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Basic immunology Flashcards

1
Q

Purpose of eosinophils

A

Kill pathogens too large to be ingested by a macrophage

Release granules that are toxic

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2
Q

Functions of complement

A

1) Opsonisation
2) Cytolysis
3) Inflammation via anaphylatoxins (C3a, C5a >C4a)
4) Immune complex clearing

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3
Q

Why is C1 esterase inhibitor important?

A

Prevents activation of classical pathway and coagulation patyway

In C1-INH deficiency
= Activates classical pathway + activates coagulation pathway (makes bradykinin)
= Bradykinin –> increased capillary permeability –> oedema
= Hereditary angioedema

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4
Q

What happens to C4, C2, and C3 in hereditary angioedema?

A

C1 esterase inhibitor deficiency

Low C4, C2, normal C3 (C4 binding protein binds to C4 and prevents activation of distal pathway including C3)

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5
Q

Hereditary angioedema clinical features

A

Recurrent attacks of oedema

  • Non-pruritic
  • No urticaria although atypical skin rashes associated - - Painless

Cutaneous angioedema
Laryngeal oedema
Bowel wall oedema –> abdo pain, fluid loss

Usually resoles within 72h

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6
Q

What precipitates Hereditary angioedema?

A 
ACEI
Estrogens
Trauma
Surgery
Concurrent illness
Emotional stress
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7
Q

Types of Hereditary angioedema

A

Type 1 (majority) - reduced level of C1-INH

Type 2 - dysfunctional C1-INH (normal or increased)

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8
Q

Who can get acquired C1 inhibitor deficiency?

A 
B cell lymphoma, MGUS (consumes C1-INH)
Autoimmune disease (generate ab against C1-INH)
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9
Q

How to diagnose/confirm Hereditary angioedema ?

A

Reduced C4, normal C3 (do this first)

C1-INH level

  • Reduced in type 1 HAE
  • Normal in type 2 HAE

Functional C1-INH assay (do it in those with normal C1-INH level)

C1q reduced

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10
Q

Acute treatment of Hereditary angioedema

A

1) Icatibant (bradykinin receptor inhibitor)
- Can reverse HAE
- Patients can do it themselves at home if they feel at attack is coming

2) Replacement of Purified C1-INH protein

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11
Q

Prevention of Hereditary angioedema

A

Anabolic steroids e.g. danazol (androgen)

Tranexamic acid (acts on fibrionlytic pathway… blocks plasminogen and lowers release of bradykinin)

C1-INH (regular infusions)

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12
Q

What infection do you get in C5, C6, C7, C8, C9 deficiency?

A

Neisseria infection

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13
Q

What diseases do you get in C3 deficiency?

A

C3 is the start of the common pathway

Recurrent pyogenic infections

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14
Q

Causes of low C3, C4

A

C4 deficiency

  • Consumption - Immune disorders - SLE (reflects disease activity), serum sickness (Ag Ab complexing in the blood, depositing in the tissue and activating complement and consuming it), mesangiocapillary GN (C3), post-infectious GN (C3), cryoglobulinemia (C4), C1-INH (C4), Chronic infections e.g. IE
  • Reduce production - malnutrition, liver disease
  • Increased loss - Nephrotic syndrome, burns
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15
Q

Eculizumab MOA

A

C5 inhibitor (common pathway)

Inhibit MAC (C5, C6, C7, C8) so cells don’t lyse

Role in PNH, atypical HUS

Risk of neisseria (vaccinate pre treatment)

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16
Q

What are the classical pathway components?

A

C1q, C1r, C1s, C2, C4, C3

Similar to lectin pathway
Replace C1q, C1r, C1s with MBL + MASP 1 + MASP 2

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17
Q

What are the alternate pathway components?

A

C3, B, D, properdin (stabilises complex)

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18
Q

What are the MAC components?

A

C5, C6, C7, C8 makes MAC

Attracts C9 = cytolysis

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19
Q

What are the anaphylatoxins made in the complement pathways?

