Apr5 M3-Innate System

Question 1

cells of the innate immune system

Answer 1

• NK cells
• phagocytic (macrophages, neutrophils)
• cells releasing inflam mediators (basophils, mast cells, eosinophils)

Question 2

innate immune system receptors

Answer 2

• PRRs (bind PAMPs like LPS, mannose, flagella, peptidoglycan)
• DAMPRs (damage associated molecular pattern) Rs (recognize DAMPs, molecules released when cell damaged)
• MISSING self-detection Rs (like missing MHC1)

Question 3

molecular component of the innate immune system

Answer 3

1. antimicrobial peptides (cationic proteins: defensins, enzymes like lysozymes, etc.)
2. cytokines (IFN)
3. complement
4. acute phase proteins

Question 4

immune function of CRP

Answer 4

• recognizes polysaccharide C on capsule of pneumococcus

- CRP will attack pneumococcus if infected with it

Question 5

neutrophils: how identified and 2 kinds of granules

Answer 5

• PMN + CD66 marker = 2 ways to recognize
• 1. primary azurophilic granules (cationic proteins like defensins)
• 2. secondary granules of mature PMNs (lysozyme, NAPDH oxidase, etc.)

Question 6

neutrophils function

Answer 6

phagocytose and die to create pus (macrophages (MQ) don’t do that)

Question 7

monocytes and MQs: 2 how IDed and 2 kinds of granules

Answer 7

• CD14 + kidney shaped nucleus
• no granules
• lysosomes and vacuoles with contents similar to neut granules (defensins, lysozymes)

Question 8

2 kinds of Rs on NK cells

Answer 8

1. natural cytotoxicity receptors (NKp46 and NKp44)

2. Killer Ig-like Rs

Question 9

what NKp46 and 44 on NK cells do

Answer 9

• sialic acid in the Rs recognizes viral hemagglutinin to help fight influenza
• infected cell killed with perforin and granzyme or ADCC pathway if through Ab binding

Question 10

what Killer Ig-like receptors on NK cells do (KIR receptors)

Answer 10

• bind MHC class 1 on all cells

- inhibit killing of the cell by the NK cell

Question 11

what happens if you have no NK cells

Answer 11

higher risk of malignancy

Question 12

3 levels at which PRRs can recognize pathogens

Answer 12

1. SECRETED (floating around) PRRs: mannose binding lectin (MBL), CRP
2. membranous endocytic (TLRs): recognize LPS and viral RNA
3. cytosolic PRRs: NOD-like Rs

Question 13

what activation of the complement means

Answer 13

create C3b (active component) *also called C3 convertase*
(we have normal amounts of C3b in the serum but they are rapidly destroyed)
In complement system, b = binding and a = active.

Question 14

3 classical pathways of ACTIVATION of the complement

Answer 14

• classical pathway
• MBL pathway
• alternative pathway

Question 15

classical pathway

Answer 15

Ag-Ab complex recognized by C1, cascade from C1 to lead to C3b

Question 16

MBL pathway

Answer 16

activation of complement because of presence of mannose on bacterial membrane (mannose is absent on our own cells)

Question 17

alternative pathway

Answer 17

• in the presence of a bacteria, factor B, properdin and factor D, stabilize C3b to bind it to the bacteria
• larger amounts of C3b can come

Question 18

steps to make C3b in the classical pathway

Answer 18

• Ab-Ag, C1, C4, C2, C3*
  1. Ab bound to Ag on cell wall
  2. C1 binds the Ab of the Ab-Ag complex
  3. C4 binds C1 and splits in C4b and C4a (b = binding so goes bind cell) and they both detach from C1
  4. C4b goes bind cell wall
  5. C2 binds C4b and splits in C2a and C2b (b = binding so will bind C3)
  6. C3 binds C2b and splits in C3a and C3b

