Masaya JimboNotes for How The Immune System Works by Lauren Sompayrac

List of Topics Page #

Physical barriers 2

Innate immune system 2

Adaptive immune system 6

Secondary lymphoid organs 19

Turning off the immune system 22

Immunological memory 22

Vaccinations 23

Immunopathology 24

Cancer 30

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Three lines of defense against invaders- Physical barriers- Innate immune system- Adaptive immune system

Physical barriers- Skin

o Covers ~2 square meters of surface area- Mucous membranes

o Lines digestive, respiratory, and reproductive tractso Covers ~400 square meters of surface area

Innate immune system- Very quick response- Complement system

o Extremely fasto Composed of ~20 different proteins (produced mainly by the liver) that work together to

punch holes in invaders and to signal to other immune system playerso 3 modes of activation

Alternative (spontaneous) pathway C3 is the most abundant complement protein C3 molecules are continuously broken spontaneously into C3a and C3b C3b is very reactive and can bind to amino or hydroxyl groups, which

tend to be found on the surfaces of bacteria. If C3b doesn’t bind to one of these reactive groups in ~60 microseconds, it is neutralized by binding to water.

Once C3b is stabilized by reacting with a surface molecule, complement protein B binds to C3b

Complement protein D clips off part of B to yield C3bBb (a convertase) C3bBb can cut nearby C3 proteins to produce more C3b (and thus

C3bBb), resulting in a positive feedback loop C3bBb can cut complement protein C5, and C5b can combine with

complement proteins C6, C7, C8, and C9 to make a membrane attack complex (MAC)

MAC can punch a hole in the surface of a bacterium, killing it Lectin activation pathway

The liver produces mannose-binding lectin (MBL). MBL binds to a carbohydrate molecule (mannose) on the surfaces of many common pathogens. MBL does not bind to surface carbohydrates of healthy human cells.

In the blood, MBL binds to mannose-binding lectin-associated serine protease (MASP)

When MBL binds to mannose on a pathogen, MASP functions as a convertase to generate C3b from C3

The complement chain reaction proceeds as described for the alternative pathway

Classical pathway (fixing complement) Depends on IgM antibodies

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In the blood and tissues, ~30 complement proteins get together to form C1

C1 cannot activate the complement cascade because it is bound to an inhibitor molecule

When Fab regions of an IgM bind to an invader, C1 complexes can bind to its Fc regions. This brings C1 complexes close together.

If two or more C1 complexes are brought together, their inhibitors fall off, and C1 can produce C3bBb to initiate the complement cascade

IgG antibodies can also fix complement, but much less efficiently because they only have one Fc region per molecule

o How human cells are protected from the complement system C3b can be clipped to an inactive form by proteins in the blood. This clipping is

accelerated by an enzyme that is present on the surface of human cells. Decay accelerating factor (DAF) on the surface of human cells accelerates the

destruction of C3bBb by other blood proteins CD59 (protectin) on the surface of human cells can kick almost-finished MACs

offo 2 other functions of the complement system

Facilitation of phagocytosis When C3b has attached to the surface of an invader, it can be clipped by

a serum protein to iC3b iC3b cannot make MACs, but acts like antibodies by opsonizing

(decorating) the surface of the invader Phagocytes have iC3b receptors on their surface

Recruitment of other immune system players C3a and C5a act as chemoattractants that can attract and activate

macrophages and neutrophils where they are needed C3a and C5a are called anaphylatoxins, because they can contribute to

anaphylactic shock- Professional phagocytes

o Phagocytosis Macrophage first engulfs bacterium in a phagosome The phagosome is taken inside the macrophage and fuses with a lysosome Lysosomes contain powerful chemicals and enzymes which can destroy bacteria

o Macrophages Sentinels that are present under the skin, in the lungs, and in the tissues

surrounding the intestines Origin

Made from stem cells in the bone marrow Exist in the bloodstream as monocytes (~2 billion circulating)

o Monocytes remain in the blood for ~3 days, traveling to capillaries and looking for openings that allow entry into tissues

o Once in the tissue, monocytes mature into macrophages with a lifetime of months

When they phagocytose bacteria, macrophages give off chemicals Some chemicals increase blood flow to the vicinity, causing redness Some chemicals cause endothelial cells to contract, leaving spaces in

capillaries through which fluid can leak out into tissues. This causes swelling.

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Some chemicals can stimulate nearby nerves, sending pain signals to the brain

3 stages of readiness Resting state

o Slowly proliferatingo Function primarily as garbage collectorso Express very few class II MHC molecules on their surface

Primed (activated) stateo Take larger gulpso Express more class II MHC molecules, thus functioning as APCs

for helper T cellso Priming is caused by interferon gamma (IFN-γ), a cytokine

produced by helper T cells and NK cells Hyperactivated state

o Attained if the macrophage receives direct signal from an invader

Example: lipopolysaccharide (LPS), a component of the outer cell wall of Gram-negative bacteria, can be shed and bind to receptors on the surface of primed macrophages

Macrophages also have receptors for mannose, the carbohydrate found on the surface of many common pathogens

o Stops proliferating and focuses on killing, growing larger and increasing the rate of phagocytosis

Number of lysosomes increases, increasing the efficiency of destruction of ingested invaders

Production of reactive oxygen molecules increases Lysosomal contents can be dumped onto multicellular

parasites that are too large to phagocytoseo Secrete the cytokine tumor necrosis factor (TNF), which can kill

tumor cells and virus-infected cells, and can help activate other immune system warriors

During an infection, activated macrophages can facilitate the complement system Macrophages produce the complement proteins C3, B, and D Macrophages can secrete chemicals that increase the permeability of

nearby blood vessels, allowing more complement proteins to be released into the tissues

o Neutrophils ~20 billion circulate in the blood in inactive state (70% of circulating white blood

cells) Produced in the bone marrow Programmed to commit apoptosis after ~5 days, in order to minimize damage to

normal tissues Not APCs Tissue delivery and activation

In response to bacterial invasion, activated macrophages give off the cytokines interleukin 1 (IL-1) and TNF. The cytokines signal endothelial

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cells lining nearby blood vessels to express selectin (SEL) on their surface.

Interaction between SEL and selectin ligand on the surface of the neutrophil causes the neutrophil to slow down in the blood vessel, but not stop

C5a and LPS signal to the neutrophil that an inflammatory reaction is taking place, and the neutrophil expresses integrin (INT) on its surface

INT binds to intercellular adhesion molecule (ICAM) on the surface of endothelial cells, and causes the neutrophil to stop

The chemoattractants C5a and f-met peptides (fragments of bacterial proteins) allow the neutrophil to exit the blood vessel into tissues, and migrate to the site of inflammation. Cytokines such as TNF activate neutrophils as they travel through the tissues, so they arrive at the battle scene ready to kill.