A

C3a, C5a (stronger)

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20
Q

Regarding Hereditary angioedema, its inheritance follows an ……. pattern

A

AD

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21
Q 
Which of the following doesn't function as a pattern recognition receptor?
A) C1q
B) CRP
C) Alpha 1 antitrypsin
D) Mannose binding protein
A

Alpha-1 antitrypsin

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22
Q

Anakinra MOA

A

IL1 blocker

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23
Q

Tociluzumab MOA

A

IL6 blocker

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24
Q

The innate immune system involves recognition of PAMPs and DAMPs by PRRs. What do the following PRRs do?

1) C-type leptin receptors (CLR)
2) Toll like receptors (TLR)
3) Nod-like receptors (NLR)
4) Rig-like receptors (RLR)
5) AIM2/cGAS

A

1) C-type leptin receptors (CLR) - “glue” to stick to pathogens, recognises CHO patterns on microorganisms, phagocytosis
2) Toll like receptors (TLR) - exist on cell surface and intracellularly (endocystic vesicles), “cell activators” = activate NFKB and release of antimicrobial peptides and cytokines
3) Nod-like receptors (NLR) - exist intracellularly; activate “inflammasomes” via IL1
4) Rig-like receptors (RLR) - exist intracellularly in the cytoplasm; sense RNA (should not be there) –> release IFN type 1
5) AIM2/cGAS - exist intracellularly in the cytoplasm; sense DNA (should not be there) –> release IFN type 1

