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HD > Immunology 13-15: Major Histocompatibility Complex, MHC. > Flashcards

Immunology 13-15: Major Histocompatibility Complex, MHC. Flashcards

1
Q

Define: cluster of genes found in all mammals?

A

Major histocompatibility complex (MHC).

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2
Q

The products of MHC play a role in discriminating what?

A

Discrimination self/non-self.

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3
Q

MHC participate in which immunity?

A

Both humoral and cell-mediated immunity.

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4
Q

MHC act as what?

A

Antigen presenting structures (APCs).

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5
Q

In humans MHC is found where?

A

On the short arm (p arm) of chromosome 6.

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6
Q

MHC in humans is referred to as what?

A

HLA complex (human leucocyte antigen).

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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.

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8
Q

List the types of MHC?

A

1- class 1 MHC.
2- class 2 MHC.
3- class 3 MHC.

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9
Q

Histocompatibility genes are inherited as what?

A

A group (haplotype), one from each parent.

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10
Q

MHC genes are __________ expressed in each individual?

A

Co-dominantly.

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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.

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12
Q

Each individual inherits a maximum of what?

A

Two alleles for each locus.

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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.

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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

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15
Q

List the gene loci in classical HLA 1 genes?

A

HLA-A, B, C

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16
Q

List the gene loci in non-classical HLA 1 genes?

A

HLA-E, F, G

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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.
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18
Q

Some NK receptors recognize only HLA-____(E, F or G?) molecules.

A

HLA-F.

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19
Q

HLA-____ (E, F or G?) expressed at high levels on maternal/fetal interface, role remains unclear.

A

HLA-G.

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20
Q

Less known about HLA-____ (E, F or G?)

A

HLA-F.

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21
Q

List the gene loci in classical HLA 2?

A

HLA-DP, DQ, DR subregions.

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22
Q

List the class 2-like genes in MHC class 2 gene region?

A

HLA-DM and HLA-DO.

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23
Q

What is the function of class 2 like genes?

A

Regulate peptides loading onto classical MHC class 2 molecules.

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24
Q

Which MHC class is not a part of the HLA complex?

A

MHC Class 3.

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25
Q

Where is MHC class 3 located?

A

Within the HLA region (between D and B regions).

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26
Q

Which genes are present in MHC class 3?

A

1- complement genes —— C4, C2, and B.
2- inflammation-associated genes —— TNF-alpha and beta.

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27
Q

Which MHC class has no role in graft rejection?

A

MHC class 3.

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28
Q

Diversity of MHC is due to what?

A

Polymorphism or the presence of multiple alleles in the population for a given locus.

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29
Q

The sequence variation between MHC alleles is clustered to the _______ (class__) and ______(class__) regions.

A

Alpha 1/alpha 2 (class 1).
Alpha 1/ beta 1 (class 2).

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30
Q

The high level of allelism creates diversity within a ______ (thus restricting ______) but does not produce diversity within an ______.

A

Creates diversity within a species (thus restricting allografting).
Does not produce diversity within an individual.

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31
Q

Where is class 1 MHC gene distributed and what is its major function?

A

Glycoprotein expressed on all nucleated cells (not RBCs or platelets).
Major function is to present peptide Ags to Tc.

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32
Q

Where is class 2 MHC gene distributed and what is its major function?

A

Glycoprotein expressed on APC (dendritic cells, macrophages, B cells, other cells).
Major function is to present processed Ags peptide to Th.

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33
Q

Where is class 3 MHC gene distributed and what is its major function?

A

Some complement components (C2, C4a, C4b, Factor B).
Transporter protein.

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34
Q

MHC gene expression is increased by what?

A

1- cytokines as IFNs and TNF.
2- transcription factors (trans activator).

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35
Q

MHC gene expression is decreased by what?

A

Some viruses as CMV, HBV, Ad12.

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36
Q

The class 1 and 2 MHC molecules belong to a group of molecules known as _________ _________ ______, which includes __________, ____, ____, _____ and others.

A

Immunoglobulin supergene family.
Includes immunoglobulin’s, TCR, CD4, CD8 and others.

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37
Q

Tc cells recognize peptides bound to class ___ MHC molecules,
Th cells recognize peptides bound to class ___ MHC molecules.

A

Tc > class 1 MHC molecules.
Th > class 2 MHC molecules.

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38
Q

What is the general structure of class 1 MHC? And how many regions does it have?

A

Two polypeptide chains, a long alpha chain and a short beta (beta 2 microglobulin).
It has 4 regions.

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39
Q

List the 4 regions of class 1 MHC?

A

1- cytoplasmic region.
2- transmembrane region.
3- a highly conserved alpha 3 domain.
4- a highly polymorphic peptide binding region.

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40
Q

The cytoplasmic region of class 1 MHC contains sites for what?

A

Phosphorylation and binding to cytoskeletal elements.

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41
Q

What does the transmembrane region of class 1 MHC contains?

