Antigen Presentation Flashcards
Antigen presenting molecules use MHCs aka
human leukocyte antigen (HLA)
Type I MHC on
all nucleated cells in the body
Type II MHC on
professional antigen presenting cells: Dendritic cells, macorphages, B lymphocytes and some thymocytes
two receptors for MHC
B cell receptors and T cell receptors
T cells do not recognize
antigens in free/soluble forms
T cells only recognizes antigens associated with
MHC/HLA
differences in HLA/MHC molecules expressed by an individual will influence the
repertoire of antigens to which T cells can respond
MHC/HLA has an unprecedented extent of
polymorphism
more then 150 separate alleles have been identified within the MHC
many alternative versions of each MHC gene
MHC location is on chromosome
6 and divided into three classes
MHC haplotype
encode protein antigens central for immune system to discriminate between self and non self
most humans are heterozygous (one from mom, one from dad) and both are codominant to generate more diversity
transplanation
want the best match possible between donor and recipient for both class I and II genes
Class I MHC genes
encoded by three separate gene regions in the MHC locus
- HLA-A
- HLA-B
- HLA-C
these are membrane bound glycoproteins
expressed on all nucelated cells
inhibitory receptor for NK cells
MHC I
present antigen to CD8 CTL
MHC I structure
membrane bound glycoprotein
4 extracellular domains
conserved
heterodimer of a chain and B2 microglobulin
MHC 1 a chain
encoded by the MHC class locus
forms three of the fourh globular domains
a1, a2, and a3
MHC I B2 microglobulin
non MHC encoded
forms fourth fomain
associates noncovalently with the a3 domain of the a chain
the area between a1 and a2 domains of the MHC I has teh
peptide binding groove
greatest polymorphism
peptides are bound and presented on teh surface of cells
bunds pepetides 8-10aa in length
closed ends limit size
key features of MHC I
all alleles of class I can be expressed at the same time on each cel (6 different MHCs)
slightly different shape –> present a differnt set of peptides
conformation of this forrve dictates what peptides can bind
each allele of class I MHC has a differetn range of peptides that can
bind in the groove
synthesis of a chain of MHC I
translated into ER as glycoproteins
in the ER, alpha chain of MHC I interacts with
B2 microglobulin and associates with peptides derived from cytosolic proteins
then MHC I peptide complex are transported to cell surface
class II genes are encoded by the
HLA-D region with three sets of genes
HLA-DP
HLA-DQ
HLA-DR
Class II MHC genes have an
A and B chain
membrane bound glycoproteins
antigen presenting cells only
MHC II present to
CD4 T cells
MHC II structure composed of
two proteins
a chain and b chain, strongly associated
four globular domains
NOT covalently linked
MHC II peptide binding groove
formed by the a1 and b1 globular domains
binds peptides 13-18aa long
open end allows for larger peptides
each allele of class II MHC has a
different range of peptides that can bind in the groove
a1 and b1 globular domains have greatest polymorphism
in MHC II, all alleles of the a and B chains are
expressed
6a chains and 6 b chains
any a chain allele may be associated with any B chain allele
adds to the diversity of the peptide-binding groove
greater range of peptides that can bind to
Class II MHC
antigen-MHC binding is
saturateable and low affinity
slow-on rate
very slow-off rate
slow MHC-antigen binding allows
peptide MHC complex to persist long enough to interact with T cells
only one peptide binds to an MCH
at any one time, either I or II
same MHC can bind multiple peptides at different times, either I or II
peptide bining
there are pockets in the peptide-binding cleft
the aa on the antigen peptides fit into these pckets and anchor the peptides in the cleft
the rest of the peptide contains residues that bow upward and are recognixed by the ag receptors on T cells
antigens coded on Y chromosome
can cause accute rejection on male grafts in female pts
capture of antigens
microbes enter the body
pahgocytosed by APC in tissues
antigens enter via periphery and filtered by the lymph
antigens in the blood are filtered by the spleen
Professional APC express a lot of
MHC II and costimulatory molexyles
can activate naive T cells
ex is classical DCs in all tissues
plasmacytoid DCs are in blood and tissues, promote innate and antiviral state
activation of DC cells
lose adheisve markers and upregulate CCR7
increase MJH and CD80
travel to regional secondary lymphoid tissue
mature as they migrate
present Ag to T cells
two processing pathways
depends on chemical nature of ag
density of peptide
specific MHC and its binding site
self vs nonself
each pathway stimualtes the T cell population most effective, I.E.
intracellular pathogens and self: MHC I
extracellular pathogens: MHC II
MHC II pathway
exogenous proteins are ingested and degraded
a and B and invarient chains are made in the ER and sent ot Golgi
peptide is not loaded until late endosome
invariant chain MHC II pathway
Ii occupies the peptide binding cleft, probotes folding, assembly, trafficking and place holder
Ii is degraded to CLIP by lysosomal enzymes
HLLA-DM acts as peptide exchanger, remvoing LCLIP and adding peptide to MCH II
unbound MHC are no displayed
MHC I pathway
cytosolic antigens
proteasome foind in cytoplasm of most cells, degrades damaged proteins, and targeted by ubiquitin
TAP-transports peptides from cytosol to ER where peptide is trimmed and loaded into MHC I
MHCs carry peptides from normal self proteins that are degraded but these do not normally
provoke an immune respone
cross presentation
dedritic cells ingest virally infected or transformed cells and display antigens to CTLs
can also display to Th cells
transplantation
a major factor limiting the success of transplantatino is the imune response of teh recipient to te donor tissue
HLA associated diseases
many autoimmune diseases and susceptibilty to infectinos are assocaited with HLA alleles
most HLA associated idseases have unknonw etiologies that contribute to the immunologic abnormalities
HLA associated disease: ankylosing spondylitis
inflammation over the spine
88% of poeple have HLA-B27 allele
each allele has limitined number of peptides it can present
possible that HLA B27 allele cnanot bind a critical antigenic peptide
or
present a critical antigenic peptide against the agent causing the disease
HLA associated disease: rheumatic fever
sequela of strep pyrogenes infection
generation of ab against the streptococci, cross reacti with cardiac tissue
patients with HLA-DR4 allele are more prone
other HLA assocaited diseases
Sjorgren’s syndrome: associated with HLADr3, defect in salivation and lacrimation
insulin dependent DM: associated with HLA-DQ w8 and others
psoriasis: associated with HLA-B3
class I antigen processing defects
renal cell carcinoma
transporter assocaited with antigen processing is down regulated (TAP)
bare lymphocytes syndrome (Class I MHC)
TAP protein is nonfunctional, so no peptides can enter the ER
class I molecules cannot leave the ER unless they have bound a peptide, cells cannot present antigens on their surface
chronic resp. infections, poor responses to viruses
bare lymphocyte syndrome class II MHC
caused by inherited decfect in CIITA leading to def. in HLA class II expression on cells and nonfunctioning T cels
HLA II genes are turned on by CIITA which induces IFNy.
mutations in any Tf lead to decrease in class II gene prpducts
reduced Th cell count due to failed thymic selection
reduced antigen presentation to mature T cells
decreased humoral and CMI repsonses incluting DTH
pt have severe recurrent infections
