Imm - inborn errors of immunity

Question 1

Give examples of immune disorders that involve phagocytes

Answer 1

Neutrophil deficiency:
- Chronic benign neutropenia
- Familial (idiopathic) neutropenia
- Severe congenital neutropenia
- Reticular dysgenesis

Neutrophil migration/function:
- Leukocyte adhesions deficiency

Generation of reactive oxygen species (ROS)/failure of oxidative killing mechanisms:
- Chronic granulomatous disease

Question 2

Describe chronic benign neutropenia

Answer 2

Disorder of neutrophil deficiency
Mild/moderate neutropenia
Common in number of ancestry groups (Africa, Middle East)
SNP in DARC gene → absent expression
Asymptomatic (Usually does not need further investigation )

Question 3

Describe Familial (idiopathic) neutropenia

Answer 3

Disorder of neutrophil deficiency
Moderate/severe neutropenia
Adult onset
Associated with organ-specific autoimmune disease
No significant increase in infection risk

Question 4

Describe severe congenital neutropenia and what is the treatment

Answer 4

Disorder of neutrophil deficiency and maturation
presents <3 months
Cyclic neutropenia (normal and low): neutrophil elastase (ELA-2) mutation
Includes genetic syndromes e.g. neutrophil elastase, Kostmann (HCLS-1associated protein X mutation), SDS, MDS, AML
Susceptible to oral, cutaneous and epithelial Staph aureus, G- enteric bacteria and fungal infection
Tx: G-CSF support and stem cell transplantation for high risk individuals

Question 5

Describe chronic granulomatous disease

Answer 5

Failure of oxidative killing mechanisms of phagocytes (respiratory burst)
Deficiency in one of the NADPH oxidase components → inability to generate oxygen-free radicals → impaired killing
NADPH: increased NF-κ β and IL-1β activation

Question 6

What investigations are treatment are indicated for chronic granulomatous disease

Answer 6

Negative Nitro-Blue Tetrazolium test (NBT). NBT is a dye that changes colour from
yellow to blue following interaction with hydrogen peroxide (free radical)

Dihydrorhodamine (DHR) flow cytometry test. DHR is oxidized to rhodamine, which is
strongly fluorescent, following interaction with hydrogen peroxide.

Management
Cotrimoxazole and itraconazole prophylaxis
Adjunctive IFN-gamma, Stem cell and gene therapy

Question 7

Describe leukocyte adhesion deficiencies

Answer 7

Failure of neutrophil migration
Deficiency of CD18 (β2 integrin subunit) which (along with CD11a) is expressed on neutrophils → binds to ligand (ICAM-1) on endothelial cells to regulate migration
Lack of adhesion molecule expression → failure to exit the bloodstream

Question 8

Describe reticular dysgenesis

Answer 8

Failure of stem cells to differentiate along myeloid or lymphoid lineage
Failure of production of: Neutrophils, Lymphocytes, Monocyte/macrophages, Platelets
Fatal in very early life unless corrected with bone marrow transplantation
Autosomal recessive severe SCID (most severe form)
Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)

Question 9

What are the types of immune disorders that involve complement

Answer 9

Protein deficiency:
Classical pathway
Alternative pathway
C3
Terminal complement pathway deficiency
Mannose-binding lectin (MBL) deficiency

Regulatory proteins:
C1 inhibitor deficiency
Factor H, I, MCP (CD46)
CD55 and CD59

Question 10

What are the features of early classical complement protein deficiencies and what does it predispose to

Answer 10

(C1/2/4)
- immune complexes fail to activate the complement pathway → increase susceptibility to infection
- Increased load of self-antigens (esp. nuclear components) → promotes auto-immunity and immune complexes
- Deposition of immune complexes → stimulates local inflammation

Predisposes to: SLE (C1/2), encapsulated bacterial infections, Hib, Strep. pneumoniae, skin disease

Question 11

What is the cause secondary classical complement protein deficiencies

Answer 11

caused by active lupus, due to persistent production of immune complexes and consequent depletion of complement

Question 12

What are the features of immune disorders involving the alternative complement pathway

Answer 12

Factor B/ Factor D/ Factor P (properdin) deficiency - rare
Inability to mobilise complement rapidly in response to bacterial infections → Recurrent
infections with encapsulated bacteria
Normally properdin stabilizes C3 convertase → triggers MAC complex
Predisposes to neisseria meningitis infection

Question 13

What are the features of immune disorders associated with primary C3 deficiency

Answer 13

Severe susceptibility to bacterial infections (esp. encapsulated – meningococcus, streptococcus, haemophiles) AND connective tissue disease

Question 14

What are the features of immune disorders associated with secondary C3 deficiency

Answer 14

nephritic factors (auto-Abs directed against the complement pathway) → stabilises C3 convertases → C3 activation and consumption
Associated with glomerulonephritis (membranoproliferative) and partial lipodystrophy

Question 15

What are the features of immune disorders associated with Terminal complement pathway deficiency and what does it predispose to

Answer 15

Inability to make membrane attack complex → Inability to use complement to lyse encapsulated bacteria

