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Pathology ICSM COPY > Immunology 2 - Primary immune deficiencies parts 1 & 2 > Flashcards

Immunology 2 - Primary immune deficiencies parts 1 & 2 Flashcards

(95 cards)

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1
Q

What receptors do phagocytes express?

A

cytokine/chemokine receptors

allow them to home to sites of infection

genetically encoded receptors

PRRs - toll-like/mannose receptors which recognise PAMPs (e.g. bacterial sugars, DNA, RNA)

Fc receptors

detection of immune complexes

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2
Q

How do phagocytes detect pathogens at the site of infection?

A

Expression of genetically-coded receptors such as toll-like receptors, which detect PAMPs

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3
Q

What receptors do NK cells express?

A

Inhibitory receptors recognise self-HLA → prevent inappropriate activation to normal self

Activator receptors (inc. natural cytotoxicity receptors) -> cytotoxicity, cytokines

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4
Q

What do activator receptors on NK cells recognise?

A

heparan sulphate proteoglycans

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5
Q

What type of macrophagesdo monocytes differentiate into in the following tissues?

liver

kidney

bone

spleen

lung

neural tissue

connective tissue

skin

joints

A

liver- Kupffer cell

kidney- mesangial cell

bone- osteoclasts

spleen- sinusoidal cell lining

lung- alveolar macrophage

neural tissue- microglia

connective tissue- histiocyte

skin- Langerhans

joints- macrophage like synoviocytes

present processed antigen to T cells

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6
Q

Recall 3 diseases that are failures of neutrophil production

A

Reticular dysgenesis(also lymphocytes, monocytes/macrophahges/platelets)
Kostmann syndrome
Cyclic neutropenia

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7
Q

What is reticular dysgenesis

A

failure neutrophil production - failure stem cells to differentiate along myeloid/lymphoid lineage

most severe SCID (fatal in early life unless BM transplant)

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8
Q

What is Kostmann syndrome

A

specific failure of neutrophil maturation

AR severe congenital neutropoenia

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9
Q

What is cyclic neutropaeniae?

A

specific failure of neutrophil maturation

Autosomal dominant episodic neutropenia every 4-6 weeks

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10
Q

What mutation causes reticular dysgenesis?

A

Adenylate kinase 2 (AKA2) - a mitochondrial energy enzyme

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11
Q

What mutation causes kostmann syndrome?

A

HCLS1-associated protein X-1 (HAX-1)

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12
Q

What mutation causes cyclic neutropaenia?

A

Neutrophil elastase (ELA-2)

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13
Q

What is the cause of Leukocyte adhesion deficiency?

A

Defect phagocyte migration

CD18 deficiency (β2 integrin subunit)- failure to express this ligand means they cannot exit the bloodstream

normally expressed → binds ICAM-1 on endothelial cells to regulate neutrophil adhesion/transmigration

deficiency → neutrophils fail to exit bloodstream

v high neutrophils → absence pus formation

due to delayed umbilical cord separation at birth

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14
Q

What will be the most obvious abnormal result on the blood count in leukocyte adhesion deficiency?

A

Very high neutrophils (they cannot exit the bloodstream)

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15
Q

What is chronic granulomatous disease?

A

A failure of phagocytic oxidative killing mechanisms

deficiency NADPH oxidase → inability to generate oxygen free radicals so impaired killing

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16
Q

Recall 2 tests that are useful in the investigation of chronic granulomatous disease

A
  1. NBT Nitroblue tetrazolium test yellow -> blue (negative = blue, positive = stays yellow)
  2. DHR Dihydrohodamine flow cytometry test (negative = not fluorescent)
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17
Q

What are the features of chronic granulomatous disease?

A

Absent respiratory burst - deficient NAPHD oxidaseto oxygen not convered to superoxide to form HOCl (oxygen free radical)

leading to:

  • Excessive inflammation
  • Granuloma formation
  • Lymphadenopathy
  • Hepatosplenomegaly
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18
Q

What immunodeficiency are recurrent skin and mouth infections most likely to be indicative of?