Once activated, neutrophils become incredibly phagocytic, produce cytokines that alert other immune system cells, and give off destructive chemicals that are pre-made and stored until needed

- Natural killer (NK) cellso Produced and mature in the bone marrowo Short-lived with half-life of ~1 weeko Mostly found in the blood, the liver, or the spleeno Like neutrophils, NK cells employ the “roll, stop, exit” strategy to leave the blood and

enter tissueso 2 functions

Produce cytokines when they receive battle signals from other immune system cells

Interferon gamma (IFN-γ)o NK cells produce IFN-γ, which can prime macrophages. These

macrophages can then be hyperactivated by LPSo Hyperactivated macrophages secrete TNF, which bind to their

own receptors and allow the macrophages to secrete IL-12o TNF and IL-12 influence NK cells to increase IFN-γ production,

which primes more macrophages and thus initiates a positive feedback loop

IL-2o NK cells produce the growth factor IL-2o During an infection, TNF produced by macrophages causes NK

cells to express IL-2 receptors on their surfaceo NK cells can now react to the IL-2 they make and begin to

proliferate Destroy bacteria, parasites, virus-infected cells, fungi, and some cancer cells by

forcing them to commit apoptosis NK cells use perforin proteins to inject suicide enzymes to target cells Fas ligand on NK cell surface can bind to Fas on target cell surface,

signaling the target cell to commit apoptosiso 2 types of receptors

Activating receptors Recognize unusual carbohydrates or proteins on the surface of target

cells5

o NK cells can be activated by the bacterial cell wall component LPS

o NK cells can be activated by interferon alpha and beta, which are given off by cells when they are attacked by viruses

When engaged, motivate the NK cell to kill Inhibitory receptors

Recognize class I MHC molecules on cell surfaces When engaged, motivate the NK cell not to kill

- Innate immune system is not very effective against viruses once they enter cells- Innate immune system activates and functions as the “coach” for the adaptive immune system

o Antigen receptors of the adaptive immune system can recognize any protein molecule in the universe, but cannot distinguish between dangerous and harmless molecules

o Receptors of the innate immune system are tuned to detect the presence of most common pathogens

o Receptors of the innate immune system can also detect when uncommon pathogens kill human cells

o The innate immune system integrates information about an invader, and formulates a game plan for the adaptive immune system

The game plan specifies which weapons of the adaptive immune system to mobilize

The game plan specifies where in the body the weapons of the adaptive immune system should be deployed

Adaptive immune system- Adapts to defend against specific invaders- Activated by the innate immune system- Antigen presentation

o Cells present antigens on their cell surface using major histocompatibility complex (MHC) proteins

o Class I MHC molecules Found on most cells in the body Inform killer T cells about what is going on inside other cells

When a cell is infected by a virus, viral peptides are presented on class I MHC molecules on the cell surface, for inspection by killer T cells

A cell’s endogenous protein fragments are also presented on class I MHC molecules

Made of 1 long chain (heavy chain) and 1 short chain (β2-microglobulin) Each chromosome 6 has 3 heavy chain genes (HLA-A, HLA-B, HLA-C) HLA proteins are polymorphic, while all humans have the same β2-

microglobulin gene The ends of the molecule’s groove are closed

Antigens must be 8 – 11 amino acids long to fit Loading class I MHC molecules

Proteasomes cut up old and defective proteins into peptides Some of these peptides are transported into the ER by TAP1 and TAP2.

TAP preferentially transports peptides that are compatible with class I MHC molecules.

Compatible peptides are loaded onto class I MHC molecules and carried to the cell surface

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o Class II MHC molecules Found only on antigen presenting cells (APCs) Inform helper T cells about what is going on outside of cells

Example: During a bacterial infection, a macrophage will eat the bacteria, and present bacterial proteins on its surface class II MHC molecules. Helper T cells scan these molecules for news of bacterial infection.

Made of 2 long chains (α and β chains) Encoded by genes in the HLA-D region of chromosome 6 Wildly polymorphic

The ends of the molecule’s groove are open Antigens of 13 – 25 amino acids can fit

Loading class II MHC molecules α and β chains are made in the cytoplasm and transported into the ER,

where they bind to the invariant chain Part of the invariant chain (called CLIP) sits in the class II MHC’s

groove and prevents it from picking up other endogenous peptides Proteins outside the cell are phagocytosed, and the phagosome merges

with an endosome. Inside the endosome, the exogenous proteins are chopped up into peptides.

The invariant chain guides the class II MHC through the Golgi stack to endosomes. Inside the endosome, most of the invariant chain is destroyed, and HLA-DM releases CLIP from the MHC’s groove.

The class II MHC is loaded with exogenous peptides, and transported to the cell surface

o CD1 Non-classical MHC molecules that allow killer T cells to examine the lipid

composition of cells Like class I MHC molecules, consist of a heavy chain paired with a β2-

microglobulin Have grooves that are designed to bind lipids, not peptides

o Antigen presenting cells (APCs) Function to activate killer T cells & helper T cells

Display both class I & class II MHC molecules Can provide co-stimulation to killer T cells & helper T cells

o B7 on the APC surface binds to CD28 on T cell surface Activated dendritic cells (DCs)

Sentinel cells that sample antigens out in the tissues Part of the innate immune system Initiate the immune response by activating virgin T cells in lymph nodes Resting state

o Express low levels of B7 and MHC molecules (not very good APCs)

o 3 ways of activation Activated by cytokines from other immune system cells

engaged in battle Activated by chemicals given off from dying cells Pattern recognition by Toll-like receptors (TLRs)

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TLR2 identifies proteins of Gram-positive bacteria

TLR3 recognizes double-stranded RNA produced during many viral infections

TLR4 on cell surface senses the presence of LPS (Gram-negative bacterial cell wall component)

TLR7 and TLR9 on phago-lysosome membranes alert the cell to viruses or bacteria that have been phagocytosed

o TLR7 detects single-stranded RNA of viruses

o TLR9 detects double-stranded DNA of bacteria and herpes simplex virus

TLRs recognize general features of invaders, and recognize patterns that are not easily mutated

Activated stateo After phagocytosis of antigens in the battle scene, the activated

DC migrates through the lymphatic system to the nearest lymph node

o Before traveling, activated DCs recruit their own replacements by secreting chemokines, which encourage monocytes to enter the tissues and become DCs

o During its journey, the activated DC prepares for activation of virgin T cells

The activated DC loads its class II MHC molecules with antigens from the battle scene

The activated DC increases expression of class I MHC molecules, in case it was infected by viruses or parasites

The activated DC increases production of B7 co-stimulatory proteins

o Once the DC reaches a lymph node, it only lives for ~1 week Activated macrophages

Remain at the battle scene Function as refueling stations for experienced T cells

o Once they have been activated by dendritic cells, T cells enter the tissues to help with the battle

o These T cells must be continually re-stimulated by activated macrophages

Part of the innate immune system Activated B cells

Once activated, B cells increase B7 and class II MHC molecules on their surface. They can act as APCs for helper T cells.

After binding its cognate antigen, the cell’s BCR is dragged into the cell. Antigen is processed and loaded onto class II MHC molecules for presentation at the cell surface.

Since B cells cannot act as APCs until after the adaptive immune system has fired up, they are most important during later stages of an infection,

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or during subsequent infections. Once activated however, activated B cells have great advantage over dendritic cells and macrophages.

o Activated B cells can use their BCRs to concentrate small amounts of antigen for presentation to helper T cells

o Antigen presentation by B cells is extremely fast- B cells & antibodies

o B cell origins Produced and mature in the bone marrow (~1 billion produced each day) Mature to become antibody-producing plasma cells ~3 billion B cells circulate in the bloodstream

o Structure of IgG antibody Made up of 2 pairs of heavy chain (Hc) and light chain (Lc) proteins Each molecule has 2 identical hands (Fab regions) that can bind to antigens Each molecule has a constant region (Fc) that can bind to Fc receptors on the

surface of cells like macrophages. The structure of the Fc region determines the antibody’s class.

o Antibody function Antibodies can opsonize (decorate) invaders, tagging them for phagocytic

destruction When a phagocyte’s Fc receptors bind to antibodies that are opsonizing

an invader, its appetite increases Neutralizing antibodies can bind to a virus, and keep the virus either from

entering the cell or from replicating once it has entered the cell Once a virus gets into a cell, antibodies cannot gain access to it

o Antibody classes Immunoglobulin M (IgM)

The default antibody class (first antibody made) Half-life of ~1 day Structure

o Looks like 5 IgG antibodies with Fc regions close together Functions

o Very good at fixing complemento Can bind to viruses and prevent them from infecting cells

Immunoglobulin D (IgD) Tiny fraction of circulating antibodies Made from the alternative splicing of the same Hc mRNA used to make

