ADDING

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Add-Drop Instructions Immunology BICD 140 Winter
2005
ADDING 1. This class is open.  Students may add
this course on a first come, first served basis
via WebReg during the first two full weeks of the
quarter (January 3rd- 14th). (NOTE If this
class was previously CLOSED and you were on a
wait list, you will need to drop yourself from
the wait list in order to add the class.) The
last day to add is Friday, January 14th. 2. I
cannot sign add cards for students who wish to
add except if the student is a concurrent
enrollment student. Concurrent Enrollment add
cards will only be signed during the 3rd week of
the quarter if spaces are available. Students in
need of pre-requisite overrides should send an
email to me including student name and PID. 3.
WITHDRAWAL PROCESS The last day to drop a class
without a W is Friday, January 28th and the
last day to drop a class with a W is Friday,
March 4th.Please direct all Add/Drop inquiries to
Student Affairs at x40557.
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Discussion Sections - Immunology BICD 140 Winter
2005Sections will discuss lectures, homework
assignments, and exams. You must choose one
discussion section and hand in your homework to
your designated TA.
Section Day Time (50') Room TA Email A01 TBA
TBA TBA Laura lhgreen_at_ucsd.edu A02 Thurs 600
PM CENTR 217b Adam jbest_at_ucsd.edu A03 Thurs
500 PM CENTR 218 Lauren laurenannd_at_yahoo.com
A05 Fri 0800 AM CENTR 218 Matt jzones_at_ucsd.e
du A06 Fri 1000 AM CENTR 220 Hart
hdengler_at_ucsd.edu A04 Fri 1100 AM CENTR 218
"
Note This page will be updated to show the
correspondence between TAs and Discussion Sections
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Web Site
Note site for last years course
Username bicd Password 140 PLEASE READ
COURSE INFORMATION If you do not check the
e-mail address listed by the registrar, you will
not receive course announcements
http//hedricklab.ucsd.edu/BICD140
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Grading Two midterm exams each worth 100
points One final worth 150 points The homework
grade (100 points total) will be automatically
substituted for your lowest midterm! However, you
must take both midterms. If you have a valid
excuse to miss a midterm (e.g., death in family,
severe illness, car accident on the way to
school), drop off a note signed by a relevant
official to Mandy Butlers Office, York 3080. In
that case, your homework will substitute for the
missing midterm. Do not miss a midterm without a
valid excuse. There will be no make-up
midterms. You must take the final. If you have a
conflict with the Final date, let me know
immediately.
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Final Exam Date (from Student Link)
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Lecture 1 Introduction to immunology

• Immunity in bacteria- there is no free lunch
• Brief history of immunology
• Overview of vertebrate immunity (Chapter 1)
• Innate vs. Acquired Immunity- conceptual and
  practical difference
• NEXT LECTURE
• How does innate immunity work?
• (Chapter 7 and 8 dealing with complement and
  innate immunity)

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The word IMMUNITY
Derives from the latin immunitas, meaning freedom
from public service (i.e., the military draft).
From Merriam-Webster dictionary a condition
of being able to resist a particular disease
especially through preventing development of a
pathogenic microorganism or by counteracting the
effects of its products
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There are two kinds of immunity
HOST DEFENSE Innate adaptive
immunity Resistance to infection can be learned
or innate. It appears that many organisms lack
learned immunity, but can have robust innate
defenses. As we shall see, learned immunity is
an evolutionary offshoot of innate immunity, and
the human immune system combines both types in
host defense.
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The Triumph of Death - Pieter Brueghel the Elder
ca. 1562
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Big bugs have little bugsUpon their backs to
bite emLittle bugs have littler bugsAnd so on
ad infinitum -Ogden Nash
Every organism needs host defense

• Colonization of large organisms by smaller
  organisms or viruses is the inverse food chain
• Large complex organisms present a source of
  energy and a habitat for smaller organisms and
  viruses via colonization
• Colonization and defense against colonization is
  a fundamental principle in biology
• The immune system is principally and most
  importantly evolved to sculpt colonization to
  benefit the host

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Concept 1 Every organism needs to distinguish
self from non-self because everyone has a parasite
Case study bacteria
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Bertani, G. Weigle, J. J. (1953)
Adapted from Murray NE. Microbiology. 2002,
1483-20.
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What restricted the phage growth?
Restriction enzymes
Example EcoRI target sequence
5...GAATTC...3 3...CAATTG...5
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A chemical difference between self and foreign is
distinguished
Strategy mark self DNA and destroy non-self
DNA
Type 2 restriction/ modification system of
bacteria
EcoR1 methylase modifies host DNA
EcoR1 restriction endonuclease cuts
incoming bacteriophage DNA NOT methylated DNA
Murray NE. Microbiology. 2002, 1483-20.
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Concept 2 Distinguishing self from non-self may
require marking of self
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Type 1 restriction/ modification enzyme complex
Eco K1 TGAme(N)8 TGCT ACT (N)8 ACGA

