Adaptive Immunity and deficiencies

Question 1

T cells: arise, mature, receptors

Answer 1

Arise in BM
Mature in Thymus
Express CD3 + a T cell receptor: CD4 (recognise HLA II) or CD8 (recognise HLA I)

Question 2

Development of CD4 T helper cells

Answer 2

Cytokines encourage development along different lines
TGF beta stimulates development into Treg cells: CD25 + FoxP3 receptors

Question 3

How are cytotoxic CD8 cells cytotoxic?

Answer 3

Directly through perforin, granzymes + expression of Fas ligands
Indirectly through cytokine secretions

Question 4

B cells: arise, mature, development

Answer 4

Arise + mature in BM
Develop as IgM plasma cells (low fidelity)
or undergo germinal centre reaction
Function highly dependent of CD4 T cells

Question 5

What is germinal centre reaction?

Answer 5

Somatic hypermutation + class switching to produce IgG, IgE or IgA
Higher fidelity receptors for antigen

Question 6

3 features of IgG

Answer 6

Monomer
Smallest- able to pass through membranes like the placenta
Maternal AI disease, IgG antibodies can affect fetus

Question 7

2 features of IgA

Answer 7

Dimer
On mucosal surfaces: part bound to mucosa, part free to bind pathogen

Question 8

Structure of IgM

Answer 8

Pentamer

Question 9

What are the broad causes of primary immunodeficiencies of the adaptive immune system?

Answer 9

Defects in lymphoid precursors
Defects of maturation (non functional)
CVID

Question 10

List 4 defects of lymphoid precursors

Answer 10

Reticular dysgenesis
X-linked SCID
ADA deficiency
Bruton’s X-linked hypo-gamma-globinaemia

Question 11

Give 6 general features common to SCID on presentation

Answer 11

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

Question 12

What mutation causes reticular dysgenesis?

Answer 12

mutation in mitochondrial energy metablism enzyme Adenylate kinase 2 (AK2)

Question 13

Is reticular dysgenesis compatible with life?

Answer 13

Fatal in very early life unless corrected with BM transplantation

Question 14

What causes SCID?

Answer 14

> 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

Question 15

3 features of X-linked SCID

Answer 15

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

Question 16

Give 3 phenotypic features of X-linked SCID

Answer 16

V low/ Absent T cells
V low/ Absent NK cells
Normal/ high B cells but low immunoglobulins, (IgM)

Question 17

2 features of adenosine deaminase deficiency

Answer 17

16.5% of all SCID
ADA: enzyme in lymphocytes required for cell metabolism

Question 18

Adenosine deaminase deficiency phenotype

Answer 18

V low or absent T cells
V low or absent B cells
V low or absent NK cells

Question 19

3 features of Bruton’s X-linked hypo-gamma-globinaemia

Answer 19

Bruton’s Tyrosine Kinase deficiency
BTK important in maturation of B cells
Pre-B cells can’t mature to B cells

Question 20

Phenotype of Bruton’s X-linked hypo-gamma-globulinaemia

Answer 20

Normal T cells
Normal cytokine levels
Absent B cells
Absent Immunoglobulins

Question 21

3 clinical features of Bruton’s X-linked hypogammaglobulinaemia

Answer 21

only Boys
Recurrent infections during childhood
Absent/ scanty LN + tonsils (primary follicles + germinal centres absent)

Question 22

List 3 defects of maturation of lymphocytes

Answer 22

22q11.2 deletion syndrome
Bare lymphocyte syndrome type II
Hyper-IgM syndrome

Question 23

What is 22q11.2 deletion syndrome also known as?

Answer 23

DiGeorge syndrome

Question 24

What is the aetiology of DiGeorge syndrome?

Answer 24

Deletion at 22q11.2
TBX1 may be responsible for some features
Usually sporadic not inherited
Developmental defect of pharyngeal pouch

Question 25

What mnemonic can be used to remember the features of DiGeorge syndrome?

Answer 25

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

Question 26

What levels of lymphocytes are seen in DiGeorge syndrome?

Answer 26

Normal B cells Low functional T cells (BM still producing, but can't mature)

Question 27

What changes with age in DiGeorge syndrome?

Answer 27

Cytokines drive homeostatic proliferation with age so immune function improves

Question 28

3 features of bare lymphocyte syndrome type II

Answer 28

Absent expression of MHC class II (HLA II) Profound deficiency of CD4 T cells Normal CD8 T cells + B cells

Question 29

Why is IgG, IgA and IgE low in bare lymphocyte syndrome type II?

Answer 29

No class switching Normal IgM as plasma B cells can mature without support of CD4 helper cells

Question 30

3 features of Hyper IgM syndrome

Answer 30

X-linked recessive Defect in CD40L on T cells Thus inability of B cells to class switch causing production of only IgM

Question 31

Describe lymphocyte and immunoglobulin presence in Hyper IgM syndrome

Answer 31

Normal no. B cells Normal no. T cells but activated cells don't express CD40 Ligand Elevated serum IgM Undetectable IgA, IgE, IgG

Question 32

How may boys with hyper IgM syndrome present?

Answer 32

Failure to thrive Recurrent infections- bacterial PCP AI diseases Malignancy

Question 33

What is combined variable immune deficiency?

Answer 33

Deficiency of a single immunoglobulin (usually IgG) Cause unknown Heterogenous group of disorders with many genetic defects

Question 34

In which patients does CVID usually present?

Answer 34

Late in life 40-50s F > M

Question 35

What can CVID present with?

Answer 35

Recurrent bacterial infections Pulmonary disease GI disease: IBD/ Sprue like AI disease: AIHA, ITP, RA, Vitiligo Malignancy: increased risk of non-Hodgkin's lymphoma

Question 36

List 4 complications patients with T cell deficiency are susceptible to

Answer 36

Viral infections: CMV Fungal infections: Pneumocystis, Cryptosporidium Bacterial infections: esp. intracellular organisms (MTB, Salmonella) Early malignancy

Question 37

List 3 complications patients with Antibody deficiency/ CD4 T cell deficiency are susceptible to

Answer 37

Bacterial infections (Staph + Strep) Toxins (Tetanus, Diphtheria) Viral infections (Enterovirus)

Question 38

How are lymphocyte deficiencies diagnosed?

Answer 38

1. WCC 2. Lymphocyte subsets 3. Serum immunoglobulin + protein electrophoresis 4. Functional tests 5. HIV

Question 39

Describe management of T cell deficiencies

Answer 39

Infection prophylaxis + Tx Ig replacement HSCT Gene therapy

Question 40

What may be considered in management of DiGeorge syndrome?

Answer 40

Thymic transplant

Question 41

Describe management of B cell deficiencies

Answer 41

Aggressive Tx of infection Ig replacement every 3w (pooled plasma with diverse IgG) BMT Immunisation in selective IgA deficiency- not effective if no IgG