IgM Significance unknown

Immunoglobulin G (IgG) 75% of the antibodies in the blood Longest-lived antibody class (half-life of ~3 weeks) Functions

o IgG antibodies come in a number of different subclasses with slightly different Fc regions

IgG1 is very good at opsonizing invaders for phagocytosis

IgG3 fixes complement better than any other IgG subclass

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IgG3 can also aid NK cells in a process called antibody-dependent cellular cytotoxicity (ADCC)

IgG3 can bind to its cognate antigen with its Fab region, and to an NK cell with its Fc region

This brings the NK cell close to its target cell, and also stimulates the NK cell to be a more effective killer

o Can bind to viruses and prevent them from infecting cellso Can pass from the mother’s blood into fetal blood by way of the

placenta Immunoglobulin A (IgA)

Most abundant antibody class Guards the mucosal surfaces of the body (digestive, respiratory, and

reproductive tracts) Structure

o Looks like 2 IgG antibodies with their Fc tails held together by a clip

o The clip functions as a passport that facilitates transport of IgA across the intestinal wall

o The clip also makes IgA resistant to acids and enzymes in the digestive tract

Functiono IgA antibodies can coat invading pathogens and keep them from

attaching to cells lining the mucosal tracts, collecting them into clumps that are swept out of the body with mucus or feces

Rejected bacteria make up ~30% of normal fecal mattero IgA is secreted into the milk of nursing mothers

IgA antibodies coat the baby’s intestinal mucosa and provide protection

o IgA antibodies cannot fix complement Immunoglobulin E (IgE)

Functiono Defends against parasites

IgE can cause mast cells to degranulate, killing parasiteso Causes allergies and anaphylactic shock

IgE antibodies live for only ~1 day in the blood. However, once bound to mast cells they have a half-life of several weeks.

o Antibody generation Modular design

In every B cell, the chromosomes encoding the Hc (chromosome 14) contain multiple copies of 4 types of DNA modules (V,D,J, and C)

Each copy of given module is slightly different from the other copies To assemble a mature Hc, each B cell randomly mixes and matches the

gene segments to generate antibody diversity The segments on one chromosome 14 need to be silenced, to prevent 2

different Hc proteins from being made. The rearranged gene segments on both chromosomes are tested.

o If the gene segments are not joined up in frame, the ribosome will encounter a stop codon and terminate protein assembly

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o If one of the chromosomes manages to join the segments in frame (productive rearrangement), that chromosome is used to construct the Hc

o If both chromosomes fail to produce a productive rearrangement, the B cell dies

Lc is assembled in a similar way. If the B cell fails to productively rearrange Lc, the B cell dies

If the completed Hc and Lc do not fit together properly, the B cell dies Junctional diversity

When gene segments are joined together by modular design, additional DNA bases are added or deleted to create greater diversity

Antibodies are expressed on the surface of B cells as B cell receptors (BCR)o Clonal selection (B cell activation)

Activation of a virgin B cell requires cross-linking of BCRs via binding to its cognate antigen, as well as a co-stimulatory signal.

Cross-linking of BCRso To generate a signal, many BCRs must be brought together on

the B cell surface (cross-linking)o The accessory proteins Igα and Igβ are associated with the Hc

protein and protrude into the cytoplasm of the B cello When enough BCRs are cross-linked, enough Igα and Igβ are

brought together to send a signal to the cell nucleuso BCR signaling is greatly facilitated by the complement system

When complement fragments opsonize an antigen, the fragments can be recognized by complement receptors (called co-receptors) on the B cell surface

This brings BCRs and co-receptors together on the B cell surface, greatly amplifying cell signaling by BCR. The number of BCRs that must be clustered to initiate signaling is decreased >100-fold.

This process serves to make B cells exquisitely sensitive to antigens that the innate immune system has identified as being dangerous

Co-stimulatory signalo T cell-dependent activation

CD40L on the surface of activated helper T cells bind to CD40 on the B cell surface

Helper T cells only recognize protein antigenso T cell-independent activation

Cytokines supplied by the innate immune system provide the co-stimulation

Can react to protein, carbohydrate, and fat antigenso Polyclonal activation

The antigen (called a mitogen) binds to molecules (mitogen receptors) on B cell surface that are not BCRs

The clustering of mitogen receptors causes associated BCRs to be clustered as well

A single mitogen can activate many different B cells with different specificities

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Once activated, B cells begin to proliferate. Each cycle of proliferation takes ~12 hours, and the process lasts ~1 week

By the end, ~20,000 identical B cells will have been producedo B cell maturation

Class switching B cell can change the class of antibody it produces When a virgin B cell is first activated, it produces mainly IgM and some

IgD Controlled by local cytokines produced by helper T cells

o In presence of IL-4 and IL-5, B cells preferentially switch their class from IgM to IgE

o In presence of IFN-γ, B cells preferentially switch their class from IgM to IgG3

o In presence of TGF-β, B cells preferentially switch their class from IgM to IgA

o In the case of T cell-independent activation, class switching does not take place and mostly IgM are produced

Somatic hypermutation (affinity maturation) BCR genes undergo mutation and selection that can increase the affinity

of the BCR toward its cognate antigeno The regions of B cell chromosomes containing the V, D, and J

segments (i.e. the regions encoding the Fab region) attain mutation rates as high as 1 per 1000 bases (normal mutation rate is 1 per 100 million)

o Maturing B cells need to be continually re-stimulated by their cognate antigen in order to continue proliferating

o Thus, mutations that increase the affinity of the BCR towards its cognate antigen are favored

Occurs after the V, D, and J segments have been selected, and usually after class-switching has taken place

Controlled by local cytokines produced by helper T cells Career decision

B cell decides to become either a plasma cell or a memory B cell Plasma cells

o Usually travel to the spleen or bone marrowo Plasma cells then begin to rapidly generate antibodies and

release them into the bloodstream (each plasma cell can generate ~2000 antibodies per second)

o After about a week of producing antibodies, most plasma cells die

Memory B cellso Produced with help from helper T cellso Remember the first exposure to a pathogen, and help defend

against subsequent exposureso Tolerance induction

Most B cells are tolerized in the bone marrow B cells with receptors that recognize self antigen are given another chance to

rearrange their light chain genes (receptor editing)

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B cells with receptors that do not bind to abundant self antigens are released from bone marrow to circulate with the blood and lymph. ~10% of B cells pass this tolerance test, and the rest die by apoptosis.

The trafficking of virgin B cells is restricted to blood, lymph, and secondary lymphoid organs. This traffic pattern usually protects them from exposure to self antigens in tissues which might activate them.

B cells with receptors that recognize antigens which are abundant in the secondary lymphoid organs usually are efficiently deleted in the bone marrow

Self antigens that are rare enough in the bone marrow to allow self-reactive B cells to escape deletion usually are also too rare to activate virgin B cells in the secondary lymphoid organs

Virgin B cells that escape into the tissues are anergized (neutered) or deleted if they recognize self antigen, but do not receive the required T cell help

Maintenance of tolerance in germinal centers Once activated in secondary lymphoid organs, B cells can modify their

receptors through somatic hypermutation. This can potentially result in receptors that recognize self antigen.

B cells in germinal centers require complement-opsonized cognate antigen for efficient BCR cross-linking, as well as co-stimulation from Th cells that recognize the cognate antigen

If somatic hypermutation causes a B cell’s receptors to recognize self antigen, that B cell can no longer be stimulated by complement-opsonized antigen or Th cells. Without continuous stimulation, the B cell dies by apoptosis.