If hemimethylated methylates other strand
If UN-methylated, cuts (nearby but not in
sequence)
Eco K1 TGA(N)8 TGCT ACT(N)8 ACGA
Q what happens during DNA synthesis?
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Redundancy An individual bacterium can carry
multiple restriction modification enzymes with
different specificities
Example, E.coli strain K12 carries these two
class II restriction enzymes
EcoKI recognizes the sequence 5'...AAC(N)6GTGC...
3' EcoBI recognizes the sequence
5'...TGA(N)8TGCT...3 (K12 has two other
restriction enzymes as well!)
Q what is the evolutionary selection for this
redundancy?
Probability of a particular 7 nucleotide sequence
is 471/16,384 Genome sizes of bacteriophage
range from 5,000-100,00 base pairs Bacteriophage
can potentially avoid certain restriction sites.
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Concept 3 Defense mechanisms must be redundant
to reduce the likelihood of escape by the
parasite.

• Phage escape mechanisms
• reduce genome size
• eliminate certain nucleotide sequences carrying
  the restriction site
• be single stranded, requiring replication of the
  second strand (and attendant methylation) prior
  to forming a double stranded substrate
  (restriction enzymes are dimers that require
  double stranded DNA, whereas methyltransferase
  work as monomers).

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Virtually all bacteria have restriction/modificati
on systems
Recognition Sequence Enzymes AA/CGTT
Acl I Arthrobacter luteus A/AGCTT Hind
III Haemophilus influenzae Causitive agent
of bacterial influenzae. A/CATGT Pci
I Planococcus citreus A/CCGGT Age
I Agrobacterium gelatinovorum ACCTGC(4/8)
BspM I Bacillus sphaericas A/CGCGT Mlu
I Micrococcus luteus
A
bacterium that degrades the compounds in sweat
into ones producing unpleasant odors. A/GATCT
Bgl II Bacillus globigii AG/CT Alu
I Arthrobacter luteus AGG/CCT Stu
I Streptomyces tubercidicus AGT/ACT Sca
I Streptomyces caespitosus . .
. .
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Diversity Restriction enzymes have been found
only within prokaryotes. Many thousands of
bacteria and archae have now been screened for
their presence. Analysis of sequenced prokaryotic
genomes indicates that they are common--all
free-living bacteria and archaea appear to code
for them. Restriction enzymes 3706 250
different sequences seen Type I
59 Type II 3634
Methyltransferases 757 Type I
49 Type II
595 (information from a supplier of
restriction enzymes, NEB) Note Most type 2 RE
see palindromic sequences and recognize 4-8 bp
seque nces. There is a natural restriction
enzyme for practically every conceivable such
palindrome.
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Concept 4 Defense mechanisms can force parasite
specialization.
Example Phage T5 produces a protein that
blocks EcoRI enzymatic activity.
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r- m-
Efficiency of growth 100
E. coli Strain C
bacteriophage
Q what happens to a bacterium that loses its
methylase gene?
Efficiency of growth 100
Efficiency of growth 100
E. coli Strain K-12
Efficiency of growth 0.02
Carries restriction/modification system rm
Adapted from Murray NE. Microbiology. 2002,
1483-20.
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Concept 5 Defense mechanisms can be toxic to
self if not properly controlled
Deletion of the modification enzyme without
concomiant elimination of the restriction enzyme
would be lethal. Restriction and modification
enzyme genes are always found closely linked in
the bacterial genome. This probably minimizes
the risks associated with DNA deletion.
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Concept 6 Defense mechanisms can affect
interactions with other individual of the same
species
Restriction enzymes also can block bacterial
conjugation (between incompatible strains).
Conjugation is a DNA transfer between bacteria
that is analagous to sex.
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Every organism needs host defense Example
bacteria 1. There is a need to distinguish self
from non-self because everyone has a
parasite. 2. Distinguishing self from non-self
often requires marking of self. 3. Defense
mechanisms must be redundant to reduce the
likelihood of escape by the parasite. 4.
Defense mechanisms can force parasite
specialization. 5. Defense mechanisms can be
toxic to self if not properly controlled. 6.
Defense mechanisms can affect interactions with
other individual of the same species.
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The notion of immunity to disease is ancient
Thucydides History of the Peloponnesian War
5th century BCE He noted that during the plague
of Athens (430 BCE) the sick were nursed by those
who had recovered from the disease (caused by a
bacterium, possibly Yersinia pestis) because they
knew that they were safe from developing, or at
least dying from, the disease a second time. It
was also clear that this resistance was specific
to the plague disease only. Thus the specificity
and memory of immunity was recognized long ago.
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Immunizations have been carried out for a long
time
Variolation was an ancient folk practice of
vaccination to smallpox (infectious agent Variola
major virus) practiced throughout Asia, Africa,
and parts of Europe. Essentially, it followed a
procedure in which blisters from diseased skin
carrying virus from a smallpox victim was
innoculated in the skin or nose. Variolation
became a common practice in England after the
Prince and Princess of Wales had their children
innoculated in 1722. The precursor to the modern
vaccine was based on the work of Jenner, who
showed in 1798 that pustules from cows diseased
with cowpox had the same smallpox protective
effect. Hence vaccination (Latin vaccus, cow).
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Germ theory and the scientific basis of immunity
Jenner didnt know why or how his vaccine worked.
In the 1870s Robert Koch, Louis Pasteur, and
others identified specific microbial agents of
several human and animal diseases, including
Anthrax (Bacillus anthracis), cholera (Vibrio
cholerae), tuberculosis (Mycobacterium
tuberculosis), Dyptheria (Corynebacterium
diphtheriae) and the Plague (Yersinia pestis).
A major breakthrough was Pasteurs
demonstration that injection of weakened
pathogenic microbes of Anthrax or fowl cholera
could protect animals from lethal infection of
the same microbe. Attenuated vaccines are
commonly used today. He later developed an
effective rabies vaccine using ground up spinal
tissue from diseased animals. However, vaccines
against some microbes, such as tuberculosis,
failed, and an effective vaccine is still not
available for this and many other important
diseases.
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Some vaccines really work!
Particulary effective are vaccines that protect
from viruses that require human-to-human
transmission

