neoplasm

metasizing 

chromosomal translocation is identical within each person, 

femal tissues contain same X chromosome 

gene expression

genetic mutation 

chemical carcinogens

radiation

viruses

predisposed to mutation 

too many divisions for it to be likely

risk increases with age

analysis of tumors 

break control systems

survive without resources

adjust to other tissues 

rate of mutation

rate of growth

number of individuals

selective advantage over healthy cells 

disregarding of external sygnals

avoid appoptosis

genetically unstable (optimal level)

invasive

metastatic

able to recruit blood supply 

epigenic

replicative senescense 

p53 w/ E6

Rb w/ E7

E6 induces ubiquitilation, resulting in proteolysis 

increases in lung cancer from smoking

decreases in stomach cancer, from diet and heliobacter

improvements in detection and treatment 

oncogenes

tumor supressor genes 

dna extracted from tumor

fragmented

each fragment introduced in to mouse derived cell line which already has some mutations

if fragment is an oncogene, tumors form

fragment is sequenced and oncogene identified 

a cell signalling molecule: first to be identified by fragmentation/introduction method

mutated in 25% of cancers 

hyperactive protein(Ras, EGFR)

elevate protein by gene amplification (myc)

Chromosomal rearangement hyperactivates expresion

find what is missing:

pick a cancer that is new, has few mutations

look for a large missing section,

cross reference with missing alleles

newer techniques: Representititve Diff. Analysis 

deliver signals from environment,

control cycle and death

govern movement and interaction 

Cdk4 and cyclin D1 phosphorylate Rb, allowing division

p16 prevents division understresses

in other words:  Rb, p16, supressors

Cdk4, cyclin D1 oncogenes 

phosphorylation prevents mdm2 binding

high p53 concentration stimulates transcription

produces CKI protein p21 

protein which is produced when p53 builds up

binds and inactivates G1/S-Cdk and S-Cdk, arresting cell in G1 

Retinoblastoma - eye tumor

when lost, cancer occurs

both copies of it must be lost 

can be found in Lung, breast, and bladder tumor 

inactivate toxins

recruit complements (part of inate immunity)

attract phagocytes 

Immunoglobulin

B-cells secrete 2000/s 

inactive, have antibodies as membrane receptors

when activated by antigens, become...

EFFECTOR CELLS!

the proliferate and differentiate to become effector cells 

activated memory and naive cells which secrete the anibody which binds to the antigen that activated them

(like Batman) 

two binding sites in a "Y" with a flexible hinge region

the flexile region allows antigen cross-binding

good for phagocytosis

 two identical light chains, 220 AA, responsible for differentation

two identical heavy chains, 440 AA, standardized

the four chains are held together by disulfide bonds 

IgM

IgD

IgG

IgA

IgE 

mu: first class produced

secreted as penamers(10 low affinity binding sites)

gamma: major class

monomer

large quantities produced in secondary response

only antibody that can pass to fetus

tail binds to macrophages and neutriphils 

alpha: major class in secretions

four chain monomer in blood

eight chain dimer in secretions 

the champagne of antibodies

 secretory epithilia and Fc

epsilon: located on surface of mast cells

on basophils in blood

binding causes the secretion of cytokines, amines, histamines...

histamine cause blood vessels to dialate and leak

kappa

lamda

no difference

always same type 

variable N-terminal ends binds

three hypervariable reginons, 

each 5-10 AA each

antigens have fewer than 25 AA 

two beta sheets with a disulfide bond

hypervariable loops form a variaty of binding surfaces 

10^12 before infection

50,000 genes

assembled by recombination and splicing

impricice joining, multiple configurations 

Rag1 and Rag2 mediate recombination.  they are double strand repari proteins

activated in marrow by B-cell development

they are reactivated if antibody matches self antigen, editing mechanism

occurs in periphery lymphoid organs after stimulation of antigen

V region mutation common

called "hypermutation"