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25
When do interferons get released?
Released from many cell types in response to viral infection Interfere with viral infection Important in fighting COVID Defects may be responsible for severe COVID
26
Example of an inflammasome mediated disease
Gout Urate crystals --> activates NLRP3 (inflammasome component) --> inflammasome gets assembled --> activates caspase 1 --> IL1b production --> inflammation Hence IL1 blockers could be helpful
27
Lack of neutrophils result in
High grade bacterial infections - staph aureus, gram neg bacteria (ecoli, pseudomonas, P. mirabilis, serratia) Invasive candiasis/aspergillus Chronic granulomatous disease (defect in NADPH oxidase --> lack of oxidative burst --> neutrophils can't kill intracellular organisms that it phagocytoses)
28
What's NETosis? (neutrophils)
When neutrophils die --> it throws all its DNA into the surrounding like a net, lined with antimicrobial peptides --> traps passing bacteria
29
What's the main difference between conventional dendritic cells vs plasmacytoid dendritic cells?
cDCs lurk in tissues as sentinels then initiate immune response by capturing the antigen and presenting it to T and B cells in spleen, LNs, MALT. Produce IL6, IL12, TNF. pDCs respond to viral infections by releasing lots of type 1
30
What are innate-lymphoid cells?
Similar to T helper cells of the adaptive immune system They contain no specific antigen receptors They sense 'distress' signals from DCs, macrophages activated by PAMPS/DAMPS, and respond by producing cytokines. ILCs are grouped into 3 groups based on the cytokines they produce. - Group 1 ILCs are like Th1 cells, make IFN-y. E.g. NK cells - Group 2 ILCs are like Th2 cells, involved in allergic disease and helminths. Activated by TSLP. - Group 3 ILCs are like Th17 cells
31
HIV and CCR5 mutation | What's the significance?
CCR5 is a chemokine receptor that HIV uses to enter CD4 cells With time/late infection, the CCR5 receptor mutates to CCR4X which allows increased expression on cells, and increased entry of HIV virion into cells = more aggressive Fun fact - if you lack CCR5, HIV can't enter CD4 cells and you can't get HIV!
32
What do NK cells do?
Kill virus infected cells and tumour cells
33
Which 3 molecules are involved in the adhesion cascade (getting leukocytes into tissues)?
1) Selectin (epithelial cell) 2) Integrin (leukocyte) 3) Cell adhesion molecule (CAM) (epithelial cell)
34
Steps in adhesion cascade (getting leukocytes into tissues)
1) Rolling - Leukocytes are rolling across epithelium 2) Integrin activation - Leukocyte interacts with chemokines - Activates integrin (on leukocyte) from inactive to active state 3) Firm adhesion - Integrin activates with CAM 4) Diapedesis - Leukocyte moves through the epithelium
35
2 examples of integrin blockers being used in Crohn's and MS
1) Vedolizumab - Blocks alpha-4-beta-7 integrin - Prevents T cells from entering gut epithelium by blocking integrin (adhesion cascade) - Used in IBD (CD, UC) 2) Natalizumab - Blocks alpha-4 integrin - Prevents T cells from entering gut epithelium and into brain - Used in Crohn's and MS - Risk of JC virus (T cells no longer monitor pathogens in the brain)
36
What's the difference between MHC/HLA class I and II?
Class I - Bind peptides derived from degraded intracellular proteins - Can be self proteins, intracellular bacteria, viruses, tumour antigens - Expressed on most cells - Present to CD8 T cells Class II - Bind peptides derived from degraded extracellular proteins - Expressed only on specialised APCs - To present to CD4 T cells
37
Why do all cells express MHC class I?
So they can signal when they've been infected
38
HLAB27 is associated with
AS
39
HLADR4 is associated with
RA
40
What test must we do before prescribing abacavir to avoid drug hypersensitivity?
HLAB5701
41
What test must we do before prescribing carbamazepine to avoid drug hypersensitivity?
HLAB1502
42
MOA of TRALI
HLA antibodies from blood donor (patients who have had previous transfusions and subsequent reactions, mothers who have had children reacting to paternal HLA) bind to HLA proteins of the recipient
43
MOA of platelet transfusion refractoriness
``` Platelets express HLA class I proteins Some patients develop anti-HLA antibodies to foreign HLA proteins and become refractory to platelet transfusions ```
44
Hyperacute rejection MOA
Ab mediated rejection Recipient ab bind proteins on donor graft cells --> complement activation + platelet accumulation leading to thrombosis and tissue necrosis Driven by - Anti-ABO antibodies (natural IgM ab that develop early in life) - Anti-HLA antibodies (rare these days as recipients are screened these days for ab). Can develop from previous exposure to foreign HLA proteins e.g. pregnancy (paternal HLA in foetus), transfusion (platelet/RBC with contaminating WCs which contain HLA proteins on their cell surface), previous transplants
45
How soon does hyperacute rejection occur?
Within minutes of reperfusion of transplanted organ --> graft destruction
46
Is hyperacute rejection common?
No Due to antibody screening and better donor-recipient matching Transplant is not performed if anti-donor HLA antibodies are detected
47
Acute rejection MOA
``` Direct pathway 1) HLA class I on donor tissue cells activate recipient cytotoxic T cells --> kills graft cells ``` 2) HLA class II on donor DCs (carried with the graft) activate recipient cytotoxic T cells - Foreign HLA molecule mistaken by T cell as 'self HLA + foreign peptide'
48
Chronic rejection MOA