Predisposes to: N. meningitis, S. pneumonia, H. influenza

Question 16

What are the features of immune disorders associated with Mannose binding lectin deficiency

Answer 16

Not clinically significant, 5-30% of population
Associated with increased infection in patients who have another cause of immune impairment
- Premature infants
- Chemotherapy
- HIV infection
- Antibody deficiency

Question 17

What are the features of immune disorders associated with C1 inhibitor deficiency

Answer 17

Recurrent episodes of bradykinin-mediated angioedema (skin, abdomen, larynx)
Low C4, Normal C3

Tx: Emergency therapy with C1 inhibitor (not adrenaline) and maintenance therapy with C1 inhibitor concentrate

Question 18

What are the features of immune disorders associated with Factor H, I, MCP (CD46)

Answer 18

C3 glomerulopathy
Atypical Haemolytic uraemic syndrome
Low C3 normal C4 absent alternative pathway function (AP50)

Question 19

What are the features of immune disorders associated with CD55 and CD59

Answer 19

Adult presentation
Triad haemolysis, thrombosis and pancytopaenia

Question 20

Give examples of immune disorders that are associated with lymphoid organs

Answer 20

Lymphoid progenitors:
- SCID
- X-linked SCID
- ADA deficiency

T cell maturation/selection in thymus:
- DiGeorge syndrome
- Bare lymphocyte syndrome type II

T cell activation and effector functions:
- IL-12, IFN-y deficiency
- Hyper IgM syndrome
- Wiskott-aldrich syndrome (WAS)

B lymphocyte maturation
- Bruton’s X-linked hypogamma globulinaemia
- Selective IgA deficiency
- Hyper IgM syndrome
- common variable immune deficiency

Question 21

Describe SCID (cause and inheritance)

Answer 21

Severe combine immune deficiency
defects in the generation of lymphoid precursors in bone marrow → Absence or dysfunction of T cells affecting both cellular and humoral immunity
Autosomal recessive or X-linked inheritance
Complete penetrance

Question 22

How does SCID present

Answer 22

Children: Unwell by 3 months of age, fatal if immune defect is not corrected with 2 years
- Persistent viral chest and GI infection (bacterial rare
- Multiple, recurrent opportunistic infections involving many organs e.g. PCP, CMV
- Infection from live vaccines e.g. BCG, rotavirus
- Persistent or severe mucosal and/or skin candida infection
- FTT, diarrhoea, unusual skin disease, early infant death (+FHx of such)

Question 23

What are the features of X-linked SCID and what is the phenotype

Answer 23

45% of SCID
Mutation of gamma chain of IL2 receptor on chromosome Xq13.1 → Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells
Phenotype: very low or absent T cell and NK cell numbers, normal or increased B cell numbers

Question 24

What are the features of ADA deficiency and what is the phenotype

Answer 24

16.5% of all severe combined immunodeficiency
Adenosine Deaminase Deficiency (Enzyme lymphocytes required for cell metabolism)
Inability to respond to cytokines causes early arrest of T cell and NK cell development and
production of immature B cells

Very low or absent T cell and NK cell numbers AND B cell numbers

Question 25

What are the features of DiGeorge syndrome

Answer 25

22q11.2 deletion syndrome
Developmental failure of pharyngeal arch (craniofacial structures, thymus, parathyroid glands aortic arch and cardiac outflow tract)
Most common chromosomal deletion syndrome
5% of children had reduced T cells number which usually resolve in early childhood.
Normal numbers of B cells and reduced numbers of T cells
Homeostatic proliferation with age → Immune function improves with age BUT Increased incidence of autoimmune disease (ITP) and humoral defects with age

Question 26

What are the clinical features of DiGeorge syndrome

Answer 26

CATCH-22
Cardiac abnormalities (especially tetralogy of Fallot)
Abnormal facies (high forehead, low set ears)
Thymic aplasia (T cell lymphopenia) → immune deficiency
Cleft palate
Hypocalcaemia/hypoparathyroidism
22 – chromosome

Question 27

What are T-regopathies

Answer 27

Diseases resulting from failure of peripheral T cell tolerance
Characterised by loss or reduction in CD4+FoxP3+ T cell function → loss of regulation → excessive effector T cell activation

Question 28

Describe Selective IgA deficiency

Answer 28

Defect in B cell class switching
Prevalence = 1:600
60% of individual are asymptomatic
Presents with allergic disorders, sino-pulmonary and enteric infections, autoimmune disease, GI cancers

Question 29

Describe Common variable immune deficiency (CVID), give its phenotype and what it is characterised by

Answer 29

Defect in B cell function, characterised by failure to make protective antibodies to polysaccharide encapsulated pathogens
Marked reduction in IgG, with low IgA or IgM
Antibody deficiency syndrome characterised by:
- Granulomatous disease
- Autoimmune disease
- Lymphoproliferative disease
- Increased susceptibility to infection

Question 30

What is the difference between the complex and infection phenotype of Common variable immune deficiency (CVID)

