L16-21 Flashcards
1
Q
Genes that have direct involvement in causing cancer:
A
TSG’s and PO’s
2
Q
Genes that have indirect involvement in causing cancer and control DNA damage?
A
DNA repair genes, genes involved in carcinogen metabolism.
3
Q
Why would DNA repair fail?
A
If a mutation is present in a PO or a TSG.
4
Q
Ataxia telangectasia:
A
Autosomal recessive & rare
5
Q
AT symptoms/features:
A
loss of coordination, dilated capillaries, immune deficiency, sensitivity to ionising radiation, predisposition to lymphoma and leukaemia. Heterozygotes have increased cancer risk due to gene being an intermediate for breast cancer (low penetrance)
6
Q
Gene involved in AT
A
ATM gene - involved in sensing DNA damage, has protein kinase activity and phosphorylates p53 after DNA damage. AT cells cannot arrest the cell cycle in response to DNA damage
7
Q
How is the ATM protein held in its inactive and active states
A
Inactive state: oligomers that are phosphorylated, when sensing DNA damage, to monomers
8
Q
Xeroderma pigmentosa:
A
Rare, AR
9
Q
XP symptoms:
A
Dwarfism, mental retardation, blindness and deafness, severe UV sensitivity, skin and eye cancers (patients ALL have UV sensitivity but may not have any/all of the others)
10
Q
What are the XP affected genes involved in?
A
gene excision and repair of thymine dimers, there are several genes involved, hence variable phenotype.
11
Q
Bloom syndrome, symptoms and why?
A
AR, lymphoma, leukaemia, chronic lung disease and diabetes. Due to mutations in DNA helicase so DNA cannot be unwound correctly. Plus high levels of chromatin exchange in the cell.
12
Q
Fanconis anaemia symptoms
A
AR, mental retardation, aniridia, skeletal abnormalities, leukaemia
13
Q
How many genes in the fanconi anaemia complex and what do they do?
A
- All could mutate to give cancer. They act to ubiquitinate D2 and I protein subunits which then form a complex with three other proteins including BRCA2 to begin homologous recombination. This brings in BRCA1, RAD51 and RAD51C. Hom rec is a high fidelity way of repairing DNA damage, when it goes wrong, increased BC and FA risk.
14
Q
Hereditary non-polyposis colon cancer key points:
A
AD, early onset colon cancer, few polyps, mutations in mismatch repair genes. MLH1 is affected in 51% of HNPCCs. Also, TGFbeta receptor gene has a repeat region in it which is known to be particularly susceptible to repeat changes and is common in HNPCC (increases risk of colon cancer)
15
Q
Features of genetic predisposition to cancer?
A
Family history, early onset cancer, multiple cancers (bilateral organs)
16
Q
Retinoblastoma:
A
Childhood eye cancer affects 1/20,000, high cure rates. 40% inherited, one parent affected = 95% penetrance. AD.
17
Q
Difference between hereditary tumours and sporadic tumours:
A
Hereditary = early onset and bilateral organs/ multiple tumours Sporadic = later onset and one tumour in one organ
18
Q
What is the two hit theory
A
That regardless of if a tumour is sporadic or hereditary, there are two ‘hits’ or limited events in cancer development.
19
Q
Evidence of the two hit theory:
A
- chromosome deletions
- allele loss (LOH) - mechanisms: non-disjunction, non-disjunction and duplication, mitotic recombination, deletion. - no LOH = gene conversion, point mutation
- Somatic cell hybrids - heterokaryon (non-tumourigenic)
20
Q
Oncogene dominant mutations are:
A
Point mutations, gene amplification, chromosome translocations - few inherited mutations
21
Q
TSG recessive mutations causing cancer
A
point mutations, deletions, epigenetic silencing.
22
Q
Does the two hit theory hold?
A
No, most cancers and more complex than that and there are multiple steps and multiple genes involved.
23
Q
What is the most common change in human cancers?
