The function of the immune system is to recognize
and to eliminate invading foreign organisms.
The immune response must be fast,
specific, and aimed exclusively against foreign
molecules or cells harboring an infective agent,
but never against its own normal cells. The effector
molecules must be prepared for contact
with a variety of organisms and molecular
structures. With these requirements, an extremely
efficient, genetically complex immune
system has evolved. Its development and function
are regulated by genes of extraordinary diversity.
Sunday, April 12, 2009
Lymphatic organs
The immune system consists of peripheral
blood lymphocytes and of the lymphatic organs
(lymphoid tissue). The primary lymphoid tissues
are the thymus and bone marrow. Secondary
lymphoid tissues are the lymph nodes in
various regions of the body, especially the nasopharynx,
axillae, groins, and intestines. The
spleen is considered a secondary lymphatic
organ.
blood lymphocytes and of the lymphatic organs
(lymphoid tissue). The primary lymphoid tissues
are the thymus and bone marrow. Secondary
lymphoid tissues are the lymph nodes in
various regions of the body, especially the nasopharynx,
axillae, groins, and intestines. The
spleen is considered a secondary lymphatic
organ.
Lymphocytes and the immune response
Lymphocytes carry the immune response. This
was shown by the following experiment. The
normal immune response of a mouse to an administered
antigen (foreign organism, foreign
molecular structure) was destroyed by a high
dose of X-irradiation, to which the immune system
is especially sensitive. The immune response
was then restored by lymphocytes of a
genetically identical (from an inbred strain)
unirradiated mouse, but not by any other cells.
Other cells are ineffective since only lymphocytes
produce an immune response.
was shown by the following experiment. The
normal immune response of a mouse to an administered
antigen (foreign organism, foreign
molecular structure) was destroyed by a high
dose of X-irradiation, to which the immune system
is especially sensitive. The immune response
was then restored by lymphocytes of a
genetically identical (from an inbred strain)
unirradiated mouse, but not by any other cells.
Other cells are ineffective since only lymphocytes
produce an immune response.
T cells and B cells
Lymphocytes exist as one of two functionally
and morphologically different types, T lymphocytes
and B lymphocytes. T lymphocytes undergo
differentiation in the thymus during
embryonic and fetal development, thus the designation
T lymphocyte or T cell. B lymphocytes
differentiate in the bone marrow in mammals
and in the bursa of Fabricius in birds (thus the
designation B cells). A series of further differentiating
steps take place in the lymph nodes (T
cells) and in the spleen (B cells).
and morphologically different types, T lymphocytes
and B lymphocytes. T lymphocytes undergo
differentiation in the thymus during
embryonic and fetal development, thus the designation
T lymphocyte or T cell. B lymphocytes
differentiate in the bone marrow in mammals
and in the bursa of Fabricius in birds (thus the
designation B cells). A series of further differentiating
steps take place in the lymph nodes (T
cells) and in the spleen (B cells).
Cellular and humoral immune response
During the first phase of the immune response
induced by an antigen (e.g., a bacterium, virus,
fungus, or foreign protein), there is rapid proliferation
of B cells (humoral immune response).
The B cells mature to plasma cells,
which form free antibodies (immunoglobulins)
directed at the antigen. The antibodies bind
specifically to the antigens. The humoral immune
response is rapid, but it does not reach
foreign organisms that have invaded body cells.
They are the target of the cellular immune response.
induced by an antigen (e.g., a bacterium, virus,
fungus, or foreign protein), there is rapid proliferation
of B cells (humoral immune response).
The B cells mature to plasma cells,
which form free antibodies (immunoglobulins)
directed at the antigen. The antibodies bind
specifically to the antigens. The humoral immune
response is rapid, but it does not reach
foreign organisms that have invaded body cells.
They are the target of the cellular immune response.
Antibody molecules (basic structure)
The basic structural motif of an antibody
molecule (immunoglobulin) is a Y-shaped protein
composed of two heavy chains (H chains)
and two light chains (L chains). They are held together
at defined sites by disulfide bonds. L
chains and H chains contain regions with variable
and constant sequences of amino acids.
molecule (immunoglobulin) is a Y-shaped protein
composed of two heavy chains (H chains)
and two light chains (L chains). They are held together
at defined sites by disulfide bonds. L
chains and H chains contain regions with variable
and constant sequences of amino acids.
