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MIC4125 - Immunology > Cytokines, Chemokines & Cell Migration > Flashcards

Cytokines, Chemokines & Cell Migration Flashcards

1
Q

Cytokines are also know as __________ mediators between immune cells.

A

communication

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2
Q

Macrophages are activated when they ingest microbes, producing _________, which activate NK cells that produce ________ which activate ________ in a positive feedback.

A

Cytokine IL-12; cytokine IFN-y; macrophages

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3
Q

Which characteristic of cytokines is true?

  1. They are a group of high molecular weight proteins which are secreted by activated leukocytes only.
  2. Cytokines are stored as performed proteins with a long-half life.
  3. Their major functions are to mediate and regulate immune response and inflammatory responses.
A

3!

  1. They are a group of LOW molecular weight proteins which are secreted by activated leukocytes OR STROMAL CELLS.
  2. Cytokines are NOT stored as performed proteins with a SHORT-half life. Their synthesis is initiated by gene transcription upon activation and their mRNAs are short-lived.
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4
Q

Cytokines induce a ______ effect. Why?

A

Transient; if cytokines concentration is too high, they start to kill human cells.

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4
Q

Receptors for cytokines often bind their ligands with _____ affinities. Most cells express _____ levels of cytokine receptors.

Cellular responses to cytokines are _______ regulated, and feedback inhibitory mechanisms exist to ____ _____ these responses.

A

high; low (it is adequate for inducing responses)

tightly; turn down

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5
Q

What are the five characteristics of cytokine action?

A
  1. Pleiotropy
  2. Redundancy
  3. Synergism
  4. Antagonism
  5. Cascade induction
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6
Q

Match the definitions to the terms:

  1. Pleiotropy
  2. Redundancy
  3. Synergism
  4. Antagonism
  5. Cascade induction

A) two or more cytokines acting together

B) one cytokine stimulates its target cells to make additional cytokines (positive feedback)

C) act on several different cell types, generating multiple biological actions

D) cytokines causing opposing activities

E) similar or shared functions can be stimulated by different cytokines

A

Pleiotropy: act on several different cell types, generating multiple biological actions

Redundancy: similar or shared functions can be stimulated by different cytokines

Synergism: two or more cytokines acting together

Antagonism: cytokines causing opposing activities

Cascade induction: one cytokine stimulates its target cells to make additional cytokines (positive feedback)

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7
Q

What are three different types of cytokine action? Briefly describe each.

A
  1. Autocrine action: cytokines may act on the cells that secrete them
  2. Paracrine action: acts on nearby cells
  3. Endocrine action: act on distant cells in some instances via blood or tissue fluids
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8
Q

(T/F) Cytokines can either be named by cell sources or by biological functions.

A

True!

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9
Q

Why can’t we use interferons as a therapeutic?

A

Severe side effects - the flu symptoms following each infection is due to interferons

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10
Q

What are the three important anti-viral genes?

A
  1. Oligo A synthetase (OAS): activate RNAse L that digests viral dsRNA to limit viral replication
  2. Protein Kinase R (PKR): limits cellular translation and induces apoptosis
  3. Mx: binds viral nucelocapsids or other viral components, to inhibit virion assembly + gene expression.
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11
Q

Which one of the statements is true?

  1. Interferon α and β are type II IFN.
  2. Interferon α/β mediate the early innate response to viral infections and interfere with the replication of a wide variety of virus.
  3. Type I interferons induce a limited amount of antiviral proteins.
A

2!

  1. Interferon α and β are type I IFN.
  2. Induce a WIDE VARIETY OF 300 antiviral proteins and establish an ANTIVIRAL STATE.

*interferons are a type of cytokines.

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12
Q

Briefly describe how Type I IFNs lead to an antiviral state.

A

Type I IFNs are produced in a virus-infected cell, which travel and bind to receptors on the surface of an uninfected cell. Binding allows expression of enzymes that block-viral replication (increased PKR, Oligo A synthetase, Mx), leading to an antiviral state.

