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Immuno-Sero LEC > IMMUNOLOGIC TOLERANCE > Flashcards

IMMUNOLOGIC TOLERANCE Flashcards

1
Q

Immune Tolerance
• Failure to recognize or mount an immune response to self-antigens that can otherwise result in…

A

autoimmune disease

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2
Q

• Lack of response to self-antigens

A

Immune tolerance (self-recognition / self-tolerance)

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3
Q

• Horror autotoxicus (19th century):
• “Body attacking itself”
• Coined by…

A

Paul Ehrlich

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4
Q

• - clinical syndrome in which the immune system attacks self-tissues

A

Autoimmunity

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5
Q

Immunogen manner if administration

A

• Subcutaneous
• Intramuscular

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6
Q

Tolerogen
Manner of administration

A

• Oral (HCl in stomach)
• Intravenous (enzyme in blood)

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7
Q

IR according to age of individual

Immunogen vs Tolerogen

A

Children, Adults

Infants, Elderly

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8
Q

Dose (concentration)

Immunogen vs Tolerogen

A

Optimal dose

Below and/or above optimal dose

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9
Q

Source of Self- Antigens

A

• Healthy tissues and organs that shed low levels of component proteins
• Normal turnover process of cells (undergo apoptosis)
• Molecules circulating in the blood plasma (no infection or injury)

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10
Q

• Protein encoded by the AIRE gene
• Transcription factor expressed in the thymic medulla that controls thymic dendritic cells

• Regulates the exposure of T cells in the thymus to normal, healthy self-antigens from all parts of the body

A

AIRE (autoimmune regulator)

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11
Q

T cell Ontogeny
•_______
• Is T cell able to bind to self-MHC?

•_______
• Does T cell bind too strongly to self-
МНС?

A

Positive selection (survival signal):

Negative selection (apoptosis signal):

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12
Q

• Events that characterize the differentiation of B cells from hematopoietic stem cells to pro-B cells, pre-B cells, immature B cells, and finally to mature B cells

A

B cell Ontogeny

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13
Q

• Occurs in primary lymphoid organs (PLOs):
• Thymus - T cells
• Bone marrow - B cells

A

Central Tolerance

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14
Q

presents self-antigens in the PLO AKA generative lymphoid organs

A

• Central tolerance

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15
Q

Initiated during fetal development by the elimination of cells with the potential to react strongly with self-antigens

A

Central tolerance

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16
Q

• Mediated by mechanisms that both foster the destruction and elimination of selected self-reactive lymphocytes

A

Central tolerance

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17
Q

• Monitor weakly self-reactive clones that survive the “weeding out” process during central tolerance

A

Peripheral Tolerance

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18
Q

• Occurs mainly in the secondary lymphoid organs or at the tissue site where the relevant self-antigen is expressed leading to immunosuppression

A

Peripheral Tolerance

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19
Q

• Important to continue maintaining self-tolerance in the periphery

A

Peripheral Tolerance

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20
Q

• Contributing factors for weakly self-reactive cells:

A

• Not all self-antigens are expressed in PLOs
• Threshold requirement for affinity before apoptosis

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21
Q

Central T cell Tolerance

Mechanisms:

A

• Cell death
• Generation of CD4+ regulatory T cells

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22
Q
  • if an immature lymphocyte interacts strongly with a self antigen, displayed as a peptide bound to self MHCs, the immature lymphocyte receives signals that trigger apoptosis, and the cell dies before it can complete its maturation

• Affects CD4+ (recognizing MHC class Il) and CD8+ (recognizing MHC class I) T cells

• Some autoreactive immature T cells that recognize self-antigens become_____

A

Negative selection

Tregs/Th3 instead

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23
Q

Mechanisms of T cell Central Tolerance
• Three pathways recognized:

A
  1. Clonal abortion
  2. Functional deletion
  3. T cell suppression
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24
Q

Mechanisms of T cell Central Tolerance

  • inhibition of actions of other autoreactive T cell subsets
A

T cell suppression

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25
Q

Mechanisms of T cell Central Tolerance

  • removal through apoptosis of autoreactive mature T cell
    subsets
A

Functional deletion

26
Q

Mechanisms of T cell Central Tolerance

  • prevention of immunocompetence of autoreactive maturing cells
A

Clonal abortion

27
Q

• responsible for deleting autoreactive T cells that have the potential to cause autoimmune disease once engaged with self-antigens

A

Thymus

28
Q

• present antigens using major histocompatibility complex (MHC) in the lymphoid organs

A

Epithelial cells or dendritic cells

29
Q

• Provides backup mechanisms for preventing autoimmunity in situations where central tolerance is incomplete

A

Peripheral T Cell Tolerance
•

30
Q

• Induced when mature T cells recognize self- antigens in peripheral tissues

A

Peripheral T Cell Tolerance

31
Q

• Antigen recognition without adequate co stimulation results in:

A
  1. T cell anergy
  2. T cell suppression
  3. T cell death
32
Q

• T cells may preferentially engage one of the inhibitory receptors of the CD28 family:

A

T cell Anergy

33
Q

• Long-lived functional inactivation that occurs when these cells recognize antigens without adequate levels of the costimulators that are needed for full T cell activation

A

T cell Anergy

34
Q

• Anergic cells survive but are incapable of responding to the antigen

A

T cell Anergy

35
Q

inhibitory receptors of the CD28 family:

A

• CTLA-4 or CD152 (cytotoxic T
lymphocyte- associated antigen 4)

• PD-1 (programmed death protein 1)

