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4 - Y5 a Path lectures 2021/22 > Immuno 6: Immune Deficiencies > Flashcards

Immuno 6: Immune Deficiencies Flashcards

1
Q

Name some cells of the innate immune system

A

phagocytes, cytokines & receptors, natural killer cells

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2
Q

Name some cells of the adaptive immune system

A

B and T cells

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3
Q

Name some types of phagocyte deficiency

A
  1. Failure to produce neutrophils
  • failure of stem cells to differentiate along myeloid or lymphoid cell lineage
  • specific failure of neutrophil maturation

2. Defect of phagocyte migration

3. Failure of oxidative killing mechanisms

4. Cytokine deficiency

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4
Q

Name the conditions caused by phagocyte deficiency of failure to produce neutrophils

A
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5
Q

Name the conditions caused by phagocyte deficiency of phagocyte migration defect

A
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6
Q

Name the condition caused by phagocyte deficiency of failure of oxidative killing mechanisms

A
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7
Q

How is chronic granulomatous disease investigated?

A
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8
Q

Name the conditions caused by cytokine deficiency (causing phagocyte deficiency)

A
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9
Q

Summarise the conditions that can cause phagocyte deficiency

A
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10
Q

How do phagocyte deficiencies present?

A

Infections

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11
Q

Which infections are common in phagocyte deficiencies?

A

Recurrent skin/mouthinfections:

  • Bacteriala: S. aureus, enteric bacteria
  • Fungala: candida, aspergillus fumigatus and flavus

Mycobacterial infection

  • Mycobacterium tuberculosis
  • Atypical mycobacterium
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12
Q

What is the treatment of phagocyte deficiencies?

A

Aggressive management of infection:

  • Infection prophylaxis:
    • Antibiotics – e.g. Septrin
    • Anti-fungals – e.g. Itraconazole
  • Oral/intravenous antibiotics as needed

Definitive therapy:

  • Haematopoietic stem cell transplantation (‘Replaces’ defective population)
  • Specific treatment for CGD (interferon gamma therapy)
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13
Q

What is the cause of leukoctye adhesion deficiency?

A

Leukocyte adhesion deficiency / LAD = deficiency of CD18 (beta-2 integrin subunit):

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14
Q

What do neutrophils bind to in the vascular endothelium, during migrations and acticvation?

A

Normal = CD11a/CD18 (LFA-1) on neutrophils binds to ICAM-1 on endothelium for adhesion and transmigration

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15
Q

What are the consequences of LAD?

A

LAD = neutrophils lack LFA-1 → cannot bind to ICAM-1 on endothelium for adhesion and transmigration

  • Very high neutrophil count in blood
  • Delayed umbilical cord separation at birth
  • Absence of pus formation
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16
Q

What is Chronic granulomatous disease?

A

failure of phagocytes’ oxidative killing mechanisms:

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17
Q

What are the main causes of chronic granulomatous disease?

A

Cause = absent respiratory burst:

  • Deficiency of one of componentsof NADPH oxidase
  • Inability to genera te O2 free radicals so impaired killing
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18
Q

What are the signs and symptom of chronic granulomatous disease?

A
  • Excessive inflammation:
    • Persistent neutrophil/macrophage accumulation
    • Failure to degrade antigens
  • Granuloma formation
  • Lymphadenopathy and. hepatosplenomegaly
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19
Q

How do you diagnose chronic granulomatous disease?

A

Tests: DHR and NBT tests (both -ve in CGD)

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20
Q

Name 3 conditions which are a failure to produce neutrophils. How do these present?

A
  • Kostmann syndrome,
  • Reticular Dysgenesis,
  • Cyclic Neutropoenia

Present as recurrent infections.

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21
Q

What is reticular dysgenesis?

A

Failure of stem cells to differentiate along myeloid or lymphoid lineage

autosomal recessive severe SCID

  • Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
  • Also has low B and T cell numbers as this is a SCID (differentiate from Kostmann’s)
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22
Q

What is Kostmann syndrome?

A

Specific failure of neutrophil maturation

autosomal recessive severe congenital neutropenia

  • Classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
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23
Q

What is Cyclic neutropenia?

A

Specific failure of neutrophil maturation

autosomal dominant episodic neutropenia every 4-6weeks

  • Mutation in neutrophil elastase (ELA-2)
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24
Q

What is IFN gamma / IL-12 network failure?

A
  • Cytokine deficiency;
  • One of… IL-12, IL-12-r, IFNg, IFNg-r deficiency
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25
Q

What is the IL-12 to IFNg network’s important function?