Antigen–antibody binding
A foreign molecule, the antigen, is recognized
and firmly bound to a specific region of the antibody
molecule, the antigen-binding site. Here,
the amino acid sequence of the antibody
molecule differs from one molecule to the next
in three hypervariable regions. The result is the
ability to bind a wide spectrum of different antigenic
molecules. The three-dimensional
structure of this region is known precisely, and
important details of the binding process are understood.
and firmly bound to a specific region of the antibody
molecule, the antigen-binding site. Here,
the amino acid sequence of the antibody
molecule differs from one molecule to the next
in three hypervariable regions. The result is the
ability to bind a wide spectrum of different antigenic
molecules. The three-dimensional
structure of this region is known precisely, and
important details of the binding process are understood.
Immunoglobulin Molecules
Immunoglobulins are the effector molecules of
the immune system. They occur either as membrane-
bound cell surface receptors or as free
antibodies. The enormous diversity of their
variable regions enables them to bind many
very different antigens. Although they differ in
details of their function, they share a relatively
simple basic pattern, which is derived from a
common ancestral molecule
the immune system. They occur either as membrane-
bound cell surface receptors or as free
antibodies. The enormous diversity of their
variable regions enables them to bind many
very different antigens. Although they differ in
details of their function, they share a relatively
simple basic pattern, which is derived from a
common ancestral molecule
Immunoglobulin G (IgG)
Immunoglobulin G is the prototype of antibody
molecules produced by derivatives of B lymphocytes,
the plasma cells. The molecule has
two H chains and two L chains, held together by
disulfide bonds. Each H chain has three constant
regions (CH1, CH2, and CH3) and one variable
region (VH). Each H chain has a total of 446
amino acids, of which the first 109 belong to the
variable region at the N-terminal end. Each L
chain has one variable (VL) and one constant
(CL) domain and consists of 214 amino acids. In
the L chains also, the first 109 amino acids form
the variable region. The variable domains of the
H chains and the L chains form the antigenbinding
sites. The three hypervariable regions
within the V region of each chain are also called
complementarity determining regions (CDR)
because the actual physical contact of
molecules based on their complementary
structure occurs in these regions. Each domain
consists of about 110 amino acid residues. A
jointlike area (hinge) between constant region 1
(CH1) and constant region 2 (CH2) of the heavy
chain allows some flexibility of the molecule.
The H chains are bound to each other and the H
to the L chains by disulfide bridges (—S—S—).
Furthermore, there are disulfide bridges within
the constant and variable domains. The L chains
are of one of two types, ! or !. In addition to immunoglobulin
G, there are other types of immunoglobulins,
which differ from each other in
the constant part of the H chain: IgA (C"), IgD
(C#), and IgE (C$). A very large immunoglobulin,
IgM, is made up of five IgG subunits. The different
types of H chains are referred to as isotypes.
molecules produced by derivatives of B lymphocytes,
the plasma cells. The molecule has
two H chains and two L chains, held together by
disulfide bonds. Each H chain has three constant
regions (CH1, CH2, and CH3) and one variable
region (VH). Each H chain has a total of 446
amino acids, of which the first 109 belong to the
variable region at the N-terminal end. Each L
chain has one variable (VL) and one constant
(CL) domain and consists of 214 amino acids. In
the L chains also, the first 109 amino acids form
the variable region. The variable domains of the
H chains and the L chains form the antigenbinding
sites. The three hypervariable regions
within the V region of each chain are also called
complementarity determining regions (CDR)
because the actual physical contact of
molecules based on their complementary
structure occurs in these regions. Each domain
consists of about 110 amino acid residues. A
jointlike area (hinge) between constant region 1
(CH1) and constant region 2 (CH2) of the heavy
chain allows some flexibility of the molecule.
The H chains are bound to each other and the H
to the L chains by disulfide bridges (—S—S—).
