Chapter 24
Immune diversity
24.1 Introduction
24.2 Clonal selection amplifies lymphocytes that respond to individual antigens
24.3 Immunoglobulin genes are assembled from their parts in lymphocytes
24.4 Light chains are assembled by a single recombination
24.5 Heavy chains are assembled by two recombinations
24.6 Recombination generates extensive diversity
24.7 Avian immunoglobulins are assembled from pseudogenes
24.8 Immune recombination uses two types of consensus sequence
24.9 Recombination generates deletions or inversions
24.10 The RAG proteins catalyze breakage and reunion
24.11 Allelic exclusion is triggered by productive rearrangement
24.12 DNA recombination causes class switching
24.13 Early heavy chain expression can be changed by RNA processing
24.14 Somatic mutation generates additional diversity
24.15 B cell development and memory
24.16 T-cell receptors are related to immunoglobulins
24.17 The major histocompatibility locus codes for many genes of the immune system
Antigen is any molecule whose entry into an organism
provokes synthesis of an antibody (immunoglobulin).
Superfamily is a set of genes all related by presumed
descent from a common ancestor,but now showing
considerable variation.
T cells are lymphocytes of the T (thymic) lineage;
may be subdivided into several functional types,They
carry TcR (T-cell receptor) and are involved in the
cell-mediated immune response.
24.1 Introduction
Figure 24.1 Humoral
immunity is conferred by the
binding of free antibodies to
antigens to form antigen-
antibody complexes that are
removed from the
bloodstream by macrophages
or that are attacked directly by
the complement proteins.
24.1 Introduction
Figure 24.2 In cell-mediated
immunity,killer T cells use
the T-cell receptor to
recognize a fragment of the
foreign antigen which is
presented on the surface of the
target cell by the MHC protein.
24.1 Introduction
Hapten is a small molecule
that acts as an antigen when
conjugated to a protein.
24.2 Clonal selection amplifies lymphocytes
that respond to individual antigens
Figure 24.3 The pool of immature
lymphocytes contains B cells and T
cells making antibodies and receptors
with a variety of specificities,
Reaction with an antigen leads to
clonal expansion of the lymphocyte
with the antibody (B cell) or receptor
(T cell) that can recognize the antigen.
24.2 Clonal selection amplifies
lymphocytes that respond to
individual antigens
C genes code for the constant regions
of immunoglobulin protein chains.
V gene is sequence coding for the
major part of the variable (N-terminal)
region of an immunoglobulin chain.
24.3 Immunoglobulin genes are assembled
from their parts in lymphocytes
Figure 24.4 Heavy
and light chains
combine to generate
an immunoglobulin
with several discrete
domains.
24.3
Immunoglobulin
genes are assembled
from their parts in
lymphocytes
Figure 24.4 Heavy
and light chains
combine to generate
an immunoglobulin
with several discrete
domains.
24.3
Immunoglobulin
genes are assembled
from their parts in
lymphocytes
Table 24.1 Each immunoglobulin family consists
of a cluster of V genes linked to its C gene(s).
24.3 Immunoglobulin genes are assembled
from their parts in lymphocytes
Family V Genes C GenesMan Mouse Man Mouse
Lambda <300 2 >6 4
Kappa <300 ~1000 1 1
Heavy ~300 >1000 9 8
Figure 24.5 The
lambda C gene
segment is preceded
by a J segment,so that
V-J recombination
generates a functional
lambda light-chain
gene.
24.3 Immunoglobulin
genes are assembled
from their parts in
lymphocytes
Figure 24.6 The
kappa C gene
segment is
preceded by
multiple J
segments in the
germ line,V-J
joining may
recognize any one
of the J segments,
which is then
spliced to the C
gene segment
during RNA
processing.
24.3 Immunoglobulin genes are assembled
from their parts in lymphocytes
Figure 24.7
Heavy genes
are assembled
by sequential
joining
reactions,
First a D
segment is
joined to a J
segment; then
a V gene
segment is
joined to the
D segment.
24.3 Immunoglobulin genes are assembled
from their parts in lymphocytes
Figure 24.8 The lambda family consists
of V gene segments linked to a small
number of J-C gene segments.