- T cellso T cell general features

There are ~1 trillion T cells in a human Produced in the bone marrow, but mature in the thymus

Because the thymus decreases in activity after puberty, the production of virgin T cells decreases as a person ages

T cell receptors (TCRs) 2 types: αβ and γδ Like antibodies and BCRs, TCRs are also made by mix-and-match,

modular design strategy Receptor signaling

o CD3 complex, made up of the proteins γ, δ, ε, and ζ, is anchored in the T cell membrane with long cytoplasmic tails

o When enough αβ receptors are clustered together (cross-linking), the associated CD3 complexes recruit kinases and dispatch the activation signal to the nucleus

o TCR signaling is versatile When T cells are educated in the thymus, TCRs trigger

apoptosis if they recognize MHC plus self peptides When TCRs recognize their cognate antigen presented

by MHC molecules, but the T cell does not receive co-stimulation, the T cell is neutered (anergized)

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When TCRs recognize their cognate antigen presented by MHC molecules, and the T cell receives co-stimulation, the TCR signals activation

CD4 & CD8 co-receptors CD4 is found on helper T cells. CD8 is found on killer T cells. After a TCR has engaged its cognate antigen presented by an MHC

molecule, CD4 and CD8 then clip on and stabilize the TCR-MHC-peptide interaction, thereby strengthening the signal sent by the TCR

When T cells begin maturing in the thymus, they express both CD4 and CD8 and are thus called CD4+CD8+ cells. As the cells mature, expression of one is down-regulated.

Co-stimulation In addition to having their TCRs ligated by MHC-peptide, virgin T cells

must also receive co-stimulation for activation. Co-stimulation amplifies TCR signaling ~100-fold.

B7 molecules on APCs provide co-stimulation by plugging into CD28 receptors on the T cell surface

Mechanismo Lipid rafts contain many of the downstream signaling moleculeso Virgin T cells do not have many lipid rafts on their surfaceo Co-stimulation recruits lipid rafts to the T cell surface

Experienced T cells have a reduced requirement for co-stimulation, since they already have many lipid rafts on their surface, where they can come together with TCRs

Like B cells, T cells also obey the principle of clonal selection When a T cell’s receptors bind to their cognate antigen, the T cell

proliferates for ~1 weeko After an invader has been repulsed, most of the invader-specific T cells die off.

However, some activated T cells are set aside as memory cells, which can fire up quickly on subsequent infections by the same invader.

o Traditional T cells >95% of T cells in circulation Have αβ receptors and either CD4 or CD8 co-receptor Recognize a complex composed of a peptide and an MHC molecule on the

surface of a cell Educated in the thymus Helper T cells (Th cells)

Quarterback of the immune system Direct the local immune system by secreting cytokines Detect problems existing outside of cells

o Th cells recognize antigens presented by APCs on class II MHC molecules

Express CD4 co-receptors that can clip onto class II MHC molecules Activation by dendritic cells

o Complete activation takes 4 – 10 hourso When the Th cell’s TCR finds its match, CD4 co-receptors clip

onto the class II MHC molecules of the DCo Engagement of TCRs up-regulates expression of adhesion

molecules that glue the Th cell and DC together

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o The clustering of TCRs and adhesion molecules at the point of contact is called an immunological synapse

o Engagement of TCRs up-regulates expression of CD40L, which plug into CD40 on the DC surface. This results in increased expression of MHC and co-stimulatory molecules by the DC, as well as secretion of cytokines that prolong the life of the DC.

o After activation is complete, the Th cell and the DC parto The activated Th cells stimulate their own proliferation (clonal

selection) Virgin Th cells make the growth-factor IL-2 Once activated, Th cells also express IL-2 receptors on

their surface Function of activated Th cells

o Travel from lymph node to lymph node, providing help for B cells or killer T cells

o Enter tissues to provide help for immune cells at the battle site Cytokines secreted by Th cells

o When virgin Th cells are activated, they mainly secrete IL-2o Once Th cells have proliferated, re-stimulation by an APC

allows them to secrete Th1 or Th2 subset of cytokines.o The initial choice of cytokine profile is determined by the type of

co-stimulation the Th cell receives. However, Th cells can later be influenced by cytokines at the battle scene, as well as by other Th cells

IL-12 (secreted by activated macrophages) influences Th cells to secrete Th1 cytokines

IL-4 influences Th cells to secrete Th2 cytokineso Th1 cytokines

Help defend against a viral or bacterial attack IL-2

Stimulates killer T cells and NK cells to proliferate

Drives Th1 cell proliferation IFN-γ

Primes macrophages Influences B cells during class switching to

produce IgG3 antibodies Indirectly influences other Th cells to secrete

Th1 cytokines (by priming macrophages which then secrete IL-12)

Decreases Th2 cell proliferation TNF

Activates primed macrophages and NK cellso Th2 cytokines

Help defend against parasitic or mucosal infection IL-4

Influences B cells during class switching to produce IgE antibodies

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Directly influences other Th cells to secrete Th2 cytokines

Drives Th2 cell proliferation IL-5

Influences B cells during class witching to produce IgA antibodies

IL-10 Decreases Th1 cell proliferation

o Some Th cells remain unbiased as Th0 cells Delayed type hypersensitivity (DTH)

o Basis of the tuberculin skin test Tuberculin protein injected underneath the skin is taken

up by dendritic cells The DCs present tuberculin fragments on class II MHC

molecules These DCs express enough MHC and B7 to re-stimulate

memory (experienced) Th cells, but not enough to activate virgin Th cells

If the patient has or had tuberculosis in the past, experienced Th1 cells are reactivated and secrete Th1 cytokines that activate/recruit macrophages and neutrophils at the site of injection. This results in a local inflammatory reaction with redness and swelling.

Killer T cells (cytotoxic T lymphocytes – CTLs) Destroy virus-infected cells by triggering them to commit apoptosis

o Killer T cells identify virus-infected cells by detecting viral peptides on their class I MHC molecules

Express CD8 co-receptors that can clip onto class I MHC molecules Virgin killer T cells are activated by activated dendritic cells, just like Th

cells Function of activated killer T cells

o Proliferate rapidly before leaving the lymph node and traveling to the battle site

o Kill infected cells at the battle site by one of 2 ways Perforin helps a CTL deliver granzyme B into the

cytoplasm of its target cell. Granzyme B triggers apoptosis of the target cell.

Fas ligand on the CTL surface binds to Fas on the target cell surface. This binding causes apoptosis of the target cell.

o When virus-infected cells die by apoptosis, the DNA of unassembled viruses is destroyed, and completed viruses are enclosed in apoptotic vesicles and phagocytosed by macrophages

When many killer T cells are needed at the battle scene, Th1 cells supply IL-2, which is required for killer T cells to proliferate

Th cell help is important in generating memory killer T cells Natural regulatory T cells (nTregs)

Help keep other T cells under control ~5% of CD4+ cells in the circulation

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Have a relatively strong affinity for self antigens presented by class II MHC molecules on thymic epithelial cells

Express a gene called Foxp3 Travel to secondary lymphoid organs and suppress the activation of

potentially self-reactive T cellso Non-traditional T cells

γδ T cells Have γδ receptors and do not express CD4 or CD8 co-receptor Recognize unpresented antigen Most abundant in areas that are in contact with the outside world (e.g.

intestine, uterus, tongue) Location of education is unknown

Natural killer T cells ~1% of T cells in circulation Have αβ receptors Mature in the thymus Recognize lipids presented by CD1 MHC molecules

o Tolerance induction Tolerance induction in the thymus

T cells which enter the thymus from the bone marrow have no CD4, CD8, or TCR. They are also resistant to apoptosis, because they express little/no Fas and express high levels of anti-apoptotic Bcl-2.

After entry into the thymus, T cells migrate to the cortex and begin to proliferate

The T cells become double positive (DP) cells that express CD4, CD8, and TCR. They express high levels of Fas on their surface and express little/no Bcl-2, becoming highly susceptible to apoptosis. Cells that fail positive or negative selection die.

MHC restriction (positive selection)o Occurs in the thymic cortexo Cortical epithelial cells present MHC-peptide complexes to the T

cellso If the T cell’s receptors do not recognize any MHC-peptide

complexes, the T cell dies by apoptosis. This ensures that all mature T cells will have TCRs that recognize MHC-antigen complexes, and not unpresented antigen.

