ANSC22 Exam 2 Immune System

Pathogens

• viruses

• Bacteria

• Fungi

• Protzoa

• Helminths

Threats: altered self

• cancer cells

• infected cells

• damaged cells

Threats: foreign non-living matter

• Toxins

• venoms

• Transplants

Levels of protection

1) Anatomic barriers

2) Complement/antimicrobial proteins

3) innate immune cells

4) adaptive immunity

Most external threats are stopped by when?

Anatomic barriers or complement/antimicrobial proteins

Most remaining threats are inhibited by which point?

Innate immune cells or adaptive immunity

Central/primary lymphoid organs

• bone marrow

• thymus

Peripheral/secondary lympoid organs

• Spleen

• Lymph nodes

• mucosal lymphoid tissues

• mucosa

Complement proteins

• Whole cocktail of proteins circulating in the plasma

• Stick to foreign particles and organisms

• When one stickes in changes shape or cleaves

• activates the next one

Membrane attack complex

• Complement inserts a hole into the bacterial membrane

• Causes cell lysis

WBC shared characteristics

• Nucleated

• Lots of types

• Mobile

• Chemical communication

• Blood is transit, not home

Dramatic variation of WBC

• Lifespan: hourse to decades

• Size: 7 um to 50 um

• Number <1% to >70%

• Production 100,000,000,000 per day to 1 per lifetime

Hematopoiesis

creates new blood cells

Macrophage

• Tissue resident

• First responders

• uses phagocytosis and activation of bacterial machanisms, antigen presentation

Neutrophil

• Rapid response

• NETosis

• uses phagocytosis and activation of bacterial mechanisms

Respiratory burst

• Increased oxygen consumption

• High production of reactive oxygen species (ROS)

• ROS kill ingested bacteria

Eosinophil

kills antibody-coated parasites

Basophil

promotion of allergic reponses and augmentation or anti-parasitic immunity

Granulocytes

• Basophils

• Neutrophil

• Eosinophil

Granules contain

• enzymes

• bleach

• reactive oxygen species (ROS)

Mast cells

Release of granules containing histamine and active agents

natural killer cells

releases lytic granules that kill some virus- infected cells; tumor killing

Dendritic cell

• Antigen uptake in peripheral sites

• Antigen presentation

T cells/T lymphocytes

• Kill infected host cells

• control immune responses

• help activate B cells

B cells/B lymphocytes

Produce antibodies

Antibodies

• Bind and neutralize foreign substances

• activate complement to destroy targets

• Facilitate recognition by phagocytes

Antibody order of function

2) Acts as opsonins

3) Causes antigen clumping and inactivation of bacterial toxins

6) Activates complement

Large numbers of macrophages are found in

the spleen and lymph nodes

Large numbers of dendritic cells are found in

Spleen, lymph nodes, bone marrow, mucosa

Large numbers of neutrophils are found in

bone marrow

Large numbers of lymphocytes are found in

the spleen, lymph nodes, and thymus

Immune cell coordination

1) Bacteria trigger macrophages to release cytokins and chemokines

2) Vasodilation and increase vascular permeability cause redness, heat, and swelling

3) Inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain

Immune cell trafficking

1. extravasation= leaving a blood vessel to enter a tissue

2. Amoenoid motion= movement within a tissue

3. Chemotaxis= migration toward a chemical signal

Steps of extravasation

1. Expression of adhesion molecules

2. Adhesion

3. Diapedesis

Steps of Amoeboid motion

1. Pesudopods extend and attach to material

2. Cell pulls itself forward

3. Pseudopods detachment and reextend to new spot

Causes inflammation

1. blood clots stop blood loss, close off wound

2. increased vascular permeability facilitates protein and cell entry

3. Activates repair processes

Innate cell characteristics

• Genome encoded

• Highly conserved

• rapid responses (minutes/hours)

• Nonspecific

• no long-term memory

Constitutive defenses

• Physical

• Chemical

• biological

Innate recognition

• Pattern-recognition receptors= recognize molecules that are commonly associated with pathogens

• Pathogen-associated molecular patterns

• Danger-associated molecular patterns

how long is the innate immune response?

day 0-5 of infection

Cytokine

• protein secreted by immune cells

• affects the behavior of nearby cells bearing appropriate receptors

Chemokine

• Proteins secreted by immune cells

• chemoattractants of immune (and non-immune) cells bearing appropriate receptors

types of cytokines

• IL-1B

• TNF

• IL-6

Sickness behavior

• Lethargy

• cold

• Headache

• anhedonia

• Anorexia

• Social isolation

What causes sickness behavior?

cytokines

Pathgoen destruction: 2 types

1. Neutrophils engulf and kill the microbes to which they bind

2. Phagosomes fuse with primary and secondary granules. Rac2 induces assembly of a functionl NADPH oxidase in the phagolysosome membrane, leading to generation of O2. Acidification as a result of ion influx releases granule proteases from granule matrix

What happens to neutrophils after they use up their granules?

they die —> major component of pus

Cytokine storm

• Uncontrolled cytokine production

• Activates repair processes

Outcome of cytokine storm

• ARDS

• Multi-organ failure

• Hyperinflammation syndrome

• Death

• Shock

Macrophage proinflammatory functions

• Leukocyte recriutment

• Activation of vascular endothelium

• Leukocyte activation

• Activation/modulation of adaptive immune system

Macrophage pro-resolution functions

• Production of anti-inflammatory factors

• Clearance of dead cells

• inhibition of leukocyte recruitment

• Tissue repair

What from the brain regulates immune response in the body?

