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79 Cards in this Set

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Define complement.
A grp of proteins that is a sequentially reacting group of proteins, which on activation, mediate a # of bio reactions important to host defense
What are 3 significant characteristics of the complement cascade?
1. Cascade - sequential activation of protein via cleavages

2. It requires activation

3. Normally not active - the alternative pathway is active at a very low level
What is C3 tickover?
Alternative pathway is active at very low levels at all times

This primes the pathway for encountering pathogens, so it can rapidly amplify to destroy pathogens.
The complement system is a part of which arm of the immune system?
innate
How many proteins are in the complement cascade? What are they?
11 proteins:
C1-C9
C1 = C1q, 2Cr, 2Cs
Which proteins are path of the classical pathway of complement?
C1-C4
Which proteins are part of the terminal/lytic pathway?
C5-C9

This is complement's ability to destroy pathogens via the membrane attack complex (MAC)
What are the 3 pathways in the complement system?
Classical
Alternative
Mannose binding lectin pathway - a shunt pathway feeding the classical pathway
Most of the proteins in teh complement system are....?
Serum soluble
Receptors are.....?

The majority of the proteins in the complement system are involved in (activation/regulation)?
membrane bound

Regulation
Many of the enzymes involved in the complement cascade are what type of enzymes?
serine proteases
Describe collectins.
Have a long collagen stalk and several globular head domains that are used for recognition of their invading pathogens or surface molecules
Describe cytolytic proteins.
Proteins that are involved in complement mediated lysis.All have a C9/perforin type domain.

Perforin is produced by cytotoxic T and NK cells and lyses virally infected cells or cells with intracellular pathogens
What are the "true" complement proteins?
C3, C4, C5

These are central to the system and almost all the biological activity of CS is derived from the cleavage of these 3 proteins
Where is the primary site of synthesis on complement components?
Hepatocytes -- accounts for 90% of complement found in the blood
Where is complement made in the brain?
neurons, astrocytes, and microglia
What is factor D made?
fat cells
What are the functions of C3a and C3b?
C3a - chemotaxis and inflammation

C3b - opsonization, neutralization of invading pathogens, B cell activation
What are the functions of C5a and C5b?
C5a - potent chemoattractant molecules and important in inflammation

C5b - starts formation of the Membrane Attack Complex
What is the main activator of classical pathway? What is the role of the immunoglobulins?
Ab-Ag complexes

Only IgM and IgG's are good at activating complement.

only need one molecule of IgM and need 2 molecules of IgG
Describe the structure of the IgM molecule.
pentamer with multiple Fc regions
What activates the mannose binding pathway? alternative pathway?
pathogens with mannose or N-acetylglucosamine residues on their surface

Alternative pathway - activated by LPS and other types of LPS
Describe C1q.
It is a collectin. It has a collagen stalk with globular heads. The globular heads recognize the Fc regions of the Ab

If the Abs are in close proximity, C1q will corss link them and activate classical pathway

Activates the enzymes C1r, C1s
What is the biological functions of C3a and C5a?
Chemotactic and Anaphylatoxic molecules - cause a gradient dependent migration of neutrophils and macrophages

Cause degranulation of mast cells, basophils, and eosinophils to release histamine

induce increased vascular permeability, edema

protects the host from complement mediated damage

induce cytokine release, adhesion molecules

induces/augments respiratory burst
What comprises the MAC?
C5b, C6, C7, C8 and C9
What are the biological functions of C3b?
Opsonization of Ag-Ab complexes for clearance and be destroyed by phagocytosis

If the immune complexes gets too large, they can deposit into tissues and it is a good activator of complement and can destroy your own damaged tissue

