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Micro Unit 3 > Immunological Tolerance > Flashcards

Immunological Tolerance Flashcards

1
Q

Immunological Tolerance

A

A state of unresponsiveness for a particular antigen
– LEARNED, very specific and induced by prior exposure to antigen
– Includes tolerance to non-self antigen

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2
Q

• Self tolerance – physiological state in which the

A

immune system does not react destructively against self tissue

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3
Q

Self-tolerance may be induced in

A

immature self-reactive lymphocytes in generative lymphoid organs (central tolerance), or in mature lymphocytes in peripheral sites (peripheral tolerance)

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4
Q

Central Tolerance-

A

occurs in generative lymphoid organs (bone marrow/thymus) involving immature self-reactive lymphocytes recognizing self antigen

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5
Q

Peripheral Tolerance-

A

in peripheral sites involving mature self-reactive lymphocytes encountering self antigen

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6
Q
  • Immunological tolerance is NOT simply a failure to recognize an
A

antigen

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7
Q

Immunological tolerance is

A

ItISanactiveresponsetoaparticularepitope and is just as specific as an immune response

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8
Q

Tolerancecanbe

A

natural(selftolerance,oral tolerance)…or induced (e.g.- prevent allergies, graft rejection or autoimmunity)

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9
Q

Reactivity is prevented by

A

y processes that occur during development rather than being genetically pre- programmed.

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10
Q

• The most important aspect of tolerance is

A

self tolerance, which prevents the body from mounting an immune attack against its own tissues.

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11
Q

Those lymphocytes that do not bind MHC through their TCR are destined to

A

die by apoptosis.

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12
Q

• During maturation in the thymus, most immature T cells that recognize antigens with high avidity are

A

deleted

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13
Q

Some self-reactive CD4+ T cells that see self antigens in the thymus are not

A

deleted but instead

differentiate into regulatory T cells

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14
Q

choice between lymphocyte activation and tolerance is determined by:

A

the properties of the antigens
– state of maturation of the antigen-specific lymphocytes
– types of stimuli received when these lymphocytes encounter self antigens

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15
Q

Central tolerance in B cells: Occurs in

A

immature B cells in the bone marrow

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16
Q

Potentially autoreactive cells can be

A

eliminated or inactivated by contact with self Ag

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17
Q

• Nature and concentration of the self Ag

determine the fate of

A

B cells

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18
Q

Multivalent Ag (membrane associated proteins) induce

A

B cell death

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19
Q

– High concentrations of Ag induce

A

B cell death

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20
Q

Lower concentrations of small, soluble self Ag induce

A

functional anergy

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21
Q

Peripheral tolerance is the mechanism by which

A

mature T cells that recognize self antigens in peripheral tissues become incapable of responding to these antigens

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22
Q

PT: Clonal deletion/apoptosis-

A

Actual elimination from the cellular repertoire by activation induced cell death

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23
Q

PT: Clonal anergy-

A

mature cell is present but is functionally inactivated (can be reversed)

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24
Q

PT Suppression- i

A

inhibition of cellular activity through interaction with other cells
– T regs (CD4+/CD25+ T cells, TGF-β or IL-10 secreting reg T cells)

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25
Q

Ignorance- co-existence of

A

self-reactive clones and antigen; cells do not respond to antigen

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26
Q

Peripheral tolerance in B cells- Not all potentially reactive cells are

A

eliminated or inactivated and enter peripheral circulation

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27
Q

• TWO SIGNAL HYPOTHESIS - how T cells affect B cell activation

A

Signal one: Generated through the Ag receptor
Signal two: mediated by CD40 and CD40L

B cell anergy results if one of the signals is mis

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28
Q

Anergic cells show a block in

A

TCR-induced signal transduction

  • Lack of costimulation by B7/B72
  • costimulation by inhibitory receptors
  • e.g. CTLA-4
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29
Q

-CTLA-4 competes with CD28 for

A

B71 and B72 -binds with higher affinity than CD28

30
Q

-CTLA-4 keeps T cells in

A

check

31
Q

-knockout mice lacking CTLA-4 develop

A
  • uncontrolled lymphocyte activation
  • massively enlarged lymph nodes and spleen
  • fatal multiorgan lymphocytic infiltrates (suggestive of systemic autoimmunity)
32
Q

– Activation in the absence of IL-2 can lead to

A

death

33
Q

Self-reactive cells may be ‘deleted’ from the repertoire.

A

Activation in the absence of IL-2 can lead to death – Persistent Ag
– Activation-induced cell death

34
Q

The state of tolerance may be maintained by

A

immune regulation

35
Q

How does ignorance happen?

A

Antigen is expressed in a privileged site/sequestered.