A

Phagocyte deficiency

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19
Q

Which phagocyte deficiency has absent neutrophils and normal leukocyte adhesion molecules?

A

Kostmann syndrome

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20
Q

Which phagocyte deficiency has absent CD18 and increased neutrophils?

A

Leukocyte adhesion deficiency

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21
Q

Which phagocyte deficiency has normal neutrophil levels and leukocyte adhesion markers, an abormal NBT/DHR test and pus is produced?

A

Chronic granulomatous disease

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22
Q

Which phagocyte deficiency has normal neutrophil levels and leukocyte adhesion markers, a normal NBT/DHR test but no pus is produced?

A

Cytokine deficiency (IL12/IFN gamma pathway)

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23
Q

Which innate immunodeficiency is characterised by recurrent infections with hepatosplenomegaly and abnormal dihydrohodamine test (does not fluoresce)?

A

Chronic granulomatous disease

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24
Q

Which innate immunodeficiency is characterised by recurrent infections with no neutrophils on FBC?

A

Kostmann syndrome

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25
Which innate immunodeficiency is characterised by infection with atypical mycobacterium, and a normal FBC?
IFN gamma receptor deficiency
26
Which innate immunodeficiency is characterised by recurrent infections with high neutrophil count on FBC but no abscess formation?
Leukocyte adhesion deficiency
27
In which infections are cytokine deficiency significant?
IL12(R), IFNγ(R) deficiencies important in mycobacteria (TB, atypical), BCG, Salmonella Inability to form granulomas infected macrophages → IL12 IL12 → T cell → secretes IFNγ IFNγ → macrophages and neutrophils → TNF activates NADPH oxidase → oxidative pathways
28
Fill in the blanks
29
What can be used to treat chronic granulomatous disease?
Interferon gamma (as this stimulates macrophages)
30
How would you manage infection in phagocyte deficiency?
Prophylaxis ## Footnote Abx - e.g. Septrin Anti-fungals e.g. itraconazole oral/IV as needed
31
Which innate immunodeficiency is characterised by severe chickenpox and disseminated CMV infection?
Classic Natural Killer cell deficiency
32
With which innate immunity deficiency is meningococcal septicaemia associated?
Deficiency of complement (C1q)
33
With which innate immunodeficiency is membranoproliferative nephritis and abnormal fat distribution associated?
C3 deficiency with presence of a nephritic factor
34
Classical vs functional NK deficiency
Classical - absence in peripheral blood Functional - NK present, but abnormal function
35
What mutations are responsible for classical and functional NK deficiencies?
classical - abnormalities in GATA2 or MCM4 genes in subtypes 1 and 2 functional - FCGR3A mutation in subtype 1
36
Treatment for NK deficiency
Prophylactic aciclovir/ganciclovir Cytokines (IFN-a) to stimulate NK cytotoxic function HSCT (severe phenotypes)
37
Susceptibility to encapsulated bacteria may be indicative of what type of immunodeficiency?
Complement deficiency
38
Name 3 encapsulated bacteria
NHS Neisseria meningitides Haemophilus influennzae Streptococcus pneumoniae
39
Describe the classical pathway of complement activation
Antibody-antigen complex (involves C1,C3,C4) 1. Ab-Ag complexese = change in Ab shape = exposes C1 binding site 2. C1 binding → activates cascade 3. Ab-Ag acquired immunity dependent
40
Describe the MBL pathway of complement activation
direct binding of MBL to microbial cell surface carbohydrates (C2,4) 1. direct MBL binding to microbial cell surface CHO 2. directly stimulates classical pathway → C2+C4 (not C1) 3. not dependant on acquired immunity MBL2 mutations not really a/w immunodeficiency
41
