HLA & antigen processing(Bowden) Flashcards
Where was histocompatability first identified
in mice
Can T cells recognize antigens in free soluble form
NO
Describe characteristic of HLA genes
tightly linked- highly polymorphic
more than 150 separate alleles
many alternative versions of each gene
What does the Class III locus of HLA encode for
complement proteins and cytokines
Where is are the HLA genes found and what are the 3 distinct classes
short arm of chromosome 6 Class II(D region) then class III then class I
Describe HLA haplotype
total set of HLA alleles are present on each chromosome. Most have 1 from mom and 1 from dad–> CO DOMINANT expression
What loci are the Class I HLA genes found on
HLA-A B and C
Where are class I HLA molecules found
on all nucleated cells
What cells do class I HLA present to
CD8+ cytotoxic T cells
What is the structure of class I HLA
membrane bound glycoproteins formed by 4 extracellular globular domains
3 domains are alpha chains and one is B2 microglobulin
What proteins oh HLA class 1 are HLA encoded
just the alpha 1 2 and 3 domains
Where is the peptide cleft of HLA class 1
between alpha 1 and 2 domains-greatest polymorphism
How big is the peptide that can fit into cleft of HLA I, and what specific structure must it have
8-10 amino acids in length with CLOSED ends!
How can different peptides bind to HLA I clefts
each allele of Class I HLA has a different range that can bind in groove
How is the class I HLA formed
alpha chain translated in ER as glycoprotein and joins with B2 micro globulin
associates with peptides derived from cytosolic proteins and transported to cell surface
Describe class I HLA gene
regulatory sequences, leader sequence, 3 alpha domains, transmembrane cytoplasmic proteins
how many alleles of class I can be expressed
all!, 6 different HLAs slgihtly different shape and present different peptides
Where are HLA class II genes encoded
D region- 3 sets DP, DQ and DR
Where are class II HLA found
APC, dendritic cells and B cells
What cells do class II HLA present to?
CD4+ T cells
Structure of Class II HLA
alpha and B chain- encoded by D region.
4 globular structure- alpha and beta not covalently linked
Where is the peptide cleft in Class II HLA
between alpha and beta globular domains
What is the general structure of peptides binding class II HLA
13-18 aa long, OPEN ENDS, conformation of groove dictates what can bind
Synthesis of class II HLA
alpha and beta synthesized into ER, interact with third protein- the invariant chain
Enters endocytic compartment then transported to cell surface
What is the role of the invariant chain in class II HLA
binds to alpha and beta, blockin peptide cleft to direct transport to endocytic compartment where it is degraded
Why are Class II molecules put inside encytotic compartments
this is where they come in contact with antigens from outside of cell. So it can bind and then present them to T helper
How many alleles are expressed in class II HLA
all alleles of both chains: 6 alpha, 6 beta. 3 from mom 3 from dad for each
what is the purpose of any alpha chain binding to any beta chain
greater range of peptides that can bind to class II HLA
What part of the peptide in the cleft is recognized by T cell
somewhere in between ends that bows outwards and sticks up
HLA restriction rule
CD4+ only recognize Ag on Class II HLA
CD8+ only recognize Ag on Class I HLA
What region in class I HLA binds to T cell R
alpha 3 regions bind CD8
What region in class II HLA binds to t cell R
Beta 2 regions bind CD4
3 maint types of APC
MAcrophages, Dendritic Cells, B cells
sometimes thymic epithelial cells
Professional APC
Dendritic cells pincytose Ag and process it for presentation
most effective
produce co stimulatory molecules
activates naive CD4+ and CD8+ T cells
How do Macrophages act as APC
phagocytose or pinocytose Ags- very good in activating memory T cells
How do B cells act as APCs
bind soluble Ag via sIgs– high affinity
Ingest by pinocytosis
very effective at presenting to memory T cells
Spleen vs lymph node caputure of Ag
spleen filters blood, lymph filets other fluid
What happens when microbes are phagocytosed of pinocytosed
lose adhesive markers and upregulate CCR7 to increase expression of HLA and B7
Intracellular pathogens activate what pathway
Extracell pathogens?
Intra= Class I HLA Extra= Class II HLA
What dictates which pathway microbe enters
self vs non self, specific HLA binding site
density of protein and the chemical nature of fragment
What stage is the endosome when HLA II loaded
late endosomes
How is the invariant chain degraded
degraded to CLIP by lysosomal enzymes- HLA DM removes CLIP
What happens if an HLA II is unbound
not presented on surface
What is TAP in I HLA pathway
transports peptides from cytosol to interior of ER so it can be trimmed and loaded into class I HLA
What is cross presentation
dendritic cells can present to both CD8 and CD4
What type of diseases are associated with mutations of HLA alleles
autoimmune diseases
Ankylosing spondylitis
inflammation of spine
problem in presentation encoded by HLA-B27 allele
What are other examples of HLA associated diseases
rheumatic fever
Sjogrens syndrome
insulin dependent diabetes mellitus
What happens wht TAP is down regulated in class I
renal cell carcinoma