A

Hydrophobic amino acids.

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42
Q

The highly conserved alpha 3 domain of class 1 MHC binds what?

A

Binds CD8.

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43
Q

The highly polymorphic peptide binding region in MHC class 1 is formed from which domains?

A

Formed from the alpha 1 and alpha 2 domains.

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44
Q

___________ helps stablize the conformation of class 1 MHC?

A

B2- microglobulin.

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45
Q

What is the general structure of class 2 MHC? And how many regions does it have?

A

Two polypeptide chains, alpha and beta, of roughly equal lengths.
It has 4 regions.

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46
Q

List the 4 regions of class 2 MHC?

A

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.

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47
Q

Which sites does the cytoplasmic region of class 2 MHC contains?

A

Phosphorylation and binding to cytoskeletal elements.

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48
Q

Which region does the transmembrane region of class 2 MHC contains?

A

Hydrophobic amino acids.

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49
Q

What does the highly conserved beta 2 domains of class 2 MHC bind?

A

CD4 binds.

50
Q

What is the highly polymorphic peptide binding region of class 2 MHC formed from?

A

Alpha 1 and beta 1 domains.

51
Q

T cells are _____ restricted.

A

MHC restricted. (i.e they must recognize antigen presented on MHC).

52
Q

CD4 T cells are class _____ MHC-restrictred.

A

CD4 > class 2 MHC.

53
Q

CD8 T cells are class _____ MHC-restrictred.

A

CD8 > class 1 MHC.

54
Q

An immunological synapse is also known as a ___________ _______.

A

Supramolecular adhesion (activation) complex (SMAC).

55
Q

What is an immunological synapse?

A

It is cell to cell contact between T cell, its co-receptors and APC.

56
Q

The site of contact in an immunological synapse is composed of ______ _____ with each containing _______ ______ of ______.

A

Composed of concentric rings with each containing segregated cluster of proteins.

57
Q

List the 3 concentric rings in immunological synapses?

A

1- central supramolecular activation complex (cSMAC).
2- peripheral supramolecular activation complex (pSMAC).
3- distal supramolecular activation complex (dSMAC).

58
Q

What is cSMAC comprised of?

A

TCR, its co-receptors (CD4 or CD8), CD2, CD28, CTLA-4.

59
Q

What is pSMAC comprised of?

A

LFA 1, ICAM-1 and talin.

60
Q

What is dSMAC comprised of?

A

Enriched in CD43, CD44 and CD45.

61
Q

List the 4 functions of immunological synapse?

A

1- enhancing signaling.
2- terminating signaling and/or effector function.
3- balancing signaling.
4- directing secretion.

62
Q

List the 5 biological activities of HLA?

A

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
Q

Endogenous Ag is presented to _______ T cell by MHC ___.

A

Endogenous Ag > presented to CD8 T cell > by MHC 1.

64
Q

Exogenous Ag is presented to _______ T cell by MHC ___.

A

Exogenous Ag > presented to CD4 T cell > by MHC 2.

65
Q

Give an example of biological activity of HLA in forensic medicine?

A

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
Q

The risk of developing immunological diseases is often influenced by the ________ or _________ of specific MHC alleles.

A

Presence or absence.

67
Q

Which MHC is associated with SLE?

A

HLA-DR2/DR3.

68
Q

Which MHC is associated with RA?

A

HLA-DR4.

69
Q

Which MHC is associated with MS?

A

HLA-B7 and DR2.

70
Q

Which MHC is associated with type 1 diabetes?

A

HLA-B8, DR3/DR4.

71
Q

Which MHC is associated with ankylosing spondylitis?

A

HLA-B27.

72
Q

What are minor histocompatibility antigens (MiHA)?

A

They are receptors on the cellular surface of donated organs.

73
Q

What donated organs have MiHA receptors on their cellular surface?

A

Include blood group antigens, tissue and organ antigens, normal cellular constituents.

74
Q

What do MiHA participate in?

A

They participate in rejection but to lesser degree.

75
Q

Disparity of several minor antigens may result in ________, Even when?

A

May result in rejection.
Even when MHC antigens are compatible between donor and recipient.

76
Q

MiHA peptides are normally around __________ amino acids in length and are bound to which MHC classes?

A

Around 9-12 amino acids in length.
And are bound to both MHC classes.

77
Q

About a _______ of the characterized MiHA comes from the ____ chromosome.

A

A third comes from the Y chromosome.

78
Q

List the 5 type of laboratory HLA typing (tissue typing)?

A

1- DNA sequencing.
2- RFLP: Restriction Fragment Length Polymorphism.
3- Microcytotoxicity assay (MCT).
4- Mixed Lymphocyte Reaction (MLR).
5- Flow cytometry or ELISA.

79
Q

Why is HLA typing (tissue typing) used?

A

To determine the closest MHC match between donor and recipient.

80
Q

How is DNA sequencing done?

A

Using PCR and specific prob to detect the different alleles.

