L15, L17- Innate Immune System Flashcards
these two molecules (CKs) are responsible for repressing the immune system
IL-10
TNF-β
these three molecules (CKs) are responsible for inflammation response
IL-1
IL-6
TNF-α
these two molecules (CK) are responsible/signal of chronic inflammation
IFN-γ
IL-12
receptors and effectors of the innate immune system come from (1), there response is described as (2) and (3), while lacking (4)
1- germ-line DNA (fully defined)
2- rapid
3- invariant
4- memory
innate immune system has (1) receptors to recognize (2) and (3) patterns
1- Toll-like receptors
2- PAMPs (pathogen-associated molecular patterns)
3- DAMPs (damage-associated molecular patterns)
describe and provide a few examples of PAMPs
(pathogen-associated molecular patterns)
-recognized patterns are from essential parts of the microbe, involved in survival/matabolism and evolutionary stable
-exs: peptidoglycan, flagellin (flagella protein), LPS, dsRNA, mannose, non-Me CpG repeats
the key receptor of innate immune system is….
Toll-like receptors- recognizes PAMPs
toll-like receptors will have signal cascade to produce (1) and (2) to induce an antiviral state
1- INF α
2- INF β
after recognition by the innate immune system, pathogen will be marked for (1) via (2) or (3)
1- phagocytosis
2- monocytes//macrophages
3- neutrophils
list the general activities of phagocytes
- survey tissue to discover microbes, particulate matter, dead/injured cells
- ingest/eliminate those materials
- extract immunogenic info from foreign matter (possibly APC)
Phagocytes use the addition of (1) as a marker to enhance phagocytosis. One example is the (2) receptor recognizing the (3) fragment in the complement cascade. Another is (4) receptors recognizing (5) region of Igs/Abs.
1- opsonin
2- CR1 receptors
3- C3b
4- Fc receptors
5- Fc
the main opsonin for Abs is (1), and there is not a Fc receptor for (2) which will activate (3) instead
1- IgG
2- IgM
3- complement
complement molecules opsonize antigens via (1) receptors on phagocytes, where these three are the main opsonins: (2)
1- CR1 receptor
2- C3b, C4b, C1q
besides Abs/Igs and complement molecules, these are the other opsonins
circulating proteins (secreted pattern recognition receptors): pentraxins, ficolins, collectins (mannose-binding lectin / MBL)
describe the step of phagocytosis
1) chemotaxis / ingestion: migration to and recognition of PAMPs => initiation and perpetuation of inflammatory response
2) phagolysosome formation: lysosome fuses with phagosome => death ~30 mins
3) destruction/elimination: via O2 dependent system / respiratory burst + liberation of lactic acid, lysozyme, NO
list the oxygen independent mechanisms of phagocytic killing (hint: there are 4)
- lysozyme: split peptidoglycan
- lactoferrin & reactive nitrogen intermediates: deprive pathogen of Fe
- proteolytic enzymes: degrade dead microbe
- defensins, cathepsin G, cationic proteins: damages microbial membrane
(1) stimulates macrophages to produce NO, which is then released to (2), this is important for (3) situations
1- INF-γ
2- kill nearby microbes
3- microbes/organisms that escape oxidative burst
the most important enzyme for oxygen-dependent phagocytosis is _______ [include rxn]
NADPH oxidase: O2 –> *O2- (superoxide ion)
after function of NADPH is complete, these following reactions occur….
1st: *O2- (superoxide anion) –> H2O2 via Superoxide Dismutase
2nd: H2O2 + Cl- –> HClO- (hypocholorite) via Myeloperoxidase
CGD, aka (1), is the result of (2) and results in (3)
1- chronic granulomatous disease
2- lack of NADPH oxidase (genetically)
3- recurrent infections (ex: pneumonia, abscesses, arthritis, osteomyelitis, bacteremia/fungemia, cellulitis, etc)
describe the test for CGD
(chronic granulomatous disease)
- Nitroblue-tetrazolium (NBT) test
- if NADPH oxidase present –> NBT is reduced and turns blue
- if absent –> negative yellow color persists
CHS, aka (1), is a (2) inherited disorder resulting from (3). This disease is characterized by (4) being present in phagocytes. Clinical presentation is (5).