Furthermore, there are disulfide bridges within
the constant and variable domains. The L chains
are of one of two types, ! or !. In addition to immunoglobulin
G, there are other types of immunoglobulins,
which differ from each other in
the constant part of the H chain: IgA (C"), IgD
(C#), and IgE (C$). A very large immunoglobulin,
IgM, is made up of five IgG subunits. The different
types of H chains are referred to as isotypes.
T-cell receptor (TCR)
Antigen receptors on the surfaces of T cells are
heterodimers of covalently bound polypeptide
chains, one " and one % chain. The basic structure
of a cell surface antigen receptor is similar
to that of the secreted immunoglobulins except
that the cell surface receptors contain just one
constant region. The % chain is the slightly
larger chain. The constant regions of the " and %
chains (C) each consist of 140–180 amino acids.
The variable regions (V) consist of 102–109
amino acids and contain three hypervariable regions,
like the immunoglobulin molecules. In
addition to those for " and %, genes for a T-cellreceptor
& and # chain exist. The loci for the
TCR", &, and # chains in man lie together on
chromosome 14; the locus for TCR% lies on
chromosome 13.
heterodimers of covalently bound polypeptide
chains, one " and one % chain. The basic structure
of a cell surface antigen receptor is similar
to that of the secreted immunoglobulins except
that the cell surface receptors contain just one
constant region. The % chain is the slightly
larger chain. The constant regions of the " and %
chains (C) each consist of 140–180 amino acids.
The variable regions (V) consist of 102–109
amino acids and contain three hypervariable regions,
like the immunoglobulin molecules. In
addition to those for " and %, genes for a T-cellreceptor
& and # chain exist. The loci for the
TCR", &, and # chains in man lie together on
chromosome 14; the locus for TCR% lies on
chromosome 13.
The different domains of an immunoglobulin molecule are encoded by different genes
Each immunoglobulin and receptor molecule is
encoded by different DNA sequences, which
belong to a large series of genes for the L chains
(types ! and !) and the H chain. Genes for the H
chain are located on chromosome 14q32 in
humans and chromosome 14 inmice. The genes
for the ! light chain are located on the short arm
of chromosome 2 (2p12) in humans and chromosome
6 in mice, and for the ! light chain on
the long arm of chromosome 22 (22q11) in
humans and on chromosome 16 in mice. The
genes are rearranged in the developing B and T
cells in a pattern that is different and specific in
each cell, as seen in the next plate.
encoded by different DNA sequences, which
belong to a large series of genes for the L chains
(types ! and !) and the H chain. Genes for the H
chain are located on chromosome 14q32 in
humans and chromosome 14 inmice. The genes
for the ! light chain are located on the short arm
of chromosome 2 (2p12) in humans and chromosome
6 in mice, and for the ! light chain on
the long arm of chromosome 22 (22q11) in
humans and on chromosome 16 in mice. The
genes are rearranged in the developing B and T
cells in a pattern that is different and specific in
each cell, as seen in the next plate.
Genetic Diversity Generated by Somatic Recombination
If each of the many different immunoglobulin
molecules with their variable regions were
coded for by separate genes, many millions of
genes would be required. This is not the case.
Rather, during lymphocyte differentiation, a
practically unlimited number of different cells
are produced by recombination of a large but
limited number of genes. This occurs by somatic
recombination of genes during the differentiation
of B cells and T cells. Antibody diversity
arises by the following genetic mechanisms:
(1) multiple DNA sequences of the germline
genes for H and L chains code for Ig
molecules with different specificities; (2) somatic
recombination of the various DNA segments
greatly increases the number of possible
combinations; (3) somatic mutations occur in
the hypervariable regions, leading to further
genetic differences.
molecules with their variable regions were
coded for by separate genes, many millions of
genes would be required. This is not the case.
Rather, during lymphocyte differentiation, a
practically unlimited number of different cells
are produced by recombination of a large but
limited number of genes. This occurs by somatic
recombination of genes during the differentiation
of B cells and T cells. Antibody diversity
arises by the following genetic mechanisms:
(1) multiple DNA sequences of the germline
genes for H and L chains code for Ig
molecules with different specificities; (2) somatic
recombination of the various DNA segments
greatly increases the number of possible
combinations; (3) somatic mutations occur in
the hypervariable regions, leading to further
genetic differences.
