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Immunology- Unit 1 > Lecture 3 > Flashcards

Lecture 3 Flashcards

1
Q

Define migration/ recruitment

A

The general process of leukocyte movement from blood into tissues

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2
Q

Define recirculation

A

The ability of lymphocytes to repeatedly home to secondary lymphoid organs, reside there transiently, and return to the blood

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3
Q

Define leukocyte homing

A

Cell migration out of the blood and into peripheral tissues or to a site of infection/ injury

At inflammatory site, see neutrophils, leukocytes, and monocytes
- produces innate response

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4
Q

Describe leukocyte and plasma cell expression when there is no pathogen/ inflammation

A

Not expressed by epithelial tissues (hidden away)

Released at inflammation via cytokines

Release adhesion molecules

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5
Q

What is a major part of inflammation process?

A

The recruitment of leukocytes and plasma proteins from the blood to sites of infection and tissue injury

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6
Q

What is inflammation triggered by?

A

Recognition of microbes and dead tissues in innate immune responses and is refined and prolonged during adaptive immune responses

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7
Q

Where does the inflammatory response deliver the cells and molecules of host defense to?

A

Sites where offending agents need to be combatted

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8
Q

Outline Leukocyte Recruitment

A
  1. Inflammatory Chemicals
  2. Margination
  3. Diapedesis
  4. Chemotaxis
  5. Phagocytosis
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9
Q

Describe the importance of mast cells in the leukocyte recruitment

A

Have granules whose contents can be released quickly
- possible because contents are presynthesized

Have receptors for by-products of fibrin

  1. As soon as sense damage/ clot formation, they are activated, release histamine + cytokines
  2. Causes the spaces between cells to open
  3. Epithelial cells express adhesion molecules on surface
  4. Leads to increased permeability
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10
Q

Define leukocyte recruitment

A

Cascade of adhesive and activation events that underlies the trafficking of all subsets of circulating leukocytes

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11
Q

What are the 4 steps of leukocyte recruitment?

A
  1. Tethering
  2. Rolling
  3. Adhesion and stop
  4. Transmigration in the tissue
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12
Q

Describe tethering

A

Slows movement of cell and allows interaction with integrins

Occurs through transient interactions of selectins and integrins with their ligands

Receptor action is slow

Specific chemokines involved that have specific receptors

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13
Q

Describe rolling

A

Allows chemokine receptors on leukocytes to bind chemokines expressed on endothelium

Selectivity is achieved by chemokine receptors

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14
Q

Describe adhesion and stop

A

Receptors signal and activate integrins on leukocytes which interact with ligands expressed on endothelium and trigger adhesion to the endothelium

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15
Q

Describe transmigration in the tissues

A

Leukocytes transmigrate into the extravascular space where they can migrate down chemokine gradients towards specific areas

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16
Q

Compare the affinity of interactions between selectins and integrins

A

S = low affinity interactions

I = high affinity interactions

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17
Q

T/F: Endothelial cells in healthy tissues do not express adhesion molecules on their surfaces facing the blood

A

True

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18
Q

How are endothelial cells at sites of infection and tissue injury activated? Upon activation what kind of molecules are expressed?

A

Activated by cytokines secreted by resident immune cells at these sites

Express adhesion molecules

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19
Q

What is the consequence of endothelial cell activation at sites of infection and tissue injury?

A

Increased adhesiveness of endothelial cells for circulating myeloid leukocytes and antigen- activated effector and memory lymphocytes

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20
Q

What does leukocyte/ lymphocyte homing and recruitment require?

A

The temporary adhesion of the leukocyte to the endothelial cells of blood vessels

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21
Q

Homing involves molecules located where?

A

On the surfaces of both the leukocytes and endothelial cells

L = homing receptors and chemokine receptors
E = chemokines
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22
Q

Define addressins

A

Comprise a set of adhesion molecules on the surface of high endothelial venules

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23
Q

Selectins provide a ___ affinity interaction with their ligands

A

Low

Grab cells and allow them to slow down

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24
Q

What kind of cells express P-selectin and E-selectin?

A

Only activated endothelial cells

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25
Q

Where is E-selectin synthesized and expressed in response to?

A

On endothelial cell surface within 1 to 2 hours in response to the cytokines IL-1 and TNF produced by mast cells and tissue-resident macrophages in response to infection

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26
Q

What kind of complexes are ligands for E-selectins and P-selectins?

A

Constitutively expressed complex of sialyated carbohydrates related to to Lewis X or Lewis family

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27
Q

What kind of cells express L-selectin?

A

Only expressed on leukocytes and lymphocytes but not on endothelial cells

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28
Q

What are L-selectin’s role with respect to T or B lymphocytes?

