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Respiratory: Immunology > Primary immunodeficiency > Flashcards

Primary immunodeficiency Flashcards

1
Q

What is the function of the immune system?

A

Identify and eliminate microorganisms and other harmful substances

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2
Q

What are the major hallmarks of immune deficiency?

A

SPUR

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3
Q

What is SPUR?

A
  • Serious infections
  • Persistent infections
  • Unusual infections
  • Recurrent infections
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4
Q

What are serious infections?

A

Unresponsive to oral antibiotics

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5
Q

What are persistent infections?

A
  • Early structural damage

* Chronic infections

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6
Q

What are unusual infections?

A
  • Unusual organisms

* Unusual sites

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7
Q

What are recurrent infections? (2)

A
  • Two major infections in one year

* or one major and many recurrent minor infections in one year

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8
Q

What are clinical features that may be suggestive of primary immune deficiency?(6)

A
  • Weight loss or failure to thrive
  • Severe skin rash (eczema)
  • Chronic diarrhoea
  • Mouth ulceration
  • Unusual autoimmune disease
  • Family history
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9
Q

What is the classification of secondary immunodeficiency? (3)

A
  • Common
  • Often subtle
  • Often involves more than one component of immune system
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10
Q

What is the classification of primary immunodeficiency?

A
  • Rare: 1:10,000 live births

* >200 primary immune deficiencies now described

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11
Q

What are conditions associated with secondary immune deficiency? (5)

A
  • Extremes of life (physiological) - ageing, prematurity
  • Infection - human immunodeficiency virus, measles
  • Treatment interventions - immunosuppressive therapy, anti-cancer agents (targets haematopoetic bone marrow stem cells), corticosteroids
  • Malignancy - cancer of the immune system (lymphoma, leukaemia, myeloma), metastatic tumours
  • Biochemical and nutritional disorders - malnutrition, renal insufficiency/dialysis, type 1 and 2 diabetes, specific mineral deficiencies e.g. iron, zinc
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12
Q

What immunodeficiencies are associated with the innate immune system?

A

Phagocytes

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13
Q

What cells are part of the innate immune system? (4)

A

Macrophages
Neutrophils
Mast cells
Natural Killer cells

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14
Q

What proteins are part of the innate immune system? (3)

A

Complement
Acute phase proteins
Cytokines

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15
Q

What are the functions of the innate immune system? (3)

A

Recognise structures (PAMPs) that are unique to infectious organisms in order to cause:

  • Rapid clearance of microorganisms
  • Stimulates the acquired immune response
  • Buys time while the acquired immune system is mobilized
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16
Q

What cells and proteins are involved in the acquired immune system? (3)

A

Cells

  • B lymphocytes
  • T lymphocytes

Proteins
* Antibodies

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17
Q

What are characteristics of the acquired immune system? (4)

A
  • Acquired as an adaptive response to exposure to antigen
  • Responsive to an unlimited number of molecules (antigens)
  • Exquisite specificity
  • Immunological memory
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18
Q

How do anti-cancer agents cause immunosuppression?

A

Impacts haematopoetic bone marrow stem cells, halting production of immune cells

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19
Q

How can malignancy cause immunosuppression?

A

Cancerous growths in bone marrow can affect immune cell production

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20
Q

What are types of phagocyte? (2)

A
  • Neutrophils

* Monocyte/Macrophages

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21
Q

What are functions of phagocytes? (4)

A
  • Initiation and amplification of the inflammatory response
  • Scavenging of cellular and infectious debris
  • Ingest and kill microorganisms
  • Resolution and repair
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22
Q

What are phagocytes important in?

A

Important in defence against bacteria and fungi (particularly important at exposed sites)

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23
Q

What are organisms that are associated with recurrent infection? (4)

A
  • Common bacteria: e.g. Staphylococcus Aureus
  • Unusual bacteria: e.g. Burkholderia cepacia
  • Mycobacteria: both tuberculosis and atypical mycobacteria
  • Fungi e.g. Candida, Aspergillus
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24
Q

What is the normal number of circulating neutrophils?

A

4,000 - 10,000 mm3

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25
Q

What happens to neutrophil numbers in chemotherapy/radiotherapy in treatment of acute leukaemia?

A
  • Neutrophil numbers initially fall to very low levels

* As the bone marrow recovers, the neutrophil numbers gradually increase

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26
Q

Why is the fall of neutrophil numbers important in chemotherapy/radiotherapy?

