Primary Immune Deficiencies 1

Question 1

Conditions with enhanced immunological activity

Answer 1

Auto-inflammatory disease
Auto-immune disease
Allergic disease

Question 2

Conditions with reduced immunological activity

Answer 2

Primary immunodeficiency 
Secondary immunodeficiency (HIV)

Question 3

Classification of immunodeficiencies

Answer 3

Primary - single gene mutations
Secondary - to some other cause
Physiological - to be expected

Question 4

Clinical features suggestive of immunodeficiency

Answer 4

Infections!!!!!!
Two major or one major and recurrent. minor infections in one year. 
Chronic infections. 
Unusual organisms 
Unusual sites
Unresponsive to treatment 
Early structural damage

Family history
Young age at presentation
Failure to thrive

Question 5

Cells of the innate immune response

Answer 5

Polymorphonuclear cells - neutrophils, eosinophils, basophils
Monocytes and macrophages
Dendritic cells
Natural killer cells

Question 6

Soluble components of the innate immune response

Answer 6

Complement
Acute phase proteins
Cytokines and chemokines

Question 7

Phagocytes

Answer 7

Cells express cytokine/chemokine receptors that allow them to home to sites of infection

Cells express genetically encoded receptors to allow detection of pathogens at site of infection
pattern recognition receptors (Toll-like receptors or mannose receptors) which recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA, RNA

Cells express Fc receptors to allow them detection of immune complexes

Cells have phagocytic capacity that allows them to engulf the pathogens

Cells secrete cytokines and chemokines to regulate immune response

Question 8

Polymorphonuclear cells (granulocytes)

Answer 8

Produced in bone marrow and migrate rapidly to site of injury

Release enzymes, histamine, lipid mediators of inflammation from granules

Question 9

Mononuclear cells (monocytes and macrophages)

Answer 9

Monocytes are produced in the bone marrow, circulate in the blood and migrate to tissues where they differentiate to macrophages

Capable of presenting processed antigen to T cells.

Question 10

Types of phagocyte deficiency

Answer 10

Failure to produce myeloid/lymphoid cells 
Failure to produce neutrophils 
Defect of phagocyte migration
Failure of oxidative killing mechanism
Cytokine deficiencies

Question 11

What is reticular dysgenesis

Answer 11

Autosomal recessive
Phagocyte deficiency in which there is a failure to produce myeloid/lymphoid cells.
Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2

Question 12

Kostmann syndrome

Answer 12

Autosomal recessive severe congenital neutropenia
Failure of neutrophil maturation
Classical form due to mutation in HCLS1-associated protein X1 (HAX1)

Question 13

Cyclic neutropenia

Answer 13

Autosomal dominant episodic neutropenia every 4-6 weeks

Mutation in neutrophil elastase (ELA-2)

Question 14

Leukocyte adhesion deficiency

Answer 14

Defect of phagocyte migration
Deficiency of CD18 (beta2 integrin subunit)

CD11a/CD18 (LFA-1) is expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration

In Leukocyte adhesion deficiency the neutrophils lack these adhesion molecules and fail to exit from the bloodstream: very high neutrophil counts in blood and absence of pus formation

Question 15

Chronic granulomatous disease

Answer 15

Failure of oxidative killing mechanism (type of phagocyte deficiency)

Absent respiratory burst
Excessive inflammation
Granuloma formation
Lymphadenopathy and hepatosplenomegaly

Question 16

Investigations of chronic granulomatous disease

Answer 16

Nitroblue tetrazolium test
Dihydrorhodamine flow cytometry test

Activate neutrophils – stimulate respiratory burst and production of hydrogen peroxide

NBT is a dye that changes colour from yellow to blue, following interaction with hydrogen peroxide

DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide

Question 17

Cytokine deficiency

Answer 17

IL12, IL12R, IFNg or IFNg R deficiency

Question 18

What is the IL12-IFNg network

Answer 18

Infection activates IL12- IFNg network

Infected macrophages produce IL12
IL12 induces T cells to secrete IFNg
IFNg feeds back to macrophages
Stimulates production of TNF 
Activates NADPH oxidase
Stimulates oxidative pathways

