BIOMS 4150 Prelim #1

The purpose of the immune system is to...

maintain a healthy state of homeostasis.

True/False: Most vaccines prevent infection.

False. Most vaccines prevent severe disease, not infection.

Describe the recognize-activate-act paradigm in the case of the smallpox vaccine.

Variola specific antibodies tag virus particles to alert immune cells, and then T calls proliferate and fight off the infection.

True/False: Immunity is the ability to resist infection.

False. It is the ability to resist disease.

What is the difference between infection and disease?

Infection is the invasion of barriers by a microbe. Disease is the state of being unhealthy due to an infection.

Cell receptors can bind to the _____ section of all antibodies.

FC (fixed composition)

What are three threats that the immune system can respond to?

(1) Microbes

(2) Damage (from microbes or from UV radiation, toxins, etc.)

(3) Our own cells malfunctioning (i.e. cancerous cells)

____________________, or intracellular destruction, is an effector mechanism.

Phagocytosis

What are the four categories of microbes?

(1) Viruses

(2) Bacteria, Archaea, Protozoa

(3) Fungi

(4) Parasites

True/False: Allergens are a kind of microbe.

False. Viruses, bacteria, fungi, and parasites are all examples of microbes.

Pregancy changes the immune response to be (more/less) allergic.

more

A commensal microbe...

exists on the outer barriers and does not cause disease (some are actually beneficial).

A pathogen...

causes disease.

An opportunistic pathogen...

is usually harmless, but can cause disease when the immune system is compromised (capitalizing on an OPPORTUNITY (i.e. AIDS patients, taking immunosuppressive drugs during and after a transplant)).

What are the four lines of defense against a new threat?

(1) Physical barriers (skin, mucus membranes)

(2) Immediate innate defenses (complement)

(3) Induced innate defenses (phagocytosis)

(4) Adaptive defenses

What are the five parts of the immune system?

Leukocytes, networks (lymphatic and circulatory), lymphoid tissues, molecules, epithelial barriers

Plasma cells are activated ___ cells.

B

What is hematopoiesis?

Hematopoiesis is the process of a stem cell evolving to become a blood cell.

True/False: Hematopoiesis can backtrack to a certain extent.

False. Developmental changes are irreversible.

A ___________________ is both a phagocyte and granulocyte.

neutrophil

What are granulocytes?

Granulocytes attack microbes by bombarding them with antimicrobial granules.

The suffix -phil at the end of an immune cell means that it is a ______________________.

granulocyte

Mast cells are (phagocytes/granulocytes).

granulocytes

Eosinophils and basophils are (phagocytes/granulocytes).

granulocytes

Macrophages and dendritic cells are (phagocytes/granulocytes).

phagocytes

True/False: Dendritic cells come from the same progenitor cell as T-, B-, NK, and IL cells.

False. T-, B-, NK, and IL cells are from the same lymphoid progenitor, and dendritic cells are from a myeloid progenitor (the same as the granulocyte progenitors).

What are the three types of phagocytes?

macrophages, dendritic cells, and neutrophils

What are the four types of granulocytes?

neutrophils, basophils, eosinophils, and mast cells

Mast cells are _____________________ and dendritic cells are ________________.

granulocytes; phagocytes

What are the two primary lymphoid tissues?

thymus and bone marrow (generate T- and B-cells, respectively)

What are some examples of secondary lymphoid tissues?

spleen, lymph nodes, Peyer's patches

T- and B-cell responses start in (primary/secondary) lymphoid tissue.

secondary

How is a T- and B-cell response generated?

Dendritic cells collect pieces of the pathogen on their surface and travel to lymph nodes, where dormant T -and B-cells are gathered. This activates the dormant cells, which mature into effectors like plasma cells and killer T-cells and leave into the bloodstream.

Immune cells are generated in (primary/secondary) lymphoid tissue and stored in (primary/secondary) lymphoid tissue.

primary; secondary

What are three ways in which antibodies mess up microbes and tag them for elimination?

(1) Neutralization: antibodies can bind to toxins and prevent them from hurting cells.

(2) Opsonization: antibodies can tag microbes and make them easier to recognize by phagocytes.

(3) Complement activation: antibodies can tag microbes and bring them to the attention of complex proteins, which can trigger cell lysis and ingestion of the remains by a phagocyte.

MAC stands for...

membrane attack complex.

What do complement proteins C5b, C6, C7, C8, and C9 do?

They form a MAC and prepare to punch holes in the membrane of a microbe.

TNFα, CXCL8, and CCL2 are examples of what kind of molecule?

cytokines

What is the difference between cytokines and chemokines?