24.4 The diversity of
germline information
Figure 24.9 The human and mouse kappa families
consist of V gene segments linked to 5 J segments
connected to a single C gene segment.
24.4 The diversity of
germline information
Figure 24.10 A single gene cluster in man contains
all the information for heavy-chain gene assembly.
24.4 The diversity of
germline information
Figure 24.11
The chicken
lambda light
locus has 25 V
pseudogenes
upstream of the
single functional
V-J-C region,
But sequences
derived from the
pseudogenes are
found in active
rearranged V-J-
C genes.
24.4 The diversity of germline information
Figure 24.12 Consensus sequences are present in inverted orientation
at each pair of recombining sites,One member of each pair has a
spacing of 12 bp between its components; the other has 23 bp spacing.
24.5 Recombination between V and C gene segments
generates deletions and rearrangements
Figure 24.13 Breakage
and reunion at consensus
sequences generates
immunoglobulin genes.
24.5 Recombination between
V and C gene segments
generates deletions and
rearrangements
Figure 24.14
Processing of
coding ends
introduces
variability at
the junction.
24.5 Recombination between V and C gene segments
generates deletions and rearrangements
Figure 15.8 Reciprocal
recombination between
direct repeats excises the
material between them;
each product of
recombination has one
copy of the direct repeat.
24.5 Recombination
between V and C gene
segments generates
deletions and
rearrangements
Figure 15.9 Reciprocal
recombination between
inverted repeats inverts
the region between them.
24.5 Recombination
between V and C
gene segments
generates deletions
and rearrangements
Figure 24.15 A V gene
promoter is inactive until
recombination brings it
into the proximity of an
enhancer in the C gene
segment,The enhancer is
active only in B
lymphocytes.
24.5 Recombination between V and C gene
segments generates deletions and rearrangements
Allelic exclusion describes the
expression in any particular
lymphocyte of only one allele
coding for the expressed
immunoglobulin.
24.6 Allelic exclusion is triggered by
productive rearrangement
Figure 24.16 A successful
rearrangement to produce
an active light or heavy
chain suppresses further
rearrangements of the
same type,and results in
allelic exclusion.
24.6 Allelic exclusion
is triggered by
productive
rearrangement
Class switching is a change in the
expression of the C region of an
immunoglobulin heavy chain
during lymphocyte differentiation.
24.7 DNA recombination causes class switching
Figure 24.17 Immunoglobulin type and function is
determined by the heavy chain,J is a joining protein
in IgM; all other Ig types exist as tetramers.
24.7 DNA recombination causes class switching
Figure 24.10 A single gene cluster in man contains
all the information for heavy-chain gene assembly.
24.7 DNA recombination causes class switching
Figure 24.18 Class
switching of heavy
genes may occur by
recombination between
switch regions (S),
deleting the material
between the
recombining S sites,
Successive switches
may occur.
24.7 DNA recombination causes class switching
Figure 24.1 Humoral immunity
is conferred by the binding of
free antibodies to antigens to
form antigen-antibody
complexes that are removed
from the bloodstream by
macrophages or that are
attacked directly by the
complement proteins.
24.7 DNA recombination causes class switching
Figure 24.19 The 3 end
controls the use of splicing
junctions so that alternative
forms of the heavy gene are
expressed.
24.7 DNA recombination causes class switching
Hybridoma is a cell line produced by fusing a
myeloma with a lymphocyte; it continues
indefinitely to express the immunoglobulins of
both parents.
Somatic mutation is a mutation occurring in a
somatic cell,and therefore affecting only its
daughter cells; it is not inherited by descendants
of the organism.
24.8 Somatic mutation generates
additional diversity
Figure 24.20 B cell differentiation is
responsible for acquired immunity,
Pre-B cells are converted to B cells
by Ig gene rearrangement,Initial
exposure to antigen provokes both
the primary response and storage of
memory cells,Subsequent exposure
to antigen provokes the secondary
response of the memory cells.
24.9 B cell development
and memory
Figure 24.21 B
cell
development
proceeds
through
sequential stages.
24.9 B cell development
and memory
Figure 24.16 A
successful
rearrangement to
produce an active light
or heavy chain
suppresses further
rearrangements of the
same type,and results
in allelic exclusion.