A
p53 mutation
24
Q
RB1 properties:
A
Rb TSG, mutated in all retinoblastomas, encodes a 110kD nuclear phosphoprotein, involved in cell cycle regulation
25
How can you get a RB1- cell to revert to a more normal phenotype?
insert a functional copy of RB1
26
How do tumour viruses affect Rb?
E1A of adenovirus binds in place of the phosphate and E7 binds to unphosphorylated Rb. Both causing the release of E2F and pushing the cell into S phase (so viral DNA is replicated). Normally highly regulated mitogenic signals disrupt the Rb:E2F interaction to trigger the cell cycle.
27
WT1 properties:
1/10,000 childhood kidney tumour 11p13 deletion
28
WT1 mutation symptoms
WAGR syndrome: Wilms tumour, Aniridia, GI abnormalities, mental Retardation
29
What does WT1 encode?
DNA/RNA binding zinc finger proteins
30
p53 properties:
Transcriptional regulator, levels rise in response to DNA damage causing G1 arrest and repair (or apoptosis)
31
What syndrome has p53 germline mutations?
Li-Fraumeni syndrome (cancer susceptibility)
32
How is p53 regulated and why is regulation stopped when p53 is mutated?
p53 up regulated production of mdm2 which forms a complex with p53 causing it to be degraded, mutant p53 does NOT up reg mdm2, so mutant p53 builds up = increased levels.
33
MEN2A is associated with what and shows what diseases:
(Multiple endocrine neoplasia 2a) and is associated with RET and mutations give three diseases:
1. Thyroid cancer
2. Parathyroid hyperplasia - (calcium metabolism)
3. Pheochromocytoma - benign tumour in adrenal medulla, can kill you due to increased adrenaline spikes
34
MEN2B is similar to MEN2A but...
does not give parathyroid hyperplasia and instead can cause gangloineuromas
35
FMTC stands for? and is due to?
Familial medullary thyroid cancer and is due to a germline mutation in RET
36
RET function:
TK receptor thats ligand is GDNF (glial derived neurotrophic factor). GDNF ligand causes receptor dimerisation between GDNFalpha and RET. Mutations in RET cause ligand independent activation = constitutive activation of the pathway. RET is expressed on neural crest cells and affects the tissues they make up.
37
MET
Encodes receptor TK, ligand = hepatocyte growth factor, gene on C7
38
MET is mutated in
hereditary papillary renal carcinoma via a germline missense mutation causing constituative activation of the TK receptor.
39
KIT
Encodes TK receptor for stem cell factor and is important in development, somatic and germline mutations of KIT are found in GI stromal tumours.
40
ALK
TK receptor with unknown ligand, somatic and germline mutations in neuroblastoma
41
CDK4/Cyclin D complexes:
phosphorylate RB1 to allow S phase entry. p16 inhibits CDK4.
42
Germline p16 mutations are seen in
familial melanoma, mutations in p16 prevent it binding to CDK4
43
Ras pathway mutations cause
developmental/ cancer syndromes
44
Screening for cancer: indicators, tests and benefits
I: family history, early onset/ multiple tumours
T: Karyotype, sequence gene (known & unknown mutations)
B: Early screening, Counselling, prenatal diagnosis.
45
An example of using chromosome translocations to find cancer genes:
RT PCR with primers specific for fusion protein. i.e. Edwings tumour t(11;22) product only appears if fusion protein is present.
46
Gene therapy for cancer involves:
TSG replacement, Antisense RNA to oncogenes (to inhibit them), RNA interference (siRNA)
47
What does anti-p53 virus do
Selectively kill of cancer cells with mutant p53 (doesn't work so well in vivo)
48
Rational drugs for cancer?
Gleevec and Gefetnib (EFGR in lung cancer)
49
B-cell receptors recognize:
native antigen
50
TCR recognise:
peptide fragment of antigen presented by an MHC molecule on the surface of an APC.
51
Professional APC's are:
DC's, macrophages, B lymphocytes. They express MHC I and MHC II
52
What are the 3 domains on a MHC I molecule:
alpha1, alpha2, alpha3
53
What do alpha1 and alpha2 of an MHC I molecule contribute to the peptide binding cleft?
an alpha helix and several beta pleated sheets.