Cytokines increase permeability of blood vessels to allow for blood to leak into infected areas, so that more leukocytes and complement proteins can arrive and fight off the infection. Chemokines are a subtype of cytokines that induce chemotaxis, or movement towards high concentrations of attractants.

What are some defenses innate in epithelial barriers like skin and mucous membranes?

leukocytes, commensal microbes, defensins, low pH

Goblet cells secrete ____________.

mucus

Paneth cells secrete __________________.

antimicrobial defensins and lysozyme

________________ cells start inflammation and transport antibodies.

Epithelial

_____________________ cells secrete antibodies.

Plasma

What are some kinds of antimicrobial peptides?

kinases (change phosphorylation of proteins), protease (breaks down protein), glucosidase (breaks down a sugar)

How do lysozyme and defensin cooperate to perforate microbes?

Lysozyme digests outer cell wall peptidoglycan and exposes the lipid membrane of the microbe. Defensin can then intercalate and forms pores.

What are some components of the immediate innate response?

mucus w/defensins, lysozyme, and antibodies; complement proteins and pattern recognition molecules

What are some components of the induced innate response?

leukocytes, inflammatory response, acute-phase response, and interferon response

What are some components of the adaptive immune response?

T- and B-cells and antibodies, which focus defenses on a target

Healthy human cells are (positively/negatively) charged at the surface.

generally neutral, may be slightly positive

What are three immediate strategies for tagging microbes?

(1) Attack highly negatively charged surfaces (like LPS on Gram negative bacteria). Healthy human cells have a positive charge, so negatively charged human cells are sick.

(2) Tag all surfaces where a threat is detected (because healthy cells will just remove the tags).

(3) Tag the tell-tale microbial patterns on microbes (like peptidoglycan).

What is the polarity on a defensin?

Defensins are amphipathic (have hydrophillic and hydrophobic parts), like phospholipid bilayers. This allows them to penetrate the membrane.

How can defensins destabilize toxins?

Defensins are amphipathic, so they can hold a toxin molecule apart and denature it, leading to aggregation and digestion with proteases and phagocytes.

True/False: The vaccine for whooping cough is aainst the virus that causes it.

False. The whooping cough vaccine is against the toxin.

How are defensins deployed (3 ways)?

(1) Neutrophils use defensins (contained in granules) in phagolysosomes.

(2) Macrophages activate defensins in phagolysosomes.

(3) Paneth cells activate defensins ars they are being secreted into the mucus on the barrier.

True/False: Defensins are kept in the active state, patrolling the body for threats.

False. Defensins are kept in an inactive state called pro-defensins. The Pro region is a peptide that is cut of fby proteases when there is a trheat.

Mannose binding lectin is a ____________________-.

pattern recognition molecule that recognizes the presence of mannose on surface sugars, which is a sign of microbes and not humans).

Pattern recognition molecule are (soluble/insoluble).

PRMs asre soluble and free-floating.

Provide four examples of microbe-associated molecular patterns.

mannose, fucose, LPS, peptidoglycan

True/False: We are born with the genes for MAMP receptors on some cells.

True. They are innate.

What is C3?

C3 is a central complement protein that tags all surfaces simultaneously or with help from other immune molecules.

Are complement proteins in tissues or blood?

Complement proteins are typically in blood and enter tissues when damage occurs.

How is C3 activated?

C3 is cleaved to C3a and C3b, which exposes a reactive thioester bond. In some cases, this thioester bond is quenched with water and nothing happens. However, sometimes the bond will attach to the pathogen in complement fixation (to hydroxyl or amino groups).

An inactive form of a protease that requires cleavage by another protease to become active is called a....

zymogen.

What is iC3Bb?

iC3Bb is a C3 convertase.

Describe the process of spontaneous iC3Bb formation.

C3 is spontaneously hydrolyzed to form iC3. Factor B binds to iC3, which causes it to form a nick. Factor D then cleaves factor B, which creates Ba and iC3Bb. Now, iC3Bb can cleave C3 into C3a and C3b.

How can surface-bound C3b reproduce?

Factor B binds to C3b, which causes it to get a nick. Factor D then cleaves factor B, creating Ba and C3bBb, which is a C3 convertase.

Why does a bunch of C3b get fixed to a cell surface?

That cell is going to be attacked.

What are the three outcomes of complement activation?

(1) C3a and C5a (the little pieces that are cut off of C3) recruit phagocytes and promote inflammation.

(2) Phagocytes with receptors for C3b engulf and destroy the pathogen.

(3) Completion of the complement cascade results in the formation of a membrane attack complex (MAC), which leads to perforation and lysis of the pathogen.

Phagocytes can recognize pathogenic cells tagged with C3b using the receptor called _______.

