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Flashcards in Major Histocompatibility Complex Deck (97):
1

Enumerate: Functions of T lymphocytes


•Defense against cell-associated microbes

•Inhibition of immune responses

•T cell functions require cell-cell interactions or cytokines that act at short range
 

2


Regulatory T cells suppress APCs or other lymphocytes is what function of T-lymphocyte



Inhibition of immune responses

 

3

What function of T-lymphocyte:
Phagocyting and killing infected cells and eliminate reservoirs of infection"


Defense against cell-associated microbes
 

4


Identify: helps phagocytes to kill ingested microbes and help B cells to make potent antibodies
 

Helper T cells

5


kills infected cells and eliminate reservoirs of infection
 

Cytotoxic T lymphocytes (CTLs) 

6

Enumerate challenges for T lymphocytes


•Very few lymphocytes in the body are specific for any one microbe (or antigen)

•Lymphocytes must be able to locate and respond to microbes that enter and reside anywhere in the body


•Lymphocytes must respond to each microbe in ways that are best able to eradicate that microbe
 

7

Specificity and diversity of antigen receptors: 


–the immune system recognizes and distinguishes between 106 - 109 antigens; the body contains ~ 1012 lymphocytes; therefore, few lymphocytes (~1,000) can recognize any one antigen and need to find that antigen 
 

8


Response to extracellular microbes?
 


 antibodies that promote phagocytosis; destruction in macrophages (need helper T cells)
 

9


Response to intracellular microbes? 
 

killing of infected cells (need CTLs)
 

10

Sites of Antigen entry

Skin

GIT

Respiratory tract

11

Sites of Initial Antigen capture

Lymphatic system

Peripheral blood circulation

12

Sites of antigen collection and capture

Lymph node

Spleen

13

Sites of microbe entry

 

skin, GI tract, airways

(organs with continuous

epithelia, populated

with dendritic cells).

Less often -- colonized

tissues, blood

14

Sites of lymphocyte activation:

peripheral

lymphoid organs (lymph

nodes, spleen), mucosal

and cutaneous lymphoid

tissues)

15

Antigens and naïve T cells come together in ???

lymphoid organs

16

Why are dendritic cells the most efficient APCs for initiating immune responses?


•Location
•Receptors for capturing and reacting to microbes:T
•Migration to T cell zones of lymphoid organs
•Maturation during migration
•Practical application
 

17

What do T cells see?


•All functions of T cells are mediated by interactions with other cells

•To ensure cellular communications, T cells see antigens NOT in the circulation but only when displayed by molecules on the surface of other cells

 

18

cells displaying the antigen are called 

APCs - Antigen Presenting Cells

19

Explain:

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During their maturation in the thymus, T cells whose TCRs see MHC molecules are selected to mature, i.e. mature T cells are MHC-restricted 

20

True or False: Mature B cells are MHC-restricted.

False.

During their maturation in the thymus, T cells whose TCRs see MHC molecules are selected to mature, i.e. mature T cells are MHC-restricted 

21

A genetic locus discovered on the basis of transplantation 

Major histocompatibility complex

22


Human MHC
 

 HLA (human leukocyte antigens)

23

Determine how antigens in different cellular compartments are recognized by different classes of T cells (CD4+ and CD8+) 

MHC molecules

24


Determines which protein antigens are recognized in different individuals
 

MHC

25


True of False: MHC genes are highly polychromic.
 

Negative

 

MHC genes are highly polymorphic; the MHC molecules in the population can display many different peptides
 

26

What are the antigen receptors of T cells that gives it dual specificities


 1. for peptide antigen (responsible for specificity of immune response)

 2. for MHC molecules (responsible for MHC restriction)
 

27


WHO first defined by discovering an ab response to circulating WBCs (HLA)
 

Jean Dausset

28

MHC is relevant in what clinical situations/conditions


•transfusion reactions, graft rejections, and autoimmune diseases 
 

29

True or False: MHC is Plays a role in humoral immunity

Negative 


MHC plays a role in both cellular and humoral immunity
 

30

True of False: 
MHC is found on all nucleated cells

TRUE 

31

Explain Classes of MHC genes.

