Download the HLA complex

the HLA complex
Hanna Mustaniemi, 28.11.2007
The Major Histocompatibility Complex
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Major histocompatibility complex (MHC) is a gene region
found in nearly all vertebrates
encodes proteins with important functions in immunity
discovered due to its role in transplantation rejection
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transplantations were accepted within any inbred strain of mice,
but rejected between individuals with genetic differences
experiments with mice lead to the conclusion that reaction
against foreign tissues were controlled by genes existing in
several alleles and inherited co-dominantly
hence the name ‘histocompatibility complex (Greek ‘histos’,
tissue)
The human MHC
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the human MHC is called the HLA complex (HLA genes)
located on the short arm of chromosome 6, contains 3.5
– 4.0 million base pairs
one of the most gene dense regions of the human
genome
estimations on the amount of functional genes vary
around 100 – 200 genes
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classical and non-classical MHC class I and MHC class II genes
MHC class III genes
also genes not involved in immunity or involved in immunity less
directly
Classical class I and II MHC genes
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code for integral membrane glycoproteins, known as peptide
antigen –presenting MHC proteins or molecules
classical MHC class I proteins are coded by genes designated HLA-A,
HLA-B and HLA-C
classical MHC class II proteins are coded by HLA-DP, HLA-DQ and
HLA-DR
Function of classical MHC proteins
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soluble antibodies recognized by B cells are effective only
against some extracellular pathogens
pathogens rarely leave traces of them on the surface of the
cell -> cells exhibit on their surface a sample of peptides
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the function of the classical MHC proteins is to bind the peptides
and display them
hence the name antigen-presenting proteins
in addition, T cells only recognize antigens, that are
associated with the same individual’s MHC proteins
T cells scan cells all the time to ensure there are no foreign
motifs on their surface
MHC proteins express both foreign and self peptides
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immune reaction depends on the T cells’ antigen recognition
Function of class I MHC proteins
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class I proteins are expressed on the surfaces of
nearly all cells
present peptides coming from intracellular
proteins
these MHC-peptide complexes are recognized by
cytotoxic T cells (killer T cells) with the help of the
coreceptor CD8
if foreign peptides are encountered, killer T cells
deduce the cell is infected and mark it for
destruction
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with the help of additional proteins the cell undergoes
apoptosis
Function of class II MHC proteins
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class II proteins expressed only on B cells,
macrophages and dendritic cells
peptides presented by them do not come from
cytoplasm, but extracellular peptides that have
been taken into the cell with the help of
endosomes
MHC-peptide complexes are recognized by helper
T cells with the help of the CD4 coreceptor
to avoid the binding of peptides from endogenous
proteins, newly synthesized class II MHC proteins
are bound by a chaperone polypeptide (the
invariant chain)
The segregation is biologically important
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peptides from cytoplasm cannot reach class II
MHC proteins, whereas peptides from endosomal
compartments cannot reach class I MHC proteins
foreign peptides encountered in association with
class I proteins signal the cell has succumbed to a
pathogen -> call for destruction
foreign peptides encountered in association with
class II proteins signal the cell has encountered a
pathogen -> call for help
Structure of MHC class I molecules
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consist of two polypeptide chains
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four domains: peptide-binding, immunoglobulin-like,
transmembrane and cytoplasmic domains
peptide-binding domain the most N-terminal
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a large alpha chain encoded by a class I MHC gene
a small beta-2 microglobulin chain encoded outside the MHC
region
has a “floor” and two “walls” -> can only bind small peptides (
around 8-11 residues)
anchor positions: “pockets” for specific residues
immunoglobulin-like domain the binding site for T-cell
accessory molecule CD8
Structure of MHC class II molecules
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consist of two chains
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peptide-binding site has “a hole in the floor”
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alpha and beta chains, both similar to the alpha chain
of class I molecules (same domains)
a separate gene controls each chain: class II MHC loci
consist of 2-3 genes
can bind longer peptides than class I molecules
(around 13-18 residues long)
immunoglobulin-like domain the binding site for
coreceptor CD4
Polymorphism of classical MHC genes
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both class I and II MHC genes highly polymorphic
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need to maximize peptide binding diversity
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exact amount of alleles is not known, around 150 or even more
(up to 500?) for some MHC loci
the likelihood of getting the same alleles from both parents is
unlikely, and alleles are expressed codominantly -> an
individual normally has 6 different class I and class II genes
alleles denoted as HLA-A2, HLA-A28, etc.
variation localized at the peptide-binding domains,
immunoglobulin-like domains highly conserved
in the case of epidemic caused by a mutated pathogen ,those
producing a new protein have a large selective advantage
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if all members of the species had identical proteins, population
would be much more vulnerable to pathogens
Nonclassical MHC genes
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MHC class I-like genes HLA-E, HLA-F, HLA-G
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encode proteins similar to class I molecules in sequence and
structure
no such polymorphism
may be encoded outside the MHC
fulfill a variety of roles, often specialized antigen-presenting
features
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some present lipids and bacterial cell wall components
some NK-receptors recognize only HLA-E molecules
HLA-G expressed at high level on maternal/fetal interface, role
remains unclear
even less known about HLA-F
MHC class II-like genes HLA-DM and HLA-DO
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regulate peptide loading onto classical MHC class II molecules
Allograft rejection
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allograft = graft from a genetically different donor
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foreign MHC proteins typically activate more T cells than nonMHC foreign proteins
class II MHC proteins play the major role in transplantation
rejection
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can be tissue or an organ
especially important are HLA-DR proteins
HLA-typing done before transplantation to ensure the best
possible match
HLA alleles of an individual’s parents are likely to be different
-> fetus is an allograft that is not rejected
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reason unclear, possible explanation is the placenta not allowing
maternal T cells to enter
HLA and diseases (1)
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HLA complex has been associated with over a 100
diseases, many of them autoimmune diseases
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includes diseases such as asthma, type I diabetes,
rheumatoid arthritis, psoriasis, MS
among all genes studied for possible association with
autoimmune diseases, the best candidate genes are
MHC genes
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most autoimmune diseases associated with class II MHC
genes, for example diabetes mellitus associated with the
combination of certain HLA-DR and HLA-DQ alleles
ankylosing spondylitis associated with HLA-B27 allele:
individuals expressing it have 90-100 times bigger risk of
developing AS than those who don’t express HLA-B27
HLA and diseases (2)
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disease-associated HLA alleles found in healthy
individuals as well
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expressing a certain HLA allele seems to be a
necessary but not a sufficient condition
according to one of the models, both genetic
predisposition determined by MHC genes and
exposure to certain environmental agents are needed
in order to develop an autoimmune diseases
certain HLA alleles encode proteins that present
autoantigens with greater efficiency than ”healthy”
ones?
References
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Berg, Tymoczko, Stryer. Biochemistry, 6th Edition.
W.H. Freeman and Company.
Alberts et al. Molecular biology of the cell, 4th Edition.
2002. (all the figures)
Pinchuck, George. Schaum's Outline of Immunology.
2001. McGraw-Hill professional.
Levinson, Warren E. Medical Microbiology &
Immunology: Examination & Board Review. 2004.
McGraw-Hill.
Allen, Rachel L. Meeting report: Non-classical
immunology. 2001. Genome Biology.
http://genomebiology.com/2001/2/2/reports/4004