Apr5 M3-Innate System Flashcards
cells of the innate immune system
- NK cells
- phagocytic (macrophages, neutrophils)
- cells releasing inflam mediators (basophils, mast cells, eosinophils)
innate immune system receptors
- 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)
molecular component of the innate immune system
- antimicrobial peptides (cationic proteins: defensins, enzymes like lysozymes, etc.)
- cytokines (IFN)
- complement
- acute phase proteins
immune function of CRP
- recognizes polysaccharide C on capsule of pneumococcus
- CRP will attack pneumococcus if infected with it
neutrophils: how identified and 2 kinds of granules
- PMN + CD66 marker = 2 ways to recognize
- primary azurophilic granules (cationic proteins like defensins)
- secondary granules of mature PMNs (lysozyme, NAPDH oxidase, etc.)
neutrophils function
phagocytose and die to create pus (macrophages (MQ) don’t do that)
monocytes and MQs: 2 how IDed and 2 kinds of granules
- CD14 + kidney shaped nucleus
- no granules
- lysosomes and vacuoles with contents similar to neut granules (defensins, lysozymes)
2 kinds of Rs on NK cells
- natural cytotoxicity receptors (NKp46 and NKp44)
2. Killer Ig-like Rs
what NKp46 and 44 on NK cells do
- 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
what Killer Ig-like receptors on NK cells do (KIR receptors)
- bind MHC class 1 on all cells
- inhibit killing of the cell by the NK cell
what happens if you have no NK cells
higher risk of malignancy
3 levels at which PRRs can recognize pathogens
- SECRETED (floating around) PRRs: mannose binding lectin (MBL), CRP
- membranous endocytic (TLRs): recognize LPS and viral RNA
- cytosolic PRRs: NOD-like Rs
what activation of the complement means
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.
3 classical pathways of ACTIVATION of the complement
- classical pathway
- MBL pathway
- alternative pathway
classical pathway
Ag-Ab complex recognized by C1, cascade from C1 to lead to C3b
MBL pathway
activation of complement because of presence of mannose on bacterial membrane (mannose is absent on our own cells)
alternative pathway
- 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
steps to make C3b in the classical pathway
- 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
steps to make C3b in the MBL pathway
- 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
diff between classical and MBL pathways
MBL = C1 replaces the Ag-Ab-C1 complex of classical
steps to make C3b in alternative pathway
- baseline C3b binds bacterial wall
- factor B splits in Ba and Bb. Bb binds C3b
- Factor D and properdin bind C3b and factor B to stabilize C3b
what happens after you activated the complement (got C3b in the 3 pathways)
- C5 binds C3b
- C5 splits in C5a and C5b
- C6, C7, C8 are activated in order
- C9 is activated and forms a MAC (with 4 C9 molecules) to make a hole
complement deficiency common infection
Neisseria organisms (family)
how to test for classical complement pathway
CH50 test for classical pathway function
complement problems other than classical pathway deficiency
- C2 and C4 problem (rare)
- problem in C5 to C8 (deficiency of MAC proteins) (more common)
- alternative pathway dysfunction
what can be the cause of an alternative pathway dysfunction (specific dysfunction of alternative pathway)
- properdin deficiency
- deficiency in the proteins stabilizing C3b
test for alternative pathway function
AH50
X-linked defect in innate immunity: think of what defect
properdin deficiency
2 molecules responsible for leukocyte adhesion to vessel wall and migration to tissue
STEP 1: WEAK binding mediated by selectins
STEP 2: STRONGER binding mediated by integrins (happens because of chemokines and mediators)
LAD (leukocyte adhesion deficiency) cause and clinical manifestation
- integrins or ICAM molecules mutations and dysfct ON NEUTROPHILS (not on endothelium)
- gingivitis, recurrent infections in resp tract, bowel, etc.
most important innate system cell found in granulomas and responsible for dealing with them
macrophages
chronic granulomatous disease (CGD) cause and inheritance
- 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)
(imp?) the big 5 infectious organisms in CGD
No BASeS
- nocardia
- burkholderia
- aspergillus
- staph aureus
- serratia
multiple severe herpes infections, varicella pneumonia and CMV and HSV + skin lesions: think of what innate cell deficiency
NK cells (because act on viruses and malignancy)
classical cause of NK cell deficiency
AD: deficiency of the TF GATA2, required for NK cell dev and survival
NK cell deficiency clinically
- higher risk of malignancies and EBV, HPV related cancers
- herpes lesions, pneumonia, CMV, HSV, skin lesions
clinical signs of phagocytic defects
- skin infections, no pus
- granulomas
- gingivitis
- no separation of umb cord
- in CGD = aspergillus and bukholderia
late complement defects clinical signs
Neisseria infections
innate defects in general: sign you see
less fever
tx of innate system deficiencies
- 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)
why HSC transplant helps for LAD
because LAD is a problem of the integrins on NEUTROPHILS (not on endothelium)