1- Chediak-Higashi Syndrome
2- autosomal recessive
3- mutation of lysosomal trafficking regulatory protein (=> no lysosomal-phagosomal fusion)
4- large lysosomal vesicles
5- albinism (silver hair), neutropenia, periodontal disease, recurrent infections
list the signs and symptoms of inflammation (hint: 5)
- rubor (redness)
- calor (hot/warm)
- tumor (swelling)
- dolor (pain)
- loss of function
in the first step of inflammatory response, injury causes (1) leading to (2)
(injury/immediate reactions)
1- release of chemical mediators, CKs, histamine
2- attraction of leukocytes to site of injury
Note- brief vasoconstriction occurs
in the second step of inflammatory response, (1) causes (2) leading to redness and warmth and functions to enhance delivery of the following to the site of injury: (3)
(vascular reactions)
1- Histamine
2- vasodilation
3- leukocytes, fluid, clotting factors
in the third step of inflammatory response, (1) helps contain the infection and attract (2) which collects debris to form (3); also, (4) is present to stimulate pain receptors
(edema/pus formation) 1- edema 2- neutrophils 3- pus 4- bradykinin
in the fourth (and final) step of inflammatory response, (1) clean the area, (2) forms granulation tissue, and (3) come to mediate long-term immunity
(resolution/scar formation)
1- macrophages
2- fibroblasts
3- lymphocytes
_______ is the migration of cells out of blood vessels into the tissues
diapedesis
______ is migration in response to specific chemical at site of injury/infections
chemotaxis
list the four types of CAMs
(cell adhesion molecules)
- selectins
- mucins
- integrins
- ICAMs (Ig CAMs)
ICAMs/Ig CAMs are expressed on (1) cells and bind to (2)
1- endothelial cells
2- integrins (on leukocytes)
Integrins are described as (1) in structure and are only expressed on (2) cells and bind to (3)
1- proteins, heterodimers
2- leukocytes
3- Ig superfamily molecules
Mucins are described as (1) in structure and are found on (2) and (3) cells; functioning to present (4) to (5)
1- proteins 2- endothelial cells 3- neutrophils 4- CHO ligands 5- selectins
Selectins are described as (1) in structure and are found on (2) and (3) cells and bind to (4)
1- glycoproteins
2- leukocytes
3- endothelial cells
4- carbohydrates
describe the four steps to leukocyte extravasation (of neutrophils and monocytes)
1) rolling: via selectins (endothelium) to mucins (leukocytes)
2) activation: chemokine binding => conformational change in integrins (leukocytes)
3) arrest/activation: integrins bind Ig CAMs (endothelium)
4) transendothelial migration: leukocytes through tight junctions of inflamed endothelium
LAD, aka (1), is an inherited deficiency in (2) which usually dimerizes with (3) and binds (4) receptors, therefore neutrophils cannot migrate through endothelium
1- leukocyte adhesion defect
2- β-2 integrin subunit (CD18)
3- CD11 subunits
4- ICAM-1
Note- no pus formation, high levels of neutrophils in blood
Hagman factor (XII) activation leads to activation of (1) causing (2) + (3) formation to stop (4) and eventually (5) to reverse (3) and activate (6)
1- bradykinin formation
2- vasodilation, permeability, pain, smooth muscle contraction
3- thrombin/clot formation
4- stop bleeding
5- plasmin (breakdown clots)
6- activates complement
the complement system as a mediator to inflammation uses (1) to activate (2) cells and increase (3) in the site of injury/inflammation
1- anaphylatoxins
2- mast cells
3- increase permeability
the following chemical mediators are responsible for the chemotaxis / infiltration of neutrophils in the inflammatory process
IL-8
LT-B4
C5a
fibrinopeptides (acting as chemokines)
these three chemical mediators released from activated tissue macrophages, (1), will act on (2) to induce fever, (3) to increase acute phase proteins, and (4) for increased leukocytosis
1- IL-1, IL-6, TNF-α
2- hypothalamus
3- liver
4- bone marrow
the main acute phase protein resulting from inflammatory process is (1) and acts to (2)
1- C-reactive protein
2- activate complement
increased leukocytosis is also known as…..