A

28% of patients with a very low neutrophil count will experience a severe bacterial infection, despite all precautions

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27
Q

Describe the life cycle of a neutrophil (6)

A
  • Mobilisation of neutrophils and precursors from bone marrow
  • Upregulation of endothelial adhesion markers
  • Neutrophil adhesion and migration into tissues via chemotaxis
  • Recognition of the organism
  • Phagocytosis and killing of organism
  • Activation of other components of immune system
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28
Q

What can cause neutrophil deficiency in the production phase (in bone marrow)? (3)

A
  • Failure to produce neutrophils
  • Failure of stem cells to differentiate along myeloid lineage (primary defect: recticular dysgenesis, secondary defect: after stem cell transplantation)
  • Failure of neutrophil maturation (Kostmann syndrome: severe congenital neutropaenia, Cyclic neutropaenia -episodic neutropaenia every 4-6 weeks)
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29
Q

What is Reticular Dysgenesis?

A

most severe form of inborn SCID (severe combined immunodeficiency disease)

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30
Q

What is the effect of reticular dysgenesis? (3)

A
  • Absence of neutrophils and other myeloid cells
  • Lymphocyte deficiency in peripheral blood
  • Lack of innate and adaptive immune functions (fatal septicemia within days of birth)
  • Production of RBCs not affected
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31
Q

What is Kostmann syndrome?

A

Rare autosomal recessive disorder (failure of neutrophil maturation)

32
Q

What does Kostmann syndrome result in?

A

Severe chronic neutropenia - absolute neutrophil count < 200/μL (normal >3000/μL)

33
Q

What are the clinical presentations of Kostmann syndrome? (7)

A
  • Infections, usually within 2 weeks after birth
  • Recurrent bacterial infection
  • Systemic or localised infection
  • Fever
  • Irritability
  • Oral ulceration
  • Failure to thrive
34
Q

What are supportive treatments for Kostmann syndrome? (2)

A
  • Prophylactic antibiotics

* Prophylactic antifungals

35
Q

Why is definitive treatment necessary for Kostmann syndrome?

A

Mortality 70% in first year of life without definitive treatment

36
Q

What I the definitive treatment for Kostmann syndrome? (2)

A
  • Stem cell transplantation - defect is in the neutrophil precursor, so strategy is to replace all precursors with allogeneic stem cells and start again
  • Granulocyte colony stimulating factor (G-CSF) - give specific growth factor to assist maturation of neutrophils
37
Q

What would happen if a patient’s phagocytes were unable to bind to epithelial adhesion molecules? (3)
What is this condition known as?

A
  • Recurrent bacterial and fungal infections
  • very high neutrophil counts
  • no pus formation (as pus mainly composed of dead/dying neutrophils)

Leukocyte adhesion deficiency

38
Q

What is leukocyte adhesion deficiency? (2)

A
  • Failure to recognise activation markers expressed on endothelial cells
  • Neutrophils are mobilised, but cannot exit bloodstream
39
Q

What kind of immunodeficiency is leukocyte adhesion deficiency?

A

Rare primary immunodeficiency

40
Q

What causes leukocyte adhesion deficiency?

A

Genetic defect in leucocyte integrins (CD18)

41
Q

What are clinical features of leukocyte adhesion deficiency?

A
  • Leukocytosis

* Localised bacterial infections that are difficult to detect

42
Q

How do phagocytes recognise pathogens directly?

43
Q

What are types of pathogen recognition receptors? (3)

A
  • Toll like receptors
  • Scavenger receptors
  • Lectin receptors
44
Q

What structures do PPRs recognise? (2)

A
  • Bacterial sugars

* Lipopolysaccharide

45
Q

Are pathogen recognition receptors the same in every individual?

A

Nah, exhibit genetic polymorphism

46
Q

What are the components of indirect pathogen recognition by phagocytes? (3)

A
  • Opsonins
  • Phagocytes express Fc receptors
  • Phagocytes express Complement receptor 1 (CR1)
47
Q

What are opsonins? Examples?

A
  • Molecules that act as binding enhancers for phagocytosis

* Complement C3b, IgG antibody, and C-reactive protein

48
Q

What are Fc receptors?

A

Expressed by phagocytes - allow binding of antibody that is also bound to antigen

49
Q

What is Complement Receptor 1 (CR1)?

A

Expressed by phagocytes - binds to complement fragments that are also bound to antigen

50
Q

What are defects of recognition in phagocytes? (2)

A
  • Defect in opsonin receptors may cause defective phagocytosis – still able to occur, just reduction in amount (does not cause significant disease)
  • Any defect of complement or antibody production will also result in decreased efficiency of opsonisation
51
Q

Why are defects in complement and antibody production known as functional defects of phagocytosis?

A

The defect is not in the phagocytes themselves but in other components of immune response

52
Q

What is failure of oxidative killing mechanisms known as?

