Adaptive Immunity and deficiencies Flashcards
T cells: arise, mature, receptors
Arise in BM
Mature in Thymus
Express CD3 + a T cell receptor: CD4 (recognise HLA II) or CD8 (recognise HLA I)
Development of CD4 T helper cells
Cytokines encourage development along different lines
TGF beta stimulates development into Treg cells: CD25 + FoxP3 receptors
How are cytotoxic CD8 cells cytotoxic?
Directly through perforin, granzymes + expression of Fas ligands
Indirectly through cytokine secretions
B cells: arise, mature, development
Arise + mature in BM
Develop as IgM plasma cells (low fidelity)
or undergo germinal centre reaction
Function highly dependent of CD4 T cells
What is germinal centre reaction?
Somatic hypermutation + class switching to produce IgG, IgE or IgA
Higher fidelity receptors for antigen
3 features of IgG
Monomer
Smallest- able to pass through membranes like the placenta
Maternal AI disease, IgG antibodies can affect fetus
2 features of IgA
Dimer
On mucosal surfaces: part bound to mucosa, part free to bind pathogen
Structure of IgM
Pentamer
What are the broad causes of primary immunodeficiencies of the adaptive immune system?
Defects in lymphoid precursors
Defects of maturation (non functional)
CVID
List 4 defects of lymphoid precursors
Reticular dysgenesis
X-linked SCID
ADA deficiency
Bruton’s X-linked hypo-gamma-globinaemia
Give 6 general features common to SCID on presentation
Unwell by 3/12 (before protected by maternal IgG through placenta + colostrum)
Infections of all types
Failure to thrive
Persistent diarrhoea
Poorly developed lymphoid tissue
FH of early infant death
What mutation causes reticular dysgenesis?
mutation in mitochondrial energy metablism enzyme Adenylate kinase 2 (AK2)
Is reticular dysgenesis compatible with life?
Fatal in very early life unless corrected with BM transplantation
What causes SCID?
> 20 possible pathways identified.
Deficiency of cytokine receptors
Deficiency of signalling molecules
Metabolic defects: Effect on different lymphocyte subsets (T, B, NK) depend on mutation
3 features of X-linked SCID
45% of all SCID (most common)
Mutation in common gamma chain on Chr Xq13.1 which is shared by multiple interleukin receptors
Inability to respond to cytokines: early arrest of T + NK cell development + production of immature B cells
Give 3 phenotypic features of X-linked SCID
V low/ Absent T cells
V low/ Absent NK cells
Normal/ high B cells but low immunoglobulins, (IgM)
2 features of adenosine deaminase deficiency
16.5% of all SCID
ADA: enzyme in lymphocytes required for cell metabolism
Adenosine deaminase deficiency phenotype
V low or absent T cells
V low or absent B cells
V low or absent NK cells
3 features of Bruton’s X-linked hypo-gamma-globinaemia
Bruton’s Tyrosine Kinase deficiency
BTK important in maturation of B cells
Pre-B cells can’t mature to B cells
Phenotype of Bruton’s X-linked hypo-gamma-globulinaemia
Normal T cells
Normal cytokine levels
Absent B cells
Absent Immunoglobulins
3 clinical features of Bruton’s X-linked hypogammaglobulinaemia
only Boys
Recurrent infections during childhood
Absent/ scanty LN + tonsils (primary follicles + germinal centres absent)
List 3 defects of maturation of lymphocytes
22q11.2 deletion syndrome
Bare lymphocyte syndrome type II
Hyper-IgM syndrome
What is 22q11.2 deletion syndrome also known as?
DiGeorge syndrome
What is the aetiology of DiGeorge syndrome?
Deletion at 22q11.2
TBX1 may be responsible for some features
Usually sporadic not inherited
Developmental defect of pharyngeal pouch
What mnemonic can be used to remember the features of DiGeorge syndrome?
CATCH-22
Cardiac abnormalities esp. Tetralogy of Fallot
Abnormal facies: high forehead, low set ears
Thymus aplasia: T cell lymphopenia
Cleft palate
Hypocalcaemia/ hypoparathyroidism
22- Chr22
What levels of lymphocytes are seen in DiGeorge syndrome?
Normal B cells
Low functional T cells
(BM still producing, but can’t mature)
What changes with age in DiGeorge syndrome?
Cytokines drive homeostatic proliferation with age so immune function improves
3 features of bare lymphocyte syndrome type II
Absent expression of MHC class II (HLA II)
Profound deficiency of CD4 T cells
Normal CD8 T cells + B cells
Why is IgG, IgA and IgE low in bare lymphocyte syndrome type II?
No class switching
Normal IgM as plasma B cells can mature without support of CD4 helper cells
3 features of Hyper IgM syndrome
X-linked recessive
Defect in CD40L on T cells
Thus inability of B cells to class switch causing production of only IgM
Describe lymphocyte and immunoglobulin presence in Hyper IgM syndrome
Normal no. B cells
Normal no. T cells but activated cells don’t express CD40 Ligand
Elevated serum IgM
Undetectable IgA, IgE, IgG
How may boys with hyper IgM syndrome present?
Failure to thrive
Recurrent infections- bacterial
PCP
AI diseases
Malignancy
What is combined variable immune deficiency?
Deficiency of a single immunoglobulin (usually IgG)
Cause unknown
Heterogenous group of disorders with many genetic defects
In which patients does CVID usually present?
Late in life 40-50s
F > M
What can CVID present with?
Recurrent bacterial infections
Pulmonary disease
GI disease: IBD/ Sprue like
AI disease: AIHA, ITP, RA, Vitiligo
Malignancy: increased risk of non-Hodgkin’s lymphoma
List 4 complications patients with T cell deficiency are susceptible to
Viral infections: CMV
Fungal infections: Pneumocystis, Cryptosporidium
Bacterial infections: esp. intracellular organisms (MTB, Salmonella)
Early malignancy
List 3 complications patients with Antibody deficiency/ CD4 T cell deficiency are susceptible to
Bacterial infections (Staph + Strep)
Toxins (Tetanus, Diphtheria)
Viral infections (Enterovirus)
How are lymphocyte deficiencies diagnosed?
- WCC
- Lymphocyte subsets
- Serum immunoglobulin + protein electrophoresis
- Functional tests
- HIV
Describe management of T cell deficiencies
Infection prophylaxis + Tx
Ig replacement
HSCT
Gene therapy
What may be considered in management of DiGeorge syndrome?
Thymic transplant
Describe management of B cell deficiencies
Aggressive Tx of infection
Ig replacement every 3w (pooled plasma with diverse IgG)
BMT
Immunisation in selective IgA deficiency- not effective if no IgG
