Immunobiology Flashcards
Cytokines
INFy - Antiviral interferon
TNFα - ^ vascular permeability (pro-inflammatory)
Interleukins
IL-6 Fever
IL-6 Acute phase response
IL-8 PMN chemotaxis
IL-12 NKT, Th1
IL-10 Anti-inflammatory
Primary cytokines in fever?
TNFα and IL-1
Classical complement pathway
C1 binds Antigen/Antibody complex > c1 is activated > Eventually activates C4 > lysed into C4a and C4b
Complement molecules
proteins made by liver, float around in inactive state.
MBL Complement Pathway
Mannose binding lectin
binds pathogen oligosaccharides
happens in mucous membranes.
Eventually activates c4 which splits into C4a and C4b.
C4b activates C3 convertase
C3 convertase breaks C3 into C3a and C3b
What is important about c3 convertase step in complement cascade?
Where classical, alternative, and MBL pathways all converge
Alternative complement pathway
Random activation of C3 in serum > C3 convertase activated > C3 broken down into C3a and C3b > C3b activates C5 > C5 split into C5a and C5b > C5b recruits additional C proteins > membrane attack complex (MAC) is formed. This MAC creates a large pore in the pathogen’s membrane so water and ions can flow in.
Mainly C3a and C4a just a little bit
major pro inflammatory cytokines
chemoattractant for PMNs
Mainly C3b but also C46 to a lesser extend
increase rate of opsinization
increase phagocytosis
acts as C5 convertase
bind any loose Ag/Ab complexes > deliver to spleen (type III reaction if we don’t properly get rid of these Ag/Ab)
C5a
Vasodilation/^ capillary permeability
Chemokine for PMN
Phagocytes receptors
MBL receptors
Complement receptors
PAMP receptors
When phagocytes gobble up pathogens they then take antigens and put them on their membrane to also become antigen presenting cells
Complement pathway leads to?
Primarily inflammation
It can also cause activation of innate immune response
Inflammation
Every pathologic process in the body involves inflammation
*Hallmark of all disease processes
Purpose is to recruit and activate white blood cells to get rid of pathogen and eventually result in healing
Only occurs in vascularized tissues. First get vascular response, then get 2ndary cellular response, all mediated by cytokines.
5 Rs of inflammation
Recognition of PAMPs or DAMPS > innate immunity
Recruitment of WBCs, Acutely PMNs, chronically, monocytes and lymphocytes
Removal > activation of phagocytes, NKTs, and cytotoxic T cells (CTL). NKTs and CTLs cause apoptosis of infected host cells
Regulation: limit inflammation and initiate repair phase
Repair phase:
3 Types of Phagocytes
Macrophages
Dendritic cells
neutrophils
2 Hallmark Signs of Inflammation?
Redness (rubor) and warmth (calor)
Inflammation
Marcrophages/Mast cells > histamine, prostaglandin, and leukotrine release > vasodilation > ^ increased blood flow to bring more WBCs to location > causes rubor and calor
Histamine, prostaglandinds, leukotrines, and bradykinin also cause ^ sensitivity > pain (dalor)
Cytokines also cause endothelial cell contraction > ^ diameter of pores between cells > ^ vascular permeability so large things like WBCs and proteins can get out of blood and into tissue where the infection is. This causes increased oncotic pressure in interstitium, so water follows causing edema.
S/S of Inflammation
Always: redness and swelling
Sometimes warmth and increased pain
IL-6 Release
At location of ^ vascular permeability where WBCs are extravating into interstitium IL-6 is released
IL6 > travels in blood stream to liver > acute phase response activation > coagulation
Cellular Changes from Inflammation
Acutely: PMNs recruited to the area. Later on: monocytes and leukocytes
Resident macrophages in the tissue recognize microbes that have been opsonized and have either antibodies and complement on them > they phagocytize the microbes > cytokine release stimulate endothelial cell activation.
pathogens with C3a and C5a on them also activate mast cells > mast cell degranulation > cytokine release > endothelial cell activation
Endothelial cell activation (within cellular response of inflammation)
Adhesion molecules on endothelial cells so that they can adhere the WBCs that are passing by. Cytokines act as chemokines and are also placed on endothelial cells to attract WBCs to the area.
Chemokines: typically sugars or proteins
Endothelium Cells
Also have selectins (which are CD# molecules) on their membranes, (or if not, the cytokines will cause them to appear there).
Selectins/ICAMs are the arms that grab and hold the WBCs, so we need them to be exposed and active. Two kinds,
The cytokines cause the selectins to go from low affinity (closed) state to a high affinity (open) state.
WBCs adhesion molecules
WBCs also have adhesion molecules on them to help them adhere to the slectins on the endothelium. They are held loosely though, and are passed down the endothelium to the location of ^ vascular permeability.
Two primary kinds: oligosaccharide and integrin (CD11) .