B-cells that express high affintiy for anibodies are stimulated for proliferation 

targets pathogens, toxins

activated by antigens, T-helpers

recepters are antibodies

can bind antigen

long range 

targets infected cells

can be activated by:

dedritic cells

macrophages

b-cells

T cell receptors are not actually antibodies

can only bind short peptides presented to them

Short range 

antigen like

large folded Ig-like domain, one part variable, one constant

only one binding site

30,000 receptors

membrane bound

alpha and beta chains, V and C

one binding site

VDJ joining

no somatic hypermutation

weak binding 

can be secreted

two of each chain, heavy, light, V and C

two binding sites

VDJ joining

somatic hypermutation

binding gets stronger 

antigen presenter

endocytose pathogens and their products

display pieces of antigen on surface as MHC complex

travel to local lymph nodes

activate T-helpers 

MHC, which present antigen

costimulator proteins, which bind to the T-cell

cell adherins 

Mechanisim I

of cytotoxic T-cells 

Perforin -dependent

releases poreforming protein, perforin

forms transmembrane channels

serine proteases

activates caspases 

Mechanism II

of T-cell killing 

Fas-dependent

Fas ligand, the binds to death receptor, initiating apoptosis 

MHC complex

Major Histocompatibility Complex

MHC I expressed on all nucleated cells,->cytotoxic

MHC II expressed on specialized anigen presenters, -> Helper T-cells 

alpha and beta chains.  alpha bind antigen

present to cytotoxic T-cells 

6 genes, 3 M, 3 p 

alpha and beta,

each has two Ig-like domains and two variable regions, the antibody-like region binds antigens to present them to Helper T-cells

more than 6 genes 

MHC:

diversity?

individuality?

range? 

not as diverse as antibodies

different between people (except twins and family)

bind a whole range of peptides 

MHC I

binding site 

smaller

binds peptides at ends

small pockets bind other AA 

MHC II

binding site 

larger

doesn't bind at end

similar to class I proteins

held in groove by peptide backbone

can accomidate a more heterogenous set of peptides than class I 

CD4, MHC II

CD8, MHC I

bind to invarient parts of MHC 

self recognition

most important part of adaptive immunity

help activate B-cells

help activate T-cells

without them, we die  of AIDS 

Signal 1:

Foreign peptide bound to an MHC protein

Signal 2:

B7, costimulatory protein, binds CD28.

Expression of B7 occurs when antigen presenter detects foreign pathogens 

interleukin-2

causes T-cells to proliferate and differentiate

fig 24-65

secretes its own extracellular signalling molecule 

differentation of T-cells following IL-2 activation

TH1:  helpers in response to cell invading infection

induces cytotoxic T-cells, macrophages, B-cells

TH2: in response to extracellular infection, parasites

 induce B-cells, which produce IgG to cover pathogens and IgE to bind to eosinophils, basophils, mast cells

only one of these can be expressed.  dominant one inhibits the other 

B-cell receptor binds antigen in a peripheral lymphoid organ, Signal 1

Antigen is dragged into cell to the endosome for deresolution

its pieces are displayed on surface bound to MHC II

T helper binds to MHC antigen complex, signal 2

receptor CD40 on B binds ligand on T to facilitate bonding 

1/3 of deaths

ulcer (H. pylori)

heart disease

10^13 cells

10^14 bacterial, fungal, protazoan cells

these are normal, non pathogenic flora

these are usually limited to areas: mouth, vagina, skin, large intestine

also you are infected with symptomless viruses

colonize

find nutritionally compatible nitche

elude immune system

replicate using host resources

exit and spread 

mostly the immune response

sometimes, symptoms are to promote disease transfer. 

fig. 25-2

bacteria

viruses

eucaryotes (fungi, protazoan, worms)

prions

obligate: replicate in body only

faculative: replicate in environment, cause a disease when they enter host

opportunistic: weak.  only cause a disease in the case of autoimmune disorder 

spheres: cocci

rods: bacilli

spirals: spirochetes 

single membrane, thick wall of crosslinked peptidoglycan.

streptococci, staphylococci 

two membranes seperated by periplasmic space.

peptidoglycan wall is much thiner, inside periplasmic space, and does not retain gram staining dye.

e coli, salmonella

many swim using flagella

cholarae has single flagellum at one pole

e coli have many all over surface

pili, aka, fimbriae, help bacterium adhere to host cell

fig 25-4

toxins and proteins needed to deliver toxins

type III secretion systems can inject a target 

bacteria are not eucaryotes, they are very different.

Antibiotics attack machinary that is either very different from ours, or completely absent in mammals, so as not to kill host cells.

fig 25-8 

fungi can be in yeast-like form or mold-type form

the transition between the two is frequently associated with infection 

much more difficult: fungi are eucaryotes

antifungal treatments are often less effective than antibiotics, while at the same time being more disruptive in human pathways. 