24.9 B cell development and memory
Figure 24.22 The B cell
antigen receptor
consists of an
immunoglobulin
tetramer (H2L2) linked
to two copies of the
signal-transducing
heterodimer (Igab).
24.9 B cell development and memory
Figure 24.23 The gd receptor
is synthesized early in T-cell
development,TCR ab is
synthesized later and is
responsible for "classical" cell-
mediated immunity,in which
target antigen and host
histocompatibility antigen are
recognized together.
24.10 T-cell receptors are related to
immunoglobulins
Figure 24.2 In cell-mediated
immunity,killer T cells use
the T-cell receptor to
recognize a fragment of the
foreign antigen which is
presented on the surface of
the target cell by the MHC
protein.
24.10 T-cell
receptors are related
to immunoglobulins
Figure 24.24 The human TCRa locus has interspersed a and d segments,A Vd segment
is located within the Va cluster,The D-J-Cd segments lie between the V gene segments
and the J-Ca segments,The mouse locus is similar,but has more Vd segments.
24.10 T-cell receptors are
related to immunoglobulins
Figure 24.25 The TCRb locus contains many V gene segments spread
over ~500 kb,and lying ~280 kb upstream of the two D-J-C clusters.
24.10 T-cell receptors are
related to immunoglobulins
Figure 24.14
Processing of
coding ends
introduces
variability at
the junction.
24.10 T-cell
receptors are
related to
immunoglobulins
Figure 24.13 Breakage
and reunion at consensus
sequences generates
immunoglobulin genes.
24.10 T-cell receptors
are related to
immunoglobulins
Figure 24.26 The TCRg locus contains a small number of
functional V gene segments (and also some pseudogenes;
not shown),lying upstream of the J-C loci.
24.10 T-
cell
receptors
are
related
to
immuno
globulins
Figure 24.27 T cell
development proceeds
through sequential stages.
24.10 T-cell receptors are
related to immunoglobulins
Figure 24.28 The two chains
of the T-cell receptor
associate with the
polypeptides of the CD3
complex,The variable
regions of the TCR are
exposed on the cell surface,
The cytoplasmic domains of
the z chains of CD3 provide
the effector function.
24.10 T-cell receptors are related
to immunoglobulins
Figure 24.22 The B cell
antigen receptor consists
of an immunoglobulin
tetramer (H2L2) linked to
two copies of the signal-
transducing heterodimer
(Igab).
24.10 T-cell
receptors are
related to
immunoglobulins
Transplantation antigen is protein
coded by a major histocompatibility
locus,present on all mammalian cells,
involved in interactions between
lymphocytes.
24.11 The major histocompatibility locus codes
for many genes of the immune system
Figure 24.29 The histocompatibility locus of the mouse
contains several loci that were originally defined genetically,
Each locus contains many genes,Spaces between clusters
that have not been connected are indicated by queries.
24.11 The major histocompatibility locus codes
for many genes of the immune system
Figure 24.30 The human major histocompatibility locus
codes for similar functions to the murine locus,although its
detailed organization is different,Genes concerned with
nonimmune functions also have been located in this region.
24.11 The major histocompatibility locus codes
for many genes of the immune system
Figure 24.31 Class I and class II
histocompatibility antigens have a
related structure,Class I antigens
consist of a single (a) polypeptide,
with three external domains (a1,a2,
a3),that interacts with b2
microglobulin (b2 m),Class II
antigens consist of two (a and b)
polypeptides,each with two
domains (a1 & a2,b1 & b2) with a
similar overall structure.
24.11 The major histocompatibility locus codes
for many genes of the immune system
Figure 24.32
Each class of
MHC genes
has a
characteristic
organization,in
which exons
represent
individual
protein
domains
24.11 The major histocompatibility locus codes
for many genes of the immune system
Immunoglobulins and T-cell receptors are proteins that
play analogous functions in the roles of B cells and T
cells in the immune system,
Each immunoglobulin protein is a tetramer containing
two identical light chains and two identical heavy chains,
Each type of chain is coded by a large cluster of V genes
separated from the cluster of D,J,and C segments.
Allelic exclusion ensures that a given lymphocyte
synthesizes only a single Ig or TCR.