A

IL-12 to IFNg network important in control of mycobacteria infection:

  • Infection activates IL12-IFNg network
  • Infected macrophages produce IL12
  • IL12 induces T cells to secrete IFNg
  • IFNg feedsback to macrophages & neutrophils
  • Stimulates production of TNF
  • Activates NADPH oxidase → oxidative pathways
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26
Q

What are some features of NK cells?

A
  • Inhibitory receptors recognise self-HLAa → prevent inappropriate activation to normal self
  • Activator receptors (inc. natural cytotoxicity receptors) recognise heparan sulphate proteoglycans
    • Cytotoxicity
    • Cytokine secretion
    • Contact-dependent regulation
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27
Q

What do NK cell deficiencies present as?

A

VIRAL infections

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28
Q

What are the most common infections that NK cell deficiencies present as?

A
  • HHV infections–HSV1/2, VZV, EBV, CMV
  • HPV infection
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29
Q

Describe Functional NK deficiency

A
  • NK cells present but function is abnormal
  • Abnormality described in FCGR3A gene in subtype 1
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30
Q

what is the Tx for NK cell deficiencies?

A
  • Prophylactic aciclovir/ganciclovir
  • HSCT(severe phenotypes)
  • Cytokines(IFN a) to stimulate NK cytotoxic function
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31
Q
A

1 E

2 A

3 D

4 C

5 B

32
Q

Describe Classical NK deficiency

A
  • Absence of NK cells within peripheral blood
  • Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2
33
Q

What are the 2 types of NK cell deficiency?

A

classical or functional NK cell deficiency

34
Q

How does NK deficiency classically present?

A

child with severe chicken pox and disseminated CMV infection (VIRAL!!!)

35
Q

What is complement?

A
  • >20 tightly regulated, linked proteins:
  • Produced by the liver
  • Present in circulation as inactive molecules
36
Q

What are the functions of complement?

A
  • Increase vascular permeability/cell chemotaxis
  • Promote clearance of immune complexes
  • Opsonisation of pathogens to promote phagocytosis
  • Activate phagocytes
  • Promote mast cell/basophil degranulation
  • Form the Membrane Attack Complex (MAC)
37
Q

Which complement component is made before activation of the final common pathway?

A

C3

38
Q

What are the 3 pathways of complement activation?

A
  • Classical pathway
  • Mannose Binding Lectin
  • Alternative pathway
39
Q

Describe the classical pathway

A

Antibody + C1a → C2, C4 → C3

  • Changed antibody site exposes C1 binding site
  • C1 binding to antibody activates cascade
  • Antibody-antigen immune complexes
40
Q

Describe the MBL pathway

A

MBL → C2, C4 → C3

  • Binding of MBL to microbial cell surface CHO
  • Direct stimulation of classical pathway (only C4, C2)
  • Not dependant on acquired immune response
41
Q

Describe the alternative pathway

A

PAMP (LPS, teichoic acid) → C3

  • C3 binding to bacterial cell wall components
  • E.G. LPS (gram -ve) or teichoic acid (gram +ve)
  • Involves factors B, P(properidin), D–regulated by factors H, I
  • Not dependant on acquired immune response
42
Q

Describe complement deficiency. Which infections are these patients more susceptible to?

A

Mayinvolve classical, alternate, C3 or final common pathway

Susceptibility to bacterial infections (especially encapsulated bacteria: NHS)

  • Neisseria meningitides – esp. properidin deficiency and C5-9 deficiency
  • Haemophilus influenzae
  • Streptococcus pneumoniae
43
Q

Are MBL deficiencies common? What are they associated with?

A

MBL2 mutations are common but not usually associated with immunodeficiency

44
Q

What are C1, C2, C4 deficiencies associated with?

A

increased risk of SLE / autoimmunity

45
Q

How does Classical pathway deficiencies lead to auto-immunity?

A
  1. Classical pathway → phagocyte mediated clearance of apoptotic/necrotic cells
  • Deficiencies → self-antigens uncleared → autoimmunity & immune complexes (i.e. SLE)
  • Self-antigens are often nuclear components
  1. Classical pathway → clearance of immune complexes by erythrocytes
    * Deficiencies → immune complex deposition → local inflammation in skin, joints and kidneys
46
Q

What is C3 nephritic factor (anti-C3-convertase) associated with?

A

depletes C3:

  • Associated with glomerulonephritis (membranoproliferative)
  • Associated with partial lipodystrophy
47
Q

What is the Mx for complement deficienices?