Question 19

What are patients with cytokine deficiencies at greater risk of

Answer 19

Mycobacterial infection

Salmonella infection

Question 20

What do phagocyte deficiencies lead to

Answer 20

Recurrent infections (skin/mouth)

Question 21

What type of infection do cytokine deficiencies lead to

Answer 21

Bacterial (staph aureus, enteric bacteria)
Fungal infections (candica albicans, aspergillus fumigatus and flavus) 
Mycobacterial infection (mycobacterium tuberculosis, atypical mycobacteria)

Question 22

Management of phagocyte deficiencies

Answer 22

Agresive management of infection (infection prophylaxis - septrin, itraconazole)
Definitive therapy (haematopoietic stem cell transplantation, specific treatment for CGD)

Question 23

Infections with atypical mycobacterium. Normal FBC

Answer 23

IFNg receptor deficiency

Question 24

Recurrent infections with no neutrophils on RBC

Answer 24

Kostmann syndrome

Question 25

Recurrent infections with hepatosplenomegaly and abnormal dihydrohodamine test

Answer 25

Chronic granulomatous disease

Question 26

Recurrent infections with high neutrophil count on FBC but no abscess formation

Answer 26

Leukocyte adhesion deficiency

Question 27

Natural Killer cells

Answer 27

Present within blood and may migrate to inflamed tissue Inhibitory receptors recognise self-HLA molecules that prevent inappropriate activation by normal self Activatory receptors including natural cytotoxicity receptors recognise heparan sulphate proteoglycans Release cytokines Contact dependent regulation

Question 28

Natural killer cell deficiencies

Answer 28

Classical NK deficiency | Functional NK deficiency

Question 29

What are the features of classical natural killer cell deficiency

Answer 29

Absence of natural killer cells within peripheral blood | Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2

Question 30

Features of functional natural killer cell deficiency

Answer 30

NK cells present but function is abnormal | Abnormality described in FCGR3A gene in subtype 1