Indirect pathway - Recipient DCs infiltrate the graft --> replace donor APCs --> process and present graft antigens with self HLA --> activate recipient T cells (Th cells) --> ab response Both T cell and ab mediated (ab can be existing or be de novo)
49
Major cause of renal graft failure after the first year
Chronic rejection
50
How do we choose donors for solid organ transplant?
1) HLA typing (HLA- A, B, C, DR, DQ, DP) - Determines level of mismatch 2) Screen for anti-HLA antibodies (donor specific ab) 3) HLA crossmatch - Positive crossX means the patient has ab against the donor HLA = hyperacute rejection = contraindicated - In vitro crossX (mix donor lymphocytes with recipient serum and see if any of the recipient antibodies bind to the donor lymphocytes) OR virtual crossX (done on computer; compare recipient anti-HLA antibodies with the HLA type of the potential donor and predict likelihood of reaction)
51
Which organ transplant do we not do HLA matching?
Heart and Lung - Small patient/donor pool - Usually fairly urgent Donor selection is based on - Negative HLA cross X - Absence of donor specific ab Liver - No HLA matching/ab testing/crossmatching unless its combined with renal transplant (liver absorbs some anti HLA antibodies)
52
Which organ transplants have the best prognosis?
Kidney > heart > liver > pancreas > lung > heart/lung
53
Can organ transplants be done with ABO incompatibility?
Yes but not ideal Will need to remove antibodies first with plasmaphareis, rituximab, IVIG
54
Most common cause of death with a functioning kidney graft 1) First year 2) After first year
1) Infection, also cardiovascular | 2) cancer
55
How does allogeneic haematopoietic stem cell transplant happen?
2 ways 1) Bone marrow harvest 2) Donor receives G-CSF --> stimulates BM to produce stem cells and release them into the bloodstream --> peripheral blood collection (more common) Recipients are given pre-transplant conditioning (chemo and radiotherapy) to wipe out their immune system before receiving HSC infusion
56
Common indications for autologous hematopoietic stem cell transplant
In order of prevalence Myeloma NHL HL
57
Common indications for autogeneic hematopoietic stem cell transplant
In order of prevalence ``` AML ALL MDS NHL CML ```
58
MOA of haematopoietic stem cell transplants
1) Antibody mediated rejection - Donor specific anti-HLA antibodies present pre-transplant - If no other options, can give plasmapharesis + rituximab pre transplant but its difficult to reduce ab to a low level 2) T cell mediated rejection - If there are residual T cells after pre-transplant conditioning
59
MOA GVHD
Gut epithelium is damaged by by pre-transplant conditioning which can activate cytokines and APCs to present to donor T cells (carried across with the transplant organ) --> activated donor cytotoxic T cells and NK cells attack the patient's organs and tissues (skin, liver, gut) --> more tissue damage and more APCs and more cytotoxic T cells activated (vicious cycle)
60
Which organs does GVHD typically affect?
Lymphocyte rich organs Hematopoietic stem cell transplant (peripheral transplant > BM transplant) Liver Blood product transfusions (need to be irradiated or leucocyte depleted)
61
When does acute and chronic GVHD occur?
Acute: 6-100 days Chronic: >100 days However there is overlap in reality
62
How does acute and chronic GVHD typically present?
Acute - Dermatitis, hepatitis, enteritis Chronic - More diverse and extensive symptoms e.g. skin, liver, eyes, mouth, lungs, GIT
63
Most common cause of death in the 1st year post allogeneic hematopoetic stem cell transplant
Disease relapse > Infection > GVHD
64
What's graft vs leukaemia?
This is good Graft T cells wipe out residual leukemic cells not removed during pre-transplant conditioning Mild GVHD can be good for the graft vs leukemia effect (Depleting T cells from the donor marrow is good to prevent GVHD, but this means less graft vs leukemia reaction and increases relapse rates. Its a fine balance!)
65
How to prevent GVHD?
1) Reduce intensity of pre-transplant conditioning 2) Manipulate gut microbiota 3) Block inflammatory cytokines 4) T cell depletion of donor marrow
66
What's a haploidentical donor for hematopoietic stem cell transplants?
A haploidentical, or half-matched, donor is usually your mom, your dad or your child. Parents are always a half-match for their children. Siblings (brothers or sisters) have a 50% chance of being a half-match for each other, and 25% of being a full match. HLA mismatch can be overcome with cyclophosphamide
67
MOA fingolimod
Inhibits SIP-1 molecule and stops lymphocytes from leaving lymph node Produces significant lymphopenia but short t1/2, so if you stop the drug, cells will go back to normal within 24h (does not increase sepsis susceptibility)
68
Which complement pathway is activated by immune complexes?
Classical pathway
69
Defects in the classical pathway results in
Autoimmunity e.g. SLE
70
Which complement pathway is activated by activated microbial cell wall products?
Alternative pathway
71
Defects in the alternative pathway results in
Infections e.g. Neisseria
72
Which organisms are susceptible to complement?
Encapsulated organisms - they need opsonisation and phagocytosis E.g. Neisseria
73
Whats CTLA4?
Inhibitory molecule APC binds to T cell via - MHC ------ TCR - B7 ------- CD28 When CTLA4 is expressed on T cell - B7 ------- CTLA4 instead (instead of CD28) - This inhibits T cell
74
How does ipilimumab work?
Binds to CTLA4 (T cell) so B7 (APC) can bind to CD28 (T cell) = activate T cell
75
How does abatacept work?
Binds to B7 (CD80/86) on APC so it can't bind to CD28 on T cell Loss of costimulation = loss of T cell activation

Immunology (6 decks)

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