Somatic recombination during the formation of lymphocytes
Somatic recombination occurs within the genes
for the L and theHchains during the maturation
of B cells and within the genes for the four T-cell
receptor chains in the maturing T cells. By
means of this process, different coding DNA
sequences (exons) of the various domains of the
particular Ig molecule are in unique combinations
in each cell. This provides each molecule
with an antigen-binding specificity that differs
from that of all other cells. Here, an example of
the genetic processes during formation of an
immunoglobulin H chain is shown. The exons
(V1 to Vn) of the variable region (V) lie at the 5!
end of the IgH locus. They are separated from
each other by different lengths of noncoding
DNA. A small exon (60–90 bp) that codes for a
signal to initiate translation (leader or signal
peptide L) lies more than 90 base pairs (bp) in
the 5! direction of the V-region exons. Signal
peptides guide the growing polypeptide into
the lumen of the endoplasmic reticulum before
they are cleaved off. The D genes of the constant
region (C) lie at different distances in the 3!
direction fromthe V genes. Each C segment consists
of different exons, corresponding to the
domains of the complete C region and different
isotypes (Cμ, C!), etc.
for the L and theHchains during the maturation
of B cells and within the genes for the four T-cell
receptor chains in the maturing T cells. By
means of this process, different coding DNA
sequences (exons) of the various domains of the
particular Ig molecule are in unique combinations
in each cell. This provides each molecule
with an antigen-binding specificity that differs
from that of all other cells. Here, an example of
the genetic processes during formation of an
immunoglobulin H chain is shown. The exons
(V1 to Vn) of the variable region (V) lie at the 5!
end of the IgH locus. They are separated from
each other by different lengths of noncoding
DNA. A small exon (60–90 bp) that codes for a
signal to initiate translation (leader or signal
peptide L) lies more than 90 base pairs (bp) in
the 5! direction of the V-region exons. Signal
peptides guide the growing polypeptide into
the lumen of the endoplasmic reticulum before
they are cleaved off. The D genes of the constant
region (C) lie at different distances in the 3!
direction fromthe V genes. Each C segment consists
of different exons, corresponding to the
domains of the complete C region and different
isotypes (Cμ, C!), etc.
gene segment
First, a D gene segment and a J segment are
joined (D–J joining). Next, this D–J segment is
joined to one of the V segments (V–D–J joining).
The combination of V, D, and J segments is
different in each cell, with at least 25000 different
possible combinations due to the number of
different segments present (100–125 V segments,
12D segments, and 4 J segments). The
joined VDJ segments form the primary RNA
transcript. At this stage, noncoding segments
(introns) are still present. In the example
shown, a D2 is joined to a J1, but not to J2–4.
J segments not directly connected to a D segment
(here, J2–4) are removed. After the RNA is
processed by splicing, the mature messenger
RNA (mRNA) is formed as template for the
translation of an H chain polypeptide. By
further processing, such as removal of the
leader segment (L) and glycosylation of the protein
at certain sites, the definitive H chain is finally
produced (of type μ in the example
shown). Unlike the H chains, the L chains have
no diversity (D) genes, so that a J and a V gene
are directly joined by somatic recombination
during DNA rearrangement in the lymphocytes.
Thus, rearrangement of the genes for the H
chain and two types of L chains in the lymphocyte
DNA leads to a new combination of genes
in each cell.
joined (D–J joining). Next, this D–J segment is
joined to one of the V segments (V–D–J joining).
The combination of V, D, and J segments is
different in each cell, with at least 25000 different
possible combinations due to the number of
different segments present (100–125 V segments,
12D segments, and 4 J segments). The
joined VDJ segments form the primary RNA
transcript. At this stage, noncoding segments
(introns) are still present. In the example
shown, a D2 is joined to a J1, but not to J2–4.
