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Immunology Test I - Jourdan > Leukocyte Circulation and Migration into Tissue > Flashcards

Leukocyte Circulation and Migration into Tissue Flashcards

0
Q

What is migration or recruitment?

A

The general process of leukocyte movement from blood into tissues

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1
Q

What is recirculation?

A

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

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2
Q

What is leukocyte homing?

A

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

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3
Q

What is a major part of the process of inflammation?

A

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

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4
Q

What is inflammation triggered by?

A

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

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5
Q

What is the inflammatory response?

A

A response that delivers the cells and molecules of host defense to the sites where offending agents need to be combated

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6
Q

What process is responsible for causing tissue damage and underlies many important diseases?

A

Inflammatory response

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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

What can circulating leukocytes do through transient interaction of selectins and integrin with their receptors?

A

They can tether to and roll on the endothelium

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9
Q

What does rolling allow leukocytes to do?

A

To sample the endothelium for chemokines which activate integrins and trigger adhesion to the endothelium

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10
Q

What happens to adherent leukocytes?

A

They migrate across the endothelium into the extravascular space, once there they can migrate down chemokine gradients towards specific areas

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11
Q

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

A

Immune cells and soluble components

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12
Q

What happens to endothelial cells at sites of infection and tissue injury?

A

They are activated by cytokines secreted by resident macrophages and mast cells at these sites

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13
Q

What is the consequence of activated endothelial cells?

A

The consequence is increased adhesiveness of the endothelial cells for circulating myeloid leukocytes and Ag-activated effector and memory lymphocytes

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14
Q

What do leukocyte/lymphocyte homing and recruitment require?

A

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

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15
Q

What does homing involve?

A

It involves molecules on the surfaces of both the leukocytes (hooming receptors and chemokine receptors) and endothelial cells (chemokines)

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16
Q

What do addressins comprise of?

A

A set of several adhesion molecules on the surface of endothelial cells which regulate lymphocyte recirculation via HEV

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17
Q

What do endothelial cells express?

A

P-selectin and E-selectin

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18
Q

What causes endothelium to express P-selectin?

A

When endothelium is activated by histamine or thrombin

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19
Q

When is E-selecting synthesized and expressed on endothelial cell surface?

A

Within 1 to 2 hours in response to the cytokines IL-1 and TNF produced by tissue macrophages in response to infection

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20
Q

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

A

Complex sialylated carbohydrates related to the Lewis X or Lewis family

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21
Q

What is only expressed on leukocytes and lymphocytes but not on endothelial cells?

A

L-selectin

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22
Q

What is L-selectin expression activated by?

A

IL-1 and TNF at sites of inflammation

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23
Q

What is L-selectin important for?

A

For naive T and B lymphocytes for homing into LNs by interacting with high endothelial venules (HEV)

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24
Q

What are peripheral node addressins (PNAd)?

A

L-selectin ligands expressed on HEV

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25
Q

What are integrins?

A

Integrins are heterodimeric cell surface proteins composed of two noncovalently linked polypeptide chains

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26
Q

How many types of integrins are there?

A

More than 30 different integrins, all with the same basic structure

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27
Q

What do integrins mediate?

A

Mediate adhesion of cells to other cells or to extracellular matrix via various specific ligands

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28
Q

What is the function of integrins?

A

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

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29
Q

Leukocytes that bind to ligand intercellular adhesion molecule 1 expressed on cytokine-activated endothelial cells express what?

A

LFA-1

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30
Q

Leukocytes that bind to vascular cell adhesion molecule 1 VCAM-1, expressed on cytokine-activated endothelial cells, express what?

A

VLA-4

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31
Q

What do leukocytes express that binds to VCAM-1 and MadCAM (that is expressed on endothelial cells)?

A

alpha4 beta7

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32
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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33
Q

What occurs in all leukocytes in response to chemokine binding to chemokine receptors?

A

Integrin activation

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34
Q

When does Integrin activation in T lymphocytes occur?

A

When Ag binds to TCRs

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35
Q

What is integrin activation mediated by?

A

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

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36
Q

What is “inside-out signaling”?

A

A type of chemokine signaling that induces conformational changes in the extracellular domains of the integrins that mediate integrin activation

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37
Q

The integrins on blood leukocytes are normally in what state?

A

Low affinity state

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38
Q

When rolling of leukocytes occurs, what can the chemokines do?

