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PathY5 > Primary Immune deficiency 1 > Flashcards

Primary Immune deficiency 1 Flashcards

1
Q

How do you get Primary Immune deficiencies?

A

Inherited (rare, 1:10,000 live births)

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2
Q

How do you get Secondary Immune deficiencies?

A

Infection, malignancy, drugs, nutritional deficiencies

Common and involves more than one component of immune system

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3
Q

How do you get Physiological immune deficiencies?

A

Neonates
Pregnancy
Old Age

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4
Q

What are the causes of secondary immune deficiencies?

A

Infection- HIV/ Measles
Biochemical disorders - Malnutrition, zinc def, renal
Malignancy- Blood
Drugs- Steroids, immunosuppressants, cytotoxic therapy

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5
Q

What suggests primary immunodeficiency?

A 
2 major or 1 major + recurrent minor infections in 1 yr
Unusual organism or site
Unresponsive to treatment
Chronic infections
Early structural damage

Specifically:
Family history
Young age at presentation
Failure to thrive

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6
Q

Where may immunodeficiency act?

A

Cells of the innate immune response:
Phagocytes
Cytokines and receptors
Natural killer cells

Complement

Cells of the adaptive immune response

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7
Q

What are the cells and soluble components of the innate immune system?

A 
Cells
Polymorphonuclear cells – neutrophils, eosinophils, basophils
Monocytes and macrophages
Dendritic cells
Natural killer cells

Soluble components
Complement
Acute phase proteins
Cytokines and chemokines

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8
Q

What do phagocytes do?

A

Receptors:
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:
PRRs like TLRs/ mannose R recognise PAMPs such as bacterial sugars, DNA, RNA

Cells express Fc receptors to allow them detection of immune complexes

Engulfment:
Phagocytic engulfment of pathogen.

Regulation:
Via secretion of chemokines and cytokines

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9
Q

What do PMNs do?

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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10
Q

How do immune cells work?

A

Mobilisation of phagocytes and precursors from bone marrow or within tissues

Endothelial cell activation with increased expression of adhesion molecules

Increased neutrophil adhesion and migration into tissues

Phagocytosis of organisms

Oxidative and non-oxidative killing

Macrophage -T cell communication

Cell death and the formation of pus

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11
Q

What are the types of phagocyte deficiency?

A

Failure to produce neutrophils

Defect of phagocyte migration

Failure of oxidative killing mechanisms

Cytokine deficiency

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12
Q

What happens in Failure to produce neutrophils?

A
  1. Failure of stem cells to differentiate along myeloid or lymphoid lineage
    Reticular dysgenesis – autosomal recessive severe SCID
    Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
  2. Specific failure of neutrophil maturation
    Kostmann syndrome - autosomal recessive severe congenital neutropenia
    Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)

Cyclic neutropenia - autosomal dominant episodic neutropenia every 4-6 weeks
Mutation in neutrophil elastase (ELA-2)

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13
Q

What is Leukocyte adhesion deficiency?

A

Deficiency of CD18 (b2 integrin subunit)

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

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14
Q

How does Leukocyte adhesion deficiency work?

A

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

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15
Q

What is the pathogenesis of Chronic Granulomatous Disease (CGD)?

A 
Absent respiratory burst
Deficiency of a one NADPH oxidase component
No oxygen free radical killing.
-> 
Excessive inflammation and Neut/ Macrophage accumulation
Failure to degrade Ag
-> 
Granuloma formation 
-> 
Lymphadenopathy and hepatosplenomegaly
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16
Q

What are the investigations for CGD?

A 
Nitroblue tetrazolium (NBT) test 
Dihydrorhodamine (DHR) flow cytometry test
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17
Q

How does NBT and DHR work?

A

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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18
Q

What is cytokine deficiency?

A

Deficiency in the IL-12 - IFNg feedback pathway

IL12, IL12R, IFNg or IFNg R deficiency

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19
Q

Why is cytokine deficiency bad?