J segments not directly connected to a D segment
(here, J2–4) are removed. After the RNA is
processed by splicing, the mature messenger
RNA (mRNA) is formed as template for the
translation of an H chain polypeptide. By
further processing, such as removal of the
leader segment (L) and glycosylation of the protein
at certain sites, the definitive H chain is finally
produced (of type μ in the example
shown). Unlike the H chains, the L chains have
no diversity (D) genes, so that a J and a V gene
are directly joined by somatic recombination
during DNA rearrangement in the lymphocytes.
Thus, rearrangement of the genes for the H
chain and two types of L chains in the lymphocyte
DNA leads to a new combination of genes
in each cell.
Mechanisms in Immunoglobulin Gene Rearrangement
The rearrangement of genes for immunoglobulin
molecules in immature B cells and for
the T cell receptor in immature T cells involves
an excision mechanism. This requires precise
recognition to ensure formation of the correct
coding information. Noncoding DNA between
genes for different regions of the molecule is excised
and the remaining DNA is subsequently
rejoined (ligation). Unlike recombination
during meiosis, IgG rearrangements represent a
special type of recombination, since nonhomologous
DNA sequences are recombined.
molecules in immature B cells and for
the T cell receptor in immature T cells involves
an excision mechanism. This requires precise
recognition to ensure formation of the correct
coding information. Noncoding DNA between
genes for different regions of the molecule is excised
and the remaining DNA is subsequently
rejoined (ligation). Unlike recombination
during meiosis, IgG rearrangements represent a
special type of recombination, since nonhomologous
DNA sequences are recombined.
DNA recognition sequences for recombination
Recombination between the DNA segments
coding for an immunoglobulin molecule is mediated
by a system of enzymes called recombinases.
Their activities are varied and comprise
lymphocyte-specific and more general activities
including exonuclease and ligase functions.
The enzymes are controlled by specific DNA
recognition sequences. These are located in adjacent
noncoding DNA segments at the 3! end of
each V exon (exons for the variable region) and
at the 5! end of each J segment. The D segments
are flanked on both sides by recognition
sequences. Recognition sequences are noncoding
but highly conserved DNA segments of
seven base pairs (heptamer) or nine base pairs
(nonamer). They are separated by precisely defined
intervals, produced by spacers of 23 or 12
base pairs (bp). Upstream (5! direction) and
downstream (3! direction) from a D segment,
the spacers are 12 base pairs long.
coding for an immunoglobulin molecule is mediated
by a system of enzymes called recombinases.
Their activities are varied and comprise
lymphocyte-specific and more general activities
including exonuclease and ligase functions.
The enzymes are controlled by specific DNA
recognition sequences. These are located in adjacent
noncoding DNA segments at the 3! end of
each V exon (exons for the variable region) and
at the 5! end of each J segment. The D segments
are flanked on both sides by recognition
sequences. Recognition sequences are noncoding
but highly conserved DNA segments of
seven base pairs (heptamer) or nine base pairs
(nonamer). They are separated by precisely defined
intervals, produced by spacers of 23 or 12
base pairs (bp). Upstream (5! direction) and
downstream (3! direction) from a D segment,
the spacers are 12 base pairs long.
nucleotide base pairs
The
sequences of the nucleotide base pairs of the
spacers are not conserved. The characteristic
rearrangement between neighboring signal
sequences for Ig molecules and TCR receptors
requires spacers of different lengths, i.e., 12 and
23 base pairs (so-called 12/23 rule). When an H
chain is formed, nonhomologous pairing of the
heptamer of a D segment and of a J segment occurs.
These D and J segments are then joined
(D–J joining) by means of recombination: the
spacer of 12 or 23 base pairs and all of the intervening
DNA forms a loop. This is excised, and
the D and J segments are joined. By pairing and
recombination of the recognition sequences at
the 5! end of a DJ segment and the recognition
sequence at the 3! end of a V gene, a V segment
is joined to the DJ segment. The recombination
of genes coding for T-cell receptors (see p. 308)
proceeds in a similar manner. Two genes, recombination-
activating genes 1 and 2 (RAG-1
and RAG-2) have been identified as stimulating
Ig gene recombination in pre-B cells and immature
T cells. Mutations in these genes cause
severe combined immune deficiency
sequences of the nucleotide base pairs of the
spacers are not conserved. The characteristic
rearrangement between neighboring signal
sequences for Ig molecules and TCR receptors
requires spacers of different lengths, i.e., 12 and
23 base pairs (so-called 12/23 rule). When an H
chain is formed, nonhomologous pairing of the
heptamer of a D segment and of a J segment occurs.