A, B, C loci = class I

D locus = class II

Class III= in between class I and II, codes for complement, cytokine (TNF)

32

State the Possible alleles of ALL MHC genes 

HLA-A = 580 possible alleles

HLA-B = 921 possible alleles

HLA-C = 312 possible alleles

33

Crossover rate of MHC genes
 

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0.5% crossover rate
 

34


Refers to sets inherited from mother or father
 


Haplotype
 

35

True of False: MHC Alleles Are Sex-linked dominantly Expressed

 

Negative

 

MHC Alleles Are Co-dominantly Expressed
–Both mother and father alleles are expressed
 

36

Counterpart of the MHC in mouse/mice/rats/rodents/shits

H-2

37

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Centromere= left side, Telomere= right side

Class I MHC locus (A,B,C)-found on telomere

Class II MHC locus [DP, DM, DQ, DR, Proteasome genes (TAP 1,2 )]   - found on centromere

Class III MHC locus [Complement proteins (C4, Factor B, C2), Cytokines (lymphotoxin beta, TNF-alpha, LT)  - In between

38

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Structure of MHC Class I 


•Glycoprotein dimer
•Alpha chain = 45 000 MW; folded into three domains (α1, α2, α3)

    - α1, α2, α3 consists of 90 aa each 

    - transmembrane domain consists of  25   hydrophobic aa plus a short stretch of 5   hydrophilic aa and an anchor or 30 aa

•Β2 microglobulin = 12 000 MW: does not penetrate the cell membrane, but is essential for proper folding the alpha chain

Ag binding cleft :  hold peptides that are between 8-10 amino acids long

Alpha3:  reacts with cytotoxic T cells

39


Two most important to match for transplantation
 


HLA-A and HLA-B expressed at higher levels than HLA-C : two most important to match for transplantation
 

40


T or F: Class I is expressed on all nucleated cells
 

T

41

Class I is highly expressed on ____ and low or undetected in ___

 



•Highest expression on lymphocytes and low or undetected on liver hepatocytes, neural cells, muscle cell and sperm
 

42


Designated as E,F,G
 

Non-classical Class I Antigens

43


Expressed on trophoblast cells during the first trimester of pregnancy and help ensure tolerance for the fetus by protecting placental tissue from the action of NK cells
 

G non-classical Class I Antigen 

 

44


Do not function in antigen recognition but play a role in the immune response
 

Non-classical Class I antigen

45


Non-classical Class I antigens expressed on the surface of cells
 

E, F

46

T or : Class I is more restricted than Class II antigens

F

47


Found on Ag-presenting cells (monocytes, macrophages, dendritic cells) and B lymphocytes
 

Class II

48


Class II  gene expressed at the highest level
 


DR
 

49


Major class II genes


DP, DQ, DR
 

50


Most polymorphic Class II gene
 

DRβ has 18 possible alleles, therefore most polymorphic

51


Peptide binding site of Class II
 

  α1 and β1

52

Class II structure

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•Has α chain = 33 000 MW and β chain = 27 000 MW
•Both are anchored to the cell membrane
•Each has 2 domains
 

53


 Binding site for the CD4.
(Class II Ag) 
 


 b2 is the binding site for the CD4.
 

54


The a and b chains of the Class II Ag

 


.
•The a chains are the HLA DR
•The b chains are the HLA DQ and DP
 

55


Products of these genes play a regulatory role in antigen processing
 

Non-classical Class II

56

Non-classical Class II genes


DM, DN, DO
 

57

Location of polymorphic residues of Class I

a-1 and a-2 domains

58

Location of polymorphic residues of Class II

a-1 and b-1 domains

59

Class I MHC nomenclature for mouse

H-2K, H-2K, H-2L

60

Class II nomenlature for mouse

I-A, I-E

61

Size of peptide-binding cleft of Class I MHC

Accomodates peptides of 8-11 residues

62

Size of peptide-binding cleft of Class II MHC

Accomodates peptides of 10-30 residues or more

63

Binding site for T cell coreceptor of Class I MHC

a3 region binds CD8

64

Binding site for T cell coreceptor of Class II MHC

B2 binds CD4

65

Polypeptide chains of Class I MHC

a (44-47 kD)

b2-microglobulin (12 kD)

66

Polypeptide chains of Class II MHC

a (32-34 kD)

 B (29-32 kD)

67


Conversion of native antigen (large globular protein) into peptides capable of binding to MHC molecules
 

Antigen processing

68

Where does antigen processing occur?


