Immunology 13-15: Major Histocompatibility Complex, MHC. Flashcards
1
Q
Define: cluster of genes found in all mammals?
A
Major histocompatibility complex (MHC).
2
Q
The products of MHC play a role in discriminating what?
A
Discrimination self/non-self.
3
Q
MHC participate in which immunity?
A
Both humoral and cell-mediated immunity.
4
Q
MHC act as what?
A
Antigen presenting structures (APCs).
5
Q
In humans MHC is found where?
A
On the short arm (p arm) of chromosome 6.
6
Q
MHC in humans is referred to as what?
A
HLA complex (human leucocyte antigen).
7
Q
List the significance of the MHC?
A
1- role in immune response.
2- role in organ transplantation.
3- role in predisposition to disease.
8
Q
List the types of MHC?
A
1- class 1 MHC.
2- class 2 MHC.
3- class 3 MHC.
9
Q
Histocompatibility genes are inherited as what?
A
A group (haplotype), one from each parent.
10
Q
MHC genes are __________ expressed in each individual?
A
Co-dominantly.
11
Q
How does a heterozygous human inherit MHC?
A
One paternal and one maternal haplotype, each containing three class-I (B, C and A) and three class-II (DP, DQ and DR) loci.
12
Q
Each individual inherits a maximum of what?
A
Two alleles for each locus.
13
Q
List the regions in class 1, 2 and 3?
A
1- class 1: B,C and A.
2- class 3: C4, C2, and BF.
3- class 2: DP, DQ, and DR.
14
Q
List the gene products of class 1,2 and 3 MHC?
A
1- Class 2: DP alpha beta, DQ alpha beta and DR alpha beta.
2- Class 3: C’ proteins, TNF alpha and TNF beta.
3- Class 1: HLA-B, HLA-C and HLA-A
15
Q
List the gene loci in classical HLA 1 genes?
A
HLA-A, B, C
16
Q
List the gene loci in non-classical HLA 1 genes?
A
HLA-E, F, G
17
Q
List the properties of non-classical HLA 1 genes?
A
- encodes proteins similar to classical molecules in sequence and structure.
- no such polymorphism.
- often specialized antigen-presenting features.
18
Q
Some NK receptors recognize only HLA-____(E, F or G?) molecules.
A
HLA-F.
19
Q
HLA-____ (E, F or G?) expressed at high levels on maternal/fetal interface, role remains unclear.
A
HLA-G.
20
Q
Less known about HLA-____ (E, F or G?)
A
HLA-F.
21
Q
List the gene loci in classical HLA 2?
A
HLA-DP, DQ, DR subregions.
22
Q
List the class 2-like genes in MHC class 2 gene region?
A
HLA-DM and HLA-DO.
23
Q
What is the function of class 2 like genes?
A
Regulate peptides loading onto classical MHC class 2 molecules.
24
Q
Which MHC class is not a part of the HLA complex?
A
MHC Class 3.
25
Where is MHC class 3 located?
Within the HLA region (between D and B regions).
26
Which genes are present in MHC class 3?
1- complement genes —— C4, C2, and B.
2- inflammation-associated genes —— TNF-alpha and beta.
27
Which MHC class has no role in graft rejection?
MHC class 3.
28
Diversity of MHC is due to what?
Polymorphism or the presence of multiple alleles in the population for a given locus.
29
The sequence variation between MHC alleles is clustered to the _______ (class__) and ______(class__) regions.
Alpha 1/alpha 2 (class 1).
Alpha 1/ beta 1 (class 2).
30
The high level of allelism creates diversity within a ______ (thus restricting ______) but does not produce diversity within an ______.
Creates diversity within a species (thus restricting allografting).
Does not produce diversity within an individual.
31
Where is class 1 MHC gene distributed and what is its major function?
Glycoprotein expressed on all nucleated cells (not RBCs or platelets).
Major function is to present peptide Ags to Tc.
32
Where is class 2 MHC gene distributed and what is its major function?
Glycoprotein expressed on APC (dendritic cells, macrophages, B cells, other cells).
Major function is to present processed Ags peptide to Th.
33
Where is class 3 MHC gene distributed and what is its major function?
Some complement components (C2, C4a, C4b, Factor B).
Transporter protein.
34
MHC gene expression is increased by what?
1- cytokines as IFNs and TNF.
2- transcription factors (trans activator).
35
MHC gene expression is decreased by what?