Smallpox


Fig 1.1 Parham
human to human transmission
Fig 1.27 Parham
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Overview of the vertebrate immune system

• Host defense is multilayered
• Innate immunity evolves with the germline and
  involves receptors, enzymes and cells that detect
  conserved aspects of microbes and parasites.
  Examples lysozyme in the eye that digests
  bacterial peptidoglycan, antibacterial peptides
  produced by epithelia, receptors for
  formyl-methionine or lipopolysaccharides on
  phagocytic cells, the complement system.
• Adaptive immunity is provided by lymphocytes
  and evolves not only in the germline, but also in
  the soma, providing immunity with its hallmark
  properties of memory, specificity, and
  self-tolerance.

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Cells of the immune system
Bone marrow/fetal liver
Thymus
Naïve, resting lymphocytes in lymph nodes, spleen
Adaptive
Innate
Fig 1.27 Parham
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Analogies between host defense and homeland
defense

• Highly complex, redundant, involving overlapping
  responsibilities, distinct specializations,
  information sharing and several levels of
  communication between components.
• Military (several types), police (several), port
  authorities (several), intelligence, hospitals,
  communications at different levels,
  indentification systems, central and local
  government coordination. Running the system is
  expensive, wasteful, and at any given time, many
  components appear to be inactive.
• Lymphocytes (several types), myeloid cells
  (several), dendritic cells (several), pattern
  recognition receptors (numerous), plasma
  components (complement, coagulation proteins,
  antibacterials), cytokines (regulate cell growth
  and function), chemokines (regulated movement),
  contact dependent cell communication, central
  regulators (fever regulation by hypothalamus,
  pain sensation by nervous system).

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Where the lymphocytes are. Yellow, primary
lymphoid organs. Blue, secondary lymphoid
organs.

See Fig 1.8 Parham
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Unlike other white blood cells (leukocytes) lympho
cytes are morphologically nondescript
Resting lymphocyte
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CD8 killer T cells kill infected host cells
B cells make antibodies
CD4 helper T cells sustain responses
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Lymphocytes have unique, clonally distributed
antigen receptors
B cells
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16
13
14
15
17
19
18
4
5
3
2
9
6
8
7
1
11
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T cells see presented antigen
Antigen presenting cell
CD8 T cells
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13
14
15
16
17
19
18
4
5
3
2
9
6
8
7
1
11
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Note for both T and B cells antigen is a growth
factor
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Innate vs. Adaptive Immunity
Figure 1.5
Memory
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One view of animal phylogeny
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Biological Inventionof Acquired Immunity
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Innate Immunity

• All animals have an innate immune system
• Innate immunity is manifest in many cells of the
  body. The basis is the recognition of molecular
  patterns, that occur in microbes but not animals
  (e. g., unmethylated DNA sequences, dsRNA, cell
  wall components, etc)
• This is the bedrock of immunity in all
  organisms--even bacteria have defense mechanisms
  against bacterial viruses

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Innate Immunity, cont

• An apparent limitation is that parasitic agents
  have a generation time orders of magnitude less
  than that of their hosts
• A second limitation is that there is only limited
  amplification of the response
• A third limitation is that there is no memory

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Adaptive Immunity

• Recognizes any biochemical determinant
• Provides a mechanism for immune recognition that
  can evolve as rapidly as the parasite (clonal
  selection)
• There is rapid amplification of a response
• There is memory

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• Origins of immunology
• Distinction between innate and adaptive immunity
• Cells of the vertebrate immune system
• Black box overview of the adaptive immune
  response
• Phylogeny of adaptive immunity
• Next time
• Innate immunity recognition mechanisms