These D and J segments are then joined
(D–J joining) by means of recombination: the
spacer of 12 or 23 base pairs and all of the intervening
DNA forms a loop. This is excised, and
the D and J segments are joined. By pairing and
recombination of the recognition sequences at
the 5! end of a DJ segment and the recognition
sequence at the 3! end of a V gene, a V segment
is joined to the DJ segment. The recombination
of genes coding for T-cell receptors (see p. 308)
proceeds in a similar manner. Two genes, recombination-
activating genes 1 and 2 (RAG-1
and RAG-2) have been identified as stimulating
Ig gene recombination in pre-B cells and immature
T cells. Mutations in these genes cause
severe combined immune deficiency
Genetic diversity in immunoglobulin and T-cell receptor genes
The total diversity, a bout 1018 possible combinations
for all types of genes for immunoglobulins
and T-cell receptors, is the result of
different mechanisms. To begin with, different
numbers of variable DNA segments are available
for different chains (250–1000 for the H
chain, 250 for the L chains, 75 for the ! chain of
the T-cell receptor TCR!, etc.). The different D
and J segments also multiply the number of
possible combinations. Finally, DNA sequence
changes (somatic mutations) occur regularly in
the hypervariable regions, further increasing
the total number of possible combinations.
for all types of genes for immunoglobulins
and T-cell receptors, is the result of
different mechanisms. To begin with, different
numbers of variable DNA segments are available
for different chains (250–1000 for the H
chain, 250 for the L chains, 75 for the ! chain of
the T-cell receptor TCR!, etc.). The different D
and J segments also multiply the number of
possible combinations. Finally, DNA sequence
changes (somatic mutations) occur regularly in
the hypervariable regions, further increasing
the total number of possible combinations.
Genes of the MHC Region
The MHC (major histocompatability complex)
region is a region of highly polymorphic genes
(about 10–50 alleles per locus). It spans about
3500 kb on the short arm of chromosome 6 in
humans and on chromosome 17 inmice. Collectively,
these genes are called immune response
(Ir) genes. They are expressed on the surface of
various cells. Their products can be demonstrated
serologically or by cellular reactions in a
mixed lymphocyte test. MHC genes control the
immune response to antigen proteins by
specific binding to T cells.
region is a region of highly polymorphic genes
(about 10–50 alleles per locus). It spans about
3500 kb on the short arm of chromosome 6 in
humans and on chromosome 17 inmice. Collectively,
these genes are called immune response
(Ir) genes. They are expressed on the surface of
various cells. Their products can be demonstrated
serologically or by cellular reactions in a
mixed lymphocyte test. MHC genes control the
immune response to antigen proteins by
specific binding to T cells.
Basic structure of the MHC gene complex in humans and in mice
The gene loci of the MHC region are grouped
into three classes (I–III). Class I in humans includes
HLA-A, HLA-B, and HLA-C; in mice, D, L,
and K of the H2 system. Many other loci also
belong to this class, such as HLA-E to -J. Class II
includes HLA-DP, -DQ, and -DR in humans and
I-A, and I-E (the letter I, not the Roman
numeral) in mice. Alleles are designated according
to a numerical system, e.g., HLA-A2,
-B5, -DR4, etc. The gene products of the alleles
of the HLA system (human leukocyte antigens;
also said by some to refer to Los Angeles, where
some of the first basic discoveries were made)
can be demonstrated by the toxicity of serum of
defined specificities to other leukocytes (serological
cytotoxicity). Cytolysis occurs unless the
specificities of the serum and of the cells being
tested are identical. The gene products of the alleles
of the HLA-D system are distinguished by
the mixed lymphocyte test, based on lymphocyte
proliferation as a reaction to foreign T cells.
