EXAM 1

introduction to the vertebrate immune system

vaccination emerged bc of smallpox

father of immunology

edward jenner

vaccinia virus - cow + horse

early history of immunology

innate vs adaptive immunity

overview of immune system development

3 lobed nucleus - PMN nuetrophil polyomorphnucleus cell

human blood

blood seperation

lymphatic vessels: the circualtory system of the immune system

Primary lymphoid Tissues

↳• Tissues where stem cells differentiate into immune cells

• Bone marrow

• Thymus

Secondary lymphoid tissues

• Tissues where adaptive immune responses are initiated

• Also called lymph nodes (the spleen too)

• Pathogens (or their by-products) are brought into these tissues via other cells or circulating lymph fluid

lymph nodes can become swollen during an immune system

Dendritic cells are one of the most important bridges between the innate and adaptive immune systems

introduction to inflammation

to signal where immune response is, the immune system relies on numerus soluble effector proteins

cytokine: general name for proteins secreted by immune cells that affect the

behavior of nearby cells bearing the appropriate receptors; the term is used only

when speaking about the immune system; analogous to a hormone

chemokine: secreted proteins that act as chemoattractants; attract cells bearing the

appropriate receptors out of the blood/lymph and into the surrounding tissue where

that the concentration is highest (termed “chemotaxis”)

three functions of inflammation

Recruit additional effector cells to the site (vessel dilation and

permeability)

Limit the spread of the pathogen (e.g., localized blood clotting)

Begin the process of tissue healing

another view of the inflammatory cascade

extravasation animation

bands vs mature nuetrophiles

Innate immunity part 1

image innate immunity

image of bacteria

movement of mucus by cilia

mechanical: epithealial cells joined by tight junctions

another one is the gut- chemical - low ph stomach bacteria destoryed chemical death

antimicrobial enzymes in tears and saliva

lysozyme degrades the cell wall of bacteria

antimicrobal peptides

surface skin, contact outside world, lungs

usually about 20-40 amino acid residues in length - Short amino acid chains

• amphipathic, cationic, and show a direct interaction with target cell membranes

Parthydrophilis) phobic

• The outer leaflet of mammalian plasma membranes is mainly charge-neutral at

physiologic pH

• The surfaces of bacterial and fungal cell walls contain large amounts of negatively

charged lipids.

• Therefore, antimicrobial peptides lead to the lysis of bacterial membranes while

eukaryotic plasma membranes remain largely unaffecteed

example of an antimicrobial peptide - human beta defensin

3 major types of phagocytes

• Macrophages

• Granulocytes

- store antimicrobal compounds "Granules"

– neutrophils are the main one

• Dendritic cells (DCs)

- takin thro Surround they themselves cannot kill microbe

– lack direct effector mechanisms

– always “sampling” their surroundings, unlike other most other phagocytes

– important in the initiation of B-cell and T-cell responses (adaptive immunity) → lymph node

@ tissue regurlaly / little blood

Neutrophil granules contain many antimicrobal compounds including

neutrophil and macrophages → phagocytes engulf microbe

neutrophil → also a granulocyte, contain many are stronger than macrophages

phagocytic process

respiratory burst and reactive oxygen species

CGD

Effector mechanisms of neutrophils revisited

Neutrophil extracellular traps (NETS) - spew out chromatin → dna +histones

contin of mechanisms

the complement system

3 ways that complent sys gets activated.

→ all converage at clevage C3 to C3a

different pathways

facts about C3C3

C3 is made mainly in the liver protein found in blood and released into the bloodstream at high levels.

• C3 is the most critical component of the complement cascade

C3 enters circulation in an inactive form (“zymogen”).

Cleavage of C3 exposes a highly reactive thioester bond that can attach to the surface of a pathogen if one is around.

• Reaction with a water molecule causes C3b to be inactive.

