Immuno 2 - The immune response to infection/Primary immune deficiencies Part 2 Flashcards
B cells emerge from the bone marrow as Ig_?__ expressing B cells
IgM
Reticular dysgenesis mutation
mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
Which features would make you suspicious of SCID
Unwell by 3 months of age* Infections of all types Failure to thrive Persistent diarrhoea o Unusual skin disease Colonisation of infant’s empty BM by maternal lymphocytes graft vs host disease
FHx of early infant death
*(before – protected by IgG from mother across placenta and then colostrum)
• Normal baby will start to produce their own IgG over the course of 6 months
X-linked SCID mutation
Mutation of common γ chain of IL2 on Chr Xq13.1
shared by cytokine receptors IL- 2 7 9 15 21
X-linked SCID
T cells
NK cells
B cells
IgG
o Cells mature but are unable to respond to cytokines
early arrest of T cell + NK cell development
production of immature B cells
- Very low/absent T cells
- Very low/absent NK cells
- Normal or increased B cells (but don’t function well)
- Low IgG
ADA deficiency
T cells
NK cells
B cells
Adenosine Deaminase deficiency
inability to respond to cytokines
- Very low/absent T cells
- Very low/absent NK cells
- Very low/absent B cells
What do CD8 cells vs CD4 cells recognise
CD8
o Peptides derived from intracellular proteins in association with HLA class I (HLA-A, HLA-B, HLA-C)
o Malignant or virus infected cells
CD4 o Peptides derived from extracellular proteins presented on HLA class II molecules (HLA-DR, HLA-DP, HLA-DQ)
Function of
• Treg
• T follicular helper cells (Tfh)
cells
- Treg – important in negatively regulating immune responses, keeping them under control
- T follicular helper cells (Tfh) – important in the development of B cell responses– play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells
DiGeorge syndrome features
characteristics
T cells
B cells
Immune function
Defects in T cell maturation/selection in thymus
CATCH22
o Complex congenital heart disease (esp. tetralogy of fallot)
o Abnormal facies (high forehead, low set ears, abnormally folded ear, cleft palate, small mouth, small jaw, oesophageal atresia)
o Thymic aplasia (T cell lymphopenia)
o Cleft palate
o Hypocalcaemia, Hypoparathyroidism
o 22 – chromosome - deletion at 22q11.2
o Reduced T cells
Over time T cells proliferate to fill up the compartment and so their immune function tends to improve with age
o Normal B cells
Low IgA, Low IgG (no T follicular helper cells to help differentiation to IgG or IgA producing B cells in germinal centre reaction)
o Homeostatic proliferation with age
Immune function usually only mildly impaired + improves with age
Bare lymphocyte syndrome
where is the problem T cells B cells IgG IgA
Defects in T cell maturation/selection in thymus
• Defect in one of the regulatory proteins involved in Class II gene expression
o Regulatory factor X
o Class II transactivator
• Absent expression of MHC Class II molecules Profound deficiency of CD4+ cells
o Normal numbers of CD8+
o Low numbers of CD4+ (profound deficiency of CD4+ cells)
o Normal numbers of B cells
o Low IgG or IgA antibodies (lack of CD4+ T cell help, no class switching)
Syndromes due to Defects in T cell maturation/selection in thymus
DiGeorge syndrome - 22q11.2 deletion
Bare lymphocyte syndrome type 2
Causes of disordered T activation/ cell effector function
Failure of
• Cytokine production – IFN
• Cytokine receptors – IL12 receptor
• T-B cell communication
• Cytotoxicity
Clinical features of T cell deficiency
• T cell deficiency clinical features
o Viral infections – CMV
o Fungal infection – pneumocystis, cryptosporidium
o Some bacterial infections, esp. intracellular organisms – TB, Salmonella
o Early malignancy
T cell deficiencies ix
• Total WCC + differential
o Remember that lymphocyte counts are normally much higher in children than in adults
• Lymphocyte subsets
o Quantify CD8 T cells, CD4 T cells, B cells, NK cells
• Immunoglobulins
o If CD4 T cell deficient (because if there is CD4 T cell deficiency, you wont be able to generate your immunoglobulins in the germinal centre reaction)
• Functional tests of T cell activation + proliferation
o Useful if signalling or activation defects are suspected
• HIV test
Management of immunodeficiency involving T cells
- Aggressive prophylaxis/ treatment of infection
- Ig replacement
• Enzyme replacement therapy
o PEG-ADA for ADA SCID
• HSCT
o To replace abnormal populations in SCID
o To replace abnormal cells – class II deficient APCs in BLS
• Thymic transplantation
o To promote T cell differentiation in Di George syndrome
o Cultured donor thymic tissue transplanted in quadriceps muscle
• Gene therapy
o Stem cells treated ex-vivo with viral vectors containing missing components
o Transduced cells have survival advantage in vivo