36
Q

• FoxP3 (forkhead box P3) AKA scurfin
- mediates the change to Treg cells (clonal diversion)

A

Immune Suppression by Treg Cells

37
Q

• Although can be CD8+, most Tregs are
CD4+, and express high levels of
CD25+

A

Immune Suppression by Treg Cells

38
Q

• As regulatory T cells, they enter the periphery and block the activation of other potentially harmful lymphocytes

A

Immune Suppression by Treg Cells

39
Q

• Produced in the thymus due to being able to weakly react to self-antigens
• “Salvaged” cells to be used as Tregs instead of being destroyed

A

Immune Suppression by Treg Cells

40
Q

The Key Role of Regulatory T cells
• Treg cells can be CD4+ or CD8+ and typically express CD25, CTLA-4, plus the master regulator transcription factor, FoxP3 (they also release immunosuppressive cytokines IL-10,TGF-B, IL-35)

The Key Role of Regulatory T cells
• Treg cells act in secondary lymphoid tissues and at sites of inflammation dampening immune responses by inhibiting, decommissioning, or killing other immune cells recognizing self antigens

A
41
Q

Deletion by Programmed Cell Death (Apoptosis)
• Apoptosis can be triggered:

A

• Death by deficiency of survival signals (20)

• Death by engagement of death receptors

42
Q

• Relative deficiency of survival signals = death

A

Deletion by Programmed Cell Death (Apoptosis)

43
Q

• This activates enzyme caspases to induce apoptosis that induce further degradation

A

Deletion by Programmed Cell Death (Apoptosis)

44
Q

• These activate the cell’s mitochondrial pathway, triggering various mitochondrial proteins to leak out, known as “leaky mitochondria”

A

Deletion by Programmed Cell Death (Apoptosis)

45
Q

• Recognition of self-antigens induces the production of pro-apoptotic proteins in T cells

A

Deletion by Programmed Cell Death (Apoptosis)

46
Q

• Recognition of self-antigens may lead to co-expression of death receptors and their ligands

A

Deletion by Death Receptors (FAS + FAS Ligand)

47
Q

• Death receptor pathway is activated, generating signals that trigger caspases:

A

• Fas (CD95) - expressed on T cells and others

• Fas ligand (FasL) - mainly on activated T cells

48
Q

= induces death of both T and B cells exposed to self antigens

• Self antigens are present throughout life and may therefore cause prolonged or repeated TCR engagement, promoting anergy and apoptosis

A

• Fas + FasL

49
Q

Mechanisms of B cell Tolerance

A
  1. Clonal abortion:
  2. Clonal exhaustion:
  3. Functional deletion:
  4. Antibody-forming cell blockade:
50
Q

B cell tolerance

• caused by low concentration of multivalent antigen

• repeated antigen challenge with a T-independent antigen

• combined absence of T helper subsets and T-dependent antigen OR an excess of T-independent antigens

• excess of T-independent antigen interferes with the secretion of antibody by antibody forming cells (plasma cells)

A
  1. Clonal abortion:
  2. Clonal exhaustion:
  3. Functional deletion:
  4. Antibody-forming cell blockade:
51
Q

CENTRAL B CELL TOLERANCE
• Occurs when immature B lymphocytes interact strongly with self antigens in the bone marrow:

A

Receptor editing
Negative selection
B cell anergy

52
Q

• Re-expression of recombination
activating genes (RAGs) to resume light chain recombination and produce a new receptor that is no longer reactive

A

Receptor editing

53
Q

• If receptor editing fails, immature B cells that recognize self antigens with high avidity (accumulated binding strength) receive death signals and die by apoptosis

A

Negative selection

54
Q

• Recognition of self antigen with low avidity, B cells in the bone marrow survive but antigen-receptor expression is reduced, rendering B cell unresponsive

A

B cell anergy

55
Q

• Mechanisms to ensure that mature B cells that encounter self antigens in the peripheral lymphoid tissues become incapable of responding to them

A

Peripheral B Cell Tolerance

56
Q

Peripheral B Cell Tolerance

• B cell can become anergic:

A
  1. Recognizes self antigens but don’t receive T cell help
  2. Self-reactive B cells may leave the lymphoid follicles and are subsequently excluded from the follicles
  3. Excluded self-reactive B cells may die due to lack of receiving survival stimuli (follicular exclusion)
57
Q

B cell Anergy
• B cells specific for T-dependent antigens require two signals to be activated:
• 1st signal = provided by the____
• 2nd signal = provided by the ____

A

antigen
T cells

58
Q

B cell anergy

• Second signal is provided by the CD40
+ CD40L used in class switching
• If second signal is missing (self-antigen): B cell will be rendered unresponsive (anergic)
• Autoreactive T cells usually get deleted in the thymus and thus not available in the periphery to provide costimulatory help to autoreactive B cells

A
59
Q
  • immunogen activates all B cells leading to maturation of cells and transient antibody synthesis, thereby exhausting and diluting B cell response
A

B cell clonal exhaustion

60
Q
  • B cell is coated with excess antigen rendering it unresponsive as all receptors on the cell surface become blocked
A

B cell receptor blockade

61
Q

• Silencing of self-reactive B cells can occur through follicular exclusion in the lymph nodes
• Anergic B cells cannot successfully compete for entry into B cell follicles in the spleen and lymph nodes
• Anergic B cells require higher concentrations of BAFF cytokine (B-cell activating factor of the tumor necrosis factor family) aka Blys for survival than naïve B cells
• Without BAFF, B cell undergoes cell death instead of entering follicles

A

Follicular Exclusion

Immuno-Sero LEC (30 decks)

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