Transcript Edward Jenner, 1796 - University of California, Los Angeles

Charles A. Janeway, Paul Travers, Mark Walport, Mark Shlomchik
Immunobiology:
The Immune System in Health & Disease
Sixth Edition
Chapter 1
Basic Concepts in Immunology
Copyright © 2005 by Garland Science Publishing
Edward Jenner 1796
•Observation that milk
maids infected with
cowpox were resistant
to smallpox (already
folklore)
•Innoculated a poor
farm boy with fluid
from a blister/pox of an
cow pox infected milk
maid.
•Weeks later he
challenged the boy with
an injection of a lethal
dose of smallpox.
•The boy was protected
from smallpox.
The eradication of smallpox by vaccination .
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
Two defining characteristics of
adaptive immunity.
• Specificity
– Response is directed against specific antigenic
determinants of a pathogen
• Memory
– The memory of having been exposed to the same
pathogen previously
– Both implicate receptor diversity
Gowens 1962, Nature
• Identificationof lymphocytes as the cellular
units of clonal selection in adaptive
immunity.
– B cells
• Humoral immunity
– T cells
• Cellular immunity
Innate Immunity
• Eli Metchnikoff (1893; nobel prize 1908 with P
Erlich in recognition of their work on immunity)
– Innate immune response of starfish (phagocytosis)
• Mediated by
– Cells; phagocytes and NK cells
– Proteins (complement)
– Anti-microbial peptides (defensins)
Use germline encoded “pattern recognition
receptors” to recognize molecular structures
(patterns) on microbes (LPS)
Two roles
– Front line defenses
– Stimulation for adaptive immunity
• Activation of the innate response cues the adaptive response to
the presence of “danger”
All the cellular
elements of
blood,
including the
lymphocytes of
the
adaptive
immune
system, arise
from
hematopoietic
stem cells
in the bone
marrow.
Figure 1-3
Myeloid cells in innate and adaptive immunity
Myeloid cells in innate and adaptive immunity
Lymphocytes are mostly small
and inactive cells prior to
infection.
Natural killer (NK) cells.
These are large granular
lymphocyte-like cells with
important functions in innate
immunity. Although lacking
antigen-specific receptors, they
can detect and attack certain
virus-infected cells
Figure 1-7
Most Infectious agents induce inflamatory
response by activating innate immunity
The course of a typical antibody response.
Serum therapy anti-toxin against diptheria
Emil von Behring1901 nobel prize
• O-4 hours Innate immunity
– Recognition by preformed non specific
effectors; removal of infectious agent
• 4-96 hrs
– Recruitment and activation of innate effector
cells
• 96 + hrs Adaptive Immunity
– Transport of antigens lymphoid organs
T and B cell recognition
Clonal expansion and recognition
Molecular basis of diversity
• Tonegawa in 1970’s (nobel prize;1987)
• Antigen receptors of B and T lymphocytes are
encoded by genes that result from somatic
recombination segments at at defined stages of
maturation
• Recombination requires RAG recombinase
• Presence of RAG genes during phylogeny
identifies the evolutionary time of acquisition of
adaptive immunity
– just past the the appearance of vertebrates
– jawless fish lack RAG and lymphoid organs whereas
the cartilagenous fish have a RAG genes and a well
developed adaptive immune response
Recombination of antigen
receptors
• Allows a vast number of receptors to be generated
from a small amount of genes
• Maximizes diversity by introducing sequence
variation at sites of recombination
• Regulates the development of individual
lymphocytes
– Signal expansion and development of only cells with
specificities
• reactivity with antigens challenging the individual
• Not reactive with self antigens
The structure of the
antibody molecule
demonstrates how
diversity in ligand
recognition is
coupled to a
common effector
mechanism
(Edelman and
Porter Nobel Prize
1972 for their
discoveries
concerning the
chemical structure
of antibodies 1959)
Diversity yes, but how do we every get enough to be effective?
Clonal Selection Hypothesis (Burnet 1959)
(Jerne,Kohler and Milstein Nobel prize 1984)
T cells see antigen in a different way
Transplantation studies revealed that tissue rejection
map to MHC region
Immune responsiveness also mapped hereVirus specific killer T cells generated in one
inbred strain only kill virus infected target cells
if they share the same MHC (Zinkernagel and
Doherty, 1974, nobel prize)
T cells have a dual specificity for antigen and MHC
TCRs bind to a composite ligand composed of
antigenic bound to a MHC molecule
There are two types of MHC which patrol for
different types of antigens
Studies on Tumor Transplantation,
identification of the MHC
• Inbred mice created by Japanese mouse fanciers
for centuries (early 1900s Loeb and Tyzer)
• Jw carcinoma transplant would grow in Jw mice
but not in common mice
• Thought they were studying immune response to
tumors
• Actually studying immune response to transplant
• Generation of congenic mice genetically identical
at all loci except for one thought to be important in
transplantation (Snell, Amos 1950s)
• Major histocompatibility complex MHC (H-2 in
mice HLA in humans a locus of tightly linked
genes (Benacerraf; Dausset;Snell Nobel Prize
1980)
MHC class II molecules present antigen originating in
intracellular vesicles
CD4+ TH1 and helper T cells (TH2) recognize
antigen presented by MHC class II molecules.
Figure 1-26
Figure 1-24 part 1 of 3
MHC class I molecules present antigen derived from
proteins in the cytosol
CD8+ Cytotoxic T cells recognize antigen presented
by MHC class I molecules and kill the cell.
Figure 1-25
Two signals are required for lymphocyte activation
The second signal is the innate immune response alerting
adaptive immune response to “danger”/infection
Adaptive immune response
• Selection (purge the repertoire of self reactivity;
ensure coopertivity)
• Expansion (clonal selection; receptor engagement
promotes proliferation)
• Peripheral tolerance mechanisms ensure no autoreactivity (active processes for antigen specific
activation and antigen specific tolerance
induction)
• Differentiation into effectors suited for response
• Contraction (induce apoptosis, self limitation)
• Development into memory response
• Maintenance of memory without cross reactivity
to self
Figure 1-33