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Kat's Pathology > Primary Immune Deficiencies 1 > Flashcards

Primary Immune Deficiencies 1 Flashcards

1
Q

Conditions with enhanced immunological activity

A

Auto-inflammatory disease
Auto-immune disease
Allergic disease

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2
Q

Conditions with reduced immunological activity

A 
Primary immunodeficiency 
Secondary immunodeficiency (HIV)
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3
Q

Classification of immunodeficiencies

A

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

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4
Q

Clinical features suggestive of immunodeficiency

A 
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

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5
Q

Cells of the innate immune response

A

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

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6
Q

Soluble components of the innate immune response

A

Complement
Acute phase proteins
Cytokines and chemokines

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7
Q

Phagocytes

A

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

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8
Q

Polymorphonuclear cells (granulocytes)

A

Produced in bone marrow and migrate rapidly to site of injury

Release enzymes, histamine, lipid mediators of inflammation from granules

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9
Q

Mononuclear cells (monocytes and macrophages)

A

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.

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10
Q

Types of phagocyte deficiency

A 
Failure to produce myeloid/lymphoid cells 
Failure to produce neutrophils 
Defect of phagocyte migration
Failure of oxidative killing mechanism
Cytokine deficiencies
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11
Q

What is reticular dysgenesis

A

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

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12
Q

Kostmann syndrome

A

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

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13
Q

Cyclic neutropenia

A

Autosomal dominant episodic neutropenia every 4-6 weeks

Mutation in neutrophil elastase (ELA-2)

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14
Q

Leukocyte adhesion deficiency

A

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

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15
Q

Chronic granulomatous disease

A

Failure of oxidative killing mechanism (type of phagocyte deficiency)

Absent respiratory burst
Excessive inflammation
Granuloma formation
Lymphadenopathy and hepatosplenomegaly

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16
Q

Investigations of chronic granulomatous disease

A

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

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17
Q

Cytokine deficiency

A

IL12, IL12R, IFNg or IFNg R deficiency

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18
Q

What is the IL12-IFNg network

A

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
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19
Q

What are patients with cytokine deficiencies at greater risk of

A

Mycobacterial infection

Salmonella infection

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20
Q

What do phagocyte deficiencies lead to

A

Recurrent infections (skin/mouth)

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21
Q

What type of infection do cytokine deficiencies lead to

A 
Bacterial (staph aureus, enteric bacteria)
Fungal infections (candica albicans, aspergillus fumigatus and flavus) 
Mycobacterial infection (mycobacterium tuberculosis, atypical mycobacteria)
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22
Q

Management of phagocyte deficiencies

A 
Agresive management of infection (infection prophylaxis - septrin, itraconazole)
Definitive therapy (haematopoietic stem cell transplantation, specific treatment for CGD)
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23
Q

Infections with atypical mycobacterium. Normal FBC

A

IFNg receptor deficiency

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24
Q

Recurrent infections with no neutrophils on RBC

A

Kostmann syndrome

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25
Q

Recurrent infections with hepatosplenomegaly and abnormal dihydrohodamine test

A

Chronic granulomatous disease

26
Q

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

A

Leukocyte adhesion deficiency

27
Q

Natural Killer cells

A

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

28
Q

Natural killer cell deficiencies

A

Classical NK deficiency

Functional NK deficiency

29
Q

What are the features of classical natural killer cell deficiency

A

Absence of natural killer cells within peripheral blood

Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2

30
Q

Features of functional natural killer cell deficiency

A

NK cells present but function is abnormal

Abnormality described in FCGR3A gene in subtype 1

31
Q

Viral infections in natural killer cell deficiencies

A 
HSV 1 and 2
VZV
EBV
CMV
PMV
32
Q

Treatment of NK deficiencies

A

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

33
Q

What is complement

A

> 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

34
Q

Three pathways of complement activation

A

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

35
Q

What is the end result of the complement pathway

A

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

36
Q

Role of complement fragments released during complement activation

A

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

37
Q

Classical pathway of complement activation

A

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)

38
Q

Complement deficiencies in classical pathway

A

Immune complexes fail to activate complement pathway

Increased susceptibility to infection

39
Q

How are deficiencies of early classical complement components associated with SLE

A

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

40
Q

What is the most common complement deficiency associated with SLE

A

C2

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

41
Q

Mannose Binding Lectin (MBL) pathway of complement activation

A

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

42
Q

Mannose Binding Lectin deficiency

A

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

43
Q

Alternative pathway of complement activation

A

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

44
Q

What occurs if there is a deficiency in the alternative pathway

A

Inability to mobilise complement rapidly in response to bacterial infection

45
Q

Clinical features of factor B, I or P deficiency

A

Recurrent infections with encapsulated bacteria

46
Q

Significance of C3 in complement activation

A

Activation of C3 is the major amplification step in the complement cascade

Triggers the formation of the membrane attack complex via C5-C9

47
Q

C3 deficiency

A

Severe susceptibility to bacterial infections
Neisseria meningitis
Streptococcus pneumonia
Haemophilus influenza

Increased risk of development of connective tissue disease

48
Q

C5-9 deficiencies

A

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

49
Q

How does active lupus lead to a functional complement deficiency

A

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

50
Q

How can secondary complement deficiencies come bout

A

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

51
Q

How can you investigate the complement pathways

A

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

52
Q

C1q deficiency

A

Normal C3
Normal C4
Low CH50
Normal AP50

53
Q

Factor B deficiency

A

Normal C3
Normal C4
Normal CH50
Low AP50

54
Q

C9 deficiency

A

Normal C3
Normal C4
Low CH50
Low AP50

55
Q

SLE

A

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

56
Q

How are patients with complement deficiencies managed

A

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

57
Q

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

A

C7 deficiency

58
Q

Membraneproliferative nephritis and bacterial infections

A

C3 deficiency with presence of a nephritic factor

59
Q

Severe childhood onset SLE with normnal levels of C3 and C4

A

C1q deficiency

60
Q

Recurrent infection when receiving chemotherapy but previously well

A

MBL deficiency

61
Q

What complement deficiencies have been described in SLE

A 
C1q
C1r
C1s
C2
C4

Kat's Pathology (105 decks)

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