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IMMUNOLOGY Exam #1- Lo > Lec 03- Leukocyte Circulation and Migration into Tissue > Flashcards

Lec 03- Leukocyte Circulation and Migration into Tissue Flashcards

1
Q

What is recirculation?

A

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

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2
Q

What is the general process of leukocyte movement from blood into tissues?

A

migration/recruitment

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3
Q

What is the migration of a leukocyte out of the blood and into a particular tissue, or to a site of an infection or injury?

A

Leukocyte homing

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4
Q

Recruitment of leukocytes and plasma proteins from the blood to the sites of infection and tissue injury is a major part of the process of ____________.

A

inflammation

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5
Q

How is inflammation triggered?

A

recognition of microbes and dead tissues in innate immune responses

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6
Q

Inflammation is refined and prolonged during _______ immune responses.

A

adaptive immune responses

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7
Q

What underlies the trafficking of all subsets of circulating leukocytes?

A

A cascade of adhesive and activation events

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8
Q

Circulating leukocytes tether to and roll on the endothelium through transient interactions of ______ and ______ with their receptors.

A

selections and integrins

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9
Q

What does leukocyte rolling allow?

A

allows leukocytes to sample the endothelium for chemokines

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10
Q

What do chemokines do?

A

-activate integrins -trigger adhesion to endothelium

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11
Q

Adherent leukocytes migrate across the endothelium into _______________.

A

the extravascular space

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12
Q

Once in the extravascular space, leukocytes can migrate down ______________ towards specific areas.

A

chemokine gradients

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13
Q

5 Steps of Leukocyte Recruitment

A

-Tethering -Rolling -Adhesion triggering -Extravasation -Chemotaxis

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14
Q

What constantly circulate through the blood, into the tissues, and often back into the blood again?

A

-immune cells -soluble components

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15
Q

Endothelial cells at sites of infection and tissue injury are activated by ________ secreted by ________ and ________ at these sites.

A

-cytokines -resident macrophages -mast cells

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16
Q

What are the consequences of activated endothelial cells at infection/injury sites?

A

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

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17
Q

What is required for leukocyte/lymphocyte homing and recruitment?

A

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

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18
Q

Homing involves molecules on the surfaces of what?

A

-leukocytes (homing receptors and chemokine receptors) -endothelial cells (chemokines)

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19
Q

What are addressing?

A

a set of several adhesion molecules on the surface of endothelial cells

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20
Q

Addressin function

A

regulate lymphocyte recirculation via HEV

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21
Q

P-selectin Distribution? Ligand?

A

Distribution: -Endothelium activated by histamine or thrombin Ligand: -Sialyl Lewis X on PSGL-1 and glycoproteins -neutrophils -monocytes -T cells

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22
Q

E-selectin Distribution? Ligand?

A

Distribution: -Endothelium activated by cytokines Ligand: -Sialyl Lewis X on glycoproteins -neutrophils -monocytes -T cells

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23
Q

L-selectin Distribution? Ligand?

A

Distribution: -neutrophils -monocytes -T cells -B cells (naive) Ligand: -Sialyl Lewis X/PNAd on: > GlyCAM-1 > CD34 > MadCAM-1 -endothelium (HEV)

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24
Q

What do selectins do endothelial cells express?

A

-P-selectin (CD62P) -E-selectin (CD62E)

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25
Q

E-selectin pathway

A

1- Infection 2- Tissue macrophages respond to infection 3- Macrophages produce cytokines IL-1 and TNF 4- 1-2 hours 5- E-selectin synthesized and expressed on endothelial cell surface

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26
Q

What are the ligands for E-selectin and P-selectin?

A

complex sialyated carbohydrates related to the Lewis X or Lewis family

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27
Q

Where is L-selectin expressed?

A

-ONLY expressed on leukocytes and lymphocytes -NOT expressed on endothelial cells

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28
Q

What is L-selectin expression activated by?

A

IL-1 and TNF at inflammation sites

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29
Q

L-selectin is important for naive T and B lymphocytes for homing into lymph nodes by ____________.

A

interacting with high endothelial venules (HEV)

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30
Q

What are L-selectin ligands expressed on HEV called?

A

peripheral node addressins (PNAd)

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31
Q

Integrin: LFA-1 (Late functional antigen-1) Distribution? Ligand?

A

[expressed by leukocytes] Distribution: -neutrophils -monocytes -T cells -B cells (naive) Ligand: -ICAM-1 -ICAM-2 -endothelium

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32
Q

Integrin: Mac-1 Distribution? Ligand?

