Complement & Cytokines

Exam 1 - Lec 5

The complement system (aka complement cascade) is a part of the immune system that _________ the ability of antibodies & phagocytic cells to __________.

enhances

clear microbes/ damaged cells, promote inflammation, & attack pathogen cell membrane

What are the 4 big functions of the complement system?

1. Cell lysis → kill pathogens

2. Opsonization/ Phagocytosis → clearance of apoptotic cells/ debris, synaptic pruning

3. Regulation → inhibition of complement cascade

4. Others → promote cell differentiation/ recruitment, modulation of immune cell migration, regulation of B-cell function, leukocyte adhesion

There are ______ pathways of complement activation.

3

All 3 complement activation pathways lead to _____ then the formation of _____________ and __________.

C3

membrane attack complex (MAC)

pathogen destruction

How does the membrane attack complex work?

a protein subunit embeds itself into the cell membrane of a pathogen causing ions to rush in/out

What is the overall goal of the membrane attack complex?

osmotic cell lysis

The classical complement activation pathway is part of ________ immunity, requires the presence of _______, and is activated after about _______ into an infection.

acquired (adaptive)

antibodies

5 days

The alternative & lectin complement activation pathways are part of _______ immunity, are triggered when _____________ in the blood, and response is seen ________.

innate

microbial cell walls meet complement proteins

immediately (no delays)

The alternative pathway is activated by the presence of a ______.

pathogen

What happens after the alternative pathway is activated by the presence of a pathogen?

C3b will bind to pathogenic surface → complement cascade ensues

If no pathogen is present, what happens to in the alternative pathway?

NO activating surfaces → cascade inhibited (under normal circumstances)

The lectin pathway relies on the presence of ______ being detected on the surface of a pathogen.

mannose

The classical pathway requires ________ antibodies to bind to the antigenic surface relatively __________.

at least 2

close together

Explain the classical pathway.

antibody binds to microorganism → exposes C’ binding site on antibody → C1 encounters bound antibody & crosslinks bt adjacent antibodies → C1 is activated & becomes an active protease → C1 cleaves C4

C1 is ______ bound together by Calcium.

3 subunits

Which antibody is more efficient in activating the classical pathway?

IgM → bigger + more binding sites

The differences in the 3 complement pathways involves the initial steps of activation leading to the formation of ________.

C3 convertase

During the complement cascade, each C component is ________ into smaller pieces a & b on the _______ surface.

cleaved

pathogen

The smaller _______ component is ________ & has other effects on the immune system and host body.

“a”

released

The larger ____ fragment _________ to the pathogen surface as part of the cascade.

b (“big bound b”)

remains bound

Exposure of the b fragment is __________ of the next complement protein (convertase).

required for activation

What happens during the amplification pathway?

• C3 convertase activates C5

• C6 & C7 rapidly bind to form a multimolecular complex that inserts on microbial cell wall

• C8 binds & 12-18 C9 molecules polymerize to form a circle

• Produces a hole in the pathogen surface

• Pathogen killed by osmotic lysis

What is the major product of the amplificatio pathway?

membrane attack compound (MAC) = “nature’s hole-punch”

What biological consequence does the activation of C2a produce?

increased vascular permeability

What biological consequence does the activation of C3a produce?

anaphaylatoxin, mast cell degranulation

What biological consequence does the activation of C3b produce?

immune recognition & opsonization

What biological consequence does the activation of C5a produce?

neutrophil chemotaxis, anaphylatoxin, lysosomal enzyme secretion, neutrophil activiation, increased vascular permeability, smooth muscle contraction

What biological consequence does the activation of C5b, C6, & C7 produce?

leukocyte chemotaxis

Biologic effects of C5a include:

1. Neutrophil activation

2. Neutrophil adhesion

3. Neutrophil emigration & chemotaxis

4. Monocyte activation

5. Mast cell degranulation = smooth muscle contraction & increased vascular permeability

C3b is one of the most powerful _________.

opsonins

What is opsonization?

biological tagging of a bacterium/pathogen by a complement for phagocytosis

What is the overall summary of the complement system.

series of protein interactions that amplifies inflammatory response → works together with innate/ adaptive immune pathways

take a gander at this chart

Cytokines are master _______ of the immune response

regulators

What are some examples of cytokines?

interleukins, chemokines, TNF, interferons, monokines

Cytokines are ________ secreted by cells of the __________ to regulate the immune system.

proteins

immune system

T/F: Cytokines only affect a small number of cells/ organs.

FALSE - affect a wide variety of cells and organs

T/F: Cells rarely secrete only one cytokine at a time.

TRUE - groups may be synergistic or anatagonistic

Without anatogonistic cytokines, ______ occurs.

pathology (immune-mediated arthritis)

What are the overall functions of cytokines?

inflammation, immune regulation, turmor surveillance, hematopoiesis, cell differentiation

Cytokines are produced by cells that are integral to _______ innate (natural) and acquired (adaptive) immune responses.

both

Cytokines are _________ as preformed molecules.

not stored → actively secreted

Secretion of cytokines is ______ and ______.

brief (pathology of COVID = sustained secretion of IL-6)

limited

Cytokines are ________ and ________ of immune and inflammatory responses.

mediators

regulators

Cytokines influence the ________ of other cytokines.

synthesis

Cytokine cascades can _________ or _________ the production of other cytokines. (+ or - regulatory mechanism)

enhance

suppress

Cytokines bind to ________ on target cells with _____ affinity.

specific receptors

high

Cellular responses to cytokines are generally _______ because they require _____ mRNA & protein synthesis.

slow (hours)

new

Pleiotrophic

an individual cytokine may be produced by many different cell types and act on many different cell types → cellular host efficiency

Redundancy

many cytokines have similar actions

Synergism

working together

Anatagonism

working against each other

T/F: Many cytokine receptors have common subunits.

TRUE - grouped in families

What are the 3 most important reactions that trigger cytokine release?

1. Antigens bind to their receptors on T & B cells

2. Pathogen-associated molecular patterns (PAMPs) bind to TLR

3. Antibodies bind to F_c receptors (F_cR)

What is the general function of Interleukin-2 (IL-2)?

promotes lymphocyte proliferation

one of the most generic cytokines

IL-2 is produced by which cell(s)?

CD4+ T cells, CD8+ T cells (cytotoxic), dendritic cells, & thymic cells → pleiotrophism

What is general function of Interleukin-12 (IL-12)?

activates T cell and NK cells → promotes Th1 pathway (pro-inflammatory)

Which cell(s) produce IL-12?

macrophages, dendritic cells, & neutrophils → pleiotrophism

IL-12 is _______ meaning it shares a common subunit with IL-23.

redundant → in host defense to many pathogens

What is IL-12 central role in cell mediated immunity?

stimulates T cells & NK cells which in turn secrete IFNγ → IFNγ further activates macrophages → collectively mediates macrophage activity & elicits a cell mediated response

Which cell(s) produce interferon gamma (IFNγ)?

Th1 cells and NK cells → pleiotrophism

IFNγ under goes ______ with TNF-α.

synergism → triggers inflammatory cell death, tissue damage, & mortality in SARS-CoV-2 infection & cytokine shock syndromes

T/F: Cytokines work in isolation.

FALSE - do not work in isolation → many overlapping cytokine networks activated during an immune response

What is the importance of cytokine networks?

control reactions, keep immune responses in balance, & activate or down-regulate various cells

Cytokine summary chart

goal = enhance overall inflammatory response