These must also be in a high affinity state.
As WBCs are pulled to the endothelium by the chemokines their adhesion molecules are activated as they move towards endothelium.
Margination
WBCS being pulled to the endothelium surface
WBC Process to get into tissues
Margination > rolling > diapedesis
Diapedesis
WBCs are held tightly at site of ^ vas permeability, and WBC change morphology squeezing. flat to fit through the whole between endothelial cells.
End of inflammation
When no more pathogens in the tissue for Monocytes, lymphocytes, and PMN to gobble up, so they start releasing IL-10 and TGFb switching from pro-inflammatory to anti-inflammatory.
IL-6
Cytokine
released by monocytes/lymphocytes/PMN that get into the tissue,
Goes to liver and activate liver to release acute phase proteins,
Also goes to brain and causes stress response
Systemic Acute Phase Response
Initiated by IL-6
Liver proteins secrete Acute Phase Response Peptides
Ferritn/Haptoglobin > bind and decrase [Fe]
CRP > bind pathogens > opsonization via classical pathway
Serum amyloid A > ^prostaglandin synthesis & functions as chemokine for WBCs
Fibrinogen > ^ coagulation (pool blood at site of increased permeability to increase
interation between pathogens and WBCs)
Complement > (CL1 & MBL)
Growth Factor > IGF1 (&glucagon) > ^ gluconeogenesis, ^ protein catabolism, ^ FA
metabolism, decreased insulin sensitivity
IL-6 also goes to brain > stress response > cortisol release > ^ glucagon
At the End of inflammation
Anti-coag factors, (R1-antitrypsin, PAI)
Acute Phase Response Proteins (APRP)
Ferritin
CRP
Serum Amyloid A
Fibrinogen
Anti-Coag factors
Complement
IGF-1
IL-6 Effects
Acute Phase Response in Liver
Stress response in Brain
Leukopoiesis left shift
IL-6 Brain Pathway
IL-6>fever/stress response in brain > ACTH & GF > ^ Cortisol and glucocorticoids > mineral corticoids > ^ Na retention > water retention > ^ BP in acute phase of inflammation
When unable to clear pathogens
Switch to chronic inflammation > activation of fibroblasts > secrete extracellular matrix proteins (mostly collagen)
Over time we can eat up this scar tissue.
Types of repair Phases
Serous
fibrinous
Suppurative
Serous repair phaes
transudative (low Protein) or exudative (high protein)
Fibrinous repair
Fibroblasts release fiver in body cavities. Pericardial cavity, pleural cavity, etc. Can cause cross linking of visceral and parietal pleura.
Suppuritive repair
big pustule with very high protein content Abscess/ulcers
Innate Immune Response
Phagocyte activated by pathogen binding through PAMP or Opsonin on the pathogen
Also
NKT activated by pathogen or self infected cell
Both lead to cytokine mediated responses
1. Acute Phase Reaction Activation
2. Recruit WBCs (Chemokines)
3. ^ blood flow and vascular permeability
4. Micro coagulation (part of acute phase response)
5. Fever
Either cytokines activate adaptive response OR antigens presented on phagocytes/NKTs? activate adaptive response
Adaptive Immune Response
Happens in Lymph Nodes
Takes time for this process to start
Initiated by antigen presenting cells with antigen on MHC1 or MHC2 or by secondary signals (cytokines from phagocytes NKTs etc)
2 requirements to start adaptive response
1. Must present antigen on MHC molecule. We need a specific attack
2. Need a second signal
Actual Process
T-helper cell activated, IL-2, IFN4, IL-4, IL-5 released and determine what kind of t cell the helper t cell will differentiate into.
Th2 cells > B cell activation via antigen presentation from Follicular dendritic cell (in follicule of lymph node) AND 2ndary signal of CD40 CD ligand interaction. B Cells > memory cells or plasma cells that secretes immunoglobulins.
Immunoglobins (antibodies)
Secreted from plasma B cells
IgG Most abbundant,
IgM 1st secreted during infection, can also act as complement
IgD B cell receptor, mast cell and beta cell degranulation
IgE anti-parasitic and mast cell degranulation > Type 1 hypersensitivity reaction
IgA dimer, mucous secretions
Immunoglobin Actions
Opsinization
fix complement
MAC lysis
Agglutinate/imobilize pathogens
neutralize bacterial toxins
prevent bacterial binding
promote inflammation
Cytotoxic T cell activation
Th0 > Th1 > cytotoxic t cell activation
OR
CD8+ activation > with Th1 activation > cytotoxic t cell activation. Or CD8+ > memory t cell if no Th1 to co activate the cytoxic t cells.
Cytoxic T Cell Actions
IFN gamma > mess up viral replication of virus
perforin release
granzymes and granulysin release go through perforins to cause apoptosis
Fas ligand > death complex > cell apoptosis