CR1 (complement receptor 1)

What does complement receptor 1 recognize?

C3b

How can a surface-bound C3 convertase (which formed as a result of the alternate complement pathway) become a C5 convertase?

C3bBb is the surface bound C3 convertase that forms as a result of the alternate complement pathway. Adding another C3b subunit will make it a C5 convertase (C3b₂Bb).

Describe the process of MAC formation.

C5b connects with C6, C7, and C8 to form C5b678, which can insert into the membrane. This then recruits many C9, which configures into a pore called the membrane attack complex (MAC).

What is the role of C9 in MAC formation?

C9 is recruited in large numbers by C5b678 and forms a pore in the pathogen cell membrane, called a MAC.

How do human cells avoid the formation of MACs?

Human cells have protectin (CD59), which bind to C5b678 and prevent the recruitment of C9 to form a MAC.

What is protectin? What does it do?

Protectin (CD59) is a regulatory complement protein found on human cells. It binds to C5b678 and prevents the recruitment of C9, which is what forms MACs.

What are anaphylatoxins? Give two examples.

Anaphylatoxins are peptides that bind receptors on the linings of blood vessels and active the inflammatory immune response. C3a and C5a are anaphylatoxins.

How did C3a, C4a, and C5a get the name anaphylatoxin?

If they are overproduced throughout the body all at once, they can cause deadly anaphylactic shock.

How do C3a, C4a, and C5a cause inflammation?

They cause blood vessel epithelial cells to partially detach from one another to make the vessel leaky, and induce cells to produce adhesion molecules that will catch leukocytes as they pass by. They also promote local coagulation to wall off the infection.

Arriving neutrophils and macrophages also use receptors for anaphylatoxins to become destructive.

What is mannose-binding lectin?

Mannose binding lectin is a protein complex that binds mannose and carries proteases to build a C3 convertase.

How does the lectin complement pathway work?

Mannose binding lectin (MBL) and ficolins recognize carbohydrates on the surface of the pathogen and bind. They then cleave C4 to create C4a (which is an inflammatory molecule that floats away) and C4b, which embeds in the membrane. Then, MBL and ficolin cuts C2 into C2a and C2b, and C2a binds to C4b. The resulting complex, C4bC2a, is a C3 convertase.

Set up parallels between the MBL and alternative pathways for complement activation.

C3 in alternate = C4 in MBL

Factor B in alternate = C2 in MBL

H2O & Factor D (cleavage) = MASP-2 in MBL

C3bBb = C4bC2a

Bb = C2a

C3b = C4b

*The part that binds to the membrane always ends in a "b"—C4b and C3b

What is ficolin?

Analogous to MBL (has MASPs that can cleave).

What is a MASP?

The part of MBL and ficolin that cleaves the C4 and C2.

Describe the classical pathway of complement activation.

C-reactive protein binds to phosphorylcholine, which is a common ingredient in bacterial cell membranes. C-reactive protein is a landing pad for C1qrs (where the C1rs are the proteases that cleave C4 and C2). The end result is C4bC2a, which is a C3 convertase.

The _____________________ complement pathway starts spontaneously and the _____________________ and _____________________ complement pathways start with pattern recognition molecules.

alternative; lectin; classical

C-reactive protein binds to ________________________.

phosphorylcholine

C-reactive protein is part of the ________________________ complement pathway.

classical

Ficolin is part of the ________________________ complement pathway.

lectin

C1qrs is part of the ________________________ complement pathway.

classical

MASP-2 is part of the ________________________ complement pathway.

lectin (it is the protease)

C1rs is part of the ________________________ complement pathway.

classical (it is the protease)

Factor D and B are part of the ________________________ complement pathway.

alternative

What is the C3 convertase formed by the alternative complement pathway?

C3bBb

What is the C3 convertase formed by the classical and lectin complement pathways?

C4bC2a

What is the C5 convertase formed by the classical and lectin complement pathways?

C4b2a3b (just add another C3b to a C3 convertase)

What is the C5 convertase formed by the alternative complement pathways?

C3b₂Bb (just add another C3b to a C3 convertase)

What are 5 ways in which complement is regulated?

(1) Soluble C3b is continually broken down. (2) Complement proteins in general are continually degraded and (3) most only act when bound to a surface. (4) Some regulatory proteins inactivate surface bound convertases (i.e. protectin, or CD59) and (5) some upregulate complement action on microbes (i.e. Factor P, or properdin).

Factor P is a ___________________ molecule that is secreted by ______________________.

pattern-recognition; neutrophils

True/False: C3bBb degrades very slowly without Factor P.

False. C3bBb degrades very quickly. Factor P stabilizes it and makes it last longer.