Primary immunodeficiency Flashcards
1
Q
What is the function of the immune system?
A
Identify and eliminate microorganisms and other harmful substances
2
Q
What are the major hallmarks of immune deficiency?
A
SPUR
3
Q
What is SPUR?
A
- Serious infections
- Persistent infections
- Unusual infections
- Recurrent infections
4
Q
What are serious infections?
A
Unresponsive to oral antibiotics
5
Q
What are persistent infections?
A
- Early structural damage
* Chronic infections
6
Q
What are unusual infections?
A
- Unusual organisms
* Unusual sites
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
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
9
Q
What is the classification of secondary immunodeficiency? (3)
A
- Common
- Often subtle
- Often involves more than one component of immune system
10
Q
What is the classification of primary immunodeficiency?
A
- Rare: 1:10,000 live births
* >200 primary immune deficiencies now described
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
12
Q
What immunodeficiencies are associated with the innate immune system?
A
Phagocytes
13
Q
What cells are part of the innate immune system? (4)
A
Macrophages
Neutrophils
Mast cells
Natural Killer cells
14
Q
What proteins are part of the innate immune system? (3)
A
Complement
Acute phase proteins
Cytokines
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
16
Q
What cells and proteins are involved in the acquired immune system? (3)
A
Cells
- B lymphocytes
- T lymphocytes
Proteins
* Antibodies
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
18
Q
How do anti-cancer agents cause immunosuppression?
A
Impacts haematopoetic bone marrow stem cells, halting production of immune cells
19
Q
How can malignancy cause immunosuppression?
A
Cancerous growths in bone marrow can affect immune cell production
20
Q
What are types of phagocyte? (2)
A
- Neutrophils
* Monocyte/Macrophages
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
22
Q
What are phagocytes important in?
A
Important in defence against bacteria and fungi (particularly important at exposed sites)
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
24
Q
What is the normal number of circulating neutrophils?
A
4,000 - 10,000 mm3
25
What happens to neutrophil numbers in chemotherapy/radiotherapy in treatment of acute leukaemia?
* Neutrophil numbers initially fall to very low levels
| * As the bone marrow recovers, the neutrophil numbers gradually increase
26
Why is the fall of neutrophil numbers important in chemotherapy/radiotherapy?
28% of patients with a very low neutrophil count will experience a severe bacterial infection, despite all precautions
27
Describe the life cycle of a neutrophil (6)
* 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
28
What can cause neutrophil deficiency in the production phase (in bone marrow)? (3)
* 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)
29
What is Reticular Dysgenesis?
most severe form of inborn SCID (severe combined immunodeficiency disease)
30
What is the effect of reticular dysgenesis? (3)
* 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
31
What is Kostmann syndrome?
Rare autosomal recessive disorder (failure of neutrophil maturation)
32
What does Kostmann syndrome result in?
Severe chronic neutropenia - absolute neutrophil count < 200/μL (normal >3000/μL)
33
What are the clinical presentations of Kostmann syndrome? (7)
* Infections, usually within 2 weeks after birth
* Recurrent bacterial infection
* Systemic or localised infection
* Fever
* Irritability
* Oral ulceration
* Failure to thrive
34
What are supportive treatments for Kostmann syndrome? (2)
* Prophylactic antibiotics
| * Prophylactic antifungals
35
Why is definitive treatment necessary for Kostmann syndrome?
Mortality 70% in first year of life without definitive treatment
36
What I the definitive treatment for Kostmann syndrome? (2)
* 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
What would happen if a patient's phagocytes were unable to bind to epithelial adhesion molecules? (3)
What is this condition known as?
* Recurrent bacterial and fungal infections
* very high neutrophil counts
* no pus formation (as pus mainly composed of dead/dying neutrophils)
Leukocyte adhesion deficiency
38
What is leukocyte adhesion deficiency? (2)
* Failure to recognise activation markers expressed on endothelial cells
* Neutrophils are mobilised, but cannot exit bloodstream
39
What kind of immunodeficiency is leukocyte adhesion deficiency?
Rare primary immunodeficiency
40
What causes leukocyte adhesion deficiency?
Genetic defect in leucocyte integrins (CD18)
41
What are clinical features of leukocyte adhesion deficiency?
* Leukocytosis
| * Localised bacterial infections that are difficult to detect
42
How do phagocytes recognise pathogens directly?