A
  • Vaccination (boost protection mediated by other arms of the immune system)
    • Meningovax, Pneumovax and HIB vaccines
  • Prophylactic antibiotics
  • Treat infection aggressively
  • Screening of family members
48
Q

What are the Ix for ?complement deficiency?

A
  • Levels of C3 and C4
  • Functional complement tests:
    • CH50 classical pathway(CH)
    • AP50 alternative pathway(AP)
      • Properidin
      • Factors B and D
49
Q
A

work out answers lol

50
Q

What are the primary lymphoid organs?

A
  • organs involved in lymphocyte development*:
  • Bone marrow (T and B cell derivation; site of B cell maturation)
  • Thymus (site of T cell maturation; most active in foetal and neonatal period à involutes after puberty)
51
Q

What are the Clinical features of T-cell deficiencies

A
  • Viral infections (CMV)
  • Fungal infection (Pneumocystis – CD4 T cell cytokines needed to control PCP; Cryptosporidium)
  • Some bacterial infections (esp. intracellular organisms → Mycobacteria tuberculosis, Salmonella)
  • Early malignancy
52
Q

How do you investigate T cell deficiencies?

A
53
Q

How do you manage T cell immunodeficiency?

A
54
Q

What is x-linked X-linked SCID (Severe Combined Immunodeficiency?

A

inability to respond to cytokine

55
Q

Describe X linked SCID

A
56
Q

How is the neonate protected from SCID and ADA deficiency in the first 3 months of life?

A
  • IgG from the maternal placental supply
  • IgG from breast milk colostrum–however this is not as good and leads to eventual drop of IgG
56
Q

How is the neonate protected from SCID and ADA deficiency in the first 3 months of life?

A
  • IgG from the maternal placental supply
  • IgG from breast milk colostrum–however this is not as good and leads to eventual drop of IgG
57
Q

What is Di George Syndrome?

A

22q 11.2 deletion syndrome – a development defect of the pharyngeal pouch

58
Q

What are the features of Di George syndrome?

A

o Not mentally retarded but higher schizophrenia as an adult

59
Q

How is Di George syndrome detected?

A

o Detected by FISH cytogenetic analysis

60
Q

What are the different phenotypes of Di George syndrome?

A
61
Q

Summarise the genetics behind Di George syndrome

A
  • Deletion at 22q11.2 (TUPLE locus)
  • TBX1 responsible for some features
  • Initially a sporadic mutation → autosomal dominant inheritance
62
Q

What is Bare lymphocyte syndrome (type 2) ?

A

absent MHC class 2:

  • Absent expression of MHC Class II molecules (BLS type 1 exists when MHC class 1 fails to express)
  • Defect in a regulatory protein involved in Class II gene expression
    • Regulatory factor X
    • Class II transactivator
63
Q

What are the phenotypes of Bare lymphocyte syndrome (type 2) ?

A

T-cells= low CD4 cells; normal CD8 cells

B-cells = normal; BUT low IgG or IgA antibody (due to lack of CD4+ T cell help)

64
Q
A

work out answers lol

65
Q

Summarise the immunodeficiencies that can occur via T cells

A
66
Q

Summarise the features of a B-cell (or CD4 T-cell) deficiency

A

antibody deficiency:

  • Bacterial infections (Staphylococcus, Streptococcus)
  • Toxins (Tetanus, Diphtheria)
  • Some viral infections (Enterovirus)
67
Q

What are the investigations for B cell deficiency?

A
68
Q

What is the management of B-cell immunodeficiency

A
69
Q

What is Bruton’s X-linked hypogammoglobinaemia

A
  • Abnormal (BTK) gene
  • Pre-B-cells cannot develop to mature B cells →
  • No circulating Ig after ~3 months (i.e. no IgG, IgA or IgM)
  • Mx: IVIG
70
Q

What is X-linked (recessive) hyper-IgM syndrome ?

A

due to CD40 ligand mutation:

71
Q

what is Common variable immunodeficiency

A
72
Q

What are the clinical features of common variable immunodeficiency?

A
73
Q

Describe IgA deficiency

A

Core features:

  • 1 in 600 prevalence
  • 2/3rds individuals symptomatic
  • 1/3rd have recurrent RTIs
  • Genetic component but cause unknown
74
Q
A

work out answers lol

75
Q

Summarise the B cell immunodeficiencies

A

4 - Y5 a Path lectures 2021/22 (37 decks)

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