The T cells stop expressing either CD4 or CD8, becoming single positive (SP) cells

Central tolerance induction (negative selection)o Occurs in the thymic medullao Thymic dendritic cells

Present MHC-peptide complexes to the T cells Thymic dendritic cells do not express tissue-

specific antigens. They can only test T cells with ubiquitous antigens that all cells produce.

If the T cell’s receptors recognize the MHC-peptide complexes, it dies by apoptosis. This ensures that mature T cells do not cause autoimmune disease by reacting against self antigens.

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o Medullary epithelial cells Present MHC-peptide complexes to the T cells

Medullary epithelial cells express both ubiquitous and tissue-specific antigens

If the T cell’s receptors recognize the MHC-peptide complexes, it dies by apoptosis. This ensures that mature T cells do not cause autoimmune disease by reacting against self antigens.

How the same TCR can signal different outcomeso Positive selection (survival) results from a relatively weak

interaction between TCRs and MHC-self peptide displayed on cortical thymic epithelial cells

o Negative selection (death) results from a strong interaction between TCRs and MHC-self peptide expressed on thymic dendritic cells or medullary thymic epithelial cells

o Activation results from a strong interaction between TCRs and MHC-peptide displayed by APCs

Only ~3% of T cells that enter the screening process will exit from the thymus

T cells that recognize self antigens that are rare in the thymus (but more abundant in tissues) may escape negative selection

The trafficking of virgin T cells is restricted to blood, lymph, and secondary lymphoid organs. This traffic pattern usually protects them from exposure to self antigens in tissues which might activate them.

T cells with receptors that recognize antigens which are abundant in the secondary lymphoid organs usually are efficiently deleted in the thymus

Self antigens that are rare enough in the thymus to allow self-reactive T cells to escape deletion usually are also too rare to activate virgin T cells in the secondary lymphoid organs

Tolerance induction in secondary lymphoid organs Occasionally, self antigens, which are too rare in the thymus to cause

deletion of potentially autoreactive T cells, are released into circulation (e.g. as a result of injury)

Natural regulatory T cells (nTregs) suppress the activation of potentially self-reactive T cells

o Only those T cells that recognize the same self antigen that the nTreg recognizes will be affected

o Direct contact between an nTreg and an APC is required for the nTreg to block activation

Semi-mature dendritic cells can tolerize potentially self-reactive T cellso Dendritic cells can carry self antigens to secondary lymphoid

organso However, many of these semi-mature dendritic cells originate in

places where there are no invaders. Thus, these cells have not been fully activated by battle cytokines, and do not express the co-stimulatory molecules needed to activate T cells.

o When a T cell recognizes self antigen presented on the dendritic cell, but does not receive the required co-stimulation, the T cell is anergized (neutered) and eventually dies

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Peripheral tolerance Some virgin T cells stray out into the tissues, where they may encounter

self antigens that can activate them However, these self-reactive T cells do not receive the co-stimulation

needed to activate them. APCs specialize in providing co-stimulation, but normal cells in tissue do not.

When a T cell recognizes its cognate antigen presented on a cell, but does not receive the required co-stimulation, the T cell is anergized (neutered) and eventually dies

If a T cell somehow becomes activated by self antigens in the tissues, it is stimulated repeatedly by the ever-present self antigens. Eventually the T cell is eliminated by activation-induced cell death (AICD).

Secondary lymphoid organs- Include lymph nodes, spleen, and mucosal-associated lymphoid tissue (MALT)- Strategically situated to intercept invaders that breach the physical barriers and enter the tissues

and blood- Create an environment in which antigen, APCs, and lymphocytes can gather to initiate an

immune response- Lymphoid follicles

o Found in all secondary lymphoid organso Primary lymphoid follicles

Loose networks of follicular dendritic cells (FDCs) embedded in a sea of B cells FDCs function to display antigen to nearby B cells

Early in an infection, complement-opsonized antigen is delivered to secondary lymphoid organs. FDCs pick up and retain the opsonized antigen.

Later in an infection, antigen opsonized by antibodies can also be captured by FDCs

By capturing large numbers of antigens and holding them close together, FDCs display antigens in a way that can cross-link BCRs on nearby B cells

Activated B cells proliferate, turning the lymphoid follicle into a secondary lymphoid follicle (germinal center)

o Secondary lymphoid follicles (germinal centers) As B cells proliferate, they need to be rescued by Th cells. If they are not

rescued, the B cells commit apoptosis. Activated Th cells in the T cell areas of the secondary lymphoid organs

migrate to the lymphoid follicle CD40L on Th cells plug into CD40 receptors on B cell surface,

providing the necessary co-stimulation. In turn, activated B cells restimulate the Th cells

When B cells take up their cognate antigen, they present the antigen fragments on class II MHC molecules

These B cells also express B7 on their surface The presented antigen and B7 function to recharge the Th cells

After proliferation, some B cells become plasma B cells and leave the germinal center. Other B cells undergo somatic hypermutation to improve their affinity for their cognate antigen, and can switch the class of antibody that they produce.

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- High endothelial venules (HEVs)o Found in all secondary lymphoid organs except the spleeno Allow B and T cells to enter the secondary lymphoid organ from the blood

- Lymph nodeso Function as “dating bars” where T cells, B cells, APCs, and antigen all gather for the

purposes of activation and re-stimulation Invaders like bacteria and viruses are carried by the lymph to nearby nodes APCs, complement proteins, and antibodies that have picked up foreign antigens

travel to lymph nodes via lymph, to present their cargo B & T cells circulate from node to node looking for their cognate antigen

Cells can enter lymph nodes from the blood via HEVs, or from the lymph

Cells can only leave the lymph nodes via the lymph There are separate areas in the lymph node for B & T cells

o Passage of lymph Incoming lymph marginal sinus cortex paracortex medullary sinus

outgoing lymph The walls of the marginal sinus are lined with macrophages that serve to clean

and filter the lymph HEVs are located in the paracortex

o Role in Th cell function If a Th cell passing through the paracortex encounters a dendritic cell presenting

its cognate antigen, it is activated and begins to proliferate. The Th cells then exit via the lymph, recirculate through the blood, and reenter lymph nodes to be restimulated.

Some Th cells move to the lymphoid follicles to rescue B cells, and some Th cells exit the blood to provide cytokine help to immune cells at the battle site

Activated Th cells express receptors for a chemokine produced in the region of the lymph node where activated Th cells and B cells meet. This causes activated Th cells to be attracted toward B cells needing co-stimulation.

o Role in killer T cell function If a killer T cell passing through the paracortex encounters a dendritic cell

presenting its cognate antigen, it is activated and begins to proliferate. The killer T cells then exit via the lymph, and recirculate through the blood.

Some killer T cells reenter lymph nodes via HEVs to be restimulated. Other killer T cells exit the blood at sites of infection to kill pathogen-infected cells.

o Role in B cell function If a B cell encounters a follicular dendritic cell presenting its cognate antigen,

and receives co-stimulation from activated Th cells, it is activated and begins to proliferate in the lymphoid follicle

Virgin B cells express receptors for the chemokine CXCL13, which is secreted by FDCs. This causes B cells to be attracted to the area of the lymph node where the FDCs are displaying opsonized antigen.

If the B cells encounter their cognate antigen, they express CCR7 receptors for a chemokine produced in the region of the lymph node where activated Th cells and B cells meet. This causes B cells to be attracted toward activated Th cells.