A

Chemokines displayed on the endothelial surface can bind chemokine receptors on the leukocyte

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39
Q

When chemokine receptor signaling occurs what happens to the leukocyte?

A

The leukocyte integrins are activated, increasing their affinity for their ligands on the endothelial cells

40
Q

When a ribbon diagram shows a bend conformation of a leukocyte integrin, what state is the integrin in?

A

Low affinity

41
Q

When a ribbon diagram shows an extended conformation of a leukocyte integrin, what state is the integrin in?

A

High affinity

42
Q

What cells are ready to be recruited into tissue sites of infection or injury without activation?

A

Neutrophils and monocytes

43
Q

How do neutrophils and monocytes enter the tissue?

A

Through post-capillary venules except parenchymal tissues (liver, lungs, kidney) where all the blood cells enter through capillaries

44
Q

What do myeloid leukocytes do?

A

Eliminate infectious pathogens, clear dead tissues, and repair the damage

45
Q

what induces the rapid induction of expression of pre-formed P-selectin on the surface of endothelial cells?

A

Activated resident macrophages produce cytokines TNF and IL-1 that induce the rapid induction

46
Q

What else can be induced on the surface of endothelial cells along with P-selectin by cytokines?

A

E-selectin

47
Q

What initiates rolling on the endothelium by the leukocytes?

A

Interaction between P-selectin on endothelial surface and ligands on leukocytes

48
Q

How is further rolling of leukocyte stabilized?

A

By L-selecting binding to ligands on endothelial cells.

49
Q

What do endothelial cells present that is recognized by receptors on neutrophils? What do these do?

A

A chemokine CXC-chemokine ligand 8 (CXCL8 or IL-8)

Activates leukocyte integrins and results in a more stable leukocyte adhesion

50
Q

What controls transmigration of monocytes?

A

CCL2 or MCP-1

51
Q

What happens once leukocytes have completed trans-endothelial migration?

A

They interact with chemokines in the underlying basement membrane

52
Q

What follows diapedesis?

A

Cells adopt an amoeboid shape

53
Q

What do the amoeboid shape leukocytes do after entering the tissue?

A

They migrate in a polarized fashion along collagen fibrils in response to a chemotactic gradient towards the site of infection/inflammation

54
Q

Where are chemotactic receptors located?

A

In the leading edge

55
Q

How do the mechanism of recruitment for neutrophils compare to the mechanism of recruitment of monocytes?

A

Recruitment of neutrophils require chemokine IL-8 and monocytes require chemokine MCP. Everything else is identical

56
Q

How do Naive T cells enter the LNs?

A

Preferentially leave the blood and enter the LNs across the high endothelial venules (HEV)

57
Q

What enters the LNs through lymphatic vessels?

A

Dendritic cells bearing Ag

58
Q

How are T cells activated in the LNs? What follows the activation?

A

If the T cells recognize Ag, they become activated and they return into the arterial circulation

59
Q

How do effector and memory T cells travel to sites of inflammation?

A

They preferentially leave the blood and enter peripheral tissues through venules at sites of inflammation

60
Q

What is expressed by both T and B lymphocytes?

A

L-selectin and cell adhesion molecules - but each type utilize a distinct cell adhesion molecule (integrin)

61
Q

What are chemokines?

A

A large family of structurally homologous cytokines of 8-to kD that contain two internal disulfide loops

62
Q

What do chemokines do?

A

Stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues

63
Q

What is the name chemokine a contraction of?

A

Chemotactic cytokine

64
Q

How many human chemokines are there?

A

50 that are classified into four families on the basis of the number and location of the N-terminal cysteine residues

65
Q

What are the four families of chemokines in humans?

A
  1. CC or beta chemokines: two defining cysteine residues are adjacent
  2. CXC or alpha chemokines: Residues are separated by one amino acid
  3. C chemokines: single cysteine
  4. CXXXC chemokines: two cysteins are separated by three amino acids
66
Q

How was the biologic importance of L-selectin demonstrated?

A

By experiments showing the L-selctin deficient lymphocytes are unable to enter peripheral nodes and “see” the Ag

67
Q

How do Naive lymphocytes enter the LN?

A

Through the HEV

High endothelial venule

68
Q

What are L-selectin ligands expressed on HEV called?

A

peripheral node addressins (PNAd)

69
Q

Why do naive T lymphocytes home to lymph nodes?