Some viruses as CMV, HBV, Ad12.
36
The class 1 and 2 MHC molecules belong to a group of molecules known as _________ _________ ______, which includes __________, ____, ____, _____ and others.
Immunoglobulin supergene family.
Includes immunoglobulin’s, TCR, CD4, CD8 and others.
37
Tc cells recognize peptides bound to class ___ MHC molecules,
Th cells recognize peptides bound to class ___ MHC molecules.
Tc > class 1 MHC molecules.
Th > class 2 MHC molecules.
38
What is the general structure of class 1 MHC? And how many regions does it have?
Two polypeptide chains, a long alpha chain and a short beta (beta 2 microglobulin).
It has 4 regions.
39
List the 4 regions of class 1 MHC?
1- cytoplasmic region.
2- transmembrane region.
3- a highly conserved alpha 3 domain.
4- a highly polymorphic peptide binding region.
40
The cytoplasmic region of class 1 MHC contains sites for what?
Phosphorylation and binding to cytoskeletal elements.
41
What does the transmembrane region of class 1 MHC contains?
Hydrophobic amino acids.
42
The highly conserved alpha 3 domain of class 1 MHC binds what?
Binds CD8.
43
The highly polymorphic peptide binding region in MHC class 1 is formed from which domains?
Formed from the alpha 1 and alpha 2 domains.
44
___________ helps stablize the conformation of class 1 MHC?
B2- microglobulin.
45
What is the general structure of class 2 MHC? And how many regions does it have?
Two polypeptide chains, alpha and beta, of roughly equal lengths.
It has 4 regions.
46
List the 4 regions of class 2 MHC?
1- cytoplasmic region.
2- transmembrane region.
3- a highly conserved alpha 2.
4- a highly conserved beta 2 domains.
4- a highly polymorphic peptide binding region.
47
Which sites does the cytoplasmic region of class 2 MHC contains?
Phosphorylation and binding to cytoskeletal elements.
48
Which region does the transmembrane region of class 2 MHC contains?
Hydrophobic amino acids.
49
What does the highly conserved beta 2 domains of class 2 MHC bind?
CD4 binds.
50
What is the highly polymorphic peptide binding region of class 2 MHC formed from?
Alpha 1 and beta 1 domains.
51
T cells are _____ restricted.
MHC restricted. (i.e they must recognize antigen presented on MHC).
52
CD4 T cells are class _____ MHC-restrictred.
CD4 > class 2 MHC.
53
CD8 T cells are class _____ MHC-restrictred.
CD8 > class 1 MHC.
54
An immunological synapse is also known as a ___________ _______.
Supramolecular adhesion (activation) complex (SMAC).
55
What is an immunological synapse?
It is cell to cell contact between T cell, its co-receptors and APC.
56
The site of contact in an immunological synapse is composed of ______ _____ with each containing _______ ______ of ______.
Composed of concentric rings with each containing segregated cluster of proteins.
57
List the 3 concentric rings in immunological synapses?
1- central supramolecular activation complex (cSMAC).
2- peripheral supramolecular activation complex (pSMAC).
3- distal supramolecular activation complex (dSMAC).
58
What is cSMAC comprised of?
TCR, its co-receptors (CD4 or CD8), CD2, CD28, CTLA-4.
59
What is pSMAC comprised of?
LFA 1, ICAM-1 and talin.
60
What is dSMAC comprised of?
Enriched in CD43, CD44 and CD45.
61
List the 4 functions of immunological synapse?
1- enhancing signaling.
2- terminating signaling and/or effector function.
3- balancing signaling.
4- directing secretion.
62
List the 5 biological activities of HLA?
1- induce the differentiation of T cell.
2- present antigen to initiate immune response.
3- HLA transplantation.
4- HLA in forensic medicine.
5- some diseases are associated with HLA genotypes.
63
Endogenous Ag is presented to _______ T cell by MHC ___.
Endogenous Ag > presented to CD8 T cell > by MHC 1.
64
Exogenous Ag is presented to _______ T cell by MHC ___.
Exogenous Ag > presented to CD4 T cell > by MHC 2.
65
Give an example of biological activity of HLA in forensic medicine?
Paternity testing: if a man and child share HLA haplotype, then there is a possibility that the man may be the father but not proven.
(We need at least 50% similarity with the father, other 50% comes from the mother).
66
The risk of developing immunological diseases is often influenced by the ________ or _________ of specific MHC alleles.