Question 19

steps to make C3b in the MBL pathway

Answer 19

• lectin bound to mannose, C4, C2, C3*
  1. lectin is bound to mannose on bacterial wall
  2. C4 binds lectin. rest is same as classical pathway
  3. C4 binds C1 and splits in C4b and C4a (b = binding so goes bind cell) and they both detach from C1
  4. C4b goes bind cell wall
  5. C2 binds C4b and splits in C2a and C2b (b = binding so will bind C3)
  6. C3 binds C2b and splits in C3a and C3b

Question 20

diff between classical and MBL pathways

Answer 20

MBL = C1 replaces the Ag-Ab-C1 complex of classical

Question 21

steps to make C3b in alternative pathway

Answer 21

1. baseline C3b binds bacterial wall
2. factor B splits in Ba and Bb. Bb binds C3b
3. Factor D and properdin bind C3b and factor B to stabilize C3b

Question 22

what happens after you activated the complement (got C3b in the 3 pathways)

Answer 22

1. C5 binds C3b
2. C5 splits in C5a and C5b
3. C6, C7, C8 are activated in order
4. C9 is activated and forms a MAC (with 4 C9 molecules) to make a hole

Question 23

complement deficiency common infection

Answer 23

Neisseria organisms (family)

Question 24

how to test for classical complement pathway

Answer 24

CH50 test for classical pathway function

Question 25

complement problems other than classical pathway deficiency

Answer 25

• C2 and C4 problem (rare)
• problem in C5 to C8 (deficiency of MAC proteins) (more common)
• alternative pathway dysfunction

Question 26

what can be the cause of an alternative pathway dysfunction (specific dysfunction of alternative pathway)

Answer 26

• properdin deficiency

- deficiency in the proteins stabilizing C3b

Question 27

test for alternative pathway function

Answer 27

AH50

Question 28

X-linked defect in innate immunity: think of what defect

Answer 28

properdin deficiency

Question 29

2 molecules responsible for leukocyte adhesion to vessel wall and migration to tissue

Answer 29

STEP 1: WEAK binding mediated by selectins

STEP 2: STRONGER binding mediated by integrins (happens because of chemokines and mediators)

Question 30

LAD (leukocyte adhesion deficiency) cause and clinical manifestation

Answer 30

• integrins or ICAM molecules mutations and dysfct ON NEUTROPHILS (not on endothelium)
• gingivitis, recurrent infections in resp tract, bowel, etc.

Question 31

most important innate system cell found in granulomas and responsible for dealing with them

Answer 31

macrophages

Question 32

chronic granulomatous disease (CGD) cause and inheritance

Answer 32

• problem in NAPDH oxidase, which makes oxygen radicals required to activate proteases to destroy bacteria
• get lot of granulomas everywhere bc engulf bacteria but can’t kill them
• can be X linked or autosomal (recessive)

Question 33

(imp?) the big 5 infectious organisms in CGD

Answer 33

No BASeS

• nocardia
• burkholderia
• aspergillus
• staph aureus
• serratia

Question 34

multiple severe herpes infections, varicella pneumonia and CMV and HSV + skin lesions: think of what innate cell deficiency

Answer 34

NK cells (because act on viruses and malignancy)

Question 35

classical cause of NK cell deficiency

Answer 35

AD: deficiency of the TF GATA2, required for NK cell dev and survival

Question 36

NK cell deficiency clinically

Answer 36

• higher risk of malignancies and EBV, HPV related cancers

- herpes lesions, pneumonia, CMV, HSV, skin lesions

Question 37

clinical signs of phagocytic defects

Answer 37

• skin infections, no pus
• granulomas
• gingivitis
• no separation of umb cord
• in CGD = aspergillus and bukholderia

Question 38

late complement defects clinical signs

Answer 38

Neisseria infections

Question 39

innate defects in general: sign you see

Answer 39

less fever

Question 40

tx of innate system deficiencies

Answer 40

• anti-fungal Tx
• inactivated vaccines regularly
• IFN gamma (activates macrophages and neutrophils)
• live vaccines in complement def and CGD
• live viral vaccines in phagocytic def
• HSC transplant (CURATIVE)
• gene therapy (CURATIVE)

Question 41

why HSC transplant helps for LAD

Answer 41

because LAD is a problem of the integrins on NEUTROPHILS (not on endothelium)