NSCI 487A Midterm 1

why is inflammation in the brain particularly bad?

neurons can’t regenerate

name the 4 reasons why we need an immune system

1. identify threats to protect host from damage

2. prevent reinfection (immunological memory)

3. promote healing

4. normal physiology (development, homeostasis, etc.)

examples of immune system identifying threats and protecting the host from damage

• identify and protect from pathogens

  • bacteria, viruses, parasites

• identify and protect from/limit damage from internal pathogens

  • tumours, cell debris, pathological protein buildup, etc.

what is the duality of the immune system

must recognize and eliminate threats but also recognize and protect host tissues

results of an underactive immune system

cancer, infections

results of an overactive immune system

chronic inflammation, autoimmune disorders

level 1 immune system includes:

barriers and innate immune system

examples of innate immune system cellular components

myeloid, natural killer cells, dendritic

examples of innate immune system molecular components

cytokines, complement system

level 2 immune system includes:

adaptive immune system

examples of adaptive immune system cellular components

lymphocyte

examples of adaptive immune system molecular components

antibodies

is innate immunity antigen INDEPENDENT or DEPENDENT

antigen-independent (non-specific)

is adaptive immunity antigen INDEPENDENT or DEPENDENT

antigen-dependent/antigen-specific

which immune system acts immediately or within hours of encountering an antigen

innate immunity

which immune system has takes time after exposure to an antigen to have maximal response

adaptive

which immune system has immunologic memory

adaptive immunity

what does a capacity for memory mean

enables the host to enact a more rapid and efficient response upon exposure

characteristics of innate immunity

• non-specific

• quick and short

• no immunologic memory

characteristics of adaptive immunity

• antigen-specific

• slow and long-lasting

• immunologic memory

the two types of barriers

physical, chemical

examples of physical barriers

• skin

• mucous membranes

  • respiratory tract

  • GI tract

example of how skin is a physical barrier

cell shedding

how do mucous membranes barricade against pathogens

mucous is sticky (catches pathogens) then cilia move the pathogen out of the body

examples of chemical barriers

• skin

• respiratory tract

• tears/saliva

• stomach

examples of skin as a chemical barrier

• anti-microbial peptides (AMPs)

• sebum

• sweat

how does sebum work

lowers pH of skin, making it a hostile area for bacterial growth

effect of AMPs on pathogens

toxic

examples of respiratory tract as a chemical barrier

AMPs

examples of tears/saliva as a chemical barrier

• enzymes in tears/saliva

• eg. lysozyme, lactoclarin

examples of stomach as chemical barrier

• acid

• digestive enzymes

how is acid in stomach a chemical barrier

is already a low pH (which is makes it hostile for pathogens)

examples of brain barriers

• skin

• skull

• meninges

• blood-brain barrier

• blood-csf barrier

which brain barriers are cns specific

• meninges

• blood-brain barrier

• blood-csf barrier

what do the BBB and BCSFB do (generally)

protect brain from immune cells and pathogens

where do all the cells in the immune system originate from

hematopoietic stem cell (in the bone marrow)

what do hematopoietic stem cells differentiate into

• common myeloid progenitor

• common lymphoid progenitor

what do common lymphoid progenitors differentiate into

• B cells

• T cells

• Natural killer cells

• (partially) dendritic cells

what do common myeloid progenitors differentiate into

• red blood cells

• platelets

• granulocytes

• monocytes

• (partially) dendritic cells

what do monocytes turn into

• macrophages

• dendritic cells

what do granulocytes differentiate into

• neutrophils

• eosinophils

• basophils

• mast cells

which cells are part of the innate immune system

• natural killer cells

• dendritic cells

• macrophages

• neutrophils

• eosinophils

• basophils

• mast cells

which cells are part of the adaptive immune system

• B cells

• T cells

which cells help with the adaptive immune system

• dendritic cells

• natural killer cells

characteristics of granulocytes

• granules of chemicals

• rapidly destroy pathogens

• non-specific

  • can drive inflammation, tissue damage and allergic responses

why can granulocytes become problematic

because they drive inflammation, tissue damage and allergic responses which can be counterproductive in the brain

which type of granulocyte is most abundant/common

neutrophils

where and how do neutrophils, eosinophils and basophils migrate to from the bone marrow

to the tissue via chemotaxis through bloodstream

when do neutrophils arrive at the site of infection

early, one of the first to arrive

neutrophil 3 MAIN mechanisms of action

1. phagocytosis

2. degranulation (cytotoxic)