C3b binding to Ag-Ab complex -- cause Ab to come off

Coats pathogen so it cannot become attached to host tissues
What do anaphylatoxins do to the body?
generate systemic affect, type I hypersensitivity, shock response if you have too much activation of the CS
What inactivates anaphylatoxins?
Carboxypeptidase -- cleaves a terminal Arg off C3a and C5a to drop biological activity
What happens if you have activation components missing?
leads to recurrent bacterial infections and lupus if C1, C2, or C4 is mission

immune complexes cannot be handled well
What happens if you have terminal components missing?
This means you have MAC components missing... most pple do well except that dont have resistance to neisserial infections -- normal flora
What happens if you have regulatory components missing?
leads to hereditary angioneurotic edema (HANE) - non-inflammatory edema spontaneously occurring in response to traumatic event due to C1-inhibitor being missing
What happens if receptors in complement are missing?
If missing complement receptors 3 and 4, kids don't live beyond age 1 or 2 b/c cant handle infections

only cured by bone marrow transplant
What are the function of adhesion molecules?
1. cell to cell contact
2. Homing - development and immune response
3. Immune trafficking
What are the fxns in immune responses?
1. Homing -
Naieve - havent seen invading pathogen
Effector - cells that are activated and now need to traffick to sites of inflammation
Memory T cells - traffick differently than naieve cells

2. Recruitment of phagocytic cells
What are the steps in leukocyte trafficking?
1. rolling
2. activation
3. firm adhesion
4. diapedesis
What are the barriers involved in leukocyte migration?
physical barriers - endothelial cells

Ability to signal cells

Blood flow in post capillary venules in not super fast, but always have blood pushing on cells to keep the blood moving and oxygenation of tissues normal
Describe selectins.
involved in rolling step
group of C type lectins
lectins bind carbs and sugar
Describe integrins.
heteromeric, multi-fxnal receptors

their expression determines what cell types are going to move where because they're not expressed at the same level in all different cell types
What adhesion molecules are part of the Ig supergene family.
CAMs - cell adhesion molecules

They are composed of immunoglobulin domains
What selectins are found on endothelial cells?
P selectins
E selectins
What selectin is found on leukocytes?
L selectin
What is a prominent ligand molecule that binds selectin?
Sialyl Lewis X
What are some inflammatory cytokines involved in activation of leukocytes?
IL-1/IL-8/TNF
What is FMLP?
N-formylmethionyl-leucyl-phenylalanine

found on lots of bacterial protins

This tri-peptide will break off and turns out to be a vary potent activator of host immune cells
What is inside out signaling?
Occurs in neutrophils

Inactive leukocytes express inactive integrins

When you get an activation signal, you have inside-out signaling occurring in the leukocyte such that this integrin molecule changes it's confirmation to an active confirmation, so that it can bind to the endothelial cell surface.
What is a classic molecule found on endothelial cell surface that integrin molecules can bind?
ICAM-1
What is leukocyte adhesion deficiency type I?
If person is missing certain enzymes that transfer fucose molecules onto these carbs, these individuals dont get any rolling events occurring because they dont get any carbs binding to the selectings
What is adhesion mediated by?
integrins
How do leukocytes crawl between cells?
1. Adhesion molecules and molecular motors: beta 2 integrins and jxnal adhesion molecules (JAMs)
-- JAMs line up on the edge of the endothelial cell layer and work to help pull the cells through.

There are number of molecular motors that help drive shap change

2. Proteinases - generated by infiltrating neutrophils because it has to break up the ECM

3. Cytoskeletal rearrangement - must flatten out and squeeze themselves through space; they have to continually do this because once they get into ECM, they still have to move between cells and basement membranes
Define phagocytosis.
Process by which cells ingest other cells. It is a receptor drive process
Define pinocytosis.
uptake of water and small molecules
What are the 2 receptors that are critical to the phagocytic process?
complement and Fc receptors

Have to have both of these for efficient phagocytosis
What are the fxns of the phagocytic process?
1. Maintenance
-- removal of apoptotic cells
-- remodeling - bone
-- eye - epithelial cells phagocytize outer rod segments that are shed from photoreceptors

2. Host defense
-- clearance for invading pathogens
-- starts antigen presentation
What are the "professional phagocytes"
Neutrophils - die after phagocytizing pathogen

Monocytes/Macrophages - APCs
-- liver - Kupffer cells
-- skin - histeocytes
-- microglia - brain
What are non-professional phagocytes?
epithelial and endothelial cells
What are the Fc receptors for IgG molecules?
Fc-gamma-R1 through Fc-gamma-R3
What part of the Fc receptors for IgG immunoglobulins bind to the Fc portion of the Ab?
the alpha chain
What is the significance of the gamma chain of the Fc receptors for IgG molecules?
These are signaling molecules that once the alpha chain has bound an Ag-Ab complex, it helps transduce signals into cells that tell them that body has encountered something that needs to be phagocytized.
What cells express Fc receptors?
neutrophils and macrophages
Describe Complement Receptor type 1 (CR1).
Composed almost completely of short consensus repeats.