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Many B cells exit via the lymph. Some become plasma cells that go to the spleen or bone marrow to pump out antibodies. Others recirculate through the lymph and blood, and reenter secondary lymphoid organs where they can proliferate, undergo somatic hypermutation, and undergo class switching. Still other B cells go back to the resting state in the spleen or bone marrow to function as memory cells.

o Lymph nodes that drain sites of infection tend to swell Due in part to proliferation of lymphocytes within the node Cytokines produced by Th cells recruit additional macrophages which tend to

plug up the medullary sinus. Fluid is retained in the node, causing further swelling.

- Peyer’s patcheso Examples of MALTo Adult human has ~200 Peyer’s patcheso Have outgoing lymphatics and HEVs, but no incoming lymphaticso M cells

Enclose intestinal antigens in endosomes, and deliver them to tissues surrounding the small intestine

Transport only antigens that can bind to the surface of intestinal cells, and thus have the potential to cause infection

o Once antigen is acquired, Peyer’s patches function similarly to lymph nodes The antigen can interact with B and T cells that have entered via HEVs, or it can

travel with the lymph to lymph nodes that drain the Peyer’s patcho Specialize in turning out Th2 cells and B cells that secrete IgA antibodies

- Spleeno No incoming lymphatics or HEVso Functions as a blood filter

Everything in the blood can enter the spleen (not just B and T cells) Blood enters from the splenic artery and is diverted out to marginal sinuses Macrophages lining the marginal sinuses clean and filter the blood As they ride along with the blood, T and B cells are temporarily retained

T cells are retained in the periarteriolar lymphocyte sheath (PALS) that surround the central arteriole

B cells are retained in the region between the PALS and the marginal sinuses

Filtered blood leaves via the splenic vein- Lymphocyte trafficking

o Traffic patterns of virgin and experienced lymphocytes are differento T cell trafficking

Virgin T cells express cellular adhesion molecules that allow them to visit all secondary lymphoid organs

L-selectin on virgin T cell surface can bind to GlyCAM-1 on HEVs of lymph nodes

α4β7 integrin on virgin T cell surface can bind to MadCAM-1 on HEVs of MALT

Experienced T cells express specific cellular adhesion molecules depending on where they were activated

Example: T cells activated in a Peyer’s patch express high levels of α4β7 integrin and low levels of L-selectin

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When activated T cells recirculate, they tend to reenter the same type of secondary lymphoid organ in which they encountered an antigen. This maximizes their chances of reencountering their cognate antigen.

Experienced T cells also carry cellular adhesion molecules that direct them to exit the blood at sites of inflammation. This enables killer T cells to kill infected cells and Th cells to provide cytokines.

o B cell trafficking Virgin B cells can visit all secondary lymphoid organs, just like virgin T cells Experienced B cells do not migrate as much as experienced T cells. They settle

down in secondary lymphoid organs or the bone marrow, produce antibodies, and let them do the traveling.

Turning off the immune system- As foreign antigen is eliminated, the level of activation of both the innate and adaptive systems

decreases- B7 proteins

o In addition to providing co-stimulation to T cells by plugging into CD28 receptors, B7 can also plug into CTLA-4 receptors on the T cell surface

o CTLA-4 ligation represses activation by antagonizing CD28 signaling. B7’s affinity for CTLA-4 is thousands of times higher than its affinity for CD28.

o Most of a virgin T cell’s CTLA-4 is stored inside the cell. Once the T cell is activated, more CTLA-4 is moved to the cell surface. Eventually, CTLA-4 outcompetes CD28 for B7 binding, shutting off the adaptive immune system.

- Regulatory T cellso When helper T cells out in the tissues are repeatedly stimulated, some of them can turn

into regulatory T cellso Secrete cytokines which help inactivate the immune system (e.g. IL-10 and TGFβ)

TGFβ binding reduces the rate of T cell proliferation, makes killer T cells less vicious, and silences helper T cells

IL-10 binding blocks co-stimulation of T cells, making it more difficult to activate T cells

- Many weapons of the immune system are short-lived, and are quickly depleted once the invader is banished. T cells are an exception, designed to live a long time.

- Activation-induced cell death (AICD)o T cells which have been repeatedly activated during the battle become increasingly

susceptible to killing by ligation of their Fas proteins

Immunological memory- Innate memory

o Hard-wired and not updatableo Depends on pattern-recognition receptors that evolved over millions of years to identify

signature structures of common invaderso All humans have the same innate memory

- Adaptive memoryo Updatableo B cell memory

When B cells are activated during the initial response to an invader, 3 kinds of B cells are generated

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Short-lived plasma B cellso Produced in lymphoid follicles of secondary lymphoid organso Travel to the bone marrow or spleen and produce huge quantities

of antibodies that are specific for the attackero Die after a few days

Long-lived plasma B cellso Take up residence in the bone marrowo Continuously produce modest amounts of antibodieso Provide life-long immunity to subsequent infections

Central memory B cellso Take up residence in secondary lymphoid organso Serve as stem cells which slowly proliferate to maintain a pool

of central memory B cells and to replace long-lived plasma B cells

o Can quickly produce short-lived plasma B cells if another attack occurs

o T cell memory After virgin T cells have been activated in response to an initial attack, they

proliferate ~1000-fold Memory effector T cells

Many activated T cells become effector T cells that travel out to tissues and battle the invader

After the invasion, most effector T cells die. However, some remain in the tissues as memory effector T cells, and wait quietly for a subsequent attack.

Central memory T cells Some activated T cells remain in the bone marrow and secondary

lymphoid organs as central memory T cells During a subsequent attack, central memory T cells activate quickly and

proliferate Most mature into effector T cells that travel out to tissues Some remain as central memory T cells and wait for another attack

o Memory B and T cells are more numerous and easier to activate than virgin B and T cellso Memory B cells are upgraded versions of virgin B cells

Instead of making the default IgM class of antibodies, memory B cells can immediately make the class of antibody best suited to defend against the invader

Memory B cells have receptors and antibodies that have been fine-tuned during the initial attack through somatic hypermutation

Vaccinations- Memory helper T cells and B cells can be produced even when an invader does not infect an APC- For memory killer T cells to be made, the invader must infect an APC

o An effective AIDS vaccine must generate memory killer T cells- Noninfectious vaccines

o Use killed/disabled pathogens, certain parts of pathogens, or weakened bacterial toxins (toxoids)

o Can generate memory Th cells and B cells, but cannot generate memory killer T cells- Attenuated vaccines

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o Use weakened (attenuated) pathogenso Can generate memory Th cells, B cells, and killer T cellso Can be harmful for individuals with weakened immune systemso The attenuated virus may mutate inside the recipient to a stronger form, before the

immune system has had the chance to subdue it- Carrier vaccines

o A single gene from a pathogenic microbe is introduced into a virus that does not cause disease

o If the engineered virus infects the recipient’s APCs, these cells will produce the pathogenic microbe’s protein as well as the carrier’s own proteins

o Can generate memory Th cells, B cells, and killer T cells- DNA vaccines

o Viral DNA is taken up by APCs, which then use the genes to manufacture viral proteins and display them in class I MHC molecules

o Can generate memory Th cells, B cells, and killer T cells

Immunopathology- Pathological conditions caused by normal immune response

o Tuberculosis TB bacteria taken into the lungs are phagocytosed normally by lung macrophages However, TB bacteria can modify the surface of the phagosome so that it cannot

fuse with the lysosome After a period of growth and proliferation, TB bacteria burst out of the

macrophage, killing it and infecting other macrophages As macrophages die by necrosis, their lysosomal contents damage the lung

tissues and initiate an inflammatory reaction. This recruits other immune system cells to the area, causing more tissue damage.

o Sepsis Kills ~250,000 Americans/year Caused by bacteria (most often Gram-negative) that enter the bloodstream and

cause a system-wide immune response Gram-negative bacteria have LPS as a component of their cell walls, and

also shed LPS into the surroundings LPS activates macrophages and NK cells Positive feedback loops amplify the immune response

TNF secreted by activated macrophages increase the permeability of blood vessels. Fluid escapes into the tissues, and decrease in blood volume can cause heart failure (septic shock).