A

Infection activates IL12- IFNg network
Infected macrophages stimulated to produce IL12
IL12 induces T cells to secrete IFNg
IFNg feeds back to macrophages & neutrophils
Stimulates production of TNF
Activates NADPH oxidase
Stimulates oxidative pathways

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20
Q

Which infections occur in phagocyte deficiency?

A

Recurrent infections – skin / mouth
Bacterial infections
Staphylococcus aureus
Enteric bacteria

Fungal infections
Candida albicans
Aspergillus fumigatus and flavus

Mycobacterial infection
Mycobacterium tuberculosis
Atypical Mycobacteria

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21
Q

What is the treatment of phagocyte deficiency?

A

Aggressive management of infection

Definitive therapy

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22
Q

What is Definitive therapy in phag deficiency?

A

Haematopoietic stem cell transplantation
‘Replaces’ defective population
Specific treatment for CGD
Interferon gamma therapy

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23
Q

How do you do Aggressive management of infection in phag deficiency?

A

Infection prophylaxis
Antibiotics – eg Septrin
Anti-fungals – eg Itraconazole
Oral/intravenous antibiotics as needed

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24
Q

What do natural killer cells do?

A

Cytotoxicity
Cytokine secretion
Contact dependent regulation

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25
Q

How do natural killer cells work?

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

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26
Q

What are the types of natural killer cell deficiencies?

A

Classical NK deficiency
Absence of NK cells within peripheral blood
Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2

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

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27
Q

What viruses can cause NK cell deficiencies?

A

Herpes Virus infection: Herpes Simplex virus I and II, Varicella Zoster virus, Epstein Barr virus, Cytomegalovirus

HPV: Papillomavirus infection

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28
Q

What is the treatment of NK cell deficiency?

A

No good trial data

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

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29
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
Results in rapid, highly amplified response

30
Q

What are the 3 pathways of complement activation?

A

Classical (C1, C2 and C4)
MBL (C2 and C4)
Alternate pathway

Common pathway - C3 triggers C5-9 and forms the Membrane Attack Complex

31
Q

How does the classical pathway work?

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)

32
Q

How does the MBL pathway work?

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

33
Q

How does the alternate pathway work?

A

Bacterial cell wall fails to regulate low level of spontaneous activation of alternate pathway
eg lipopolysaccharide of gram negative bacteria
teichoic acid of gram positive bacteria

Not dependent on acquired immune response

Involves factors B, D and Properidin

Factor H – control protein

34
Q

What is the common pathway 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

35
Q

What does complement do?

A

Increases vascular permeability and cell trafficking to site of inflammation

Opsonisation of pathogens to promote phagocytosis

Promotes clearance of immune complexes

Activates phagocytes

Promotes mast cell/basophil degranulation

Punches holes in bacterial membranes

36
Q

What does complement deficiency cause?

A

Susceptibility to bacterial infections [Especially encapsulated bacteria (NHS-M)]:

> Neisseria meningitides – esp properidin and C5-9 deficiency
Haemophilus influenzae
Streptococcus pneumoniae
Meningococcal septicaemia

Complement deficiency
May involve classical, alternate, C3 or final common pathway

37
Q

What does MBL deficiency cause?

A

MBL deficiency

MBL2 mutations are common but not usually associated with immunodeficiency

38
Q

What is the problem caused by deficiency in this part of the pathway:

Classical complement pathway activation promotes phagocyte mediated clearance of apoptotic/necrotic cells

A

Auto immunity

Deficiencies results in increased load of self antigens – particularly nuclear components – which may promote auto-immunity and formation of immune complexes

39
Q

What is the problem caused by deficiency in this part of the pathway:

Classical complement pathway activation promotes clearance of immune complexes by erythrocytes

A

Local Inflammation

Deficiencies result in deposition of immune complexes which stimulates local inflammation in skin, joints and kidneys

40
Q

How are deficiencies of early complement components associated with SLE?