• People lacking this protein due to a genetic mutation are prone

to multiple, recurring infections (mostly bacterial) that can be severe.

first pathway to act

opsonization

C5 activation

anaphylatoxins

summary of the concepts

Overview of induced response

If too many inflammatory cytokines = it means that it is an autoimmune disease

Global effects: pain, fever, cold, and heat

Pathogens actually recognized as foriegn (non-self)

1. Recognition/detection/ binding - bacterium binds to PRR

2. signal cascade - bacterium binds to receptor and then heads to nucleus (multi-setp) (transmitting for transcription and translation)

3. output and response

what triggers? to induce cytokines and chemokines for induce inflammation

if the response is not good then it will hurt the host

Concepts on pathogen structure and recognition

How does the immune system recognize something as non-self?

Pathogen-associated Molecular Patterns (PAMPs)

i.e., the “stuff” that gets recognized as foreign (non-self)

Recognition of Pathogen-Associated Molecular Patterns (PAMPs)

• structures, patterns, and/or molecules unique to invading microbes (“non-self”)

• examples of bacterial products

– components of the cell wall, such as lipopolysaccharide (LPS)

– flagellin protein

– cytoplasmic DNA

• examples of viral products

– uncapped ssRNA (i.e., no 5-prime cap) in the cytoplasm

– dsRNA (made during the replication cycle of many viruses)

– cytoplasmic DNA

Pathogen recognition by the host is through

PRRs pattern recognition receptors

a.k.a. pathogen recognition receptors

a.k.a. PAMP-recognition receptors

Host - PRR (receptor)

Pathogen - PAMPs. Microbe has the PAMP

Image of the process

Red - englufment

Dendritic cells deliver micro fragements to intiate adaptive immune response

+opmitized by complementary C3B induces phagocytosis OR direct recognition of a PAMP

Do not memorize chart

PRR - pamp receptors found on macrophages binding to PAMPs

Ligan or PAMP - LPS makes phagocytosis more efficient

Definitions

Dectin-1: recognizes components common to the cell walls of fungi and some bacteria

Mannose receptor: recognizes mannosylated ligands found on some fungi, bacteria, and viruses

Scavenger receptors: recognize various types of lipoproteins common to bacterial cell walls

Complement receptors: bind to and ingest complement C3b-coated microbes (makes phagocytosis better) inducing phagocytosis

IF microbe is coated/optimized with complemntary C3B = better phagocytosis

Diagram with process

Recognition of PAMP can lead to release of inflammatory cytokines

LOCAL EFFECTS - Cytokines

IL-1B AND TNF-ALPHA

IL-6

CXCL8

Systemic (global) effects

cytokines - not just act in tissue @ site of infection, but when released float in blood stream

Liver - activation of complement opzonization ( increase production of immune)

endogenous pyrogens “made by are own bodies, molecules that induces fever”

Image of mosquitoes

Toll-like receptors

Remember that RNA, while certainly a normal component of mammalian cells, is usually confined to the nucleus or the cytoplasm. It is not typically present within endosomes.

TLR - Recognize - bacterial and fungal (physical structure will find their ligand)

endosome - small intraellular compartment, recognizes only when in endosome/normal bio process = do not occur

Recognize - viral pamps

TLR can initiate downstream signaling

process of the signaling

Mice with defective or deleted TNF or its receptor are resistent to septic

What’s another way to experimentally manipulate a mouse to make it resistant (i.e., no disease) to bacterial sepsis? remove bacteria?

Extracellular pathogen detection

Outermembrane PRR induce pathogens

toll like receptors - induce signaling

Intracellular pathogen detection

endosome

some PRR are intracellular

Intracellular pathogen detection

Cytoplasm

PAMP receptors

in cytoplams trigger for cytokine production

trigger for inflammatory response

if 5 end of rna is absent can lead to recognize forigen microbe

The ability to detect pathogens also needs to happen in the cytoplasm

The sensing of foreign nucleic acid in endosomes or the cytoplasm results in the production of interferons

interferons - type of cytokines

TLR - in endosomes detect viral pamps turn on interferon alpha and beta

Interferons alert neighbring cells that a virus is lurking about

interferons alert neighboring cells that a virus is lurking about

Interferons stimulated gene or ISGs

PKR activation results in the shut-off of host cell translation

Image of the PKR actiavtion etc

continuingtion of process

Summary of innate immunity