MHC Class I
HLA = MHC
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.