54
In MHC II what chains contribute to the peptide binding cleft?
alpha 1 and beta 1
55
How does a TCR recognise MHC and peptide?
The TCR has hypervariable loops on its variable domains, which interact with the side chains of the alphahelices AND the peptide. It is essential that the T cells recognise the complex of peptide and MHC to allow them to scan for infected cells or APCs
56
Where do T cells and DC's reside in the lymph node?
Paracorticol area
57
How do B cells get activated by T cells? *check this
T cells present peptide to B cells, B cells internalise foreign material and present in on the surface in the context of MHC, T cells recognize the antigen and then provide help to activate the B cell by trafficking to just under the LN capsule. Here B cells become blast cells and are activated to enlarge and differentiate to plasma cells which produces specific antibodies that are then secreted.
58
CD4 associates with which and were on an MHC?
MHC II on the beta2 domain
59
CD8 associates where and with which MHC?
MHCI and with alpha3
60
T helper cell function:
Cytokine production, macrophage activation, "help" for B cells (IL-4)
61
T cytotoxic cell function:
cytotoxic lysis of infected or tumour cells
62
Congenic mouse:
Mice that are genetically identical except at a single locus or region
63
How are congenic mice bred?
By cycles of backcrossing, interbreeding and skin grafting
64
The major histocompatibility locus in mice.
```
complex: H-2
MHC Class: I
Region: K GP: H-2K
Region: D GP: H-2D, H-2L
MHC class: II
Region: IA GP: IAalpbet
Region IE GP: IEalpbet
```
65
What is the human leukocyte antigen regions and gene products in relation to class
check on paper if right p16 L19
66
HLA E, F & G are
non classical HLA
67
HLA locus is:
polymorphic
68
HLA genes are
polymorphic
69
Why are most people heterozygous for MHC?
One allele inherited from mother and one from father, there are many different polymorphisms so they are highly unlikely to be the same.
70
What is TAPBP and where is it encoded?
In the MHC class II locus, tapasin is a component that proteates transporters associated with antigen processing with MHC molecules
71
TAP1 and TAP2 are:
In the MHC class II locus and are part of a heterodimer that transports peptides from the cytosol into the ER so the peptide can be loaded in the MHC class I molecule.
72
LMP2 & LMP7 on the MHC II locus are:
Components of proteosomes which are multi-enzyme complexes that chew up protein within the cytosol and generate peptides to be transported by TAP etc...
73
Which HLA genes are highly polymorphic?
HLA A, B, C and DRB1
74
What chain are the polymorphic AA around the peptide-binding groove on MHC I?
alpha1 and alpha2
75
What chain are the polymorphic AA around the peptide-binding groove on MHC II?
beta1
76
What is the key function of HLA?
To present peptides to T cells.
77
xenogenic
transplantation between different species
78
allogenic
Transplant between genetically distinct members of the same species
79
synergenic
genetically identical grafts
80
Cyclosporin A
inhibits T cel proliferation and stops IL-2 secretion
81
Tacrolimus
Dampens t cell responses
82
What is the most commonly transplanted tissue?
Blood
83
What is hyperacute rejection mediated by and how long does it take?
Antibody and complement, rapid/minutes
84
What is acute immune rejection mediated by and how long does it take?
CD4 and CD8 T cell mediated with antibody deposition, days to weeks
85
What causes chronic rejection of grafts and how long does it take?
macrophage infiltration and fibrosis. Months to years.
86
What is the mechanism that causes hyperacute rejection?
Vascular endothelial cells have blood group antigens on them. If the host already has antibodies against these antigens (donor blood group antigens) it will lead to rapid organ rejection. This occurs in minutes and is complement dependent. Antibodies to blood group antigens may arise as a result of: previous transplant, transfusion or pregnancy
87
What do anti-donor blood group antibodies bind to and cause?
They bind to the vascular endothelium of the graft initiating and inflammatory response that occludes the blood vessels, this causes the graft to haemorrhage and graft failure.
88
Immune responses to grafts are...?