24.12 Summary
Immune diversity
24.1 Introduction
24.2 Clonal selection amplifies lymphocytes that respond to individual antigens
24.3 Immunoglobulin genes are assembled from their parts in lymphocytes
24.4 Light chains are assembled by a single recombination
24.5 Heavy chains are assembled by two recombinations
24.6 Recombination generates extensive diversity
24.7 Avian immunoglobulins are assembled from pseudogenes
24.8 Immune recombination uses two types of consensus sequence
24.9 Recombination generates deletions or inversions
24.10 The RAG proteins catalyze breakage and reunion
24.11 Allelic exclusion is triggered by productive rearrangement
24.12 DNA recombination causes class switching
24.13 Early heavy chain expression can be changed by RNA processing
24.14 Somatic mutation generates additional diversity
24.15 B cell development and memory
24.16 T-cell receptors are related to immunoglobulins
24.17 The major histocompatibility locus codes for many genes of the immune system
Antigen is any molecule whose entry into an organism
provokes synthesis of an antibody (immunoglobulin).
Superfamily is a set of genes all related by presumed
descent from a common ancestor,but now showing
considerable variation.
T cells are lymphocytes of the T (thymic) lineage;
may be subdivided into several functional types,They
carry TcR (T-cell receptor) and are involved in the
cell-mediated immune response.
24.1 Introduction
Figure 24.1 Humoral
immunity is conferred by the
binding of free antibodies to
antigens to form antigen-
antibody complexes that are
removed from the
bloodstream by macrophages
or that are attacked directly by
the complement proteins.
24.1 Introduction
Figure 24.2 In cell-mediated
immunity,killer T cells use
the T-cell receptor to
recognize a fragment of the
foreign antigen which is
presented on the surface of the
target cell by the MHC protein.
24.1 Introduction
Hapten is a small molecule
that acts as an antigen when
conjugated to a protein.
24.2 Clonal selection amplifies lymphocytes
that respond to individual antigens
Figure 24.3 The pool of immature
lymphocytes contains B cells and T
cells making antibodies and receptors
with a variety of specificities,
Reaction with an antigen leads to
clonal expansion of the lymphocyte
with the antibody (B cell) or receptor
(T cell) that can recognize the antigen.
24.2 Clonal selection amplifies
lymphocytes that respond to
individual antigens
C genes code for the constant regions
of immunoglobulin protein chains.
V gene is sequence coding for the
major part of the variable (N-terminal)
region of an immunoglobulin chain.
24.3 Immunoglobulin genes are assembled
from their parts in lymphocytes
Figure 24.4 Heavy
and light chains
combine to generate
an immunoglobulin
with several discrete
domains.
24.3
Immunoglobulin
genes are assembled
from their parts in
lymphocytes
Figure 24.4 Heavy
and light chains
combine to generate
an immunoglobulin
with several discrete
domains.
24.3
Immunoglobulin
genes are assembled
from their parts in
lymphocytes
Table 24.1 Each immunoglobulin family consists
of a cluster of V genes linked to its C gene(s).
24.3 Immunoglobulin genes are assembled
from their parts in lymphocytes
Family V Genes C GenesMan Mouse Man Mouse
Lambda <300 2 >6 4
Kappa <300 ~1000 1 1
Heavy ~300 >1000 9 8
Figure 24.5 The
lambda C gene
segment is preceded
by a J segment,so that
V-J recombination
generates a functional
lambda light-chain
gene.
24.3 Immunoglobulin
genes are assembled
from their parts in
lymphocytes
Figure 24.6 The
kappa C gene
segment is
preceded by
multiple J
segments in the
germ line,V-J
joining may
recognize any one
of the J segments,
which is then
spliced to the C
gene segment
during RNA
processing.
24.3 Immunoglobulin genes are assembled
from their parts in lymphocytes
Figure 24.7
Heavy genes
are assembled
by sequential
joining
reactions,
First a D
segment is
joined to a J
segment; then
a V gene
segment is
joined to the
D segment.
24.3 Immunoglobulin genes are assembled
from their parts in lymphocytes
Figure 24.8 The lambda family consists
of V gene segments linked to a small
number of J-C gene segments.