A

Important for naive T and B lymphocytes for homing into lymph nodes by interacting with high endothelial venules

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29
Q

Define peripheral node addressins

A

L-selectin ligands expressed on HEV (PNAd)

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30
Q

Give the alternate name for, the distribution, and ligand for: P-selectin

A

CD62P

Endothelium activated by histamine or thrombin

  • Sialyl Lewis X on PSGL-1 and other glycoproteins
  • Neutrophils
  • Monocytes
  • T cells (effector, memory)
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31
Q

Give the alternate name for, the distribution, and ligand for: E-selectin

A

CD62E

Endothelium activated by cytokines (TNF, IL-1)

  • Sialyl Lewis X on glycoproteins
  • Neutrophils
  • Monocytes
  • T cells(effector and memory)
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32
Q

Give the alternate name for, the distribution, and ligand for: L-selectin

A

CD62L

Neutrophils, monocytes, T cells (naive and central memory), B cells (naive)

  • Sialyl Lewis X/ PNAd on GlyCAM-1, CD34, MasCAM-1, others
  • Endothelium (HEV)
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33
Q

What is the functional role of Selectins?

A

Selectin- mediated adhesion to leukocyte sialyl- lewis is weak and allows leukocytes to roll along the vascular endothelial surface

Allows for interaction with integrins

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34
Q

Integrins provide a ___ affinity interaction with their ligands

A

High

Stops rolling and find gaps between endothelial cells

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35
Q

What is the function of integrins?

A

Integrate signals triggered by extracellular ligands with cytoskeleton- dependent motility, shape change, and phagocytic responses

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36
Q

Define Lymphocyte function- associated antigen 1 (LFA-1)

A

An integrin expressed by all leukocytes

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37
Q

What does LFA-1 bind to?

A

Its ligand (ICAM-1, CD54)

Expressed on cytokine-activated endothelial cells

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38
Q

Define Very Late Antigen-4 (VLA-4)

A

An integral expressed by some leukocytes

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39
Q

What does VLA-4 bind to?

A

Its ligand (VCAM-1, CD106)

Expressed on cytokine-activated endothelial cells

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40
Q

Define alpha(4)beta(7) integrin

A

Integrin expressed by some leukocytes

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41
Q

What does alpha(4)beta(7) integrin bind to?

A

VCAM-1 and mucosal addressin cell adhesion molecule MadCAM expressed on endothelial cells

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42
Q

Give the alternate name for, the distribution, and ligand for: LFA-1

A

Lymphocyte function- associated antigen 1

Neutrophils, monocytes, T cells (naive, effector, memory), B cells (naive)

ICAM-1
ICAM-2
Endothelium (cytokine - induced)

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43
Q

Give the alternate name for, the distribution, and ligand for: Mac-1

A

Macrophage-1 antigen (CR3)

Neutrophils, monocytes, dendritic cells

ICAM-1
ICAM-2
Endothelium (cytokine - induced)

44
Q

Give the alternate name for, the distribution, and ligand for: VLA-4

A

Very Late Antigen-4

Monocytes, T cells (naive, effector, memory)

VCAM-1
Endothelium (cytokine - induced)

45
Q

Give the alternate name for, the distribution, and ligand for: alpha(4)beta(7) integrin

A

alpha(4)beta(7) integrin

Monocytes, T cells (gut homing, naive, effector, memory), B cells (gut homing)

VCAM-1
MadCAM-1
Endothelium in gut and gut-associated lymphoid tissues

46
Q

How do integrins respond to intracellular signals?

A

Rapidly increasing their affinity

Integrin activation

47
Q

Where/ how does integrin activation occur?

A

Occurs in all leukocytes in response to chemokine binding to chemokine receptors

48
Q

What is integrin activation mediated by?

A

Chemokine- induced conformational changes in the extracellular domains of the integrins that lead to an increased affinity

49
Q

Inside- out signaling

A

The chemokine signaling involved in integrin activation

Changes affinity confirmation of integrins on surface

50
Q

Describe activation of integrins

A
  1. Integrins on blood leukocytes are normally in a low- affinity state
  2. When rolling of leukocytes occurs, chemokines displayed on the endothelial surface can bind chemokine receptors on the leukocyte
  3. Chemokine receptor signaling then occurs, which activates integrins of leukocyte, increasing their affinity for their ligands on the endothelial cells
51
Q

What does chemokine activation and conformational change of integrins allow for?

A

Adhesion and transmigration

52
Q

What do chemokines stimulate and regulate?

