Self Non-Self Discrimination Flashcards Preview

Microbiology and Immunology > Self Non-Self Discrimination > Flashcards

Flashcards in Self Non-Self Discrimination Deck (73):
1

What is tolerance?

mechanism by which lymphocytes with self-antigens are either removed or controlled

2

Where are central tolerance mechanisms active?

Where the lymphocyte is devloping: thymus for T cells and bone marrow for B cells

3

Where are peripheral tolerance mechanisms active?

secondary lymphoid tissue (nodes; adaptive response) or peripheral tissues (reaction or trigger)

4

What are the two types of tolerance?

central and peripheral

5

What are the mechanisms used to induce tolerance?

delete: eliminate the cell
anergize: turn off the cell
ignore: ignore the trigger
regulate: contain the problem (Tregs)

6

Tregs are a subset of

T helper/CD4+ T cells

7

What are the mechanisms of central B cell tolerance?

Deletion and anergy

8

What are the mechanisms of peripheral B cell tolerance?

Ignorance, anergy, death (lack of co-stimulation/T cell help)

9

T/F B cell tolerance is less efficient than T cell tolerance

True

10

Why is B cell tolerance less efficient than T cell tolerance?

it's common to identify self-Ag Abs in normal healthy people - ie in diagnosing viral infections; they tend to be transient

11

B cell tolerance occurs

in the bone marrow during development

12

Normal mature B cells are produced from

non-self-reacting immature B cells that appropriately express Ag receptors on the cell surface (ie no cross-linking)

13

Clonally ignorant B cells result from

Immature B cells with low-affinity binding for self-antigens that is not strong enough to initiate cross-linking that activates the molecule tf it matures but does not react to its Ags

14

Anergic B cells result from

soluble self-molecules (eg serum proteins) with inefficient cross linking that is still able to trigger the cell; this inappropriate activation turns the cell off (anergy)

15

B cell apoptosis occurs in tolerance when

Multivalent self-molecules (eg membrane associated ones) cross link extensively with self antigens, inducing cell death by clonal deletion or receptor editing

16

The major peripheral tolerance mechanism for B cells is

survival signals

17

What are the 2 survival signals for mature B cell response and survival?

Signals via the surface Ig-Ag interaction (cross-linking) and T cell help (CD40L and some cytokines)

18

Affinity maturation and isotype switching are dependent on

T cell help, esp CD4+T cells with CD40L

19

Peripheral B cell tolerance is dependent on

T cell tolerance functioning, because CD4+ T cell help is required for affinity maturation and isotype switching

20

B cells see

whole proteins or components or whole proteins or pathogens

21

T cells see

peptide fragments that are processed and presented at the cell surface by MHC

22

T/F TCR only recognises peptide fragments

False; it also recognizes the MHC - it interacts with the complex of protein fragment and MHC

23

Why is there a 'fine balance' between auto-reactivity and pathogen-specific reactivity in T cells?

because TCRs recognize MHCs, they are self-reactive to a degree - they see self-antigen (MHC)

24

What is positive selection?

Thymocytes that express TCRs that recognize self-MHC are selected to survive

25

What is negative selection?

Removal of immature lymphocytes that have strong reactivity to self-peptide

26

Which lymphocytes survive positive selection?

thymocytes with TCRs that can recognize self-MHC

27

Negative selection terminates

immature lymphocytes with TCRs that see self-MHC w/self-peptide too well

28

AIRE

autoimmune regulator of expression

29

What is the function of AIRE?

it non-specifically turns on gene expression in the thymus of peripheral tissues and their antigens (eg insulin/pancreas) such that immature T cells get exposure to these self-Ags and can be deleted

30

Where is AIRE expressed?

medullary epithelial cells of the thymus

31

What is the consequence of defects in AIRE?

failure of negative selection for some self-Ags resulting in autoimmunity

32

What are the central tolerance mechanisms for T cells?

Deletion (main); selection of Tregs (type of CD4+T cell)

33

What are the peripheral tolerance mechanisms for T cells?

Deletion, anergy, ignorance, and regulation

34

T/F Positive selection = tolerance

False; it is more a mechanism of self restriction that is part of tolerance

35

What are the 2 signals required for T cell activation?

recognition of MHC-peptide by the TCR; costimulation eg CD28 (T cell) ligating CD80/86 on DCs (upregulated by DC ligation of PAMPs - NOD, TLR, etc.)

36

How does anergy arise in peripheral T cell tolerance?