Occurs in cellular compartments where MHC molecules are synthesized and assembled

–Determines how antigen in different cellular compartments generates peptides that are displayed by class I or class II MHC molecules
 

69

stimulates T helper cell in the case of bacterial infections

Class II

70


bind exogenous protein and present it to CD4 T   cells
 

Class II

71

watchdogs of viral, tumor & certain parasitic Ags   that are synthesized w/in the cell (endogenous Ags)

Class I

72


present peptides that have been   synthesized within the cell to CD8 T cells
 

Class I

73

Class I MHC pathway 

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Protein antigen in cytosol (cytoplasm) 

74

Class II MHC pathway

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Protein antigen in vesicles 

75

must be transported from ER to an endosomal compartment before they can bind peptides

Class II 

76

bind peptides while still in the ER

  binding stabilize association of α with   β2 microglobulin

Class I 

77

Both Class I and II molecules are synthesized in the ___ and for a time anchored in the ____

Both Class I and II molecules are synthesized in the RER, and for a time anchored in the ER

78

88 kd molecule, membrane bound in the ER, keeps the α chain partially folded while it awaits binding to β2 microglobulin, once β2 microglobulin binds it is released , and other chaperone molecules (calreticulin, tapason, and ERp57) are   associated w/complex and help to stabilize it for the peptide binding

Calnexin

79

Pathways of antigen processing

1. Antigen uptake

2. Antigen processing

3. MHC biosynthesis

4. Peptide-MHC association

80

 Explain: The class I MHC pathway of processing of endogenous cytosolic protein antigens

1. Production of proteins in the cytosol

2. Proteolytic degradation of proteins

3. Transport of peptides from cytosol to the ER

4. Assembly of peptide-class I complexes in the ER

5. Surface expression of peptide-class I complexes

81

Defective ribosomal products, peptides that fail to correctly fold and hence defective, about 20-70percent of all proteins synthesized by the cell, must be digested by the proteases (by proteasome)

DRiPs

82

Peptides derived from proteins found in the cytosol that are then degraded by the multiproteolytic _________complex into peptides. (Class I pathway)

Proteasome

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83

Brings the TAP transporters into close proximity to the newly formed MHC molecules and mediates interaction with them so that the peptides can be loaded to MHC class I

Tapasin

84

 are cooperatively folded into the newly synthesized MHC-I molecule. 

transporter associated with antigen processing (TAP)

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85


The first step in the activation of a CD8+ cellular program 
 

The MHC-I molecule allows the APC bearing a particular MHC–peptide complex to engage an appropriate alpha beta T cell receptor 

86


The activation of a CD8+ cellular program that might lead to ________________________.


cytolysis of the APC as a target and/or to the secretion of lymphokines by the T cell. 
 

87

The class II MHC pathway of processing of internalized vesicular protein antigens

1. Uptake of extracellular proteins into vesicular compartments of APC

2. Processing of internalized proteins in endosomal/lysosomal vesicles

3. Biosynthesis and transport of Class II MHC molecules to endosomes

4. Association of processed peptides with with Class II MHC molecules in vesicles

5. Expression of peptide-MHC molecule  on cell surface

88

31 kd protein that is made in excess to make sure all Class I molecules have Ii, prevents interaction of Class II binding site to the endogenous proteins of ER, helps to bring α and β chains together in the ER lumen and then moving them thru the golgi apparatus to the endocytic vesicles where digested Ag is found 

Invariant chain

89

serves as a chaperone to direct the ab heterodimer to an endosomal, acidic protein–processing location.  

invariant chain (Ii)

90

Help to mediate the reaction by removing the CLIP fragment

HLA-DM

91

Class II invariant chain peptide, attached to the peptide-binding cleft

CLIP

92

inside-out pathway

MHC-I

93

outside-in pathway

MHC-II

94

How does class I-associated antigen presentation

influence the nature of the host T cell response/Activation of a CD4+ cellular program might lead to

Macrophage activation: destruction of phagocytosed antigen

B cell antibody secretion: antibody binding to antigen

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95

How  class II-associated antigen presentation

influence the nature of the host T cell response

Killing of antigen-expressing taget cell

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96


Association of Human MHC Alleles and Risk for Diseases
 

 Disease   Associated HLA Allele               Relative Risk**

   Ankylosing Spondylitis*                B27                        90

   Hereditary Hemochromatosis      A3/B14                   90

   Insulin Dependent Diabetes*       DR4/DR3               20

   Multiple Sclerosis*                         DR2                       5

   Myasthenia Gravis*                        DR3                       10

   Rheumatoid Arthritis*                     DR4                       10

   Systemic Lupus Erythromatosis*   DR3                       5

* Autoimmune Disease  **Percent of Patients with Allele Divided by Percent of                       Non-Affected Persons with this Allele

   Narcolepsy  DR2                                    130

97

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