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EXTRA
Summary
INTRA
Li
Proteasome
MHC II
TAP
Golgi
Vesicle
MHC I
Golgi
Calnexin
CLIP
HLA-DM
CD4 TH
Calreticulin
Tapasin
CD8 TC
Exam EE129 Thursday 7:00pm
Help session: Tomorrow 6-8pm CIVL 3153
Alleles: different forms of one gene
Allotypes: different forms of one protein (isoforms)
Polymorphic: alternative forms of one gene = Many
alleles
Oligomorphic: a few forms of one gene = Few alleles
Monomorphic: no polymorphism
Homozygous: same allele on both inherited
chromosomes
Heterozygous: different allele on both inherited
chromosomes
MHC in humans is called HLA (human leukocyte
antigen complex)
Figure 3-13 part 1 of 2
Variable
Invariant
No rearrangements or somatic changes
Diversity is derived from 1) Gene families
2) Genetic polymorphism
HLA-A,B,C
-present peptide
antigens to CD8
Tcells and
interact
with NK-cells
HLA-E,G
-interact
with NK-cells
HLA-F
-?
HLA-DP,DQ,DR
- present peptide
antigens to CD4
Tcells
HLA-DM,DO
-regulate peptide
loading of
DP,DQ,DR
Human leukocyte antigen complex
Abs used to ID MHC molecules react with leukocytes not RBCs
Figure 3-24 part 1 of 2

Heavy Chain

Heavy Chains
Chromosome Organization of HLA complex
Chr6
2-microglobulin on chr15
•  and  chain = GeneA and GeneB
• Complicated nomenclature you don’t need to know
• Haplotype - combination of alleles inherited from Chr6
• 2% meiotic recombination rate generates population
diversity
• Cytokines coordinately regulate the group of genes class I heavy chain and other associated genes
• TAP transporter, Tapasin, Proteasome subunits - LMP2
and LMP7
Interferon , , and  ----> Class I , 2M, TAP, LMP2, LMP7
Interferon  ----> CIITA ---> HLA II genes, li chain
MHC class II transactivator (CIITA) - deficiency leads
to bare lymphcyte syndrome
MHC I (single peptide binding chain ): 3 genes
present antigen
HLA-A, HLA-B, HLA-C
MHC II (two chains,  and ): 3 genes present
antigen
HLA-DQ, HLA-DP, HLA-DR
Each MHC II locus encodes a gene for the  chain
and a gene for the  chain:
e.g. HLA-DQA, HLA-DQB => MHC II isoforms
HLA-DPA, HLA-DPB => MHC II isoforms
HLA-DRA, HLA-DRB => MHC II isoforms
Maternal: 3 MHC I genes
HLA-AM, HLA-BM, HLA-CM
Paternal: 3 MHC I genes
HLA-AP, HLA-BP, HLA-CP
6 different MHC I
proteins on all cells
Heterozygous
Maternal: 3 MHC II genes
HLA-DPAM, HLA-DPBM
HLA-DQAM, HLA-DQBM
HLA-DRAM, HLA-DRBM
Paternal: 3 MHC II genes
HLA-DPAP, HLA-DPBP
HLA-DQAP, HLA-DQBP
HLA-DRAP, HLA-DRBP
6 different MHC II
proteins on all cells
(some individuals
have 8 due to two
HLA-DRB genes)
Homozygous = one DR type
Heterozygous = up to four
DR types
Figure
Correlation is
3-34mainly with
HLA class I
Red – heterozygous for all the highly polymorphic HLA I
and II
Yellow - Homozygous for one locus
Blue - Homozygous for two or three loci
Figure 3-28 part 1 of 2
MHC
MHC isoform can bind multiple peptides
Figure 3-28 part 2 of 2
Figure 3-29
L-lysine
V- valine R-arginine
Y-tyrosine W-tryptophan
Figure 3-30
Co-
Large circles- totalFigure
#
antigenic
peptides that can be
presented
via MHCI & MHCII
small circles- total #
antigenic
peptides that can be
presented
via an individual
MHCI & MHCII haplotype
3-31
Advantages for heterozygous for the MHC
Figure 3-32 part 1 of 2
Figure 3-32 part 2 of 2
Recombination
between
alleles of the
same gene
Generation of
new MHC alleles
HLA B*5301Found in African
populations and
associated with
resistance to
severe malaria
Figure 3-33 part 2 of 2
Recombination between
alleles of the different
gene
Generation of new
MHC alleles
HLA B*4601- Found in southeast Asian
populations and
associated with susceptibility to
nasopharyngeal carcinoma.
MHC selection by Infectious Disease
• Pathogens adapt to avoid MHC - recent MHC isoform may
provide a survival advantage (hence higher frequency level)
• Epidemic diseases place survival advantages on those who
can best present pathogenic peptides
• Only a minority of HLA alleles are common to all humans
- most are recent and specific to ethnic groups
HLA Type and Disease Susceptibility
Ankylosing spondylitis
IDDM
Multiple Sclerosis
Narcolepsy
Rheumatoid arthritis
Lupus (SLE)
AIDS (rapid)
AIDS (slow)
B27
DR4/DR3
DR2
DR2
DR4
DR3
HLA-A29, HLA-B22
HLA-C16, HLA-DR11
HLA-B14, B27, B57
HLA-C8, C14
MHC polymorphism and Organ Transplants
• Developing T cells that recognize complexes of peptide
and MHC molecules on HEALTY tissue (self-peptides
presented by self MHC) are DESTROYED
• This results in the preservation of T cells that recognize
non-self MHC (allogenic MHC). Called alloreactive T
cells (1-10%) of total T-cell repertoire
• IS is primed for rejection of foreign organs that express
allogenic MHC