81
Q

Which type of HLA typing (Tissue typing) is highly specific and highly sensitive?

A

DNA sequencing.

82
Q

How is RFLP HLA typing done?

A

Digestion of genomic DNA with certain restriction enzymes followed by hybridization with radio-labeled MHC gene probes.

83
Q

List the 5 steps of microcyrotoxicity assay (MCT)?

A

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
Q

Which stain determines cell death in microcytotoxicity assay (MCT) in HLA typing?

A

Ethidium bromide stain.

85
Q

Specific Ig binds to which protein in microcytotoxicity assay (MCT) HLA typing?

A

Specific Ig binds to the polymorphic protein of the HLA.

86
Q

What is mixed lymphocyte reaction (MLR) used for?

A

Used to quantify the degree of MHC 2 compatibility between potential donor and recipient.

87
Q

What are the 4 steps of mixed lymphocyte reaction (MLR) HLA typing?

A

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
Q

How is flow cytometry or ELISA for HLA typing done?

A

By using panels of monoclonal antibodies to different MHC alleles.

89
Q

Definition: the transfer of living cells, tissues and organs from one part of the body to another or from one individual to another?

A

Graft or transplant.

90
Q

List the 4 types of grafts?

A

1- autografts.
2- syngeneic (isografts).
3- allografts.
4- xenografts.

91
Q

Definition: graft transplanted from one site on the body to another in the same person.

A

Autografts.

92
Q

Definition: grafts between identical twins.

A

Syngeneic (isografts).

93
Q

Definition: transplants between individuals that are not identical twins, but belong to the same species.

A

Allografts.

94
Q

Definition: grafts taken from another animal species.

A

Xenografts.

95
Q

What is the success rate of autografts?

A

Permanently accepted.

96
Q

What is the success rate of allografts?

A

Usually rejected unless the recipient is given immunosuppressives.

97
Q

What is the success rate of syngeneic (isografts)?

A

Almost accepted.

98
Q

What is the success rate of xenografts?

A

Always rejected.

99
Q

List the 3 types of graft rejections?

A

1- hyperacute rejection.
2- acute rejection.
3- chronic reaction.

100
Q

What is hypercute rejection due to? And how long does it take?

A

Due to preformed antibodies to HLA and ABO blood group system.
Takes hours or first days.

101
Q

What is acute rejection due to? And how long does it take?

A

T cell mediated.
Takes days or weeks.

102
Q

What are the 2 mechanisms of chronic rejection? And how long does it take?

A

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
Q

What happens to a second graft by the same donor after the first graft has been rejected by the recipient?

A

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
Q

What is the role of Tc cells in graft rejection?

A

Tc cells destroy graft cells by direct contact.

105
Q

What is the role of Th cells in graft rejection?

A

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
Q

What is the role of B cells in graft rejection?

A

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
Q

What is the role of immune complexes in graft rejection?

A

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
Q

Which type of immune cells are critical in graft rejection?

A

T cells.

109
Q

Definition: a common complication when an immunologically competent graft (bone marrow) is transplanted into an immunologically suppressed recipient (host).

A

Graft versus host (GVH).

110
Q

What causes graft versus host (GVH)?

A

Due to the presence of alloreactive T cells in the graft (the graft cells survive and react against the host cells).

111
Q

What are the results of graft versus host (GVH)?

A

Severe tissue damage, fever, pancytopenia, weight loss, rash, diarrhea, hepatosplenomegaly and death.

112
Q

What is graft versus host (GVH) manifested by?

A

Manifested by a marked rise of several cytokines in patient’s serum (IFN-gamma, TNF, IL-1, IL-2, IL-4).

113
Q

What is graft versus host (GVH) avoided by?

A

Avoided by careful typing, removal of mature T cells from the graft and by immunosuppressive drugs.

114
Q

List the 4 ways we can prevent graft rejection?

A

1- proper choice of donors.
2- postoperative immunosuppressive therapy.
3- antigen specific immunosuppression.
4- TLI-total lymphoid irradiation.

115
Q

How can we make a proper choice of donors to prevent graft rejection? (3)

A

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
Q

How can postoperative immunosuppressive therapy be used to prevent graft rejection? (4)

A

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
Q

List 3 immunosuppressive drugs that can be used to prevent graft rejection? And how do they work?

A

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
Q

How does antigen specific immunosuppression prevent graft rejection?

A

By induction of tolerance to the graft antigen is under trial.

119
Q

How does TLI-total lymphoid irradiation prevent graft rejection?

A

Recipient’s lymphoid tissues are irradiated before grafting (bone marrow is not).

120
Q

Why is the fetus not rejected? (4)

A

1- protected site.
2- progesterone > immunosuppressive.
3- placenta express FasL.
4- local immunosuppression.

121
Q

What are the local immunosuppression factors that make the fetus not rejected? and what do they express?

A

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
Q

What does the outer layer of placenta not express?

A

It doesn’t express MHC class 1 and class 2 antigens.

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