Inborn Errors of Immunity - Adaptive

Question 1

What is the most common inborn error of immunity?

Answer 1

Selective IgA deficiency

Question 2

What is the most common SYMPTOMATIC inborn error of immunity?

Answer 2

Common Variable immunodeficiency (CVID)

Question 3

Describe the 3 types of B-cell/antibody IEIs

Answer 3

Selective IgA deficiency
- can be inherited or sporadic (gene mutations unknown)
- 2/3rds are asymptomatic
- Some individuals develop severe anaphylactic reactions, when they’re transfused with blood containing IgA, because the IgA is treated like a foreign antigen

Common Variable Immunodeficiency (CVID)
- Particularly low levels of IgG (also IgA and IgM)
- Various possible mutations in CD19 and CD20
- Bimodal onset (<10 or adult)

X-linked agammaglobulinemia (XLA) aka Bruton’s agammaglobulinemia
- x-linked recessive (only affects boys)
- Mutation in BTK gene so B cell maturation stops (at the pre-B cell to immature B cell stage), resulting in the absence of adult B cells and all immunoglobulins
- symptoms typically appears after 3 months of age because that’s when the maternal immunoglobulins from the placenta start to disappear

Question 4

Management of the 3 types of B-cell/antibody IEI

Answer 4

ALL: Prophylaxis

Selective IgA defiency: no treatment (although 2/3rds are asymptomatic, there is still no treatment for symptomatic 1/3rd)

Common Variable Immunodeficiency (CVID): lifelong IVIG

X-linked agammaglobulinemia (XLA) aka Bruton’s agammaglobulinemia: lifelong IVIG

Question 5

What is IVIG? Which IEIs is it useful to treat?

Answer 5

Intravenous immunoglobulin G

Both have low IgG
* Common Variable Immunodeficiency (CVID)
* X-linked agammaglobulinemia (XLA) aka Bruton’s agammaglobulinemia

Question 6

Describe the 2 types of T cell IEIs

Answer 6

DiGeorge syndrome or 22q11.2 deletion syndrome
- denovo deletion of q11.2 portion of DNA on chromosome 22
- Developmental failure of pharyngeal arch (craniofacial structures, absent thymus, parathyroid glands aortic arch and cardiac outflow tract)
- Partial digeorge syndrome is mild dysfunction of thymus and NOT life-threatening. Complete DiGeorge syndrome, though, where thymic dysfunction is severe, it can be fatal within the first year of life.
- Symptoms: (CATCH 22)
* - Cardiac abnormalities (TOF)
* - Abnormal faces
* - Thymic aplasia
* - Cleft palate
* - Hypoparathyroidism
* - Chromosome 22

Tregopathies
- reduced function of Treg cells so get excessive effector T cell activation and loss of immune tolerance
- Can be caused by defects in FoxP3, CD25, CTLA-4, LRBA, BACH2 and STAT-3
- Get multiorgan autoimmunity

Question 7

What are the biomarkers for Treg cells?

Answer 7

CD3+, CD4+, CD25+, FOXP3+

Question 8

Management of the 2 types of T cell IEIs?

Answer 8

DiGeorge syndrome or 22q11.2 deletion syndrome - thymus transplantation

Tregopathies - stem cell transplant, mutated gene correction therapy, drugs (Treg expansion etc)

Question 9

Which is the most severe form of inborn error of immunity?

Answer 9

Severe Combined Immunodeficiency (SCID)

of which reticular dysgenesis is the most severe form of SCID

Question 10

What is Severe Combined Immunodeficiency (SCID)?

Answer 10

• Combined B and T cell immunodeficiency
• Defective generation of lymphoid precursors in bone marrow
• Can be autosomal recessive (e.g. reticular dysgenesis is the WORST with mutation in AKA2) or X-linked (most common)
• Caused by a variety of gene mutations
• Onset of disease is normally after 3 months and less than 1 year, fatal if immune defect is not corrected with 2 years
• Present with Multiple, recurrent opportunistic infections involving many organs

Question 11

When do antibody-affecting IEIs present?

Answer 11

3-6 months
because they are partly protected by antibodies that passed from mother to baby across the placenta during the first few months of life.

Question 12

How would you diagnose SCID?

Answer 12

**Day 5 Newborn baby heel prick test: **low TRECs ( T cell receptor excision circles) which are a marker of thymic function byand thus can be used to identify low T cells in neonates.

Following this, flow cytometry can be used to enumerate T cell counts in those with low TREC counts and direct further investigation

FBC: Low lymphocyte count and lymphocyte subset count
Low serum immunoglobulins
Flow cytometry (T- B+ SCID / T- B- SCID)
Targeted gene panels

Question 13

Management of SCID

Answer 13

Haematopoeitic stem cell transplant
Gene therapy

Question 14

What is the most severe form of SCID?

Answer 14

Reticular dysgenesis

Question 15

What is the most common form of SCID?

Answer 15

X-linked SCID

Question 16

Which disease is marked by a reduction in IgA only?

Answer 16

Selective IgA deficiency

Question 17

Which disease is marked by reduction in IgG only (+sometimes IgM/A)

Answer 17

Common Variable Immunodeficiecny (CVID)

Question 18

What % of selective IgA deficiency patients are symptomatic?

Answer 18

33%

Question 19

Symptoms of DiGeorge Syndrome

Answer 19

• Symptoms: (CATCH 22)
• • Cardiac abnormalities (TOF)
• • Abnormal faces
• • Thymic aplasia
• • Cleft palate
• • Hypoparathyroidism
• • Chromosome 22