A

Distribution: -neutrophils -monocytes -dendritic cells Ligand: -ICAM-1 -ICAM-2 -endothelium

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33
Q

Integrin: VLA-4 (very late antigen-4) Distribution? Ligand?

A

[expressed by leukocytes] Distribution: -monocytes -T cells Ligand: -VCAM-1 -endothelium

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34
Q

Integrin: alpha4 beta7 Distribution? Ligand?

A

[expressed by leukocytes] Distribution: -monocytes -T cells -B cells (gut homing) Ligand: -VCAM-1 -MadCAM-1 -endothelium in gut -gut associated lymphoid tissues

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35
Q

What are integrins?

A

heterdimeric cell surface proteins

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36
Q

What are integrins composed of?

A

two noncovalently linked polypeptide chains

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37
Q

Integrin functions

A

-mediate adhesion of cells to other cells to to extracellular matrix via various specific ligands -integrate signals

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38
Q

What triggers the integrin signals?

A

Extracellular ligands with cytoskeleton-dependent: -motility -shape change -phagocytic responses

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39
Q

How are integrins able to respond to intracellular signals?

A

by rapidly increasing their affinity for their ligands (integrin activation)

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40
Q

Integrin activation occurs in all leukocytes in response to what?

A

chemokine binding to chemokine receptors

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41
Q

When does integrin activation occur in T lymphocytes?

A

when Ag bonds to TCRs

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42
Q

How is integrin activation mediated?

A

-by chemokine-induced conformational changes in the extracellular domains of the integrins -leads to increased affinity

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43
Q

What is “inside-out signaling”?

A

-a type of chemokine signaling -involved in integrin activation -inside causes something to change on the surface

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44
Q

Integrins on blood leukocytes are normally in a _____ affinity state

A

low

45
Q

Integrin activation steps

A

1- Rolling of leukocytes 2- Chemokines on endothelial suface bind leukocyte chemokine receptors 3- Chemokine receptor signaling 4- Leukocyte integrins activated 5- Integrin affinity for their ligands increases

46
Q

What are chemokines?

A

-large family of structurally homologous cytokines - 8-10kD -contain 2 internal disulfide loops

47
Q

Chemokine function

A

-stimulate leukocyte movement -regulate migration of leukocytes from blood to tissues

48
Q

4 families of chemokines (based on number and location of N-terminal cysteine residues)

A
  1. CC or Beta chemokines
    • 2 cysteine residues are adjacent
  2. CXC or Alpha chemokines
    • residues separated by one amino acid
  3. C chemokines
    • 1 cysteine
  4. CX3C chemokines
    • 2 cysteines separated by 3 amino acids
49
Q

Chemokine: CCL1

  • Original name?
  • Chemokine receptor?
  • Major function?
A
  • Original name?
    • I-309
  • Chemokine receptor?
    • CCR8
  • Major function?
    • monocyte recruitment
    • endothelial cell migration
50
Q

Chemokine: CCL2

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL2

  • Original name?
    • MCP-1
  • Chemokine receptor?
    • CCR2
  • Major function?
    • mixed leukocyte recruitment
51
Q

Chemokine: CCL3

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL3

  • Original name?
    • MIP-1a
  • Chemokine receptor?
    • CCR1
    • CCR5
  • Major function?
    • mixed leukocyte recruitment
52
Q

Chemokine: CCL4

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL4

  • Original name?
    • MIP-1b
  • Chemokine receptor?
    • CCR5
  • Major function?
    • Recruitment of:
      • T cells
      • dendritic cells
      • monocytes
      • natural killer cells
    • HIC coreceptor
53
Q

Chemokine: CCL5

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL5

  • Original name?
    • RANTES
  • Chemokine receptor?
    • CCR1
    • CCR3
    • CCR5
  • Major function?
    • mixed leukocyte recruitment
54
Q

Chemokine: CCL11

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL 11

  • Original name?
    • Eotaxin
  • Chemokine receptor?
    • CCR3
  • Major function?
    • Recruitment of:
      • Eosinophils
      • Basophils
      • Th2
55
Q

Chemokine: CCL17

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL 17

  • Original name?
    • TARC
  • Chemokine receptor?
    • CCR4
  • Major function?
    • T cell recruitment
56
Q

