Immune Deficiencies

Question 1

Summarise primary phagocyte deficiencies

Answer 1

Question 2

Summarise primary complement deficiencies

Answer 2

Question 3

Summarise primary T cell deficiencies

Answer 3

Question 4

Summarise primary B cell deficiencies

Answer 4

Question 5

Most severe form of SCID

Answer 5

Reticular dysgenesis (Autosomal Recessive)

Question 6

Mutation for Reticular dysgenesis

Answer 6

Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)

Question 7

Mutation for classical Kostmann syndrome

Answer 7

HCLS1-associated protein X-1 (HAX1)

Question 8

Mutation for cyclic neutropenia

Answer 8

Neutrophil elastase (ELA-2)

Question 9

Pathophysiology of Leukocyte adhesion deficiency

Answer 9

No CD11a/CD18 and CD11b/CD18 → failure to bind to ligands on endothelial cells → failure of neutrophil adhesion/transmigration → neutrophil accumulation in blood

Question 10

Specific deficiency in LAD1

Answer 10

CD18 deficiency (b2 integrin subunit)

Question 11

Features of LAD

Answer 11

High neutrophils
Absence of pus formation
Delayed umbilical cord separation

Question 12

Pathophysiology of CGD

Answer 12

Absent resp burst - NADPH oxidase deficiency
→Excessive inflammation

Question 13

Features of CGD

Answer 13

Granuloma formation
Lymphadenopathy
hepatosplenomegaly

Question 14

What bacteria are CGD patients susceptible to?

Answer 14

Catalase positive - PLACESS

Question 15

PLACESS bacteria

Answer 15

Question 16

CGD Ix

Answer 16

NBT - negative - stays yellow
DHR - negative - no fluorescence

Question 17

CGD Mx

Answer 17

IFN-gamma

Question 18

Pathophysiology of opsonisation defects

Answer 18

Prevent endocytosis and lysozyme formation

Question 19

Normal IL-12 IFN-gamma network

Answer 19

Infected macrophage → IL-12 → T cells secrete IFN-gamma → feeds back to phagocytes → TNF production → NADPH oxidase activation → oxidative pathway stimulation

Question 20

What bacteria are IL12 and IFN gamma deficiency

Answer 20

Mycobacteria, BCG, Salmonella

Question 21

What can you not form with IL12/IFNgamma deficiency?

Answer 21

Granulomas

Question 22

What type of bacteria are people with Complement deficiencies more susceptible to?

Answer 22

Encapsulated bacteria (NHS)

Question 23

What factors could be deficient in an alternative complement pathway deficiency and what regulates them?

Answer 23

B, D and P
Regulated by factors H and I

Question 24

What is the pathophysiology of alternative complement pathway deficiency and Factor P deficiency?

Answer 24

Can’t quickly mobilise complement
Properdin (Factor P) deficiency → can’t stabilise C3 convertase → no MAC

Question 25

Pathophysiology of primary classical (C1/2/4) deficiency

Answer 25

1. Immune complexes don't activate complement pathway → infection 2. Reduced clearance of apoptotic/necrotic cells → self-antigens (usually nuclear components) uncleared → increased risk of SLE (Anti-dsDNA) 3. Reduced clearance of immune complexes → complex deposition in tissue (skin, joints, kidneys) → local inflammation (severe skin disease)

Question 26

Most common classical pathway deficiency

Answer 26

C2

Question 27

What autoimmune disease is associated with C2 deficiency?

Answer 27

SLE

Question 28

How is secondary classical pathway deficiency different from primary?

Answer 28

In 2ndary: SLE → increased immune complexes → depletion of complement (rather than deficiency)

Question 29

What mutation may cause MBL deficiency?

Answer 29

MBL2 - doesn't cause immunodeficiency

Question 30

When may you get immune deficiency in MBL deficiency?

Answer 30

When it is additional to another immune impairment

Question 31

What complement factors are involved in MBL pathway?