Presence or absence.
67
Which MHC is associated with SLE?
HLA-DR2/DR3.
68
Which MHC is associated with RA?
HLA-DR4.
69
Which MHC is associated with MS?
HLA-B7 and DR2.
70
Which MHC is associated with type 1 diabetes?
HLA-B8, DR3/DR4.
71
Which MHC is associated with ankylosing spondylitis?
HLA-B27.
72
What are minor histocompatibility antigens (MiHA)?
They are receptors on the cellular surface of donated organs.
73
What donated organs have MiHA receptors on their cellular surface?
Include blood group antigens, tissue and organ antigens, normal cellular constituents.
74
What do MiHA participate in?
They participate in rejection but to lesser degree.
75
Disparity of several minor antigens may result in ________, Even when?
May result in rejection.
Even when MHC antigens are compatible between donor and recipient.
76
MiHA peptides are normally around __________ amino acids in length and are bound to which MHC classes?
Around 9-12 amino acids in length.
And are bound to both MHC classes.
77
About a _______ of the characterized MiHA comes from the ____ chromosome.
A third comes from the Y chromosome.
78
List the 5 type of laboratory HLA typing (tissue typing)?
1- DNA sequencing.
2- RFLP: Restriction Fragment Length Polymorphism.
3- Microcytotoxicity assay (MCT).
4- Mixed Lymphocyte Reaction (MLR).
5- Flow cytometry or ELISA.
79
Why is HLA typing (tissue typing) used?
To determine the closest MHC match between donor and recipient.
80
How is DNA sequencing done?
Using PCR and specific prob to detect the different alleles.
81
Which type of HLA typing (Tissue typing) is highly specific and highly sensitive?
DNA sequencing.
82
How is RFLP HLA typing done?
Digestion of genomic DNA with certain restriction enzymes followed by hybridization with radio-labeled MHC gene probes.
83
List the 5 steps of microcyrotoxicity assay (MCT)?
1- anti-HLA serum, or monoclonal antibody is mixed with live lymphocytes.
2- specific Ig binds to the polymorphic protein of the HLA.
3- exogenous complement is added to the well which will result in lysis of cells to which antibody has been bound.
4- cell death is determined by ethidium bromide stain.
5- failed to identify certain alleles were detected.
(Lysis = compatible).
84
Which stain determines cell death in microcytotoxicity assay (MCT) in HLA typing?
Ethidium bromide stain.
85
Specific Ig binds to which protein in microcytotoxicity assay (MCT) HLA typing?
Specific Ig binds to the polymorphic protein of the HLA.
86
What is mixed lymphocyte reaction (MLR) used for?
Used to quantify the degree of MHC 2 compatibility between potential donor and recipient.
87
What are the 4 steps of mixed lymphocyte reaction (MLR) HLA typing?
1- “stimulator” lymphocytes from donor are first killed by irradiation and then mixed with live “responder” lymphocytes from the recipient > cell culture.
2- if MHC 2 antigens on the two cell are same > no reaction with donor and recipient > graft can be transplanted to the recipient.
3- if MHC 2 on two cell are different > the recipient T cell rapidly proliferate which can be measured by the uptake of (‘H) thymidine (radioactive nucleotides) into synthesized nuclear DNA.
4- the greater the amount of DNA synthesis in the responder the more foreign are MHC 2 of donor cells > graft is likely rejected.
88
How is flow cytometry or ELISA for HLA typing done?
By using panels of monoclonal antibodies to different MHC alleles.
89
Definition: the transfer of living cells, tissues and organs from one part of the body to another or from one individual to another?
Graft or transplant.
90
List the 4 types of grafts?
1- autografts.
2- syngeneic (isografts).
3- allografts.
4- xenografts.
91
Definition: graft transplanted from one site on the body to another in the same person.
Autografts.
92
Definition: grafts between identical twins.
Syngeneic (isografts).
93
Definition: transplants between individuals that are not identical twins, but belong to the same species.
Allografts.
94
Definition: grafts taken from another animal species.
Xenografts.
95
What is the success rate of autografts?
Permanently accepted.
96
What is the success rate of allografts?
Usually rejected unless the recipient is given immunosuppressives.
97
What is the success rate of syngeneic (isografts)?
Almost accepted.
98
What is the success rate of xenografts?
Always rejected.
99
List the 3 types of graft rejections?