PAMPS:PRR
43
What are types of pathogen recognition receptors? (3)
* Toll like receptors
* Scavenger receptors
* Lectin receptors
44
What structures do PPRs recognise? (2)
* Bacterial sugars
| * Lipopolysaccharide
45
Are pathogen recognition receptors the same in every individual?
Nah, exhibit genetic polymorphism
46
What are the components of indirect pathogen recognition by phagocytes? (3)
* Opsonins
* Phagocytes express Fc receptors
* Phagocytes express Complement receptor 1 (CR1)
47
What are opsonins? Examples?
* Molecules that act as binding enhancers for phagocytosis
| * Complement C3b, IgG antibody, and C-reactive protein
48
What are Fc receptors?
Expressed by phagocytes - allow binding of antibody that is also bound to antigen
49
What is Complement Receptor 1 (CR1)?
Expressed by phagocytes - binds to complement fragments that are also bound to antigen
50
What are defects of recognition in phagocytes? (2)
* 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
Why are defects in complement and antibody production known as functional defects of phagocytosis?
The defect is not in the phagocytes themselves but in other components of immune response
52
What is failure of oxidative killing mechanisms known as?
Chronic granulomatous disease
53
What is chronic granulomatous disease? (2) Results in? Commonest cause?
* 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
What are clinical features of chronic granulomatous disease?(2) Why do these occur? (2)
* Excessive inflammation
* Granuloma formation
* Failure to degrade chemoattractants and antigens
* Persistent accumulation of neutrophils, activated macrophages and lymphocytes
55
What are the effects of chronic granulomatous disease? (5)
* Recurrent bacterial infections
* Recurrent fungal infections
* Failure to thrive
* Lymphadenopathy and hepatosplenomegaly
* Granuloma formation
56
What is the NBT (nitroblue tetrazolium) test?
For chronic granulomatous disease - to investigate whether neutrophils can kill through production of oxidative radicals
57
What is the process of NBT test? (3)
* 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
What is the treatment of chronic granulomatous disease? (2)
Supportive treatment
* Prophylactic antibiotics
* Prophylactic antifungals
Definitive treatment
* Stem cell transplantation
* (Gene therapy)
59
What are intracellular organisms?
Hide from immune system by entering cells
| some can also hide within immune cells - especially macrophages e.g. mycobacteria species
60
What are examples of intracellular organisms? (4)
Salmonella
Chlamydia
Rickettsia
Mycobacteria species (in macrophages)
61
What response does infection with mycobacteria (TB) cause in phagocytes?
Activates IL-12 : IFNy network
62
Explain the IL-12 : IFNy network (5)
* 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
What can defects in the IL-12 : IFNy pathway cause? (2)
* Increased susceptibility to mycobacterial infections (TB and atypical bacteria)
* Increases susceptibility to salmonella
64
What is interleukin 12?
Pro-inflammatory cytokine
65
What are single gene defects associated with activation of other components of the immune system? (3)
* IFNy receptor deficiency
* IL-12 deficiency
* IL-12 receptor deficiency
66
How would you investigate mobilisation of phagocytes from bone marrow?
Full blood count
67
How would you investigate migration of phagocytes to site of infection? (2)
* Presence of pus
| * Expression of neutrophil adhesion moleucles
68
How would you investigate chemotaxis of phagocytes?
Chemotactic assays
69
How would you investigate the formation of phagolysosomes?
Phagocytosis assays
70
How would you investigate oxidative killing by phagocytes?
NBT test of oxidative killing
71
In congenital neutropenia, what is the neutrophil count, pus formation, leukocyte adhesion markers and NBT?
* Neutrophil count - absent
* Pus formation - No
* Leukocyte adhesion markers - normal
* NBT - Usually absent (because no neutrophils)
72
In leukocyte adhesion defect, what is the neutrophil count, pus formation, leukocyte adhesion markers and NBT?
* Neutrophil count - increased during infection
* Pus formation - No
* Leukocyte adhesion markers - absent
* NBT - normal
73
In chronic granulomatous disease, what is the neutrophil count, pus formation, leukocyte adhesion markers and NBT?
* Neutrophil count - normal
* Pus formation - Yes
* Leukocyte adhesion markers - Normal
* NBT - abnormal
74
What is the treatment for phagocyte deficiencies? (5)
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
What is the specific treatment for CGD? (2)
* gamma interferon therapy
| * gene therapy