Chemokine: CCL19

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL 11

  • Original name?
    • MIP-3b
  • Chemokine receptor?
    • CCR7
  • Major function?
    • T cell and dendritic cell migration into parafollicular zones of lymph nodes
57
Q

Chemokine: CCL20

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL20

  • Original name?
    • MIP-3a
  • Chemokine receptor?
    • CCR6
  • Major function?
    • Th17 recruitment
    • DC positioning in tissue
58
Q

Chemokine: CCL21

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL20

  • Original name?
    • SLC
  • Chemokine receptor?
    • CCR7
  • Major function?
    • T cell and dendritic cell migration into parafollicular zones of lymph nodes
59
Q

Chemokine: CCL22

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CCL22

  • Original name?
    • MDC
  • Chemokine receptor?
    • CCR4
  • Major function?
    • Recruitment of:
      • NK cells
      • T cells
60
Q

Chemokine: CXCL1

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CXCL1

  • Original name?
    • GROa
  • Chemokine receptor?
    • CXCR2
  • Major function?
    • Neutrophil recruitment
61
Q

Chemokine: CXCL5

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CXCL5

  • Original name?
    • ENA-78
  • Chemokine receptor?
    • CXCR2
  • Major function?
    • Neutrophil recruitment
62
Q

Chemokine: CXCL8

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CXCL8

  • Original name?
    • IL-8
  • Chemokine receptor?
    • CXCR-1
    • CXCR-2
  • Major function?
    • Neutrophil recruitment
63
Q

Chemokine: CXCL10

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CXCL10

  • Original name?
    • IP-10
  • Chemokine receptor?
    • CXCR3
    • CXCR3B
  • Major function?
    • Effector T cell recruitment
64
Q

Chemokine: CXCL11

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CXCL11

  • Original name?
    • I-TAC
  • Chemokine receptor?
    • CXCR3
    • CXCR7
  • Major function?
    • Effector T cell recruitment
65
Q

Chemokine: CXCL12

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CXCL12

  • Original name?
    • SDF-1ab
  • Chemokine receptor?
    • CXCR4
  • Major function?
    • mixed leukocyte recruitment
    • HIV coreceptor
66
Q

Chemokine: CXCL13

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CXCL13

  • Original name?
    • BCA-1
  • Chemokine receptor?
    • CXCR5
  • Major function?
    • B cell migration into follicles
    • T follicular helper cell migrationinto follicles
67
Q

Chemokine: CXCL14

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CXCL14

  • Original name?
    • BRAK
  • Chemokine receptor?
    • none
  • Major function?
    • Monocyte and dendritic cell migration
68
Q

Chemokine: XCL1

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: XCL1

  • Original name?
    • Lymphotactin
  • Chemokine receptor?
    • XCR1
  • Major function?
    • Recruitment of:
      • T cells
      • Natural killer cells
69
Q

Chemokine: CX3CL1

  • Original name?
  • Chemokine receptor?
  • Major function?
A

Chemokine: CX3CL1

  • Original name?
    • Fractalkine
  • Chemokine receptor?
    • CX3CR1
  • Major function?
    • Recruitment of:
      • T cells
      • Natural killer cells
      • Monocytes
    • Activation of:
      • CTL
      • Natural killer cells
70
Q

How are neutrophils and monocytes recruited into tissue sites of infection or injury?

A

Without activation

71
Q

How do neutrophils and monocytes enter the tissues?

A

through post-capillary venules

except parenchymal tissues (liver, lungs, kidney) >> through capillaries

72
Q

Functions of myeliod leukocytes

A
  1. eliminate infectious pathogens
  2. clear dead tissues
  3. repair the damage
73
Q

Transmigration of Leukocytes

A
  1. Capture (Selectins)
  2. Rolling (Selectins)
  3. Activation (Chemokines)
  4. Arrest (Adhesion molecules)
  5. Firm adhesion (Adhesion molecules)
  6. Transmigration from blood vessel lumen through endothelial cells
74
Q

What do activated resident macrophages produce?

A

Cytokines IL-1 and TNF

75
Q

Function of cytokines IL-1 and TNF

A

induce rapid induction of expression of pre-formed P selectins on the surface of endothelial cells

76
Q

What initiates rolling of leukocytes on the endothelium?

A

The interaction between P-selectins and ligands on the leukocytes

77
Q

How is rolling of leukocytes stabilized?

A

By L-selectin binding to ligands on the endothelial cells

78
Q

What chemokine does endothelial cells present that is then recognized by receptors on neutrophils?