most common is malaria

contracted by the bite of female mosquitos carrying plasmodium

plasmodium requires both the mosquito and the human host to complete its reproductive cycle

gametes form in humans, zygotes in mosquitos

rely on host machinery, not living, very small

come in a variety of shapes/sizes, fig.25-12 

disassembly of infectious virus particle

replication of its genome

synthesis of its proteins using cellular machinery

assembly into its progeny virus particles

smallest can have RNA genomes w/ just a few genes

largest have hundreds, double stranded DNA genome 

peculiar ends and circular genomes overcome difficulty in transcription of the end of strand

enveloped viruses bud off of infected cell

nonenveloped leave by lysing the cell

enveloped more likely to cause chronic infection leading to cancer 

ones for highjacking the cell

ones for replicating genome

ones for packaging the other

misfolded human protein

causes other proteins to misfold

if ingested, can cause misfolding in host

most well known of is BSE, or Mad cow disease

epithelial surfaces densely populated by flora

the goal is to get inside

can enter a wound, or by insect vector 

Uropathogenic e. coli and P pili use long projections to adhere to cell surface of urinary tract, resisting the washing action by pentrating past mucus layer

Helicobacter pylori colonize the stomach dispite its pH of 2 by producing urease, conveting urea into basic NH3.  They do this just long enough until they can insert themselves between epithelial cells of stomach lining.  now believed to be major cause of ulcers and stomach cancer

membrane fusion

pore formation

membrane disruption

phagocytosis (even in non-phagocytic cells) 

humans and chimps: 2% difference in 8 million years

poliovirus, five days

antigenic variation (trypanosoma): changing coat to escape immune detection

error prone replication: HIV, 1 pt. mutation per cycle 

horizontal gene transfer in bacteria

antibiotic resistance saved to plasmids and shared 

produce an enzyme which destroys the drug

alter the target molecule

pump drug out

typical time to resistance, 1-2 years

drug-resistant normal flora can emerge due to missue

fast, during critical time

pathogens have a 1 hr doubling time

20 million progeny a day

adaptive takes about a week 

inspecific

dependent on backup

found in invertibretes and plants too

required to activate adaptive 

skin, gut lining, lung lining

tight junctions, mucus layers, cilia

consists of mucin and glycoproteins

defensins 

short peptides

positively charged

have hydrophobic or amphipathic domains

broad spectrum as

the most abundant proteins in neutrophils 

still uncertain

probably insert in membrane of pathogen

pathogen membrane low in colesterol

reacts with negatively chargd targets DNA

first amino acid in bacteria

peptidoglycan in cell wall and flagella

lipopolysacharide on gram negative bacteria

teichoid acid on positive

paprasites

certain dna segments 

zymosan

glucan

chitin

toll receptors

initiate phagocytosis

stimulate innate response

immunostimulants 

about 20 proteins

inactive in absence of infection

can be activated by IgG and IgM (classical pathway)

binding manose and fucose in bac. cell wall by lectin

can be activated spontaneously

triggers proteolytic cascade

all 3 pathways lead to activation of complement C3

activated by cleavage into C3a C2b

C3b bindsto pathogen surface, activating macrophage

C3a acts as a diffuse signal, recruiting macrophages and lymphocytes to the infection site

spontaneously activated at low levels

C3b covalently attaches to both host cells and pathogens

host cells produce proteins that prevent the complement reaction

pathogens can't

C3b can convert more C3 to C3b, amplifying effect 

pattern recognizing, bind to small consistant regions

are abundant on macrophage/neutriphil surfaces

epithelial cells lining the lung and gut

activation initiates inflamatory response, helps induce adaptive immune responses 

phagocytic cell in vertibres and inverts, but not plants

macrophages reside in tissues,

long lived,

survive killing

reside in blood and travel to tissues only in case of infection

shortlived,

die upon killing 

toll like

Fc receptors ( for tails of IgG)

Receptors for C3b

actin polymerization at site of attachment

plasma mebrane wraps around

engulfed in phagosome

phagosome is acidified and fused with lysomes

lysozyme

acid hydrolases (degrade walls and proteins)

defensins

NADPH oxidase complex bleaches pathogen 

pain, redness, heat, swelling at site of infection

all caused by blood vessel changes

dialate, become leaky

endothelial cells call adhesion proteins

local swelling includes components of complement cascade 

cells that release inflamatory signals

mast cells release histamine and prostaglandin in response to activation of stretch receptors in trauma

macrophages release signals in response to activation of toll like receptors

lipid signaling molecules - prostaglandins

protein signalling molecules - cytokines chemokines

complement fragments 

attract neutriphils, monocytes, dendritic cells

trigger fever

trigger clotting to prevent pathogen entrance through wound

induce apoptosis in virus infected cells

some viruses inhibit MHC I synthesis to escape cytoxic T cells

some cancer cells have low levels of MHC I

NK cells recognize cells with low level of MHC I and kill them