Specific for antigenic epitopes that differ between donor and recipient due to genetic difference between these members of the same species.
89
First set rejection is:
what an allogenic graft is rejected from the recipient within 10-13 days
90
Second set rejection is when
When a recipient is grafted for the second time from the same donor and the graft is rejected at a much more rapid rate (6-8 days)
91
What do allogenic sin grafts onto nude mice show?
no rejection of the graft.
92
If you introduced normal t cell into a nude mouse what does it restore and what does this show?
the ability to reject allogenic grafts, showing that the T cells are responsible for acute rejection.
93
Acute renal graft rejection is caused by
alloreactive T cells responding to HLA differences between the donor and the recipient
94
What pathological effects can be seen on a kidney being attacked by alloreactive T cells?
Swelling, haemmorrhage, necrosis, develops over days, can be prevented by immunosuppressive drugs.
95
How do donor DCs from an allogenic graft stimulate rejection?
DCs from the donor travel in the blood to the 2ndary lymphoid tissue and stimulate effector T cells. These then travel to the donor organ via the blood and the graft is destroyed by effector t cells.
96
Direct allorecognition involves:
Recipient t cell recognition of donor DCs in the spleen or draining LN
97
Effector CD8 cells do what in acute rejection?
kill cells on the transplant
98
In acute rejection, how are t cells activated?
On recognition of allogenic HLA I or II
99
effector Th1 calls activate what in direct allorecognition?
macrophages to produce inflammatory cytokines; IL-1B, IL-6 and TNF. these recruit more leukocytes to the area of 'damage'
100
What doe CD4 t cells present with indirect allorecognition?
self-HLA present polymorphic graft HLA peptides (peptides formed by degradation in a host DC)
101
What are minor histocompatibility antigens?
peptides of polymorphic cellular proteins bound to MHC molecules that can lead to graft rejection when they are recognized by T cells.
102
Polymorphic self antigens (minor H antigens):
Differ in amino acid between individuals, so even if the individuals are major HC matched. These polymorphisms in self-peptides when presented by donor MHC will be recognized and cause rejection (slower than normal but still rejection = up to 60 days)
103
CD4 t cells responding to antigens presented via the indirect pathway can lead to:
macrophage activation, chronic inflammation, vascular damage and fibrosis.
104
The indirect pathway of allorecognition causes B cells to produce what?
Anti-HLA class I/II antibodies to reject the donor.
105
What do alloantibodies do?
They bind to donor MHC receptors on vascular endothelial cells and recruit inflammatory cells to the blood vessel walls of the transplanted organ, this increases damage and enables immune effectors to enter the tissue of the blood vessel wall and to inflict increasing damage.
106
Even though immunosuppressive drugs decrease the rate of acute rejection, they do not?
Change the rate of chronic rejection.
107
what is the half life of renal allografts?
8 years
108
What is kidney rejection caused by?
concentric arteriosclerosis of graft blood vessels with glomerular and tubular fibrosis and atrophy.
109
what causes chronic graft rejection:
macrophage infiltration and scarring. Ischemia-reperfusion injury at the time of graft with damaging effects occurring later
110
Problems associated with organ transplantation:
Availability of organs, graft rejection, disease attacking donor organ, toxicity of immunosuppressants ie cyclosporin A, risk of infection etc when on immunosuppressants to stop T cell activation, Infection from the donor organ.
111
HSC transplantation can be used to cure:
genetic disease that affect blood cells: SCID, SCA, chronic granulatomous disease.
Treatment for WBC malignancies: leukaemia and lymphoma
112
Why might recipients of HSC transplant receive conditioning treatment?
Myeloablative therapy, to prevent graft rejection by T cells to kill recipient HSCs in the BM and malignant WBCs and to make space for donor stem cells
113
How is bone marrow transplanted
initially by intravenous transfusion, pluripotent SC's from the donor BM engraft within the bone and then reconstitute all the haematopoietic lineages
114
What is graft versus host disease?
When donor effector T cells enter inflamed tissue and cause more damage. Due to interaction with host DC's causing them to proliferate. The donor effector cells enter tissue inflamed by the conditioning regiment and cause further tissue damage.