Strictly speaking, the class III genes do not
belong to the MHC loci. They contain genes for
different complement proteins and a few other
genes.
into three classes (I–III). Class I in humans includes
HLA-A, HLA-B, and HLA-C; in mice, D, L,
and K of the H2 system. Many other loci also
belong to this class, such as HLA-E to -J. Class II
includes HLA-DP, -DQ, and -DR in humans and
I-A, and I-E (the letter I, not the Roman
numeral) in mice. Alleles are designated according
to a numerical system, e.g., HLA-A2,
-B5, -DR4, etc. The gene products of the alleles
of the HLA system (human leukocyte antigens;
also said by some to refer to Los Angeles, where
some of the first basic discoveries were made)
can be demonstrated by the toxicity of serum of
defined specificities to other leukocytes (serological
cytotoxicity). Cytolysis occurs unless the
specificities of the serum and of the cells being
tested are identical. The gene products of the alleles
of the HLA-D system are distinguished by
the mixed lymphocyte test, based on lymphocyte
proliferation as a reaction to foreign T cells.
Strictly speaking, the class III genes do not
belong to the MHC loci. They contain genes for
different complement proteins and a few other
genes.
Genomic organization of the MHC loci
The class II loci are located closest to the
centromere. Each consists of a series of genomic
subunits. The HLA-D region is about 900 kb long
and contains a far greater number of loci than
shown here. In addition, some have been renamed.
For example HLA-DP has two ! and two
" genes, now called A1, A2 and B1, B2, respectively.
centromere. Each consists of a series of genomic
subunits. The HLA-D region is about 900 kb long
and contains a far greater number of loci than
shown here. In addition, some have been renamed.
For example HLA-DP has two ! and two
" genes, now called A1, A2 and B1, B2, respectively.
Class I and class II MHC molecules
Corresponding to the general organization of
the individual class I and class II genes, the class
I and class II molecules are basically similar.
Both consist of two different polypeptide
chains. In class I molecules, an MHC-coded !
chain is associated with a non-MHC-coded "
chain ("2-microglobulin). The extracellular portion
of the ! chain consists of three domains,
!3, !2, and !1, each with about 90 amino acids.
!1 and !2 form the highly polymorphic peptide-
binding region; !3 and "2-microglobulin
structurally correspond to an immunoglobulinlike
region. Elucidation of the crystalline structure
of the class I MHC molecules showed that
!1 and !2 interact to form a type of platform of
eight-stranded "-folded proteins. The cleft
formed between !1 and !2 (25 Å!10 Å!11 Å)
can bind a protein fragment consisting of
10–20 amino acids. Class II MHC molecules
consist of two polypeptide chains, ! and ", each
with two domains, i.e., !1, !2 and "1, "2, each
with about 90 amino acids and a transmembrane
region of about 25 amino acids. As with
the class I molecules, the peptide-binding regions
(!1 and "1) are highly polymorphic. Unlike
the "1 domain, !1 does not contain a disulfide
bridge.
the individual class I and class II genes, the class
I and class II molecules are basically similar.
Both consist of two different polypeptide
chains. In class I molecules, an MHC-coded !
chain is associated with a non-MHC-coded "
chain ("2-microglobulin). The extracellular portion
of the ! chain consists of three domains,
!3, !2, and !1, each with about 90 amino acids.
!1 and !2 form the highly polymorphic peptide-
binding region; !3 and "2-microglobulin
structurally correspond to an immunoglobulinlike
region. Elucidation of the crystalline structure
of the class I MHC molecules showed that
!1 and !2 interact to form a type of platform of
eight-stranded "-folded proteins. The cleft
formed between !1 and !2 (25 Å!10 Å!11 Å)
can bind a protein fragment consisting of
10–20 amino acids. Class II MHC molecules
consist of two polypeptide chains, ! and ", each
with two domains, i.e., !1, !2 and "1, "2, each
with about 90 amino acids and a transmembrane
region of about 25 amino acids. As with
the class I molecules, the peptide-binding regions
(!1 and "1) are highly polymorphic. Unlike
the "1 domain, !1 does not contain a disulfide
bridge.
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