3. neutrophil extracellular traps (NETs)

what is degranulation

release of cytotoxic or non-cytotoxic granules

what happens when neutrophils release cytokines

the immune response is amplified

when are granules made

premade, when maturing in the bone marrow

how does chemotaxis work

1. detect chemical signals from pathogens

2. they roll along endothelium

3. there is upregulation of adhesion molecules which slow the rolling

4. adhesion to endothelium

5. transmigration into interstitium

what is transmigration

neutrophil, basophil and eosinophil from blood passing through endothelium into the tissue (interstitium) where the pathogen is located

what direction do neutrophils, basophils and eosinophils travel in

in the direction of blood flow

what is NETosis

releasing NETs comprised of DNA and proteases

what is suicidal NETosis

releasing so much DNA that the neutrophil ends up killing itself

what are cytokines

small proteins that mediate and regulate immunity, inflammation and hematopoiesis

how do cytokines work

• released from cytokine-producing cells after an inducing stimulus

• attach to receptors on target cells

• send signal to activate gene in target cell

• create biological response

examples of cytokines

• interleukins

  • IL-1, IL-6

• chemokines

• interferons (INF)

• tumor necrosis factors (TNF)

what tissues do eosinophils migrate to

GI tract, thymus

what is the main response to parasite infection

eosinophils

characteristics of eosinophils

• main response to parasite infection

• mediator of allergic responses

eosinophil main mechanisms of action

1. degranulation (cytotoxic)

2. eosinophil extracellular traps (EETs)

3. cytokine release

which immune cells are rare

basophils

characteristics of basophils

• large

• rare

• inflammatory and allergic responses

basophils main mechanisms of action

• degranulation (NOT cytotoxic)

• cytokine release

what is not cytotoxic degranulation

release of histamines, heparins and other molecules to promote inflammation

what is histamine

vasodilator (acts on blood vessels)

what is heparin

anticoagulant (prevents blood clotting)

where do mast cells reside

tissues (not circulating in blood)

characteristics of mast cells

• longer lived (than basophils)

• inflammatory and allergic responses

which cells are similar but develop separately from a common precursor

basophils and mast cells

mast cells main mechanisms of action

• degranulation (not cytotoxic)

• cytokine release

where do monocytes mature and live

bone marrow, circulate in blood

characteristics of monocytes

agranulocytes (don’t release granules)

monocytes main mechanisms of action

1. phagocytosis

2. release cytokines

3. antigen presenting cells (APCs)

4. travel to tissues and differentiate into macrophages and dendritic cells

what is the deal with monocytes and phagocytosis

not as effective as other types of phagocytes

where do macrophages live

in the tissue

where do macrophages derive from

some from monocytes, most self-renew locally during embryogenesis

example of macrophages in brain

microglia

characteristics of macrophages

• large

• long-lived

macrophages main mechanisms of action

1. phagocytosis

2. co-ordinate immune response by releasing cytokines

3. professional antigen presenting cells

process of antigen presentation

1. pathogen is phagocytosed by macrophage/dendritic cell

2. pathogen is lysed into antigen (fragment of pathogen)

3. MHC-II protein binds to antigen fragment

4. MHC-II protein present the antigen to the T cell receptor

what is an antigen

substance that can cause an immune response

where do dendritic cells live

in tissue

what do dendritic cells do

provide a link between innate and adaptive immune systems

dendritic cells main mechanisms of action

1. professional antigen-presenting cells (APCs)

2. secrete cytokines

what does it mean for a cell to be a “professional” APC

samples the environment and processes pathogens into fragments that become antigens, then present them to T-cells (adaptive immune system)

where are natural killer cells found

in blood and tissue

what type of cell are natural killer cells

lymphocyte belonging to innate lymphoid cell (ILC) family

natural killer cell response

non-specific cytotoxic response (innate)

what do natural killer cells do

rapid removal of once healthy cells that are now a threat

examples of types of cells natural killer cells target

• viral infected cells

• stressed or damaged cells

• tumor cells

what kinds of receptors do natural killer cells have

inhibitory and activating receptors

what is the purpose of the missing-self strategy

to determine host vs damaged cells

what is the missing-self strategy

• MHC-I on healthy.cells inhibit cytotoxicity because they are recognized by the inhibitory receptors on natural killer cells

• missing MHC-I means no inhibitory recognition, so they get killed

• stress induced ligands activate the activating receptor, so they get killed

what a cell (typically) needs to be killed by natural killer cells

both no MHC-I and stress induced ligand

natural killer cells mechanisms of action

1. release proteins (perforin, granzyme)

2. release cytokines

3. antibody-dependent cellular cytotoxicity (ADCC)