Answer 31

C2, C4

Question 32

Pathophysiology of primary C3 deficiency

Answer 32

Can't form MAC → increased susceptibility to encapsulated bacteria (NHS)

Question 33

Pathophysiology of secondary C3 deficiency and its associations

Answer 33

Nephritic factors stabilise C3 convertase → inappropriate C3 activation and consumption Associations: glomerulonephritis, lipodystrophy

Question 34

Pathophysiology of final common pathway (C5-9) deficiency

Answer 34

No MAC formation → encapsulated bacteria (NHS) infections

Question 35

Very low/absent T cells & NK cells, increased B cells, very low Ig

Answer 35

X-linked SCID

Question 36

Unwell by 3 months Persistent infections of all types Failure to thrive Poorly developed lymphoid tissue and thymus FHx of early infant death

Answer 36

SCID clinical phenotype

Question 37

Most common form of SCID

Answer 37

X-linked SCID (45%)

Question 38

Genetic pathophysiology of X-linked SCID

Answer 38

Mutation - gamma chain of IL2 receptor on Chr Xq13.1 → receptor shared by IL-2, 4, 7, 9, 15, 21 → can't respond to cytokines → 1. early arrest of T&NK cell production, 2. increased production of immature B cells

Question 39

Very low/absent T and NK cell numbers, very low B cell numbers, very low Ig

Answer 39

ADA deficiency

Question 40

Pathophysiology of ADA deficiency

Answer 40

ADA - enxyme for lymphocyte cell metabolism Deficiency → can't respond to cytokines → early arrest of T & NK cell production with NO B cell porduction

Question 41

Features of DiGeorge Syndrome

Answer 41

CATCH-22

Question 42

Bare Lymphocyte Syndrome Type 2 pathophysiology

Answer 42

Defect in either a) Reg factor X or b) Class II transactivator → Absent expression of MHC class II → profound CD4+ T cells & failure to make IgG/A (no class switching)

Question 43

Low CD4+, normal CD8+ T cells, normal B cells, normal IgM, low IgG, IgA

Answer 43

Bare lymphocyte type II

Question 44

Hyper IgM syndrome genetic pathophysiology

Answer 44

Mutation on CD40L gene on Xq26 → No expression of CD40L on activated T cells → failure of B-T cell costimulation → no germinal centre reaction (no isotype class switching) → High IgM, low IgA, IgE, IgG

Question 45

Genetic pathophysiology of Wiskott-Aldrich syndrome

Answer 45

Mutation in WAS gene → failure to stabilise T-cell-APC interaction

Question 46

Low IgM high IgA, E Low/normal/high IgG Thrombocytopenia, eczema and lymphopenia triad

Answer 46

Wiskott-Aldrich syndrome

Question 47

Genetic pathophysiology of Bruton's

Answer 47

Bruton's X-linked agammaglobulinaemia Defective Bruton's Tyrosine Kinase gene → pre-B cells do not mature → no mature B cells → no circulating Ig after 3 months

Question 48

Most common primary immune deficiency

Answer 48

Selective IgA deficiency

Question 49

Clinical phenotype of selective IgA deficiency

Answer 49

2/3 asymptomatic 1/3 recurrent resp infections

Question 50

Clinical phenotype of Hyper IgM

Answer 50

Boys (X-linked) failure to thrive in first few years of life Recurrent infections - bacterial Pneumocystis Jirovecii, autoimmune disease, malignancy

Question 51

Common variable immunodeficiency description

Answer 51

Failure of differentiation/function of B cells Low IgG + low IgA/M Poor response to immunisation No other immune deficiency

Question 52

Clinical features of CVID

Answer 52

Recurrent serious bacterial infections Pulmonary and GI inflammation Autoimmune disease Malignancy

Question 53

Phagocyte deficiencies diagnosis

Answer 53

Flow cytometry NBT or DHR

Question 54

Phagocyte deficiencies management

Answer 54

Acute: treat infection aggressively Chronic: Infection prophylaxis Definitive: HSCT

Question 55

Complement deficiency diagnosis

Answer 55

CH50 - classical pathway AP50 - alternative pathway

Question 56

Answer 56

Question 57

Complement deficiency management

Answer 57

Vaccination - NHS ABx prophylaxis Treat infections early with high suspicion Screen family

Question 58

Likely infections for T cell deficiency

Answer 58

Question 59

Likely infections for antibody/CD4+ T cell deficiency

Answer 59

Question 60

Lymphocyte deficiency diagnosis

Answer 60

1. WCC 2. lymphocyte subsets 3. Serum Ig and protein electrophoresis 4. Functional tests 5. HIV test

Question 61

T cell deficiency management

Answer 61

Infection prophylaxis and treatment Ig replacement Definitive: HSCT Experimental: gene therapy, thymic transplant for DiGeorge

Question 62

B cell deficiency management

Answer 62

Treat infections aggressively Ig replacement every 3/52 Bone marrow transplant Immunisation in selective IgA deficiency