Lecture 34 - Immunodeficiencies Flashcards
What factors are taken into account for diagnosis of immunodeficiencies?
- Recurrent infection history
- Also asthma, autoimmunity, cancer
- Tests:
- Serum Ab
- B/T cell n°s in blood
What are the two broad categories of immune deficiency?
- Primary
- Inherited, genetic mutations
- Secondary
- Acquired
- Varied aetiology:
- Viral infection
- Malnutrition
- Leukaemia
- Lymphoma
- Chemotherapy
List some B cell deficiencies
- X-linked agammaglobulinaemia
- Hyper-IgM syndrome
- Common variable immunodeficiency
- Selective IgA immunodeficiency
Describe XLA
- X-linked agammaglobulinaemia
- Genetic mutation resulting in
- No circulating B cells
- No Ab production
- Susceptible to pyogenic infections
- Streptococci
- Pneumococci
- Treatment
- (weekly, bimonthly) Intragam
- Intravenous immunoglobulin
When is XLA usually diagnosed?
At 6-9 months, after maternal Ab wanes
Describe the aetiology of XLA
- Mutation in Btk
- Bruton’s Tyrosine Kinase
- Needed for transduction of ‘success signal’ from pre-BCR at the pre-B cell stage
- After heavy chain rearrangement
- B cells can’t progress to Immate B cell stage
Describe HIGM syndrome
- Primary immune deficiency
- No isotype switching
- No IgG, IgA
- High levels of IgM
- Susceptibility to recurrent bacterial infections
- Streptococci
- Pneumocystis carinii
- Treatment
- Recurrent IVIg
- Aetiology
- X-linked-HIGM: Genetic mutation in CD40L
- AID mutation
- CD40 mutation
Describe Selective IgA immunodeficiency
- Unknown genetic mutation
- Increased susceptibility to respiratory infections
- Most common immunodeficiency
Describe CVID
- Common variable immunodeficiency
- ‘Umbrella’ term
- Variable reductions in IgA and IgG
- Varying degrees of disease
- Presents later in life
- 30-40 yrs
- Aetiology
- Mutations not known
- Result in defects in B cell maturation events in the GC (like some types of HIGM)
List some T cell deficiencies
- Wiskott-Aldrich syndrome (WAS)
- Familial haemophagocytic lymphohistocytosis (FHL)
- DiGeorges syndrome
- Bare lymphocyte syndrome
Describe WAS
- Wiskott-Aldrich syndrome
- Features:
- Thrombocytopaenia
- ⇒ Severe haemorrhage, bruising
- Impaired T cell function
- Low serum Ig levels
- Thrombocytopaenia
- Aetiology
- Genetic mutation in WAS protein
- Pathogenesis
- Normal T cell development, decreased peripheral T cell n°s
- WAS plays a role in:
- Immunological synapse
- Secretion of granzymes & perforin
-
Through:
- Actin polymerisation
- Cytoskeleton reorganisation upon TCR ligation
Describe FHL
- Aetiology
- Features
- Familial haemophagocytic lymphohistocytosis
- Presents very early in children
- ‘Cytokine storm syndrome’
- Aetiology
- Missense mutation in Perforin
- Features
- Polyclonal CD8 T cell accumulation in LNs
- Uncontrolled T cell activation
- Progressive inflammation
- Lethal, unless immunosuppressants are used
Describe DiGeorges syndrome
- Features
- No T cell responses
- No T cell dependent Ab responses
- Aetiology
- Mutation in T-box 1 (TBX1)
- Transcription factor
-
Spontaneous mutation in chromosome 22 during embryogenesis
- Not inherited
- Mutation in T-box 1 (TBX1)
- Pathogenesis
- No development of thymic epithelium during development
- No T cell maturation
Describe Bare Lymphocyte syndrome
- Aetiology
- Mutation in any of the genes that control MHC II gene function
- (not in MHC genes proper)
- Bare lymphocyte syndrome I
- TAP-1/2
- Bare lymphocyte syndrome II
- RFX
- Class II transactivator (CIITA)
- Pathogenesis
- Little to no expression of MHC II on APCs
Describe SCID
- Severe combined immune deficiency
- Features
- Profound deficiencies in B, T and NK cell function
- Death before age 1 if no treatment
- Recurrent infections
- Candida albicans
- Pneumocystis carinii
- Parainfluenza
- Cytomegalovirus
- EBV
- Mycobacteria
- Treatment
- Only BM transplant
- Aetiology
- X-linked SCID: common γ chain
- Most common mutation (50%)
- Many cytokines signal through receptors that involved the γc chain
- Autosomal recessive SCID:
- JAK3
- ADA
- RAG
- X-linked SCID: common γ chain
List some cytokines that signal through receptors that involved the γc chain
- IL-2
- IL-4
- IL-7
- IL-9
- IL-15
- IL-21
Describe the role of JAK3
- Needed for downstream signalling through receptors that use yc chain
- Mutation results in X-linked SCID-like syndrome
Describe the role of ADA
- Adenosine deaminase
- Found in all tissues, most prominent in lymphocytes
- Defect
- Accumulation of toxic purine intermediates
- This is felt most profoundly in lymphocytes, as they proliferate much more rapidly than other cells in the body
Describe the role of RAG
- RAG-1/2 required for Ig and TCR gene rearrangement
- Defect:
- Lack of B cells and T cells
List the various treatments for immune deficiencies
- IVIg
- HIGM
- XLA
- Antibiotics
- Gene therapy
- Viral vectors deliver functional copy of gene
- Trialled for SCID (ADA and yc chain def.)
- BM transplant
- SCID
- GvHD
- Enzyme replacement
In general, what is the most common cause of secondary immunodeficiencies?
Infection, leading to suppression of immune responses or depletion of immune cells:
- Measles
- HIV
How does measles infection cause immune deficiency?
- Characterised by lack of B and T cell responses
- Precise mechanism is unclear
- Evidence that measles virus infects DCs
- Kills / inactivates the DC
- Production of a suppressive factor?
- → anergy
- Evidence that measles virus infects DCs
What is the implication of the fact that many of the mutations causing primary immunodeficiencies are on the X chromosome?
Boys are much more commonly affected
Describe CD40L
- Member of the tumour necrosis superfamily
- Expressed on activated T cells
- Essential for:
- T cell help
- T cell co-stimulation of APCs
- DCs, Macrophages
Compare the severity of HIGM syndrome with different mutations
- CD40L mutation: most severe
- X-linked
- AID mutation: less severe
What is the importance of AID?
- Essential for:
- Class switch recombination
- Somatic hypermutation
- Mutation results in HIGM syndrome
What does a perforin mutation result in?
FHL: familial haemophagocytic lymphohistocytosis
What syndrome does mutation in the common γ chain result in?
SCID: severe combined immune deficiency
Which cytokine is vital for NK cell function?
- IL-15
- Signals through the γc chain
Which was the first mutation to be treated with gene replacement therapy?
ADA mutation: SCID
List mutations that lead to SCID
- γc chain
- JAK4
- ADA
- RAG1/2
What are the considerations for repeated antibiotic therapy for immune deficiencies?
- Selection of resistant mutants
- Associated toxicity
What is the best treatment for primary immune deficiencies?
- Gene therapy
- Adresses the underlying defect of the disease
- Still very experimental
Which bacteria produces superantigens?
Staph. aureus