A

Stimulate leukocyte movement

Regulate migration of leukocytes from the blood to tissues

53
Q

Describe C chemokines

A

Single cysteine

54
Q

Describe CC (beta) chemokines

A

2 adjacent cysteine residues

55
Q

Describe CXC (alpha) chemokines

A

2 cysteine residues separated by 1 amino acid

56
Q

Describe CX3C chemokines

A

2 cysteine residues separated by 3 amino acids

57
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: CCL2

A

CC Chemokine

MCP-1

CCR2

Mixed leukocyte recruitment (monocytes)

58
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: CCL5

A

CC Chemokine

RANTES

CCR1, CCR3, CCR5

Mixed leukocyte recruitment

59
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: CCL19

A

CC Chemokine

MIP- 3Beta

CCR7

T cell and dendritic cell migration into parafollicular zones of lymph nodes

60
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: CCL21

A

CC Chemokine

SLC

CCR7

T cell and dendritic cell migration into parafollicular zones of lymph nodes

61
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: CXCL8

A

CXC Chemokine

IL-8

CXCR1, CXCR-2

Neutrophil Recruitment

62
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: CXCL10

A

CXC Chemokine

IP-10

CXCR3, CXCR3B

Effector T cell recruitment

63
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: CXCL12

A

CXC Chemokine

SDF- 1 alpha beta

CXCR4

Homing naive B cells into lymph nodes

64
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: CXCL13

A

CXC Chemokine

BCA-1

CXCR5

B cell migration into follicles
T follicular helper cell migration into follicles

65
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: XCL1

A

C Chemokine

Lymphotactin

XCR1

T cell and NK cell recruitment

66
Q

Give the class of chemokine, original name, chemokine receptor, and major function of: CX3CL1

A

CX3C Chemokine

Fractalkine

CX3CR1

T cell, NK cell, and monocyte recruitment
CTL and NK cell activation

67
Q

Describe the circulation of neutrophils and monocytes

A
  1. Neutrophils and monocytes arise in bone marrow and circulate into the blood
  2. Ready to be recruited into tissue sites of infection/injury without activation
  3. Enter tissue via post-capillary venules except when entering parenchymal tissues
    • blood cells enter parenchymal tissues via capillaries
  4. Myeloid leukocytes eliminate infectious pathogens, clear dead tissues, and repair the damage
68
Q

Describe the influence of selectins, chemokines, and adhesion molecules on leukocyte recruitment

A

Selectins have a low affinity interaction which contributes to the slowing down and rolling of leukocytes

Chemokine activation contributes to conformational changes of integrins to higher affinity

Adhesion molecules and the high affinity of integrins leads to arrest and firm adhesion to the endothelial cells

69
Q

Describe CXCL8’s role in leukocyte recruitment

A

IL-8

Mediates recruitment of neutrophils

70
Q

Describe CCl2’s role in leukocyte recruitment

A

MCP-1

Mediates recruitment of monocytes

71
Q

What results from transmigration of leukocyte recruitment?

A

Histamine is released by endothelial cells and inflammation loosens contact

72
Q

Describe the transmigration of leukocytes

A
  1. Activated mast cells and tissue- resident macrophages produce cytokines TNF and IL-1 that induce the rapid expression of pre-formed P-selectin on the surface of endothelial cells
  2. E- selectin expression can be induced on the surface of endothelial cells by cytokines
  3. Interaction between P-selectin and ligands on leukocytes initiates rolling on the endothelium
  4. Rolling is further stabilized by L- selectin binding to ligands on endothelial cells
  5. Endothelial cells present chemokine CXCL8 which is recognized by receptors on neutrophils
73
Q

What is the role of CCL2?

A

Controls transmigration of monocytes

74
Q

Inside-out signaling occurs during what part of leukocyte recruitment and how does this impact integrins?

A

During integrin activation by chemokines

Integrins change from low affinity state to high affinity state

75
Q

What is triggered by transmigration of neutrophils and what does this result in?

A

Activation of leukocyte integrins

Results in more stable leukocyte adhesion

76
Q

What occurs after leukocytes have completed trans-endothelial migration?

A

They interact with chemokines in the underlying basement membrane

77
Q

Describe what occurs after diapedesis

A
  1. Cells adopt an amoeboid shape
  2. Cells migrate in polarized fashion along collagen fibrils in response to a chemotactic gradient toward the site of infection/ inflammation
  3. Chemotactic receptors are located in the leading edge
78
Q

Describe the migration and recirculation of naive T cells

A

Preferentially leave the blood and enter lymph nodes across the high endothelial venues

Dendritic cells bearing antigens enter the lymph nodes through afferent lymphatic vessels

If the T cells recognize the antigen, they are activated > retained in lymph node for 2-3 days

If T cell doesn’t find anything, leaves after 5 hours > return into circulation

79
Q

Describe the migration and recirculation of effector and memory T cells

A

Preferentially leave the blood and enter peripheral tissues through venues at sites of inflammation

80
Q

Describe how naive lymphocytes enter lymph nodes and leave circulation

A

Enter LN through an artery

Leave circulation by moving across wall of HEV

81
Q

What causes B and T cells to migrate to the different zones of the lymph node?