A

CXC-chemokine ligand 8

CXCL8 or IL-8

79
Q

Which cytokine controls the transmigration of monocytes?

A

CCL2 or MCP-1

80
Q

What happens after leukocytes have completed trans-endothelial migration?

A

they interact with cytokines in the underlying basement membrane

81
Q

What happens to leukocytes after diapedesis?

A
  • the cells adopt an amoeboid shape
  • migrate in polarized fashion along collagen fibrils in response to chemotactic gradient toward site of infection/inflammation
82
Q

On which edge are the chemotactic receptors located?

A

the leading edge

83
Q

Naive T cell migration/recirculation pathway

A
  1. Naive T cells leave blood preferentially
  2. Enter lymph nodes across the HEVs
  3. DCs with Ag enter lymph nodes through lymphatic vessels
  4. T cells activated if they recognize the Ag
  5. Return to arterial ciruclation
84
Q

Effector and Memory T cell migration/recirculation pathway

A
  1. Effector and memory T cells leave blood preferentially
  2. Enter peripheral tissues through venules at sites of inflammation
85
Q

By which lymphocytes is L-selectin expressed?

A

By both T and B lymphocytes

86
Q

How was the biological importance of L-selectin demonstrated?

A

Experiments showing that L-selectin deficient lymphocytes are:

unable to enter peripheral nodes and “see” the Ag

87
Q

What are L-selectin ligands expressed on HEVs called?

A

PNAd

peripheral node addressins

88
Q

Naive T lymphocytes home to lymph nodes as a result of ________.

A

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

89
Q

HEVs are ONLY present on which organs?

A

secondary lymphoid organs

90
Q

Which cytokines are displayed on the surface of the HEV?

A

CCL19 and CCL21

91
Q

Why do naive T cells have low levels of SIPR1?

A

because the receptor is internalized after binding S1P in the blood

92
Q

S1PR1

A

Sphingosine-1-phosphate receptor 1

93
Q

What happens to the naive T cells that have recently entered a lymph node?

A
  • they cannot sense S1P concentration gradient between the T cell zone of the node and the lymph
  • they cannot exit the node for several hours until S1PR1 is re-expressed
94
Q

Where do activated effector T cells home to?

A

sites of infection in peripheral tissues

95
Q

How is effector T cell migration into peripheral tissue mediated?

A

mediated by E-selectins, P-selectins, integrins, and CXCL10 which are produced at the sites of infection

96
Q

What is CD44 important for?

A

Important for the mobilization of effector T cells in sites of infection or inflammation

97
Q

What is secreted and expressed by endothelial cells at the site of infection or inflammation?

A
  • Secreted = chemokines
  • Expressed =
    • E-selectins
    • P-selectins
    • Hyaluronic acid (HA)
98
Q

What can mediate rolling interactions with vascular endothelial cells that express HA or even E-selectins?

A

CD44

99
Q

Chemokine signaling via GPCRs results in ______.

A
  • Increased integrin affinity (such as VLA-4)
    • Which enhances adhesiveness (inside-out signaling)
100
Q

Engagement of CD44 with HA may also trigger what?

A

GPCR-dependent “inside-out” upregulation of VLA-4-VCAM binding

101
Q

What mechanism do naive B cells use to home to secondary lymphoid tissues throughout the body?

A

use the same basic mechanisms as do naive T cells

102
Q

What is the pathway of immature B cells once they leave the bone marrow?

A
  1. Leave bone marrow through blood
  2. Enter red pulp of spleen
  3. Migrate to the periphery of the white pulp
103
Q

What chemokine receptor do B cells express as they mature further?

A

CXCR5

104
Q

What does CXCR5 do?

A

promotes movement of B cells into the white pulp of spleen in response to CSCL13

105
Q

What happens once B cell maturation is completed within the white pulp of the spleen?

A
  1. Mature naive B cells reenter the circulation
  2. Home to lymph nodes and mucosal lymphoid tissues
106
Q

What is required for the homing process of mature naive B cells?

A
  • cytokines CXCL12 and CCL19/CCL21 on HEV
    • their chemokine receptors CXCR4 and CCR7 on naive B cells
107
Q

What drives the B cell migration into follicles in the stroma?

A

CXCL13 recognized by CXCR5 which is expressed on naive B cells

108
Q

How can the B cells in follicles become activated?

A

B cells may encounter Ag to become activated

109
Q
A

IMMUNOLOGY Exam #1- Lo (6 decks)

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