Primary Immunodeficiency (2) Flashcards
Name the components of the adaptive immune system.
- T lymphocytes
- CD4 T cells
- CD8 T cells
- B lymphocytes
- B cells
- Plasma cells
- Antibodies
- Soluble cytokines
- Cytokines and chemokine
Define primary lymphoid organs
Organs involved in lymphocyte development
What are the primary lymphoid organs
- Bone marrow
- Both T and B lymphocytes are derived from haematopoetic stem cells
- Site of B cell maturation
- Thymus
- Site of T cell maturation
- Most active in the foetal and neonatal period, involutes after puberty
Describe the T lymphocyte development and the things that can go wrong.
Describe reticular dysgenesis
- most severe form of severe combined immunodeficiency (SCID)
- mutation in mitochondrial energy metablism enzyme adenylate kinase 2 (AK2)
Failure of production of:
- Lymphocytes
- Neutrophils
- Monocyte/macrophages
- Platelets
Fatal in very early life unless corrected with bone marrow transplantation
What are the causes of sever combined immunodeficiency?
• >20possible pathways identified
– Deficiency of cytokine receptors
– Deficiency of signalling molecules
– Metabolic defects
• Effect on different lymphocyte subsets (T, B, NK) depend on mutation
Describe X-linked SCID
– 45% of all severe combined immunodeficiency
– Mutation of common gamma chain on chromosome Xq13.1
Shared by cytokine receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells
– Phenotype
Very low or absent T cell numbers
Very low or absent NK cell numbers
Normal or increased B cell numbers but low Igs
Describe ADA deficiency.
– 16.5% of all severe combined immunodeficiency
– Adenosine Deaminase Deficiency
• Enzyme required for cell metabolism in lymphocytes
– Phenotype
Very low or absent T cell numbers
Very low or absent B cell numbers
Very low or absent NK cell numbers
What protects the SCID neonate in the first 3 months of life?
Still have maternal IgG circulating.
Describe the Clinical phenotype of severe combined immunodeficiency
- Unwell by 3 months of age • Infections of all types
- Failure to thrive
- Persistent diarrhoea
• Unusual skin disease
– Colonisation of infant’s empty bone marrow bymaternal lymphocytes
– Graft versus host disease
• Family history of early infant death
Describe T-lymphocyte maturation.
What receptors to T cells express? What do they recognise?
They recognise peptides presented on HLA molecules.
Describe selection and central tolerance in the thymus.
How do T cells differentiate into CD8+ and CD4+ cells?
Describe CD8+ T cells.
Specialised cytotoxic cells
Recognise peptides derived from intracellular proteins in association with HLA class I
– HLA-A, HLA-B, HLA-C
Kill cells directly
– Perforin (pore forming) and granzymes
– Expression of Fas ligand
Secrete cytokines eg IFNg TNFa
Particularly important in defence against viral infections and tumours
Describe CD4+ T cells
– Recognise
- peptides derived from extracellular proteins
- presented on HLA Class II molecules (HLA-DR, HLA-DP HLA-DQ)
– Immunoregulatory functions via cell:cell interactions and expression of cytokines
- Provide help for development of full B cell response
- Provide help for development of some CD8+ T cell responses
Describe the CD4+ T cell subsets.
What is the first place after the marrow where T cell maturation/selection can be affected?
In the thymus.
Describe DiGeorge syndrome.
- Di George Syndrome (22q 11.2 deletion syndrome) – a development defect of the pharyngeal pouch:
- Features – CATCH 22:
- C Cardiac abnormalities (ToF / Teratology of Fallot)
- A Abnormal facies (high forehead, low-set and folded ears, micrognathia, broad nasal bridge)
- T Thymic aplasia (± oesophageal atresia)
- C Cleft palate
- H Hypocalcaemia, hypoparathyroidism
- 22 22q 11.2
- Detected by FISH cytogenetic analysis
- Not mentally retarded but higher schizophrenia as an adult
- Phenotype:
- Normal B cell number
- Reduced T cell number only a mild impairment of immunity that improves with age
- Could present with PCP pneumonia and atypical viral infections
- Need T-cells to control these
- Genetics:
- Deletion at 22q11.2 (TUPLE locus)
- TBX1 responsible for some features
- Initially a sporadic mutation autosomal dominant inheritance
What can go wrong in the selection of CD4+ T cells?
If you don’t express class II, cannot select CD4+ cells
Describe Bare lymphocyte syndrome (type 2)
- Absent expression of MHC Class II molecules (BLS type 1 exists when MHC class 1 fails to express)
- Defect in a regulatory protein involved in Class II gene expression
- Regulatory factor X
- Class II transactivator
- Phenotype:
- T-cells = low CD4 cells; normal CD8 cells
- B-cells = normal; BUT low IgG or IgA antibody (due to lack of CD4+ T cell help)
Describe the clinical phenotype of bare lymphocyte syndrome.
- Unwell by 3 months of age
- Infections of all types
- Failure to thrive
- Family history of early infant death
What can go wrong in T cell activation and effector function?
Disorders of T cell effector function
- Cytokine production – IFN
- Cytokine receptors – IL12 receptor • Cytotoxicity
- T-B cell communication
Summarise all the failures in T cells.
What is this looking at
Each dot represents a cell
In left: 59.62% CD4+ and 28.46% CD8+
Fill out.
Di George- may be subtle effect on IgG
BLS - lack IgG - no isotype switch
Describe B lymphocyte maturation
Describe B-cell central tolerance
What happens when there is an antigen encounter with a B cell? (T cell independent)
What happens when there is an antigen encounter with a B cell? (T-cell dependent)
What is the genetic mutation in Hyper IgM syndrome?
Mutation in CD40 ligand gene
T cell CD28
(CD40L, CD154)
– Member of TNF Receptor family
– Encoded on Xq26
– Involved in T-B cell communication
– Expressed by activated T cells – NOT on B cells
Summarise the B cell maturation defects.
Describe this.
Protein electrophoresis.
Fill out.
Summarise the Types of Primary Immunodeficiency.