Question 31

Viral infections in natural killer cell deficiencies

Answer 31

``` HSV 1 and 2 VZV EBV CMV PMV ```

Question 32

Treatment of NK deficiencies

Answer 32

Prophylactic antiviral drugs such as acyclovir or gancyclovir Cytokines such as IFN alpha to stimulate NK cytotoxic function Haematopoietic stem cell transplantation in severe phenotypes

Question 33

What is complement

Answer 33

>20 tightly regulated linked proteins Produced by liver Present in circulation as inactive molecules When triggered, enzymatically activate other proteins in a biological cascade, resulting in rapid highly amplified respone

Question 34

Three pathways of complement activation

Answer 34

Classical (C1,2,4) Alternative MBL (C4,C2)

Question 35

What is the end result of the complement pathway

Answer 35

Final common pathway of C5-9 to form the membrane attack complex

Question 36

Role of complement fragments released during complement activation

Answer 36

Increase vascular permeability and cell trafficking ot site of inflammation Promotes clearance of immune complexes Opsonisation of pathogens to promote phagocytosis Activates phagocytes Promotes mast cell/basophil degranulation Punches holes in bacterial membranes

Question 37

Classical pathway of complement activation

Answer 37

Formation of antibody-antigen immune complexes Results in change in antibody shape – exposes binding site for C1 Binding of C1 to the binding site on antibody results in activation of the cascade Dependent upon activation of acquired immune response (antibody)

Question 38

Complement deficiencies in classical pathway

Answer 38

Immune complexes fail to activate complement pathway | Increased susceptibility to infection

Question 39

How are deficiencies of early classical complement components associated with SLE

Answer 39

Classical complement pathway activation promotes clearance of apoptotic/necrotic cells by phagocytosis - Deficiencies results in increased load of self antigens – particularly nuclear components – which may promote auto-immunity and formation of immune complexes Classical complement pathway activation promotes clearance of immune complexes by erythrocytes - Deficiencies result in deposition of immune complexes which stimulates local inflammation in skin, joints and kidneys

Question 40

What is the most common complement deficiency associated with SLE

Answer 40

C2 Almost all patients with C2 have deficiency have SLE Usually hvae severe skin disease Also have increased incidence of infections

Question 41

Mannose Binding Lectin (MBL) pathway of complement activation

Answer 41

Activated by the direct binding of MBL to microbial cell surface carbohydrates Directly stimulates the classical pathway, involving C4 and C2 but not C1 Not dependent on acquired immune response

Question 42

Mannose Binding Lectin deficiency

Answer 42

30% of all individuals are heterozygote for mutant protein 6-10% have no circulating MBL Associated with increased infection in patients who have another cause of immune impairment (Premature infants, Chemotherapy, HIV infection, Antibody deficiency

Question 43

Alternative pathway of complement activation

Answer 43

Bacterial cell wall fails to inactivate C3b generated spontaneously eg lipopolysaccharide of gram negative bacteria, teichoic acid of gram positive bacteria Not dependent on acquired immune response Involves factors B, I and P

Question 44

What occurs if there is a deficiency in the alternative pathway

Answer 44

Inability to mobilise complement rapidly in response to bacterial infection

Question 45

Clinical features of factor B, I or P deficiency

Answer 45

Recurrent infections with encapsulated bacteria

Question 46

Significance of C3 in complement activation

Answer 46

Activation of C3 is the major amplification step in the complement cascade Triggers the formation of the membrane attack complex via C5-C9

Question 47

C3 deficiency

Answer 47

Severe susceptibility to bacterial infections Neisseria meningitis Streptococcus pneumonia Haemophilus influenza Increased risk of development of connective tissue disease

Question 48

C5-9 deficiencies

Answer 48

If defect in the terminal (“common”) pathway Inability to make membrane attack complex Inability to use complement to lyse encapsulated bacteria Infection Neisseria meningitis Streptococcus pneumonia Haemophilus influenza

Question 49

How does active lupus lead to a functional complement deficiency

Answer 49

Active lupus causes persistent production of immune complexes and consequent consumption of complement leading to functional complement deficiency

Question 50

How can secondary complement deficiencies come bout

Answer 50

Nephritic factors are auto-antibodies directed against components of the complement pathway Nephritic factors stabilise C3 convertases resulting in C3 activation and consumption Often associated with glomerulonephritis (classically membranoproliferative) May be associated with partial lipodystrophy

Question 51

How can you investigate the complement pathways

Answer 51

Quantitation of complement compounds (C3, C4 are routinely measured) Functional complement tests (CH50 classical pathway, AP50 alternative pathway)

Question 52

C1q deficiency

Answer 52

Normal C3 Normal C4 Low CH50 Normal AP50

Question 53

Factor B deficiency

Answer 53

Normal C3 Normal C4 Normal CH50 Low AP50

Question 54

C9 deficiency

Answer 54

Normal C3 Normal C4 Low CH50 Low AP50

Question 55

SLE

Answer 55

Normal/low C3 Low C4 Normal/low CH50 Normal AP50

Question 56

How are patients with complement deficiencies managed

Answer 56

Vaccination (boost protection mediated by other arms of the immune system; meningovax, pneumovax, HIV) Prophylactic antibiotics Treat infection aggressively Screening of family members

Question 57

Meningogoccus meningitis with family history of sibling dying of same condition aged 6

Answer 57

C7 deficiency

Question 58

Membraneproliferative nephritis and bacterial infections

Answer 58

C3 deficiency with presence of a nephritic factor

Question 59

Severe childhood onset SLE with normnal levels of C3 and C4

Answer 59

C1q deficiency

Question 60

Recurrent infection when receiving chemotherapy but previously well

Answer 60

MBL deficiency

Question 61

What complement deficiencies have been described in SLE

Answer 61

``` C1q C1r C1s C2 C4 ```