1- hyperacute rejection.
2- acute rejection.
3- chronic reaction.
100
What is hypercute rejection due to? And how long does it take?
Due to preformed antibodies to HLA and ABO blood group system.
Takes hours or first days.
101
What is acute rejection due to? And how long does it take?
T cell mediated.
Takes days or weeks.
102
What are the 2 mechanisms of chronic rejection? And how long does it take?
1- cell-mediated.
2- deposition of antibodies or antigen-antibody complexes with subsequent obliteration of blood vessels and interstitial fibrosis.
Takes months or years.
103
What happens to a second graft by the same donor after the first graft has been rejected by the recipient?
Once a graft has been rejected a second graft from the same donor, or a donor with the same histocompatibility antigens, will be rejected in a much shorter time.
104
What is the role of Tc cells in graft rejection?
Tc cells destroy graft cells by direct contact.
105
What is the role of Th cells in graft rejection?
Th cells secrete cytokines that attract and activate macrophages, NK cells and polymorphs leading to cellular infiltration and destruction of the graft.
I.e. type IV hypersensitivity reactions.
106
What is the role of B cells in graft rejection?
B cells recognize foreign Ag on the graft and produce antibodies which bind to graft cells, and (type II hypersensitivity reactions):
- activate complement causing cell lysis.
- enhance phagocytosis, i.e. opsonization.
- lead to ADCC by macrophages, NK cells and polymorphs.
107
What is the role of immune complexes in graft rejection?
Immune complex disposition on the vessel walls induce platelet aggregation, and microthombi formation leading to ischemia and necrosis of the graft, i.e. type III hypersensitivity reactions.
108
Which type of immune cells are critical in graft rejection?
T cells.
109
Definition: a common complication when an immunologically competent graft (bone marrow) is transplanted into an immunologically suppressed recipient (host).
Graft versus host (GVH).
110
What causes graft versus host (GVH)?
Due to the presence of alloreactive T cells in the graft (the graft cells survive and react against the host cells).
111
What are the results of graft versus host (GVH)?
Severe tissue damage, fever, pancytopenia, weight loss, rash, diarrhea, hepatosplenomegaly and death.
112
What is graft versus host (GVH) manifested by?
Manifested by a marked rise of several cytokines in patient’s serum (IFN-gamma, TNF, IL-1, IL-2, IL-4).
113
What is graft versus host (GVH) avoided by?
Avoided by careful typing, removal of mature T cells from the graft and by immunosuppressive drugs.
114
List the 4 ways we can prevent graft rejection?
1- proper choice of donors.
2- postoperative immunosuppressive therapy.
3- antigen specific immunosuppression.
4- TLI-total lymphoid irradiation.
115
How can we make a proper choice of donors to prevent graft rejection? (3)
1- ABO blood group compatibility.
2- tissue typing for HLA (HLA typing).
3- cross matching: to test the recipients’ serum for the presence of preformed antibodies against the donor’s HLA antigens.
116
How can postoperative immunosuppressive therapy be used to prevent graft rejection? (4)
1- most drugs are nonspecific.
2- monoclonal antibodies (anti-CD3, anti-IL-2) that block T cell response.
3- antibody therapy to block co-stimulatory molecules (anti-CD40L).
4- immunosuppressive drugs.
117
List 3 immunosuppressive drugs that can be used to prevent graft rejection? And how do they work?
1- Cyclosporin A, Rapamycin: inhibit T cell activation and blocks cytokine production.
2- Corticosteroids: anti-inflammatory.
3- Methotrexate: are mitotic inhibitors that inhibit DNA synthesis and block T cell growth.
118
How does antigen specific immunosuppression prevent graft rejection?
By induction of tolerance to the graft antigen is under trial.
119
How does TLI-total lymphoid irradiation prevent graft rejection?
Recipient’s lymphoid tissues are irradiated before grafting (bone marrow is not).
120
Why is the fetus not rejected? (4)
1- protected site.
2- progesterone > immunosuppressive.
3- placenta express FasL.
4- local immunosuppression.
121
What are the local immunosuppression factors that make the fetus not rejected? and what do they express?
1- uterine epithelium and trophoblast secrete cytokines that suppress TH1.
2- placenta secretes a substance that depletes: tryptophan: T cell starvation, tolerance of paternal MHC antigens.
122
What does the outer layer of placenta not express?
It doesn’t express MHC class 1 and class 2 antigens.