Describe the alternate pathway of complement activation
Involves bacterial cell wall PAMP (LPS, teichoic acid) → C3 Bacterial cell wall fails to regulate low level of spontaneous activation of alternate pathway 1. C3 binds bacterial cell wall components 2. Involves factors B, P (properidin), D – regulated by factors H 3. Not dependant on acquired immune response
42
In which complement pathway is properdin found?
Alternative
43
How do the complement pathways converge?
Activate C3 → major amplification step triggers formation of MAC via C5-9
44
What does classical complement pathway deficiency increase susceptibility to?
SLE/autoimmunity
45
How does SLE affect complement?
Persistent production of immune complexes --\> activation of classical pathway --\> low levels of C3 and C4 (functional complement deficiency) C4 depleted first. If severe → also C3
46
What are the standard tests in suspected complement deficiency?
C3,4 routinely measured (others CH50, AP40 not routinely done)
47
What does CH50 measure?
Classical complement pathway
48
What does AP50 measure?
Alternative complement pathway Properidin Factors B and D
49
Which complement function test would be abnormal in C1q deficiency?
CH50
50
Which tests would be abornmal in C9 deficiency?
CH50 and AP50
51
Which complement deficiency is most associated with developmental SLE?
C1q deficiency
52
Which complement deficiency is most associated with meningococcal disease?
C7 deficiency
53
What is C3 deficiency associated with?
C3 nephritic factors (anti C3 convertase) deplete C3 nephric factors stabilise C3 → C3 activation and consumption a/w/ * glomerulonephritis (membranoproliferative) * partial lipodystrophy
54
How does autoimmune disease affect complement?
Complement (C1q + C2) deficiency → SLE Autoimmune disease → complement deficiency * SLE → consumption of complement * autoantibodies directed against components of complement pathway → consumption of complement (C3)
55
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56
What mutation is causative of X-linked SCID?
Common gamma chain on chromosome Xq13.1
57
What is the most common form of SCID?
X-linked SCID
58
What is the most severe form of SCID?
Reticular dysgenesis
59
Describe the phenotype of X-linked SCID in terms of T, B and NK cell numbers
T cells: very low or absent B cells: Normal or increased B cells, but LOW Igs NK cells: very low or absent inability to respond to cytokines → early arrest of T cell and NK cell development and immature B cells
60
Why are SCID babies initially protected?
IgG from maternal placental supply IgG from breast milk colostrum (not as good as eventually drops off)
61
How does adenosine deaminase (ADA) deficiency affect the immune system?
enzyme necessary for cell metabolism in lymphocytes. When it is deficient, there is early arrest of T and NK cell development and production of immature B cells.
62
Describe the phenotype of ADA deficiency in terms of T, B and NK cell numbers
All very low or absent LOW Ig TOO
63
Describe the clinical phenotype of SCID
1. Unwell by 3 months of age 2. Infections of all types 3. Failure to thrive 4. Persistent diarrhoea 5. Unusual skin disease (colonisation of infant's empty BM by maternal lymphocytes/GvHD) 6. Family history of early infant death
64
Recall the levels of T, B and NK cells in ADA deficiency
All very low or absent
65
Recall 3 causes of T cell deficiencies
Di George syndrome Bare lymphocyte syndrome (type 2) Disorders of T effector functions
66
What is the gene mutation implicated in DiGeorge syndrome?
22q11.2 deletion
67
How does DiGeorge syndrome affect B and T cell levels?
B cell normal T cell number ↓ (mild impairment immunity improves with age) * Could present with PCP pneumonia and atypical viral infections * Need T-cells to control these
68
Why does Di George syndrome produce immunodeficiency?
Abnormality of development of pharyngeal pouch --\> absent thymus
69