A

Drawn by chemokines to their respective zones

82
Q

Describe the path of dendritic cells into the lymph node

A

Antigen- loaded dendritic cells enter the lymph node through afferent lymphatic vessels coming from sites of antigen entry

Dendritic cells migrate to the T cell rich areas

83
Q

Describe the role of L- selectin with respect to lymphocytes entering lymph nodes

A

L- selectin is expressed by both T and B lymphocytes

L- selectin deficient lymphocytes are unable to enter peripheral nodes and see the antigen

84
Q

Where do naive lymphocytes enter the lymph nodes?

A

Through the HEVs

85
Q

Define peripheral node addressins (PNAd)

A

L-selectin ligands expressed on HEV

86
Q

What are the 2 ways that naive T cells can enter a draining lymph node?

A

In the blood

In afferent lymph coming from an upstream lymph node

87
Q

What happens to lymphocytes that do not find their antigens?

A

Leave the lymph node via efferent lymphatics and enter downstream lymph node without entering the circulation

88
Q

Naive T lymphocytes home to lymph nodes as a result of what?

A

L- selectin binding to peripheral lymph node addressin (PNAd) on HEV

89
Q

HEV are only found where?

A

Secondary lymphoid organs

90
Q

Which chemokines are displayed on the surface of the HEV?

A

CCL19 and CCL21

91
Q

Chemokines binding to what activates integrins? What occurs after binding?

A

CCR7

After binding, integrin affinity changes and there is a conformational change

92
Q

Describe S1PR1 and its levels in naive T cells

A

Naive T cells have low levels of S1PR1 because the receptor is internalized after binding S1P in blood

Naive T cells that have recently entered a lymph node cannot sense S1P concentration gradient between T cell zone of node and lymph

Naive T cells cannot exit the node for 6 hours until S1PR1 is re-expressed and the cells exit lymph node by chemotaxis

S1PR1 is re-expressed after several days
- Activated and differentiated effector T cells then sense the S1P gradient and exit the node

93
Q

What is the role of S1PR1?

A

Stops T and B cells for 3 days to complete its education

High concentration in circulation

Low concentration in lymph nodes

94
Q

Where do activated effector T cells home to?

A

Sites of infection in peripheral tissues

95
Q

What is effector T cell migration into peripheral tissue mediated by?

A

E-selectin and P-selectin, integrins, and chemokine (CXCL10) that are produced at sites of infection

At this point, cell is no longer naive

96
Q

Give the location, ligand on endothelial cell, and function of receptor (ligand pair) for the following T cell homing receptor: CCR7

A

Lymph node

CCL19 or CCL21

Activation of integrins and chemokinesis

97
Q

Give the location, ligand on endothelial cell, and function of receptor (ligand pair) for the following activated T cells: CXCR3

A

Peripheral tissues

CCL10

Activation of integrins and chemokinesis

98
Q

Give the location, ligand on endothelial cell, and function of receptor (ligand pair) for the following activated T cells: CCR5

A

Peripheral tissues

CCL4

Activation of integrins and chemokinesis

99
Q

What is CD44 important for?

A

Mobilization of effector T cells in sites of infection and inflammation

100
Q

What do endothelial cells secrete and express at sites of infection and inflammation?

A

Secrete chemokine

Express E- and P- selectin and hyaluronic acid

101
Q

What does CD44 mediate?

A

Rolling interactions with vascular endothelial cells that express hyaluronic acid or E-selectin

102
Q

T/F: Chemokine signaling via GPCRs results in increased integral affinity which enhances adhesiveness

A

True

103
Q

Engagement of CD44 with hyaluronic acid may trigger what?

A

GPCR- dependent inside out up regulation of VLA-4-VCAM binding

104
Q

Describe the maturation of Follicular B lymphocytes

A
  1. Immature naive B cells leave the bone marrow through the blood
  2. Enter red pulp of the spleen
  3. Migrate to the periphery of the white pulp
  4. Once maturation is completed in white pulp, mature naive B cells re-enter the circulation and home to lymph nodes and mucosal lymphoid tissues
105
Q

What does homing of mature naive B cells from the blood into lymph nodes involve?

A

Rolling interactions on HEVs, chemokine activation of interns, and stable arrest

106
Q

What does the homing of mature naive B cells require?

A

Chemokines CXCL12 and CCL19/CCL21 on HEV and their chemokine receptors

107
Q

In the storm, B cells migrate into follicles driven by ___ recognized by ___ expressed on native B cells.

A

CXCL13; CXCR5

Immunology- Unit 1 (3 decks)

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