Failure of Signal 2: costimulation (CD28 on T cell w/ CD80/86 on DC)

37

What happens without Signal 2 in T cell activation?

failure to proliferate, inactivation (anergy), and tolerance

38

Treg cells can suppress

all T helper cell and CD8+ T cell responses

39

nTregs

natural Tregs - derived from thymus during T cell development

40

iTregs

induced Tregs - derived following activation of naïve CD4 T cells in the presence of TGFb

41

How do iTregs suppress autoreactivity?

expression of immunosuppressive cytokines IL-10 and TGFb; expression of CTLA4, an inhibitory receptor; release of suppressive molecules

42

How does CTLA4 (iTregs) work?

CTLA4 also binds CD86 on DCs with higher affinity than CD28; this inhibits co-stimulation (signal 2) and tf activation of naïve T cells

43

Autoimmune disease is defined by

loss of tolerance

44

How is tolerance lost?

Self-reactive T or B cells escape regulatory mechanisms (they are deficient)

45

What are the 3 key components necessary in pathogenesis of immune disease?

genetic susceptibility
environmental factors
loss of self-tolerance

46

How can ignorance (tolerance) be lost?

Ag becomes available or something that looks like it that is a self-Ag that triggers the response causing these quiescent cells to become self-reactive

47

How can anergy be lost?

if signal 2 somehow becomes supplied, autoreactive T and B cells can be activated and trigger autoimmunity

48

How can peripheral B cell tolerance be lost?

CD4+ T cell help is provided from elsewhere, eg co-infection with viruses etc - thought to be why these trigger some autoimmune diseases

49

T/F Autoimmune responses always result in autoimmune disease

False; they do not always result in AI disease

50

T/F All autoimmune diseases involve autoimmune responses

True

51

Autoimmunity results from

a chronic/ongoing autoimmune response with ongoing tissue damage

52

What are the 2 classes of autoimmune disease?

Organ specific
Systemic

53

Organ-specific autoimmune diseases are

confined to particular organs or cell types and the Ags recognized are organ specific

54

Examples of organ specific autoimmunity are

thyroid, ovarian, islet cells, gastric parietal cells (pernicious anaemia); neurological: MS, MG

55

Systemic autoimmune diseases

affect multiple tissues of the body and the Ags recognized are more ubiquitous

56

Examples of systemic autoimmune disease are

rheumatoid arthritis, systemic lupus erythematosus (SLE)

57

B cells are involved in which hypersensitivities?

II (ligand-mediated reactions) and III (IC deposition)

58

T cells are involved in which hypersensitivities?

IV delayed type

59

Loss of central tolerance is linked to defects in which gene?

AIRE

60

Loss of peripheral tolerance is linked to defects in which gene?

FOXP3 (X-linked) leading to loss of Tregs and peripheral tolerance mechanisms

61

What are examples of B cell mediated autoimmunity?

Graves disease (stimulatory Ab; II); Myasthenia Gravis (inhibitory Ab); SLE (III/IC deposition)

62

Examples of T-cell mediated autoimmunity are

Type 1 insulin-dependent diabetes mellitus; MS

63

T1 IDDM occurs more frequently in which HLA types?

HLA DR3-DQ2 and HLA DR4-DQ8

64

How are T cells implicated in Type 1 IDDM?

destruction of pancreatic B cells by T cell reactivity to islet proteins

65

How are the particular MHCs for Type 1 IDDM related to its pathogenesis?

thought that these MHCs promote or help present self-antigens more readily

66

How are T cells implicated in MS?

T cells specific for myelin antigens promote an inflammatory response that degrades the myelin sheath of nerve axons

67

Which Th cells are predominant in MS destruction?

Th1 and Th17 - pro-inflammatory w/IFNy

68

Which Th cells are associated with MS remission?

Th2

69

Dysregulation of what cell type is associated with MS?

Tregs

70

Which HLA types are more associated with MS?

HLA-DR15 and HLA-DQ6

71

What is thought to initiate autoimmune diseases?

self-Ags released from injured cells are recognized by B cells; T cells specific for that self peptide activate B cells to differentiate into plasma cells; plasma cells secrete self-Ag Abs that cause inflammation at the injury site, perpetuating the cycle

72

What is the bystander role in autoimmune disease?

infection of tissue releases self Ags and infects DCs at the same time; get a B cell with self-Ag reacting with a DC with same Ags; T cell can activate B cell or become self-reactive

73

What is the role of molecular mimicry in autoimmune disease?

Ags from a pathogen are similar to those of self-Ags causing cross-reactivity reactions when the immune system is activated of B cells (eg rheumatic fever) and T cells