115
What does organs does GVHD affect and how?
Skin - reddening and exfoliation
Intestines - various degrees of diarrhoea
Liver - increased bilirubin levels.
116
How is GVHD treated?
Methotrexate - cytotoxic, inhibits DNA replication (affects T cells)
117
What does cyclosporin A bind to and inhibit?
immnophilin and inhibits calcineurin and hence T cell activation
118
Where can HSC's be sourced from for therapeutic use?
Bone marrow, Peripheral blood and in the future, umbilical cord blood.
119
What proteins with antigen processing and presentation ae encoded within the MHC locus?
TAP1 and TAP2
LMP7 and LMP2
TAPBP - tapasin
DMalpha and DMbeta encoding HLA-DM chains involved in MHC II peptide loading. .
120
What is the process of loading peptides into MHC I in the ER?
Calnexin + alpha
Calrectin + alpha + beta2 micro --> Tapesin: TAP
Proteosome degradation of cytosolic peptides and DRiPs. In cytosol.
peptides move into ER via TAP. and one associates with MHC I.
MHC I dissociates from TAP and is exported to the cell membrane.
121
How is HLA II associated with peptides and then presented on the cell surface?
Ii:MHC II in ER --> Acidified endosome
Ii cleaved, CLIP remains in peptide binding cleft.
Endocytosed antigen are degraded to peptides in endosome but CLIP blocks binding to MHC II.
HLA-DM binds to the MHC II = CLIP release and peptide binding. MHC II then travels to the cell surface.
122
Other proteins that are encoded in the MHC III region that are not involved in peptide pres on MHC:
C2 and C4 and factor B
TNF-alpha
Lymphotoxin A and B
21 hydroxylase
123
What contributes to the diversity of MHC molecules in an individual?
polygeny and polymorphisms.
124
How are HLA genes expressed?
Co-dominantly of maternal and paternal chromosomes
125
Which is the only functionally morphic HLA locus?
HLA-DRalpha.
126
Relative risk is:
Frequency of an allele in a patient population, compared to the frequency in the normal population.
127
What HLA association causes most autoimmune diseases?
HLA II alleles so CD4 T cells are linked most strongly.
128
Ankylosing spondylitis is:
Chronic inflammation of the axial skeleton and can involve fusion of the spinal vertebrae.
129
What allele is associated with increased relative risk of ankylosing spondylitis?
HLA.B27 with relative risk of 87.4
130
What causes TID?
Autoimmune T cell destruction of beta cells that produce insulin in the islets of langerhans in the pancreas.
131
HLA whats increase relative risk and what is protective in TID?
HLA-DQ8 - RR= 14
HLA-DQ2 + DQ8 - RR= 20
Protective = DQ6 RR=0.2
132
What is correlated with susceptibility and protection from TID?
Amino acids at position 57 of DQbeta. In people with resistance this position as an asparagine with forms a salt bridge with arg. In people with susceptibility this position is a valine/serine where no salt bridge forms.
133
What is hypothesised that HLA alleles affect autoimmune diseases by influencing T cell repertoire selection:
1. HLA alleles may bind to particular self peptides too poorly to drive negative self-reactive developing thymocytes leading to autoimmunity.
2. Self-reactive T cells may not be deleted during their development in the thymus
134
HLA alleles may not be the reason for autoimmune disease...
They may just be in linkage with a locus that is the true cause of the disease.
135
xenogenic
transplantation between different species
136
allogenic
Transplant between genetically distinct members of the same species
137
synergenic
genetically identical grafts
138
Cyclosporin A
inhibits T cel proliferation and stops IL-2 secretion
139
Tacrolimus
Dampens t cell responses
140
What is the most commonly transplanted tissue?
Blood
141
What is hyperacute rejection mediated by and how long does it take?
Antibody and complement, rapid/minutes
142
What is acute immune rejection mediated by and how long does it take?
CD4 and CD8 T cell mediated with antibody deposition, days to weeks
143
What causes chronic rejection of grafts and how long does it take?
macrophage infiltration and fibrosis. Months to years.