24.4 The diversity of
germline information
Figure 24.9 The human and mouse kappa families
consist of V gene segments linked to 5 J segments
connected to a single C gene segment.
24.4 The diversity of
germline information
Figure 24.10 A single gene cluster in man contains
all the information for heavy-chain gene assembly.
24.4 The diversity of
germline information
Figure 24.11
The chicken
lambda light
locus has 25 V
pseudogenes
upstream of the
single functional
V-J-C region,
But sequences
derived from the
pseudogenes are
found in active
rearranged V-J-
C genes.
24.4 The diversity of germline information
Figure 24.12 Consensus sequences are present in inverted orientation
at each pair of recombining sites,One member of each pair has a
spacing of 12 bp between its components; the other has 23 bp spacing.
24.5 Recombination between V and C gene segments
generates deletions and rearrangements
Figure 24.13 Breakage
and reunion at consensus
sequences generates
immunoglobulin genes.
24.5 Recombination between
V and C gene segments
generates deletions and
rearrangements
Figure 24.14
Processing of
coding ends
introduces
variability at
the junction.
24.5 Recombination between V and C gene segments
generates deletions and rearrangements
Figure 15.8 Reciprocal
recombination between
direct repeats excises the
material between them;
each product of
recombination has one
copy of the direct repeat.
24.5 Recombination
between V and C gene
segments generates
deletions and
rearrangements
Figure 15.9 Reciprocal
recombination between
inverted repeats inverts
the region between them.
24.5 Recombination
between V and C
gene segments
generates deletions
and rearrangements
Figure 24.15 A V gene
promoter is inactive until
recombination brings it
into the proximity of an
enhancer in the C gene
segment,The enhancer is
active only in B
lymphocytes.
24.5 Recombination between V and C gene
segments generates deletions and rearrangements
Allelic exclusion describes the
expression in any particular
lymphocyte of only one allele
coding for the expressed
immunoglobulin.
24.6 Allelic exclusion is triggered by
productive rearrangement
Figure 24.16 A successful
rearrangement to produce
an active light or heavy
chain suppresses further
rearrangements of the
same type,and results in
allelic exclusion.
24.6 Allelic exclusion
is triggered by
productive
rearrangement
Class switching is a change in the
expression of the C region of an
immunoglobulin heavy chain
during lymphocyte differentiation.
24.7 DNA recombination causes class switching
Figure 24.17 Immunoglobulin type and function is
determined by the heavy chain,J is a joining protein
in IgM; all other Ig types exist as tetramers.
24.7 DNA recombination causes class switching
Figure 24.10 A single gene cluster in man contains
all the information for heavy-chain gene assembly.
24.7 DNA recombination causes class switching
Figure 24.18 Class
switching of heavy
genes may occur by
recombination between
switch regions (S),
deleting the material
between the
recombining S sites,
Successive switches
may occur.
24.7 DNA recombination causes class switching
Figure 24.1 Humoral immunity
is conferred by the binding of
free antibodies to antigens to
form antigen-antibody
complexes that are removed
from the bloodstream by
macrophages or that are
attacked directly by the
complement proteins.
24.7 DNA recombination causes class switching
Figure 24.19 The 3 end
controls the use of splicing
junctions so that alternative
forms of the heavy gene are
expressed.
24.7 DNA recombination causes class switching
Hybridoma is a cell line produced by fusing a
myeloma with a lymphocyte; it continues
indefinitely to express the immunoglobulins of
both parents.
Somatic mutation is a mutation occurring in a
somatic cell,and therefore affecting only its
daughter cells; it is not inherited by descendants
of the organism.
24.8 Somatic mutation generates
additional diversity
Figure 24.20 B cell differentiation is
responsible for acquired immunity,
Pre-B cells are converted to B cells
by Ig gene rearrangement,Initial
exposure to antigen provokes both
the primary response and storage of
memory cells,Subsequent exposure
to antigen provokes the secondary
response of the memory cells.
24.9 B cell development
and memory
Figure 24.21 B
cell
development
proceeds
through
sequential stages.
24.9 B cell development
and memory
Figure 24.16 A
successful
rearrangement to
produce an active light
or heavy chain
suppresses further
rearrangements of the
same type,and results
in allelic exclusion.