Mnemonic to remember features of Di George syndrome
CATCH 22: Cardiac abnormalities (ToF / Teratology of Fallot) Abnormal faces (high forehead, low-set and folded ears, micrognathia, broad nasal bridge) Thymic aplasia (± oesophageal atresia) Cleft palate Hypocalcaemia, hypoparathyroidism 22 22q 11.2 -\> DETECT BY CYTOGENETIC ANALYSIS
70
What is bare lymphocyte syndrome type 2?
Absent expression of MHC class II causing severe deficiency of CD4+ T helper cells --\> results in low IgG OR IgA
71
What inherited immunodeficiency might cause a profound deficiency of CD4+ T cells specifically?
Bare lymphcoyte syndrome type 2
72
Describe the phenotype of Bare lymphocyte syndrome
T-cells ↓↓ CD4 cells; normal CD8 B-cells = normal; BUT low IgG or IgA antibody (due to lack of CD4+ helper)
73
Recall some clinical signs of bare lymphocyte syndrome
Hepatomegaly and jaundice May be associated with sclerosing cholangitis
74
What are some clinical features of T cell deficiencies
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
75
Fill in the blanks
76
How would you treat T cell deficiencies?
**HSCT:** Replace abnormal populations in SCID Replace abnormal cells – BLSII **Enzyme replacement therapy:** PEG-ADA for ADA SCID **Gene therapy:** Stem cells treated ex-vivo with viral vectors containing missing components The transduced cells have survival advantage in vivo **Thymic transplantation:** Promote T cell differentiation in Di George syndrome Cultured donor thymic tissue transplanted to quadriceps muscle
77
What type of B cells produce IgM?
Pro B cells (early response does not requirie T cell)
78
describe the germinal centre reaction for B cells
79
What test can be used to see lymphocyte subsets in a blood sample?
FACS (flow cytometry)
80
Name 4 causes of B cell deficiency
Bruton’s X-linked hypogammaglobulinaemia X-linked hyper IgM syndrome Common variable immunodeficiency IgA deficiency
81
What is Bruton's X-linked hypogammaglobinaemia?
Abnormality in B cell tyrosine kinase gene (BTK): Pre B cells don't mature -\> no Ig after around 3 months Only affects boys
82
Management for Bruton's X linkekd hypogammaglobulinaemia
IVIG
83
What is the inheritance pattern of hyper IgM syndrome?
X linked
84
What is hyper IgM syndrome?
B cell maturation defect which results in T cells not expressing CD40 (Failure of T cell co-stimulation) CD 40 * Involved in T-B-cell communication * Ligand expressed by activated T cells (NOT on B cells)
85
Recall 3 clinical features of hyper IgM syndrome
Pneumocystis jiroveci infection Autoimmune disease Malignancy
86
In which disease is CD40 not expressed on activated T cells?
Hyper IgM syndrome
87
Descirbe the phenotype for hyperIgM syndrome
B-cells = normal T-cells = normal (but no CD40 ligand expressed) No germinal centre development within lymph nodes and spleen Failure of isotype switching IgM high IgA, IgE, IgG undetectable
88
Which syndrome is characterised by elevated IgM and undetectable IgA, IgE and IgG?
Hyper IgM syndrome
89
Which disease is marked by reduction in IgG with low either IgA/IgM
Common variable immune deficiency
90
What are the clinical features of common variable immune deficiency?
Recurrent bacterial infections Pulmonary disease (in particular granulomatous interstitial lung disease) GI disease Autoimmune disease NHL
91
What % of Selective IgA deficiency patients are symptomatic, and what are these symptoms?
1/3 Recurrent GI and resp infections
92
How are B cell deficiencies managed?
Lifelong immunoglobulin replacement Immunisation (ONLY IN SELECTIVE IgA DEFICIENCY) Not otherwise effective because of defect in IgG antibody production
93
At what age does common variable immune deficiency present?
Adulthood
94
Which mutation is most likely to be the cause of CVID?
MHC class III - causing aberrant class switching
95
Fill in the blanks

Pathology ICSM COPY (90 decks)

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