144
What is the mechanism that causes hyperacute rejection?
Vascular endothelial cells have blood group antigens on them. If the host already has antibodies against these antigens (donor blood group antigens) it will lead to rapid organ rejection. This occurs in minutes and is complement dependent. Antibodies to blood group antigens may arise as a result of: previous transplant, transfusion or pregnancy
145
What do anti-donor blood group antibodies bind to and cause?
They bind to the vascular endothelium of the graft initiating and inflammatory response that occludes the blood vessels, this causes the graft to haemorrhage and graft failure.
146
Immune responses to grafts are...?
Specific for antigenic epitopes that differ between donor and recipient due to genetic difference between these members of the same species.
147
First set rejection is:
what an allogenic graft is rejected from the recipient within 10-13 days
148
Second set rejection is when
When a recipient is grafted for the second time from the same donor and the graft is rejected at a much more rapid rate (6-8 days)
149
What do allogenic sin grafts onto nude mice show?
no rejection of the graft.
150
If you introduced normal t cell into a nude mouse what does it restore and what does this show?
the ability to reject allogenic grafts, showing that the T cells are responsible for acute rejection.
151
Acute renal graft rejection is caused by
alloreactive T cells responding to HLA differences between the donor and the recipient
152
What pathological effects can be seen on a kidney being attacked by alloreactive T cells?
Swelling, haemmorrhage, necrosis, develops over days, can be prevented by immunosuppressive drugs.
153
How do donor DCs from an allogenic graft stimulate rejection?
DCs from the donor travel in the blood to the 2ndary lymphoid tissue and stimulate effector T cells. These then travel to the donor organ via the blood and the graft is destroyed by effector t cells.
154
Direct allorecognition involves:
Recipient t cell recognition of donor DCs in the spleen or draining LN
155
Effector CD8 cells do what in acute rejection?
kill cells on the transplant
156
In acute rejection, how are t cells activated?
On recognition of allogenic HLA I or II
157
effector Th1 calls activate what in direct allorecognition?
macrophages to produce inflammatory cytokines; IL-1B, IL-6 and TNF. these recruit more leukocytes to the area of 'damage'
158
What doe CD4 t cells present with indirect allorecognition?
self-HLA present polymorphic graft HLA peptides (peptides formed by degradation in a host DC)
159
What are minor histocompatibility antigens?
peptides of polymorphic cellular proteins bound to MHC molecules that can lead to graft rejection when they are recognized by T cells.
160
Polymorphic self antigens (minor H antigens):
Differ in amino acid between individuals, so even if the individuals are major HC matched. These polymorphisms in self-peptides when presented by donor MHC will be recognized and cause rejection (slower than normal but still rejection = up to 60 days)
161
CD4 t cells responding to antigens presented via the indirect pathway can lead to:
macrophage activation, chronic inflammation, vascular damage and fibrosis.
162
The indirect pathway of allorecognition causes B cells to produce what?
Anti-HLA class I/II antibodies to reject the donor.
163
What do alloantibodies do?
They bind to donor MHC receptors on vascular endothelial cells and recruit inflammatory cells to the blood vessel walls of the transplanted organ, this increases damage and enables immune effectors to enter the tissue of the blood vessel wall and to inflict increasing damage.
164
Even though immunosuppressive drugs decrease the rate of acute rejection, they do not?
Change the rate of chronic rejection.
165
what is the half life of renal allografts?
8 years
166
What is kidney rejection caused by?
concentric arteriosclerosis of graft blood vessels with glomerular and tubular fibrosis and atrophy.
167
what causes chronic graft rejection:
macrophage infiltration and scarring. Ischemia-reperfusion injury at the time of graft with damaging effects occurring later
168
Problems associated with organ transplantation:
Availability of organs, graft rejection, disease attacking donor organ, toxicity of immunosuppressants ie cyclosporin A, risk of infection etc when on immunosuppressants to stop T cell activation, Infection from the donor organ.
169
HSC transplantation can be used to cure:
genetic disease that affect blood cells: SCID, SCA, chronic granulatomous disease.