24.9 B cell development and memory
Figure 24.22 The B cell
antigen receptor
consists of an
immunoglobulin
tetramer (H2L2) linked
to two copies of the
signal-transducing
heterodimer (Igab).
24.9 B cell development and memory
Figure 24.23 The gd receptor
is synthesized early in T-cell
development,TCR ab is
synthesized later and is
responsible for "classical" cell-
mediated immunity,in which
target antigen and host
histocompatibility antigen are
recognized together.
24.10 T-cell receptors are related to
immunoglobulins
Figure 24.2 In cell-mediated
immunity,killer T cells use
the T-cell receptor to
recognize a fragment of the
foreign antigen which is
presented on the surface of
the target cell by the MHC
protein.
24.10 T-cell
receptors are related
to immunoglobulins
Figure 24.24 The human TCRa locus has interspersed a and d segments,A Vd segment
is located within the Va cluster,The D-J-Cd segments lie between the V gene segments
and the J-Ca segments,The mouse locus is similar,but has more Vd segments.
24.10 T-cell receptors are
related to immunoglobulins
Figure 24.25 The TCRb locus contains many V gene segments spread
over ~500 kb,and lying ~280 kb upstream of the two D-J-C clusters.
24.10 T-cell receptors are
related to immunoglobulins
Figure 24.14
Processing of
coding ends
introduces
variability at
the junction.
24.10 T-cell
receptors are
related to
immunoglobulins
Figure 24.13 Breakage
and reunion at consensus
sequences generates
immunoglobulin genes.
24.10 T-cell receptors
are related to
immunoglobulins
Figure 24.26 The TCRg locus contains a small number of
functional V gene segments (and also some pseudogenes;
not shown),lying upstream of the J-C loci.
24.10 T-
cell
receptors
are
related
to
immuno
globulins
Figure 24.27 T cell
development proceeds
through sequential stages.
24.10 T-cell receptors are
related to immunoglobulins
Figure 24.28 The two chains
of the T-cell receptor
associate with the
polypeptides of the CD3
complex,The variable
regions of the TCR are
exposed on the cell surface,
The cytoplasmic domains of
the z chains of CD3 provide
the effector function.
24.10 T-cell receptors are related
to immunoglobulins
Figure 24.22 The B cell
antigen receptor consists
of an immunoglobulin
tetramer (H2L2) linked to
two copies of the signal-
transducing heterodimer
(Igab).
24.10 T-cell
receptors are
related to
immunoglobulins
Transplantation antigen is protein
coded by a major histocompatibility
locus,present on all mammalian cells,
involved in interactions between
lymphocytes.
24.11 The major histocompatibility locus codes
for many genes of the immune system
Figure 24.29 The histocompatibility locus of the mouse
contains several loci that were originally defined genetically,
Each locus contains many genes,Spaces between clusters
that have not been connected are indicated by queries.
24.11 The major histocompatibility locus codes
for many genes of the immune system
Figure 24.30 The human major histocompatibility locus
codes for similar functions to the murine locus,although its
detailed organization is different,Genes concerned with
nonimmune functions also have been located in this region.
24.11 The major histocompatibility locus codes
for many genes of the immune system
Figure 24.31 Class I and class II
histocompatibility antigens have a
related structure,Class I antigens
consist of a single (a) polypeptide,
with three external domains (a1,a2,
a3),that interacts with b2
microglobulin (b2 m),Class II
antigens consist of two (a and b)
polypeptides,each with two
domains (a1 & a2,b1 & b2) with a
similar overall structure.
24.11 The major histocompatibility locus codes
for many genes of the immune system
Figure 24.32
Each class of
MHC genes
has a
characteristic
organization,in
which exons
represent
individual
protein
domains
24.11 The major histocompatibility locus codes
for many genes of the immune system
Immunoglobulins and T-cell receptors are proteins that
play analogous functions in the roles of B cells and T
cells in the immune system,
Each immunoglobulin protein is a tetramer containing
two identical light chains and two identical heavy chains,
Each type of chain is coded by a large cluster of V genes
separated from the cluster of D,J,and C segments.
Allelic exclusion ensures that a given lymphocyte
synthesizes only a single Ig or TCR.
24.12 Summary
