• “A fascinating and personal portrait of the immune
system. In Callahan’s picture, it’s the immune system, not
our brains that defines our humanity.”
– Joe Palca, NPR Science Correspondent
• “Sophisticated yet easy to understand… Callahan takes
his readers on a poetic and exploratory voyage.”
– Rocky Mountain News
• “Drawing poignantly on the stories of his own life,
Callahan contends that experiences as complex as love
and madness are intricately bound up with our
immunological makeup.”
– Discovery
• Each of the dozen essays in this far-ranging collection
could be expanded into a book… ‘the Flame Within’ is …a
detective story about the best-documented instance of
human spontaneous combustion which occurred in Florida
in 1951…”
– Booklist
Today…
•
•
•
•
•
Student course evaluation…
Complete group 7’s presentation…
Complete presentation on complement…
Present statement about monoclonal Ab’s…
Attend to mechanical concerns…
• Return of take home quizzes…
• Anticipating the nature of the final comprehensive
exam
CANCER
Cancer Vaccines
• Genetic
• Biochemical
HPV
Human Papilloma Virus
• E6
• E7
From Normal to Abnormal:
For more info
• HPV
• Cancer Vaccines
This Day Has Been
Brought to you By
the Letter…
C
C is for Cancer!
COMPLEMENT
The overview….
• Complement has
three functions:
• Complement functions
in two (three?) systems:
– Opsonin
– Alternative
– Chemoattractant
– Classical
– Membrane Attack
Complex (MAC)
– Lectin-based
The CLASSICAL pathway
Stimulated by antibodies:
specifically: IgM and IgG
(subclasses 1, 2, 3)
Start with C1q a HUGE
protein (410,000 daltons!)
Composed of 18 peptides.
Peptides can associate to
form trimers; six sets of
trimers make C1q.
C1q has helical “stalks” and
globular “heads.”
(N. B. the heads are the
carboxy end and the stalks
are the amino ends)
The CLASSICAL pathway
Also associated
with C1 are C1r
and C1s which
associate to
make dimeric
pairs (C1r2s2);
the dimeric pair
joins C1q to form
C1qr2s2.
The CLASSICAL pathway
• C1qr2s2 binds to TWO immunoglobulins.
– The complement binding sites of circulating
IgM are too far apart to bind complement;
– only when IgM is bound does it fold so that
C1qr2s2 can “see” nearby complement binding
domains.
– IgG concentrations must be high in the vicinity
of antigens for threshold levels of complement
binding domains to be present.
The CLASSICAL pathway
When C1qr2s2 is bound to requisite number of
immunoglobulins, C1r “autocatalytically” converts to C1[r].
C1[r], in turn, converts C1s to C1[s].
C1[s] cleaves C2 and C4.
C4 is cleaved to C4a and C4b; C4b associates with its
“target” which is C2.
C2 is cleaved by C1[s] making C[4b2a] which is a C3
convertase! (Note that 2a is bigger than 2b, this nomenclature being the on
exception to the convention that “a” is smaller than “b.”)
As with the other C3 convertase, C3b can join C[4b2a] to
make C[4b2a]3b which is also a C5 convertase.
The CLASSICAL pathway
The CLASSICAL pathway
The CLASSICAL pathway
The complement pathways…
The LECTIN pathway
Lectins are proteins which bind to carbohydrates.
Many bacteria have many mannose residues on
their surface. The lectin-based complement
system begins with a “mannose-binding protein”
(MBP).
MBP reacts, in turn, with a MBP-associated
serine protease (MASP).
MASP functions, in effect, like activated C1q[r2s2],
that is a C3 convertase.
The most
amazing
circumstance:
Erythrocytes (!)
deliver the
complex of
antigen –
antibody –
complement
to the liver and
spleen for
consumption
by phagocytes.
Monoclonal Ab’s
Contrast with the normal circumstance…
• The normal response to an immunogen
is polyclonal Ab’s
• The immunogen most commonly has
multiple epitopes
• The multiple epitopes select multiple Bcell lineages
• Multiple clones mature to produce Ab’s
for the multiple epitopes
Monoclonals are just what
they say they are:
• Remember: a single B-cell makes a
single type of antibody
– or, more precisely, a single idiotype
• The B-cell is made immortal
– The clone, if stable, continues to secrete the
single type of Ab
The scheme…
+
“HGPRT ” =‘s
hypoxanthine-guanine
phosphoribosyl
transferase
The enzyme is used
in the “salvage
pathway” for DNA
synthesis
“HAT” =‘s
hypoxanthine -aminopterin -thymidine medium
aminopterin inhibits de
novo DNA synthesis
thymidine is needed for
pyrimidine synthesis in the
salvage pathway
hypoxanthine for purines...