    • T cells cannot get to the antigen across an endothelial barrier
    • Perhaps the antigen is not expressed in the context of MHC molecules.
36
Q

• Foreign antigens may be administered in ways that preferentially

A

induce tolerance rather than immune responses

37
Q

protein antigens administered subcutaneously or intradermally with adjuvants

A

favor immunity

38
Q

high doses of antigens administered systemically without adjuvants tend to

A

induce tolerance

39
Q

• Oral administration of Ag favors

A

tolerance induction

40
Q

• A state of immune hyporesponsiveness follows

A

oral administration of an antigen

41
Q

Oral tolerace is

A

Responsible for maintenance of homeostasis

– No immune response to food antigens

42
Q

Human disease trials utilizing fed proteins to abrogate autoimmune disease

A

lack of toxicity, ease of administration over time, and antigen-specific mechanism of action
• MS (glatiramer acetate/cop1 - resembles human myelin (4 a.a) • Uveitis (peptide B27PD – resembles retinal autoantigen protein) • Type 1 Diabetes (Human insulin)

43
Q

• T cells (Cell mediated responses)–

A

Recognize processed antigen in the context of MHC to irradicate infection
– Effector functions include cytokine production and release of cytotoxic factors

44
Q

B cells (Humoral responses)-

A

Recognize free antigen via Ig receptor to irradicate infection

Effector functions include antibody mediated destruction of antigen

45
Q

What is Autoimmune Disease?

A

Group of more than 80 serious, chronic illnesses/syndromes that can involve almost every organ system
– includes diseases of the nervous, gastrointestinal, and endocrine systems as well as skin and other connective tissues, eyes, blood, and vasculature.
• Occurs when the immune system
becomes dysregulated and attacks the
very organs it was designed to protect

46
Q
  • AUTOIMMUNITY RESULTS WHEN CENTRAL AND PERIPHERAL TOLERANCE IS
A

broken

47
Q

Mechanisms that lead to autoimmunity

A

remain unclear

48
Q

Genetic Factors: •Autoimmune diseases tend to occur in

A

families and this concordance is largely genetic.
•Greater concordance between identical twins for some diseases.
•Strong HLA/MHC association.

49
Q

Many autoimmune diseases affect

A

women much more commonly than men

50
Q

Severity/course of autoimmune disease may also differ between

A

sexes

51
Q

Rheumatoid arthritis is typically more aggressive in

A

females

52
Q

Multiple Sclerosis can differ in clinical course between females and males

A
  • Females tend to have a relapsing-remitting disease course

* Males tend to exhibit a chronic progressive disease course

53
Q

What initiates an autoimmune response???

A

Incomplete deletion of self reactive cells
• Aberrant stimulation of “normally” anergic self reactive cells
• Altered regulation of anergic self reactive cells

54
Q

Systemic

A

Immune cells target multiple organ systems and tissues

– Thought to be due to aberrant regulation of many clones of lymphocytes

55
Q

Organ Specific

A

Immune cells target specific organs or tissue
– Thought to be due to failure of self tolerance in only a few clones of cells which react to a limited number of antigens

56
Q

Systemic Lupus Erythematosus (SLE) –

A

A systemic disorder in which a variety of autoantibodies (DNA, nucleoproteins, platelets, lymphocytes) can cause multisystem damage

57
Q

Multiple Sclerosis (MS) –

A

Immune System targets Central Nervous System via myelin specific T cells

58
Q

SLE Clinical Features

A 
• Multisystem disorder characterized by a variety of autoantibodies
• Increased risk associated with HLA DR2 and HLA DR3
• Female/male predominance 10:1
• Initial onset of symptoms typically occurs between 15-25 years of age
• Typical symptoms include – Fatigue
– Fever
– Alopecia
– Mucosal ulceration
– Butterfly rash
– Joint and muscle pain
• Severe complications
– Kidney, Heart, lung, CNS
59
Q

SLE Pathogenesis

A

Immune complex disease (type III hypersensitivity)

60
Q

Large amounts of autoantibodies produced against

SLE pathogenesis

A

self antigens
– DNA
– Nucleoproteins – Platelets
– Lymphocytes

61
Q

SLE pathogenesis: • Immune complexes deposit in

A

kidneys, joints and vessel walls

62
Q

Nonsteroidal anti-inflammatory drugs (NSAIDS) are used to treat

A

arthritic symptoms of lupus

63
Q

• Corticosteroid creams are used to treat

A

skin rashes

64
Q

Antimalarial drugs sometimes used for

A

skin and arthritis symptoms.

65
Q

Corticosteroid therapy or cytotoxic (anti-proliferative) drugs may be used in

A

severe or life-threatening manifestations of the disease

66
Q

• Kidney transplant indicated for

A

advanced Lupus nephritis

67
Q

MS Clinical Features

A

The most common inflammatory disorder of the central nervous system
• Increased risk associated mainly with HLA DR2
• Female/male predominance is 3:2
• Those affected can exhibit a relapsing-remitting or a chronic progressive disease
• Pathologic hallmark is the CNS plaque with loss of myelin and depletion of oligodendrocytes with or without axon loss
• Typical onset
– women of childbearing years
– In men onset is typically >40 years of age
• Symptoms include
– Impaired vision (optic neuritis)
– Ataxia
– Spasticity
– Bladder dysfunction
– Weakness/Paralysis of one or more limbs – Sensitivity to temperature
– Cognitive impairment

68
Q

MS Pathogenesis

A

• T cell mediated autoimmune disease in which T cells are specific for components of the myelin sheath

69
Q

MS: Also evidence of macrophage and microglial cell involvement in

A

myelin degradation

70
Q

MS: • Damage to/loss of myelin impairs

A

nerve conduction

71
Q

MS Treatments

A

Immunomodulatory Drugs • Corticosteroids

• Immunosupressive therapy

Micro Unit 3 (6 decks)

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