Answer 30

Complex: autoinflammatory → enteropathy, nodular regenerative hyperplasia, cirrhosis, portal HTN and cirrhosis, interstitial lung disease, Increased risk of B cell NHL and gastric cancer
Infection: recurren bacterial sino-pulmonary infection → bronchiectasis, otitis media, conjunctivitis, GI infection, cellulitis BUT Normal life expectancy with IgG replacement therapy

Question 31

Describe X-linked agammaglobulinaemia (XLA) (Bruton’s)

Answer 31

Mutation in BTK gene encoding Bruton Tyrosine Kinase (B cell) → pre-B cells cannot develop into mature B cells → absence of all immunoglobulins + marked B cell reduction (after 3 months)
± neutropenia

Question 32

How does X-linked agammaglobulinaemia (XLA) (Bruton’s) present

Answer 32

Only in boys, usually <5yo
Recurrent infections in childhood e.g. ENT< resp, GI
Absent/scanty lymph nodes and tonsils (1° follicles and germinal centers absent)

Question 33

Describe hyper IgM syndrome

Answer 33

inability of B cells to class switch → production of only IgM due to a T cell defect
X-linked recessive
Mutation in CD40 ligand gene (expressed by activated T cells, member of TNF receptor family on Xq26)

Question 34

What does hyper IgM syndrome present with

Answer 34

Boys
FTT
Recurrent bacterial infections
Pneumocystis jiroveci infection, autoimmune disease and malignancy

Question 35

What are the features of Hyper IgM syndrome on investigation

Answer 35

Normal number circulating B cells
Normal number of T cells but activated cells do not express CD40 Ligand
Elevated serum IgM
Undetectable IgA, IgE, IgG (failure of class switching)
No germinal centre development within lymph nodes and spleen

Question 36

Describe Wiskott-Aldrich syndrome

Answer 36

X-linked recessive disorder of T-cell APC inferaction
Mutation in WAS gene (actin cytoskeleton arrangement), needed to stabilise T cell-APC interaction
Thrombocytopenia, eczema (raised IgE), lymphopenia
Reduced IgM, IgA and IgE raised
Increased risk of malignant lymphoma

Question 37

Describe Deficiency of IL-12 and IFNγ and their receptors

Answer 37

Susceptibility to infection with mycobacteria (TB and atypical), BCG, Salmonella.

Inability to form granulomas

Question 38

What investigations should be done for immune disorders associated with neutrophils

Answer 38

Immunoglobulins (usually raised)
Lymphocyte subsets
Bone marrow biopsy
Neutrophil function assay
- Look for neutrophil oxidative burst
- Stimulate neutrophils and measure hydrogen peroxide
- DHR-123 assay: DHR-13 is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide
Genetic neutrophil panels

Question 39

What investigations should be done for immune disorders associated with complement

Answer 39

FBC
Serum immunoglobulin
Lymphocyte subsets
C3 and C4
Functional complement tests
- CH50 classical pathway
- AP50 alternative pathway
Complement genetic test

Question 40

What is the management for patients with complement cascade protein deficiencies

Answer 40

Vaccination
- Boost protection mediated by other arms of the immune system
- Tetravalent Meningococcal vaccine , Pneumovax and HIB vaccines
Prophylactic antibiotics
Treat infection aggressively
Screening of family members

Question 41

What are the diagnostic features of SCID on investigation

Answer 41

Low lymphocyte count (counts are normally much higher in children than in adults
CD3 T cell count < 300cells/uL
T cell proliferation < 10% of control
Low serum immunoglobulins
Flow cytometry
- T-B+ SCID
- T-B-SCID
Targeted gene panels

Question 42

What is the management for SCID

Answer 42

Stem cell transplantation
No suitable donors → gene therapy
Screening in neonates using T-cell receptor excision analysis (TREC)

Question 43

What are the diagnostic criteria for CVID

Answer 43

Marked reduction in IgG, with low IgA or IgM
Poor/absent response to immunisation
Absence of other defined immunodeficiency
>4yo

Question 44

What is the management for CVID

Answer 44

Bronchiectasis management: physio, saline nebuliser, carbocysteine, Abx, address co-morbs
IgG replacement therapy (IV/SC): pneumococcus, Haemophilus, tetanus, measles, mumps, hepA/B
Treatment of complications

Question 45

What are the clinical features of chronic granulomatous disease

Answer 45

Skin, lymph node, liver, bone, chest bacterial , fungal, TB and NTM infections
Macrophage infiltration → granulomas
Lymphadenopathy and hepatosplenomegaly
Susceptibility to bacteria esp. catalase positive bacteria i.e. PLACESS (Pseduomonas, Listeria, Aspergillus, Candida, E.Coli, Staph Aureus, Serratia)

Question 46

What are the clinical features of leukocyte adhesions deficiency

Answer 46

• Delayed separation of the umbilical cord
• Very high neutrophil counts in blood (20-100 x106/L)
• Absence of pus formation

Question 47

What is Bare lymphocyte syndrome type II

Answer 47

Defect in one of the regulatory proteins involved in Class II gene expression
Absent expression of MHC Class II molecules
Profound deficiency of CD4+ cells, normal CD8+and no. of B cells
No class switching (no IgG or IgA)