Treatment for WBC malignancies: leukaemia and lymphoma
170
Why might recipients of HSC transplant receive conditioning treatment?
Myeloablative therapy, to prevent graft rejection by T cells to kill recipient HSCs in the BM and malignant WBCs and to make space for donor stem cells
171
How is bone marrow transplanted
initially by intravenous transfusion, pluripotent SC's from the donor BM engraft within the bone and then reconstitute all the haematopoietic lineages
172
What is graft versus host disease?
When donor effector T cells enter inflamed tissue and cause more damage. Due to interaction with host DC's causing them to proliferate. The donor effector cells enter tissue inflamed by the conditioning regiment and cause further tissue damage.
173
What does organs does GVHD affect and how?
Skin - reddening and exfoliation
Intestines - various degrees of diarrhoea
Liver - increased bilirubin levels.
174
How is GVHD treated?
Methotrexate - cytotoxic, inhibits DNA replication (affects T cells)
175
What does cyclosporin A bind to and inhibit?
immnophilin and inhibits calcineurin and hence T cell activation
176
Where can HSC's be sourced from for therapeutic use?
Bone marrow, Peripheral blood and in the future, umbilical cord blood.
177
What proteins with antigen processing and presentation ae encoded within the MHC locus?
TAP1 and TAP2
LMP7 and LMP2
TAPBP - tapasin
DMalpha and DMbeta encoding HLA-DM chains involved in MHC II peptide loading. .
178
What is the process of loading peptides into MHC I in the ER?
Calnexin + alpha
Calrectin + alpha + beta2 micro --> Tapesin: TAP
Proteosome degradation of cytosolic peptides and DRiPs. In cytosol.
peptides move into ER via TAP. and one associates with MHC I.
MHC I dissociates from TAP and is exported to the cell membrane.
179
How is HLA II associated with peptides and then presented on the cell surface?
Ii:MHC II in ER --> Acidified endosome
Ii cleaved, CLIP remains in peptide binding cleft.
Endocytosed antigen are degraded to peptides in endosome but CLIP blocks binding to MHC II.
HLA-DM binds to the MHC II = CLIP release and peptide binding. MHC II then travels to the cell surface.
180
Other proteins that are encoded in the MHC III region that are not involved in peptide pres on MHC:
C2 and C4 and factor B
TNF-alpha
Lymphotoxin A and B
21 hydroxylase
181
What contributes to the diversity of MHC molecules in an individual?
polygeny and polymorphisms.
182
How are HLA genes expressed?
Co-dominantly of maternal and paternal chromosomes
183
Which is the only functionally morphic HLA locus?
HLA-DRalpha.
184
Relative risk is:
Frequency of an allele in a patient population, compared to the frequency in the normal population.
185
What HLA association causes most autoimmune diseases?
HLA II alleles so CD4 T cells are linked most strongly.
186
Ankylosing spondylitis is:
Chronic inflammation of the axial skeleton and can involve fusion of the spinal vertebrae.
187
What allele is associated with increased relative risk of ankylosing spondylitis?
HLA.B27 with relative risk of 87.4
188
What causes TID?
Autoimmune T cell destruction of beta cells that produce insulin in the islets of langerhans in the pancreas.
189
HLA whats increase relative risk and what is protective in TID?
HLA-DQ8 - RR= 14
HLA-DQ2 + DQ8 - RR= 20
Protective = DQ6 RR=0.2
190
What is correlated with susceptibility and protection from TID?
Amino acids at position 57 of DQbeta. In people with resistance this position as an asparagine with forms a salt bridge with arg. In people with susceptibility this position is a valine/serine where no salt bridge forms.
191
What is hypothesised that HLA alleles affect autoimmune diseases by influencing T cell repertoire selection:
1. HLA alleles may bind to particular self peptides too poorly to drive negative self-reactive developing thymocytes leading to autoimmunity.
2. Self-reactive T cells may not be deleted during their development in the thymus
192
HLA alleles may not be the reason for autoimmune disease...
They may just be in linkage with a locus that is the true cause of the disease.