Multiple binding sites for the complement binding fragments C3b/C4b
-- Remember C3b/C4b can covalently attach to the surface of invading pathogen
-- CR1 is one of the molecules that will recognize these fragments on the surface of the invading pathogens and help aid in binding of that complex to the phagocytic cell and ultimately in phagocytosis
Where are CR1 receptors expressed?
neutrophils, monocytes/macrophages, RBCs

RBCs are a major reservoir for clearing immune complexes in the blood.
Describe complement receptor type 3.
Member of the beta-2 integrin family of adhesion molecules

It's also a complement molecule.

There's a complement called CR4. CR3 and CR4 have a common chain called CD18. CR3 is CD11b and CR4 is CD11c.

Binds C3bi, a degradation fragment of C3b
What happens if the CD18 beta chain is missing?
If this is missing, none of these other beta-2 integrins molecules are expressed on the surface of the cell and you're seriously immunocompromised.
Where are CR3 receptors expressed?
neutrophils and macrophages
Describe Complement Receptor type 1 (CR1).
Composed almost completely of short consensus repeats.

Multiple binding sites for the complement binding fragments C3b/C4b
-- Remember C3b/C4b can covalently attach to the surface of invading pathogen
-- CR1 is one of the molecules that will recognize these fragments on the surface of the invading pathogens and help aid in binding of that complex to the phagocytic cell and ultimately in phagocytosis
Where are CR1 receptors expressed?
neutrophils, monocytes/macrophages, RBCs

RBCs are a major reservoir for clearing immune complexes in the blood.
Describe complement receptor type 3.
Member of the beta-2 integrin family of adhesion molecules

It's also a complement molecule.

There's a complement called CR4. CR3 and CR4 have a common chain called CD18. CR3 is CD11b and CR4 is CD11c.

Binds C3bi, a degradation fragment of C3b
What happens if the CD18 beta chain is missing?
If this is missing, none of these other beta-2 integrins molecules are expressed on the surface of the cell and you're seriously immunocompromised.
Where are CR3 receptors expressed?
neutrophils and macrophages
Describe the type of binding between antibodies and antigens and the complement system and antigens.
Antibodies bind non-covalently to antigens

Complement system is covalently attached to surface of antigen.
What are the stages of phagocytosis?
Ligand binding
Activation of phagocytic cell
Englufment
Internalization/fusion with lysosomes to form phagolysosomes
Bacterial killing
What is the zipper hypothesis?
If you have a phagocytic cell that has F(c) receptors binding antibodies and complement receptors binding complement fragments, they can basically "zipper up" around the pathogen and engulf it into a vesicle inside the cell.

It is dependent on actin and other cytoskeletal elements.

You end up extending pseudopodia around this bacteria
How is bacteria killed when inside a phagolysosome?
free radicals, defensins (natural antibiotics that your body makes)
What system does the respiratory burst utilize?
NADPH oxidase system, which is a complex of a number of different enzymes that generate free radical molecules that are toxic to invading pathogens
What is myeloperoxidase?
Enzyme found in phagolysosome. It generates HOCl (bleach) - very toxic to invading pathogens
What are azurophilic granules? Where are they located?
It's an enzyme found in the phagolysosome. It has almost every enzyme that you want. These enzymes will basically degrade every class of biomolecules. Some of the material can be reused by the host cell as an energy source

Found on neutrophils
What is Chronic Granulomatus disease?
genes missing in NADPH system will make you sick
What is Chediak-Higashi Syndrome?
rare disease, enzymes found in these granules don't very well to lysosomes. As a result, you dont get all of these proteins put together at the site where the bacteria are and you end up with all kinds of infections.
What is Leukocyte Adhesion deficiency type 2?
If missing any of the beta-2 integrin molecules, because of the CD18 chain, none of the beta-2 integrins molecules get put on the surface and you dont have good phagocytosis