- Diseases caused by defects in immune regulationo Allergies

Non-allergic people respond weakly to allergens, and produce mainly IgG antibodies

Allergic (atopic) people respond strongly to allergens, and produce excessively large quantities of IgE antibodies

Mast cells On first exposure to an allergen, some people produce lots of IgE

directed against the allergen

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Mast cells have receptors on their surface that can bind to Fc regions of IgE

On second exposure to the allergen, IgE already bound to the surface of mast cells can bind the allergen

This causes the mast cell to degranulate and release chemicals (e.g. histamine) into the tissues

The chemicals increase capillary permeability so that fluid escapes into tissue. In extreme cases, blood volume can reduce so much that a heart attack occurs.

The chemicals also cause bronchoconstriction, making breathing difficult. In extreme cases, this can cause suffocation.

Basophils and eosinophils also have receptors for IgE antibodies, and cross-linking of these receptors can lead to degranulation

2 phases of allergic reactions Immediate

o Caused by mast cells (stationed out in the tissues) and basophils (recruited from the blood by activated mast cells)

Delayedo Caused by eosinophilso Before an attack by an allergen, there are relatively few

eosinophils present in the tissues or in the bloodo Once an allergic reaction has begun, Th cells secrete cytokines

that recruit eosinophils from the bone marrow Susceptibility to allergies

Atopic individuals have allergen-specific Th cells that are strongly polarized toward a Th2 cytokine profile, resulting in the overproduction of allergen-specific IgE antibodies

Hygiene hypothesiso During pregnancy, maternal Th cells are biased toward Th2 cells

and away from Th1 cells. This serves a protective function for the fetus, because maternal killer T cells and NK cells activated by Th1 cytokines could potentially attack the placenta.

o Placental cytokines also have a strong influence on fetal Th cells. Bias toward Th2 profile in the mother also causes most humans to be born with Th cells that are strongly biased toward making Th2 cytokines.

o Microbial infections in early childhood can elicit a Th1 response, and thus reprogram the immune system to have a more balanced population of Th1 and Th2 cells

o In Western cultures, where improved personal hygiene has led to a decrease in childhood infections, the incidence of allergies to environmental allergens has increased dramatically

Regulatory T cellso Help bias the immune system away from IgE production in

response to allergenso Th cells in the tissues can be induced to become regulatory T

cells when they are stimulated repeatedlyo Thus, routine exposure to environmental allergens may produce

lots of protective regulatory T cells

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o In non-atopic individuals, regulatory T cells represent the majority of CD4+ T cells that are specific for common environmental allergens

The genes a person inherits can make him more or less susceptible to allergies

o Atopic individuals tend to have particular class II MHC genes that may be especially efficient at presenting allergens

o Some atopic individuals produce mutant forms of IgE receptor, which may send unusually strong signals when they are cross-linked

o Some atopic individuals have mutations in the promoter region of the IL-4 gene, which may result in increased production of IL-4

Treatment Glucocorticoid steroids

o Block cytokine production by Th cells fewer B cells are activated total number of antibodies made (all classes) is reduced

o Can result in increased susceptibility to infectious diseases Omalizumab

o Antibodies that can grasp the Fc region of IgE antibodies, and thus block their binding to mast cells

o Expensive Specific immunotherapy

o Only known cure for allergieso Involves the injection of gradually increasing doses of crude

extracts of allergens until a maintenance dose is achieved. After several years of regular injections, some patients become tolerant to the allergens in the extract.

o The injections encourage allergen-specific B cells to switch their antibody class away from IgE, possibly via the generation of regulatory T cells

o Autoimmune disease Present in ~5% of Americans Autoimmunity due to genetic defects

Autoimmune lymphoproliferative syndrome & Canale-Smith syndromeo Individuals have genetic defects in either Fas or Fas ligand

self-reactive T cells cannot be eliminated by activation-induced cell death

o Massive swelling of lymph nodes, production of antibodies that recognize self-antigens, and accumulation of large numbers of T cells in secondary lymphoid organs

Autoimmunity in genetically normal individuals More common 3 criteria for autoimmunity

o Individual must inherit and express MHC molecules that efficiently present a peptide derived from the target self antigen

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o Individuals must produce T and B cells with receptors that recognize a self antigen

o There must be environmental factors (e.g. microbial infections) that lead to the failure of tolerance mechanisms to eliminate self-reactive lymphocytes

Molecular mimicry During a microbial invasion, lymphocytes

whose receptors recognize microbial antigens will be activated

Sometimes these receptors also recognize (cross-react with) a self antigen, and an autoimmune response can result

Before the microbial infection, the potentially self-reactive lymphocytes were not activated either because the affinity of their receptors for the self-antigen was too low to trigger activation, or because the restricted traffic pattern of virgin lymphocytes never brought them into contact with the self antigen

An inflammatory reaction must take place in tissues where the self antigen is expressed. The inflammation can be caused either by the mimicking microbe itself, or by another, unrelated infection or trauma.

T cells activated by molecular mimics still need to be restimulated out in the tissues, or die of neglect

Cells of the innate system secrete inflammatory cytokines (e.g. IFN-γ, TNF) that activate APCs. Activated APCs express the MHC and co-stimulatory molecules needed to restimulate T cells.

In addition, inflammatory cytokines can upregulate class I MHC expression on normal tissue cells, making them better targets for destruction by self-reactive killer T cells

Types of autoimmune diseaseso Organ-specific

Insulin-dependent diabetes mellitus Immune cells attack the insulin-producing β

cells of the pancreas Strong genetic component

o Some individuals have a variant gene for CTLA-4, and are less able to limit the activity of self-reactive T cells that recognize β cell antigens

>90% of β cells are destroyed before symptoms appear. However, antibodies that bind to β cell antigens can be detected early in the disease.

Myasthenia gravis

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Self-reactive antibodies bind to ACh receptors at neuromuscular junction muscle weakness and paralysis

A poliovirus infection may provide one mimic that could activate lymphocytes whose receptors cross-react with the ACh receptor

Multiple sclerosis Inflammatory disease of the CNS initiated by

self-reactive T cells Chronic inflammation destroys myelin sheaths,

causing paralysis and defects in sensory inputs Strong genetic component Virgin T cells cannot cross the blood-brain

barrier, but activated T cells can T cells isolated from MS patients can recognize

components of myelin basic protein, herpes simplex virus, and Epstein-Barr virus

When individuals are infected with herpes virus or Epstein-Barr virus, the activated T cells they produce can potentially cross-react with myelin basic protein

o Multi-system Rheumatoid arthritis

Chronic inflammation of the joints T cells from arthritic patients can recognize

components of a certain cartilage protein and tuberculosis bacteria

When individuals are infected with TB, the activated T cells they produce can potentially cross-react with the cartilage protein

IgM-IgG antibody complexes found in the joints can activate macrophages, increasing the inflammatory reaction via their secretion of tumor necrosis factor (TNF)

Treatment includes antibodies that bind to TNF and prevent it from working, as well as fake receptors for TNF

Lupus erythematosus Affects 250,000 people in the USA (90%

women) Strong genetic component Multiple manifestations

o Red rash on the forehead and cheekso Inflammation of the lungso Arthritiso Kidney damageo Hair losso Paralysiso Convulsions

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Caused by a breakdown in T & B cell tolerance, that results in production of IgG antibodies that recognize many self antigens (DNA, DNA-protein complexes, and RNA-protein complexes)

The self antigen-IgG complexes clog organs that contain filters (kidney, joints, brain, etc.), causing chronic inflammation

May involve a defect in activation-induced cell death, in which lymphocytes that should die due to chronic stimulation survive to cause the disease