Left shift (inc immature/band cells)
chronic inflammation is defined as (1) and is mainly mediated by (2) and (3)
1- inflammation > 2 wks (failed acute inflammatory response)
2- IFN-γ, TNF-α
the main anti-inflammatory drugs are….
- corticosteroids
- NSAIDs
these two molecules are the main two chemokines signalling for neutrophil migration
IL-8
C5a
list the groups of soluble proteins of the innate immune system
- antimicrobial serum agents
- proteins produced by cells
- Complement system: series of proenzymes
______ is a Fe binding protein that competes with microbes for Fe (an essential metabolite)
lactoferrin
CRP is an acute-phase protein that binds to (1) on bacterial membranes and functions as an (2) and to activate complement via the (3) pathway.
(C-reactive protein)
1- phosphocholine
2- opsonin
3- classic pathway
(1) recognizes carbohydrate patterns found on various microbes to activate the (2) pathway of the complement system
1- MBL (mannose-binding lectin)
2- lectin pathway
(1) recognizes LPS on bacterial cell walls and serves as a receptor for (2). It is also implicated in several (3) diseases.
1- SAP (serum amyloid A protein)
2- phagocyte attachement
3- chronic inflammatory diseases
list some antimicrobial serum agents
- lactoferrin
- CRP (C-reactive protein)
- MBL (mannose-binding lectin)
- SAP (serum amyloid A protein)
INF-α/β are small proteins produced by (1) and (2) in response to (3) to work on (4) cells via (5) mechanism.
1- WBCs
2- virally infected cells (any cell type)
3- virus, RNA, immune products, various antigens
4- neighboring cells (unaffected)
5- inhibit transcription / translation of viral proteins
INF-α/β are considered INF type (1/2).
type 1
INF-γ is considered INF type (1/2).
type 2
INF-γ is produced by (1) cells and list some of its functions: (2)
1- Th1, CTLs (CD8+), NK cells
2- promote NK activity, inc macrophage activity, inducible NO synthase (vasodilation, SM relaxation), induce Ig production, inc MHC I/II on normal cells, promote leukocyte adhesion/migration, induce antiviral defense mechanisms. responds to cancerous growth
INF-γ is heavily involved in (1) formation as the body cannot remove such a substance- describe mechanism of (1): (2)
1- granuloma formation
2- macrophages activate Th1 via IL-1, IL-12 –> Th1 cells aggregate around macrophages –> INF-γ is released to activate macrophages –> repeat until macrophages wall off infection
Complement makes up (1)% of serum globulin, with >20 serum glycoproteins synthesized by (2). These complement proteins circulate as (3) and are activated by (4)
1- 5%
2- mainly hepatocytes + monocytes, macrophages, epithelial cells
3- proenzymes (inactive)
4- cleavage => cascade reaction
complement system is generally important to (1) and (2)
1- recruitment of inflammatory cells
3- killing/opsonization of pathogens
what are the three inactive precursors of complement in blood
C2, C3, C4
list the complement pathways
- Classic: Ab-antigen
- Alternative: microbial or non-microbial foreign substances
- Lectin: MBL
all complement pathways lead to the production of (1) opsonin, recognized by (2) receptor
1- C3b
2- CR1
list the three inflammation inducing complement proteins
C3a, C4a, C5a
Classical Complement Pathway is apart of (innate/adaptive) system with the following steps: (2)
1- adaptive
2- C1 binds Ag-Ab complex –> activated C1 cleaves C4/C2 –> C3 convertase formation –> C3 cleaved (C3a, C3b) –> C5 (a/b) cleaved –> sequential binding of C5b, C6-C9 + inflammation (C5a) –> MAC formation (hole in pathogen membrane –> cell lysis)
Alternative Complement Pathway is apart of (innate/adaptive) system with the following steps: (2)
1- innate
2- spontaneous C3 cleavage (into a/b) via multiple initiators –> factors B/D required –> less stable C3 convertase formed (requires properdin) –> opsonization + inflammation
MBL Complement Pathway is apart of (innate/adaptive) system with the following steps: (2)
1- innate
2- MBL + acute phase protein (serum) binds carb residue on cell/pathogen –> MBL-associated serine protease binds MBL –> C2/C4 into C2a/b + C4a/b –> C2a/C4b activate C3 –> C3b (opsonization, cytolysis) + C3a (inflammation)
all three complement pathways converge with activation of (1) where the product (2) binds to antigenic surface leading to (3) formation by the following components: (4)
1- C5 convertase
2- C5b
3- MAC
4- C5b, C6, C7, C8, C9 (Poly-C9 => perforin-like molecule)
list the functions of complement (hint- 5) and their associated molecules
- Cell lysis, C5b-C9 (Ab dep. or indep.)
