MHC and AG Presentation1 MHC and Antigen Presentation Chapters 6 & 7 Self-Test Questions: Chap 6 A:...

MHC and AG Presentation 1

MHC and Antigen Presentation

Chapters 6 & 7

Self-Test Questions:Chap 6

A: 1 – 5, 8 Note: for A-5 know MHC I - III

B – D: allChap 7

A: allB1: 1, 4 – 8, 11, 12B2-4: allC1: 1,3C2-4: allD: allE: 1, 3


What is the structure of MHC-I proteins?

MHC-I α chain

Β-microglobulin

Binding cleftClosed endsAnchor residuesPeptide may bend

Expressed in all nucleated cells


What is the structure of MHC-II proteins?

MHC-II α and β chains

Binding cleftopen endsAnchor residuesPeptide lies flat

Expressed only in pAPC

MHC 3D Models


MHC proteins bind to peptides based upon general properties

each MHC protein can bind to many different peptides

Shared properties of peptides binding to two different MHC-II

Shared properties of peptides binding to a MHC-I

From Grey et al., Sci Amer November, 1989


How are MHC genes arranged on Chromosome 6?

MHC is polygenic

Confusing terminology!HLA complex in humansH-2 complex in mice

Class II loci DP, DQ and DRα and β peptide genes

Class I lociA, B, C1 gene each(β-microglobin gene is elsewhere)

Class III locimisc other genes

Also, non-classic MHC-I and -II genese.g., DM, DO


(Single gene for DRα peptide)

Further polygenicity of MHC genes

There are multiple copies of some A and B genes!

e.g., DRB1, DRB3, … DRB9DPA1, DPA2 and DPB1, DPB2DQA1, DQA2 and DQB1, DQB2, DQB3-- many pseudogenes also (e.g DRB2)

DR locus yieldsdifferent MHC-IIproteins

(Multiple genes for DRβ peptide)

γ gene

DRβ1/DRα DRβ3/DRα DRβ4/DRα


MHC genes are also “Polymorphic”

Different people may possess slightly different alleles for MHC peptides!

*01*02*03*04*05…*16

*01*02*03

*01*02*03

γ geneBroad allele

classesDR53

= HLA “serotypes”-- MHC proteins with distinct antigenic properties

DR3 DR4 DR5…DR

DR52A

ll yield

All yield


“DRβ” = name of MHC peptide subunit“DR3” = HLA serotype family

-- occurs in many different polymorphic forms…

At the DNA level“DRB1” = a locus of gene“DRB1*03” = broad allele type

“DRB1*0301” = minor allele type

*01*02*03*04*05…*16

Minor alleles also exist

withinbroad allele

Alleles are further polymorphic

*0101*0102*0103…*0122

*0301*0302*0303…*0341

MHC-II DRβ Loci

Are all forms of HLA… DR3 DR1


How polymorphic is HLA?

MHC-I alleles

580

921

312

0 200 400 600 800 1000

HLA-A

HLA-B

HLA-CMHC-II Alleles

23

127

34

86

3

577

0 200 400 600 800 1000

HLA-DPα1

HLA-DPβ1

HLA-DQα1

HLA-DQβ1

HLA-DRA

HLA-DRB

Polygenetism is good Polymorphism is goodfor the individual. Why? for the species. Why?

Good explanation Class II alleles Class I alleles


MHC genes/serotypes are inherited as a set (haplotype)1 from mother, one from father

Crossing-over can create new haplotypes


Different HLAs predispose individuals toward disorders

Fraction of afflicted population with HLA AgFraction of normal population with HLA Ag

RR=

Associated RelativeAutoimmune Disorders HLA antigens RiskAutoimmune hepatitis DR3 14Primary Sjögren syndrome DR3 10Diabetes mellitus type 1 DR3 5Rheumatoid arthritis DR4 4Diabetes mellitus type 1 DR4 6Diabetes mellitus type 1 DR3 + DR4 15

Diseasesleprosy DR2tuberculosis DR2Chlamydia pneumoniae DR52aspergillosis DR15ragweed allergy DR5asthma, mite sensitive DR11

CancersKaposi's sarcoma DR5thyroid carcinomas DR8 + DR 11ovarian/cervical cancer DR10 + DR 11 + DR15


How many forms of HLA exist on cells?

Genes display ‘codominance’-- up to 6 forms of MHC-I-- 12+ forms of MHC-II

Peptides from different chromosomes can combine

MHC proteins: ~ 105 copies / cell

~1018 in species


How is HLA tissue typing performed?-- Determine HLA antigens/genes of recipient and potential donors

“HLA antigen typing” -- use lymphocytes-- serological (antibody) testing -- genetic testing (e.g., PCR)

“Mixed Lymphocyte Culture”-- culture together donor and recipient lymphocytes-- look for immunological response from recipient cells

HLA polymorphism (HLA serotype variation) is the primary cause of organ transplant rejection


How is the mouse H-2 complex organized?

MHC-I at K, D and L -- K & D (& L sometimes)

MHC-II at A and E loci-- IA & IE

I II II I (I)

I I I II II II

Mice can be bred: -- Syngeneic e.g. H-2k, H-2d

-- both chromosomes have same haplotype -- Congeneic

C3H x BALB/C - H-2d/k

Mouse Strain Haplotype

H-2 alleles

MHC-I _ MHC-II_ MHC-IK IA IE D

C3H k k k k k

BALB/c d d d d d

C57BL/6 b b b b b

A a k k k d

B10.A (3R) i3 b b d d


How does MHC haplotype in influence recognition of antigens by TCRs?

From H-2k mice the genes for a TH-cell TCR against a hen-egg lysozyme (HEL) peptide were transferred to H-2d , H-2k and H-2d/k mice. The mice were also transfected with the HEL gene, which is expressed only in the periphery (not thymus).

A. HEL peptides will presented on which cells and on which MHC type?

B. In mice of which haplotype(s) would the HELT-cells be released from the thymus?

C. In mice of which haplotype(s) would the HELT-cells bind to the HEL peptides?

D. Why was HEL-expressing virus used, instead of injecting HEL directly?


Antigen Presentation -- chapter 7

How are peptides loaded into MHC-II?

• Exogenous antigens• Prof APCs• Endolysosome• Invariant chain (Ii) & CLIP• HLA-DM


How are peptides loaded into MHC-I?

• Endogenous antigens• All nucleated cells• Protein synthesis• Ubiquitin & Proteasomes • -- special immuno-proteosomes• TAP transporters• Chaperone proteins


Antigen “Cross presentation”

Exogenous AG on MHC-I

Possibly only certain DCs

Why is this necessary?

strongest evidence for 2.


Other mechanisms of antigen presentation

CD1 family (a-d)-- non-peptide antigens-- e.g., lipopeptides, glycolipids

& phospholipids

Some T-cells are CD1-restricted

MHC and AG Presentation1 MHC and Antigen Presentation Chapters 6 & 7 Self-Test Questions: Chap 6 A:...

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