Glucocorticoids (Cortisol)

What regulates the immune system from the body to the brain?

IL-1B, TNF, IL-6

Core immune system functions

1. Recognizes: Identifies threats

2. Removes: Kills pathogens, clears debris and dead cells

3. Remembers: Immune memory allows recall of previous encounters

4. Regulates: prevents itself from going out of control

Adaptive immune chracteristics

• Not genome encoded

• Slow response (days)

• Pathogen-specific

• Long lasting memory

Antigen receptors

• T cells have T cell receptors (TCRs)

  • detects intracellular targets

• B cells have B cell receptors (BCRs)

  • Like cell-surface antibdoies

  • Detects extracellular targets

Antigen

antibody generating substance

Epitope

specific part of the antigen that an antibody recognizes

what do TCRs recognize?

peptides presented by MHC

Major histocompatibility complex proteins

a little hand to hold peptides

displays intracellular proteins (allows virus detection)

MHC class II

displays extracellular proteins

When is diversiy generated?

during T cell, B cell development

Positive selection

T cells only mature is their TCR is able to signal

Negative selection

T cells only mature if they do NOT strongly target self tissues

What kind of T cells mature and leave the thymus?

only useful T cells

When does the adaptive immune response occur?

Day 2-10

What happens to adaptive immune cells during clonal selection?

• Some stay and help B cells get activated

• Some leave the lymph node to go fight the infection

• Some prevent harmful responses

Cytotoxic T cells

• Very specific, with little or no collateral damage

• Perforin and granzyme are molecules used to kill cells

Antibody functions

• Bind and neutralize foreign substances

• Activate complement to destroy targets

• Facilitate recognition by phagocytes

Where is antibody IgA found?

mucosa

where is antibody IgD found?

Naive B cells

What does antibody IgE do?

attacks helminths and plays a role in allergic reactions

Where is antibody IgG found?

plasma

What does anitbody IgM do?

initial response

Immune memory cells

• Long-lived plasma cells in the bone marrow

• Memory B cells

• Memory T cells in lymphoid organs

• Memory T cells in the tissues

Vaccine types

• mRNA vaccine

• DNA vaccine

• Subunit vaccine

• Live attenuated vaccine

• Inactivated vaccine

• Recombinant vector vaccine

Vaccine components

• active ingredient/antigen

• Adjuvants

• stabilizers

• Water, salt, buffers

• Delivery ingredients

• Manufacturing traces

Live attenuated vaccines approach

acutal infection with related but less harmful pathogen

Live attenuated vaccine pros

• 1 dose= strong immune activation

• Multiple or all epitopes present

• Activation in relevant tissues

Live attenuated vaccine cons

• Storage and transport

• can cause disease in susceptible poeple

• can revert to disease-causing form

Inactivated vaccine approach

kill the pathogen, then administer

Pros of inactivated vaccine

• Stable

• Easy to store and transport

• Cannot cause disease

Cons of inactivated vaccines

• 3D pathogen structure maintenance is difficult

• Weaker immune response- boosters required

subunit vaccine approach

administer pathogen protein component paired to adjuvant

Subunit vaccine pros

• very stable

• No containment requirements (harmless if released)

Subunit vaccine cons

• needs an adjuvant

• Stable but cannot be frozen

• Multiple doses required

Toxoid vaccine appraoch

administer pathogen toxin paired to adjuvant

Toxoid vaccine pros

• Cheapest of all options

• well understood so new vaccines require minimal testing

Toxoid vaccine cons

• Needs an adjuvant

• stable but cannot be frozen

• Injection only

• multiple doses required

• personal (not community) protection

Conjugate vaccines approach

• bacterial sugar attached to carrier protein

• Immune system treats the sugar like a protein, generating a strong response

Conjugate vaccine pros

• high quality anti-sugar anitbodies

• Effective in infants (highest risk population)

• Stable storage and shipment)

Conjugate vaccine cons

• Many sugars used by different bacteria, and use can change

• Multiple doses needed

• Difficult to grow and prepare ($$$)

Viral vector vaccine approach

• Take surface protein from a harmful pathogen

• Engineer a harmless virus to express that surface protein

Pros of viral vector vaccines

• 1 dose= strong immune activation

• Fast redesign

• Some are 4 degrees stable

Cons of viral vector vaccines

• Immune response also against vector (VSV)

• Unstable, unltracold storage

mRNA vaccine approach

Inject with mRNA that encodes target antigen

mRNA vaccine pros

• can vaccine against any protein

• Easy to modify and update

mRNA vaccine cons

unstable, ultracold storage

herd immunity

indirect protection from an infectious disease that happens when a large percentage of a population becomes immune