- Opsonization (C3b)
- Inflammation (C3a, C5a)
- Clearance of Immune complexes (C3b)
- Viral neutralization (C3b, C5b-C9)
anaphylatoxins include….
C3a, C5a
list the three targets of complement inhibitors and include some examples
1) C1 inhibitor (classical)
2) MAC formation: CD59, clusterin, protein S (all pathways)
3) C3 or C5 convertase (all pathways)
what are the MAC formation inhibitors (hint- 3)
CD59
clusterin
protein S
list the two types of complement deficiencies
- Activator disorder => under-reactive system => more susceptible to infections
- Inhibitor disorder => over-reactive system
classical pathway component deficiencies include loss of (1) molecules leading to individuals prone to immune complex disease with (2) and (3) characteristics; examples include: (4)
1- C1, C2, C4
2- inability to clear circulating immune complexes
3- deposition in tissues and associated inflammatory response
4- lupus (SLE), vasculitis, glomerularnephritis
MBL deficiency leads to (1) presentation and susceptibility to (2) infections
1- recurrent pyogenic infections in childhood (via Staph.)
2- Saccaromyces cerevisiae, pneumococcal, Neisseria infections
alternative pathway components that can be lost include (1) molecules and leave individuals prone to (2)
1- properdin, factor B, factor D
2- pneumoccocal, meningococcal infections + Neisseria infections (if properdin)
C3 deficiency is critical as C3 is necessary for (1) and presentation is as follows: (2)
1- opsonization
2- early in life with many infections via encapsulated organisms (more in CTs)
MAC deficiencies is a lack of one of the following components: (1), and (2) as its presentation
1- C5-C9
2- recurrent infections (commonly Neisseria meningitidis)
loss of C1-INH, which regulates (1) pathway, results into (2) via (3) accumulation
1- classical pathway
2- angioedema
3- C2b accumulation (vasoactive substance)
DAF, aka (1), and (2) are responsible for (3) and its deficiency leads to (4)
1- decay accelerating factor, CD55
2- CD59
3- dissociation of C3 convertase
4- Paroxysmal Nocturnal Hemoglobinuria (lysis of RBCs)
most complement diseases are inheirted via (1) or acquired via (2); note (3) and (4) are also possible
1- autosomal recessive
2- acquired post-infection
3- X-linked (properdin deficiency)
4- AD (MBL deficiency can be AD or AR)
hereditary angioedema is characterized by the Sxs (and absence of a Sx)
-episodic, nonpruritic localized SQ/submucosal swelling
[-laryngeal edema can => fatal respiratory obstruction]
-absence of urticaria/rush (distinguishes it from allergic reaction)
list the mechanism of hereditary angioedema
Dysregulation of 3 systems:
- Complement (classical): no C1-INH => high [C3a, C5a] (anaphylatoxins) => inflammation
- Coagulation- factor XI/XII => fibrin build-up => Edema
- Contact cascade- inc Bradykinin levels => pain, inflammation, coagulation
would a C1-INH defect result in elevated or decreased C4
decreased C4