Diseases due to immunodeficiency Genetic defects leading to immunodeficiency

o Afflict 1 in 10,000 newbornso Individuals with nonfunctional CD40 or CD40L are unable to

mount a T cell-dependent antibody responseo DiGeorge syndrome

Essentially all thymic tissue is missing Patients lack functional T cells

o Severe combined immunodeficiency syndrome (SCIDS) Patients lack functional B and T cells

o Individuals with defective complement proteins have lymph nodes with abnormal architecture (no germinal centers) and B cells which mainly produce IgM antibodies

AIDSo Affects >60 million people worldwide (>5 million new

infections/year)o Caused by human immunodeficiency virus-1 (HIV-1)o Acute phase

HIV-1 enters human cells, and uses them to proliferate Viral RNA is converted to cDNA by reverse

transcriptase Viral cDNA is inserted into cellular DNA Newly made viruses burst out of each cell, and

go on to infect other cells In the early stages (before the adaptive immune system

kicks in), the number of viruses (viral load) increases dramatically

After ~1 week, activated virus-specific killer T cells cause a marked decrease in viral load

o Chronic phase Can last for >10 years Viral load remains low, and virus-specific killer T cells

and Th cells remain high (indicating an ongoing effort by the immune system to defeat the virus)

As Th cells are killed, their total number decreases. Eventually there are not enough Th cells left to provide

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help to killer T cells, and they decline in number as well viral load increases dramatically

Individual becomes highly susceptible to opportunistic infections, which can be lethal

o When viral cDNA is inserted into cellular DNA, the virus can enter a stealthy latent state in which the infected cell cannot be detected by killer T cells

o Reverse transcriptase is very error prone, and can introduce mutations that allow newly-made viruses to evade the immune system. The mutation of HIV-1 is so high that it can effectively stay one step ahead of killer T cells or antibodies directed against it.

o HIV-1 binds to CD4, and thus specifically targets Th cells, macrophages, and dendritic cells. These crucial immune cells are killed by the virus, or by killer T cells that recognize them.

o HIV-1 can attach to the surface of dendritic cells and be transported from the tissues (relatively few CD4+ cells) to lymph nodes (many CD4+ cells)

o HIV-1 that has been opsonized by complement or antibodies is retained in lymph nodes by follicular dendritic cells. CD4+ cells can be infected as they pass through the lymph node.

Cancer- Arises when growth control systems within a cell are corrupted- Cells can proliferate inappropriately when a proto-oncogene is mutated into an oncogene- Tumor suppressor genes code for proteins (e.g. p53) that help safeguard against uncontrolled cell

growth- Cancer cells suffer from high mutation rates that can disrupt growth control systems- Classification of cancer cells

o Solid tumors vs. blood-cell cancers Non-blood-cell cancers (solid tumors)

Carcinomaso Cancers of epithelial cellso Most commono Include lung, breast, colon, cervical, and other cancerso Generally kill by metastasizing to vital organs, where they grow

and crowd the organ until it can no longer function Sarcomas

o Cancers of connective tissues and structural tissueso Include bone cancer (osteosarcoma) and others

Blood-cell cancers Arise when immature blood cells proliferate continuously without

maturing Leukemias

o Immature blood cells fill up the bone marrow and prevent other blood cells from maturing

o Patient usually dies from anemia (deficit of red blood cells) or from infections (deficit of immune system cells)

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Lymphomaso Clusters of immature blood cells for in secondary lymphoid

organso Patient usually dies from infections or from organ malfunction

o Spontaneous vs. virus-associated Spontaneous

More common Arise when a single cell accumulates a collection of mutations that

causes it to acquire the properties of a cancer cell Mutations can result from errors in DNA replication, carcinogens,

radiation, etc. Virus-associated

~1/5 of all human cancers Some viruses produce proteins that can interfere with the proper

functioning of growth-control systems in infected cells The viruses decrease the total number of cellular genes that must be

mutated to turn a normal cell into a cancer cell Only a small fraction of infected individuals actually get cancer The virus or viral genes can usually be recovered from tumors

- Immune surveillance against cancero The immune system is designed to preserve tolerance to self (and avoid autoimmune

disease). However, this results in a compromised ability to destroy cancer cells.o Killer T cells and solid spontaneous tumors

The trafficking of virgin T cells is such that normally, they would never venture out into the tissues. Thus, virgin T cells never see tumor antigens expressed in tissues.

Even if the virgin T cell somehow ventures out into tissues where it can recognize the tumor antigen, it still requires co-stimulation by APCs in order to survive. Because the cells expressing tumor antigens are not APCs, the T cell would be anergized or killed.

Even if the virgin T cell somehow manages to break the traffic laws AND avoid being anergized or killed, the tumor cells mutate at such a high rate that they are always one step ahead of surveillance by killer T cells

Thus, killer T cells do not provide serious surveillance against solid spontaneous tumors

o Killer T cells and cancerous blood cells Because blood cell cancers are found in the blood, lymph, and secondary

lymphoid organs, the traffic patterns of cancer cells and virgin T cells intersect Some cancerous blood cells express high levels of B7, and therefore can provide

co-stimulation to the T cells Thus, killer T cells provide some surveillance against solid spontaneous tumors

o Killer T cells and virus-associated tumors Viruses which only cause acute infections do not play a role in cancer. All

viruses which play a role in causing cancer are able to establish chronic infections during which they enter a stealthy latent state, invisible to killer T cells.

Thus, killer T cells do not provide serious surveillance against virus-infected cells once they have become cancerous

o Immune surveillance by macrophages and NK cells

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In some circumstances, macrophages and NK cells may provide surveillance against certain kinds of cancer cells

Bacille Calmette-Guerin (BCG) Cousin of tuberculosis bacterium Hyperactivates macrophages When injected directly into a tumor, the tumor fills up with highly

activated macrophages that can destroy the cancer The abnormal expression of surface molecules on tumor cells may allow

activated macrophages to differentiate between cancer cells and normal cells NK cells target cells that express low levels of class I MHC molecules, and

which display unusual surface molecules Advantages of the innate immune system

Unlike killer T cells, macrophages and NK cells are quick acting Both NK cells and macrophages recognize diverse target structures, so

the chances of them being fooled by a single mutation is small Macrophages are located out in the tissues where most tumors arise, so

they can intercept cancer cells at any stage Because NK cells do not need to be activated to kill, NK cells circulating

in the blood may be able to destroy either blood-cell cancers or cancer cells that are metastasizing through the blood from a primary tumor

Disadvantages of the innate immune system Macrophages need to be hyperactivated before they can kill cancer cells.

If there is no inflammatory reaction at the site of the tumor, macrophages will remain in a resting state and simply ignore cancer cells.

NK cells are mainly found in the blood, and are recruited by activated macrophages and dendritic cells. If there is no inflammatory reaction at the site of the tumor, NK cells will just continue to circulate in the blood.

Cancer cells begin to die when the tumor becomes very large, or when they accumulate mutations that are lethal. Dying cancer cells may provide the signals required to activate macrophages, which can then recruit NK cells from the blood.

- Immunotherapy as cancer treatmento Expensive and not very effectiveo Most successful in treating minimum residual disease – cancer cells which remain after

the primary tumor has been removedo Chemotherapy and radiation therapy are most effective against rapidly growing tumors,

where the cells have less time to repair DNA damage. Immunotherapies do not depend on damaged DNA causing cells to commit apoptosis, so they may be suited to destroying slow-growing tumors.

o Active immunotherapy Based on the idea that the immune system might be able to destroy a tumor, if

only a sufficient number of tumor-specific killer T cells could be mobilized via physician assistance

o Passive immunotherapy The patient’s immune system plays a less active role in combating the tumor Physicians do most of the work by removing potential cancer-destroying immune

cells from a patient’s body, engineering these cells to become more potent fighters, and injecting them back into the patient

- Vaccinations to prevent virus-associated cancer

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o Very successful

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