A

Because of the result of L-selectin binding to peripheral lymph node addressin on HEV

70
Q

Where are HEV present?

A

Only in secondary lymphoid organs

71
Q

What are displayed on the surface of HEV?

A

Chemokines CCL19 and CCL21

72
Q

Chemokines binding to _________activates integrins?

A

CCR7 (chemokine receptor on Naive T cell)

73
Q

What do Naive T cells that have recently entered the LN have? Why?

A

Low levels of S1PR1 because the receptor is internalized after binding S1P in the blood

74
Q

What cant Naive T cell, that have recently entered the LN, sense?

A

Cant sense S1P concentration gradient between the T cell zone of the node and the lymph

75
Q

Why and how long are naive T cells stuck in the LN if there is no antigen recognition?

A

They cant exit the node for several hours until S1PR1 is re-expressed and the cell can then exit

76
Q

What happens if naive T cells recognize antigens in the LN?

A

They continue to have low levels of S1PR1 and stay in the LN. S1PR1 is re-expressed after several days. Then activated/differentiated effector T cells then sense the S1P gradient and exit the node

77
Q

Where do activated effector T cells home?

A

To sites of infection n peripheral tissues

78
Q

How is T cell migration into tissue mediated?

A

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

79
Q

What are involved in effector/memory T cell migration?

A

Many chemokines and chemokine receptors

80
Q

What is the function of the receptor, L-selectin, and ligand, PNAd pair? on naive t cell

A

Initial weak adhesion of naive T cells to high endothelial venule in lymph node

81
Q

What is the function of the CCR7 (chemokine receptor on naive T cell) and CCL19 or CCL21?

A

Activation of integrins and chemokinesis

82
Q

What is the function of LFA-1 (beta2 integrin) receptor and ICAM-1?
-on naive T cells

A

Stable arrest on HEV in lymph node

83
Q

On activated (effector and memory) T cells, what is the initial weak adhesion of the T cells to cytokine activated endothelium at peripheral sit of infection?

A

E and P selectin ligand on the T cell with the E or P selectin on the endothelium surface

84
Q

On activated (effector and memory) T cells, what activates integrins and chemokinesis?

A

CXCR3 or CCR5 with CXCL10 or CCL4 respectively

85
Q

On activated (effector and memory) T cells, what gives stable arrest on cytokine-activated endothelium at peripheral site of infection?

A

Beta 1 or 2 integrin with ICAM-1 or VCAM-1

86
Q

What is CD44 important for?

A

The mobilization of effector T cells in sites of infection and inflammation

87
Q

At sites of infection and inflammation, what do endothelial cells secrete?

A

Secrete chemokines and express E and P selectin and hyaluronic acid (HA)

88
Q

What can CD44 mediate?

A

Rolling interactions with vascular endothelial cells that express HA, its natural ligand, or even E-selectin

89
Q

What does chemokine signaling via GPCRs result in?

A

Increased integrin affinity, such as VLA-4, which enhances adhesiveness (“inside-out” signaling)

90
Q

What does the engagement of CD44 with HA also trigger?

A

GPCR-dependent “inside-out” upregulation of VLA4-VCAM binding

91
Q

How do Naive B cells home to secondary lymphoid tissues?

A

Same basic mechanisms as do naive T cells

92
Q

Once immature B cells leave the bone marrow, where do they go?

A

Through the blood, enter the red pulp of the spleen, and migrate to the periphery of the white pulp

93
Q

As B cells mature further, what do they express? What does this do for the B cell?

A

Chemokine receptor CXCR5, which promotes their movement into the white pulp in response to a chemokine called CXCL13

94
Q

Once the maturation is completed within the white pulp, what happens to the Naive B cell?

A

Reenter the circulation and home to lymph nodes and mucosal lymphoid tissues

95
Q

What does the homing of mature naive B cell from the blood into LNs involve?

A

Rolling interactions on HEVs, chemokine activation of integrins, and stable arrest.
Same for naive T cells

96
Q

What chemokines does the homing process of Naive B cells require?

A

CXCL12, CCL19/CCL21 on HEV and their chemokine receptors CXC$4 and CCR7 on naive B cells

97
Q

In the stroma, how are B cells migration into follicles driven?

A

By CXCL13 recognized by CXCR5 expressed on naive b cells

98
Q

What may B cells encounter in follicles?

A

Ag and become activated

Immunology Test I - Jourdan (3 decks)

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