A

Chronic granulomatous disease

53
Q

What is chronic granulomatous disease? (2) Results in? Commonest cause?

A
  • Deficiency of intracellular killing mechanism of phagocytes
  • Inability to generate oxygen free radicals (ROS/RNS)
  • Impaired killing of intracellular micro-organisms

Commonest cause - deficiency of p47phox component of NADPH oxidase (x-linked)

54
Q

What are clinical features of chronic granulomatous disease?(2) Why do these occur? (2)

A
  • Excessive inflammation
  • Granuloma formation
  • Failure to degrade chemoattractants and antigens
  • Persistent accumulation of neutrophils, activated macrophages and lymphocytes
55
Q

What are the effects of chronic granulomatous disease? (5)

A
  • Recurrent bacterial infections
  • Recurrent fungal infections
  • Failure to thrive
  • Lymphadenopathy and hepatosplenomegaly
  • Granuloma formation
56
Q

What is the NBT (nitroblue tetrazolium) test?

A

For chronic granulomatous disease - to investigate whether neutrophils can kill through production of oxidative radicals

57
Q

What is the process of NBT test? (3)

A
  • Feed patient’s neutrophils source of E coli
  • Add dye that is sensitive to H202
  • If hydrogen peroxide is produced by neutrophils, dye changes colour
58
Q

What is the treatment of chronic granulomatous disease? (2)

A

Supportive treatment

  • Prophylactic antibiotics
  • Prophylactic antifungals

Definitive treatment

  • Stem cell transplantation
  • (Gene therapy)
59
Q

What are intracellular organisms?

A

Hide from immune system by entering cells

some can also hide within immune cells - especially macrophages e.g. mycobacteria species

60
Q

What are examples of intracellular organisms? (4)

A

Salmonella
Chlamydia
Rickettsia
Mycobacteria species (in macrophages)

61
Q

What response does infection with mycobacteria (TB) cause in phagocytes?

A

Activates IL-12 : IFNy network

62
Q

Explain the IL-12 : IFNy network (5)

A
  • Infected macrophages produce IL-12
  • IL-12 causes TH1 and NK cells to secrete IFNγ
  • IFNγ stimulates macrophages & neutrophils to produce TNF
  • Activates NADPH oxidase
  • Stimulates oxidative pathways
63
Q

What can defects in the IL-12 : IFNy pathway cause? (2)

A
  • Increased susceptibility to mycobacterial infections (TB and atypical bacteria)
  • Increases susceptibility to salmonella
64
Q

What is interleukin 12?

A

Pro-inflammatory cytokine

65
Q

What are single gene defects associated with activation of other components of the immune system? (3)

A
  • IFNy receptor deficiency
  • IL-12 deficiency
  • IL-12 receptor deficiency
66
Q

How would you investigate mobilisation of phagocytes from bone marrow?

A

Full blood count

67
Q

How would you investigate migration of phagocytes to site of infection? (2)

A
  • Presence of pus

* Expression of neutrophil adhesion moleucles

68
Q

How would you investigate chemotaxis of phagocytes?

A

Chemotactic assays

69
Q

How would you investigate the formation of phagolysosomes?

A

Phagocytosis assays

70
Q

How would you investigate oxidative killing by phagocytes?

A

NBT test of oxidative killing

71
Q

In congenital neutropenia, what is the neutrophil count, pus formation, leukocyte adhesion markers and NBT?

A
  • Neutrophil count - absent
  • Pus formation - No
  • Leukocyte adhesion markers - normal
  • NBT - Usually absent (because no neutrophils)
72
Q

In leukocyte adhesion defect, what is the neutrophil count, pus formation, leukocyte adhesion markers and NBT?

A
  • Neutrophil count - increased during infection
  • Pus formation - No
  • Leukocyte adhesion markers - absent
  • NBT - normal
73
Q

In chronic granulomatous disease, what is the neutrophil count, pus formation, leukocyte adhesion markers and NBT?

A
  • Neutrophil count - normal
  • Pus formation - Yes
  • Leukocyte adhesion markers - Normal
  • NBT - abnormal
74
Q

What is the treatment for phagocyte deficiencies? (5)

A

Aggressive management of infection

  • Infection prophylaxis (Septrin – anti bacterial, Itraconazole – anti-fungal)
  • Oral/intravenous antibiotics
  • Surgical draining of abscesses

Definitive therapy

  • Bone marrow transplantation
  • Specific treatment for CGD (IFNy therapy, gene therapy)
75
Q

What is the specific treatment for CGD? (2)

A
  • gamma interferon therapy

* gene therapy

Respiratory: Immunology (4 decks)

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