HLA, Ag Processing & Presentation

Question 1

which gene segments are closely linked in HLA genes?

Answer 1

DQ/DR (class II) and B/C (class I) show linkage disequilibrium

Question 2

class I HLA - characteristics

Answer 2

encoded by 3 separate gene regions in HLA locus: HLA-A, B and C
membrane-bound glycoproteins
expressed on ALL NUCLEATED CELLS
present Ag to CD8+ CTLs

Question 3

class I HLA - structure

Answer 3

4 extracellular globular domains

heterodimer of 2 proteins: alpha chain (alpha-1, 2 and 3) and beta-2 microglobulin (non-HLA encoded)

peptide binding groove btw alpha-1 and alpha-2 domains shows greatest polymorphism; closed ends limits Ag size to 8-10 aas

Question 4

how class I HLA has ability to present many different types of self Ag

Answer 4

all alleles of class I HLA can be expressed at the same time on a cell -> 6 different HLAs

each allele has a different range of peptides it can bind

Question 5

class I HLA - synthesis

Answer 5

1) alpha chain translated into ER
2) in ER, alpha chain and beta-2 microglobulin interact
3) in cytosol, proteosome degrades ubiquitinated proteins -> transported by TAP into ER for loading onto class I HLA

Question 6

class II HLA - characteristics

Answer 6

3 sets of genes: HLA-DP, DQ and DR

membrane-bound glycoproteins

primarly on Ag-presenting cells (macrophages, dendritic cells and B cells)

present Ag to CD4+ T cells

Question 7

class II HLA - structure

Answer 7

4 extracellular globular domains

2 proteins, both encoded by HLA-D region

alpha and beta chains strongly associated

peptide binding groove has open ends, allows larger peptides to bind (13-18 aas)

Question 8

class II HLA - synthesis

Answer 8

1) alpha and beta chains synthesized into ER
2) both chains interact with invariant chain -> blocks peptide binding groove, directs transport of class II molecule to endocytic compartment
3) in endocytic compartment, invariant chain -> CLIP
4) HLA-DM removes CLIP, facilitates binding of endocytosed peptides (protein Ags from outside cell) to class II HLA

Question 9

how class II HLA is able to present many different types of non-self Ag

Answer 9

all allels of alpha and beta chains are expressed on the same cell (one pair HLA-DP, one pair HLA-DQ, one HLA-DRalpha and 1/2 HLA-DRbeta genes)

different alleles of class II HLA can bind different range of peptides

Question 10

compare/contrast class I HLA and class II HLA for:

constituent chains

locations of polymorphic residues

binding site for T cell co-receptor

size of peptide binding groove

nomenclature

Answer 10

1 alpha chain, 1 beta-2 microglobulin/1 alpha, 1 beta chain

alpha-1 and alpha-2 domains/alpha-1 and beta-1 domains

alpha-3 binds CD8/beta-2 binds CD4

8-11 aas/10-30 aas

HLA-A, B and C/HLA-DP, DQ and DR

Question 11

list types of APCs and which effector cells they activate

Answer 11

dendritic cells: naïve CD4+ and CD8+ T cells

macrophages: memory T cells

B cells: memory T cells

for naïve CD4+/CD8+ T cells: DCs > macros > B cells

Question 12

cross-presentation by dendritic cells

Answer 12

dendritic cells can ingest virally-infected cells and display Ag to CTLs or T helper cells

use class I HLA/CD8 interaxn

Question 13

types of diseases associated with HLA

Answer 13

ankylosing spondylitis: B2702 and B2705 alleles; odds ratio 100-200

rheumatoid arthritis

type I diabetes

MS

SLE

Celiac disease