A

C1q, C1r, C1s, C2, C4 deficiency are all described
All are rare
C2 deficiency most common

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

41
Q

What does active lupus cause persistent production of?

A

Immune complexes

Consequent consumption of complement -> functional complement deficiency

42
Q

What are secondary causes of complement deficiency?

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

43
Q

How do you investigate complement?

A

Quantitation of complement components
C3, C4 routinely measured
C1 inhibitor – decreased in hereditary angiodema
Other components not routinely quantified, but can be performed if deficiency is suspected

Functional complement tests
CH50 classical pathway
AP50 alternative pathway

44
Q

How do you manage patients with complement deficiencies?

A

Vaccination- Meningovax, Pneumovax and HIB vaccines

Prophylactic antibiotics

Treat infection aggressively

Screening of family members

45
Q

Which cells are affected by Kostmann syndrome?

A

Phagocytes

46
Q

Which cells are affected by Reticular dysgenesis?

A

Haematopoietic stem cells

47
Q

Which cells are affected by 22q11.2 deletion syndromes?

A

T cells

48
Q

Which cells are affected by Terminal pathway deficiencies?

A

Complement

49
Q

Which cells are affected by Leukocyte adhesion deficiency?

A

Phagocytes

50
Q

Which cells are affected by C3 deficiency?

A

Complement

51
Q

Which cells are affected by Severe combined immunodeficiency?

A

Lymphoid precursors

52
Q

Which cells are affected by Common variable immunodeficiency?

A

B cells

53
Q

Which cells are affected by IgA deficiency?

A

B cells

54
Q

Which cells are affected by Classical pathway deficiencies?

A

Complement

55
Q

Which cells are affected by X-linked hyperIgM syndrome?

A

B cells

56
Q

Which cells are affected by

IL12 and IL12 receptor deficiency?

A

Cytokines

57
Q

Which cells are affected by X-linked agammaglobulinaemia?

A

B cells

58
Q

Which cells are affected by Functional NK deficiency?

A

NK cells

59
Q

Which cells are affected by Alternative pathway deficiencies?

A

Complement

60
Q

Which cells are affected by IFNg and IFNg receptor deficiency?

A

Cytokines

61
Q

Which cells are affected by Chronic granulomatous disease?

A

Phagocytes

62
Q

Which cells are affected by Severe combined immunodeficiency?

A

Lymphoid precursors

63
Q

Which cells are affected by Bare lymphocyte syndrome?

A

T cells

64
Q

Which cells are affected by Classical NK deficiency?

A

NK cells

65
Q

What lab tests do you nee for PID?

A

White cells
Full blood count
Lymphocyte subsets
Special tests for white cell migration/function

Immunoglobulins
IgM, IgG, IgA
Specific Igs and response to vaccination

Complement
Complement function
Individual complement components

66
Q

What do monocytes do?

A

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

67
Q

What are the macrophages?

A 
Liver Kupffer cell
Kidney Mesangial cell
Bone Osteoclast
Spleen Sinusoidal lining cell
Lung Alveolar macrophage
Neural tissue Microglia
Connective tissue Histiocyte
Skin Langerhans cell
Joints Macrophage like synoviocytes
68
Q

What is SLE associated with?

A

C3 /4 Deficiency

69
Q

What do C3 nephritic factors do?

A 
• Nephritic factors are autoantibodies 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 (upper body)
lipodystrophy
70
Q

Is MBL deficiency associated with important clinical consequences?

A

No

71
Q

Meningococcal meningitis, FHx of sibling with death age 6, No SLE no proteinuria, normal fat distribution. What is the problem?

A

C7 deficiency

72
Q

9 yo girl with SLE and normal C3/4 what is the complement deficiency?

A

C1q deficiency

PathY5 (98 decks)

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