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13
Q

Receptors for different cytokines are classified into families on the basis of:

A

a) conserved extracellular domain structures

b) signaling mechanisms

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14
Q

Answer the following questions regarding the JAK-STAT pathway:

1) What do they stand for?

2) What do they induce (5 things)?

3) Which one has the DNA binding domain and the two kinase domains?

A

1) Janus Kinase - Signal Transducer and Activator of Transcription (STAT)

2) Proliferation, differentiation, migration, apoptosis, and cell survival

3) STAT because it is a transcriptional factor has the DNA binding domain while the JAK has the two kinase domains

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15
Q

Protein ____________ is one type of post-TRANSLATIONAL modification which can turn many protein enzyme on and off, thereby altering their function, activity and localization.

It results in a _________ change in the structure in many enzymes and receptors, either activating or deactivating them.

A

phosphorylation

conformational

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16
Q

(T/F) Protein phosphorylation is irreversible.

A

False! It is reversible.

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17
Q

Briefly describe how an interferon activates the JAK-STAT signaling pathway, leading to an anti-viral state.

A
  1. Type I interferons (cytokines) bind to cytokine receptors, dimerizing them.
  2. Dimerization leads to JAK-mediated phosphorylation of receptor chains.
  3. There is recruitment of STATs to cytokine receptors.
  4. STATs get phosphorylated by JAK, causing them to leave the receptor and dimerize, activating STAT proteins.
  5. Active STAT proteins translocate to nucleus, where they bind to sequences in the promoters, leading to transcription of cytokine-responsive genes (PKR, RNAse L, Mx, and others).
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18
Q

1) What are chemokines?

2) What is their function in the immune system?

A

1) Cytokines with chemotactic activities (induce cell migration).

2) They stimulate leukocyte movement and regulate migration of leukocytes from the blood to tissues. CHEMOKINE SIGNALING ACTIVATES INTEGRINS ON LEUKOCYTES.

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19
Q

State statements as true or false:

1) Chemokines are a large family of structurally non-homologous cytokines

2) They are small proteins consisting 60-100 aa

3) Chemotaxis is also know as movement of a cell in a direction corresponding to a gradient of increasing or decreasing of a chemokine.

4) There is a low chemokine concentration at the site of infection.

A
  1. False. Chemokines are a large family of structurally HOMOLOGOUS cytokines.
  2. True!
  3. True!
  4. False. There is a HIGH chemokine concentration at the site of infection, helping leukocytes find the site of infection.
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20
Q

1) What kind of receptors are chemokine receptors? Briefly describe.

2) What is the outcome of an activated chemokine receptor?

3) Which chemokine receptors act as CORECEPTORS for HIV? What happens if these receptors are not present in a fetus?

A
  1. G-protein-coupled receptors (GPCRs). They thread through the plasma membrane SEVEN times.
  2. Activated chemokine receptor initiates intracellular responses through TRIMERIC G proteins which stimulate cytoskeletal changes and polymerization of ACTIN and MYOSIN filaments, resulting in INCREASED CELL MOTILITY. They change the confirmation of CELL SURFACE INTEGRINS and INCREASE THE AFFINITY of integrins for their ligands.
  3. CCR5 and CXCR4. If these receptors are not present in a fetus, the baby will be HIV resistant. However, the baby will lack a proper immune response.
21
Q

(T/F) Chemokine and chemokine receptors are partnered one to one.

A

False! Not one to one partnering. A receptor can recognize many chemokines and a chemokine can be recognized by many receptors.

22
Q

What is a unique property of the immune system?

A

DYNAMIC: the constant and highly regulated movement of immune cells through the blood, into the tissues.

Native lymphocytes continuously migrate into secondary lymphoid tissues, while activated lymphocytes and myeloid leukocytes preferentially home into tissues where there is infection or injuiry.

23
Q

Leukocyte homing and recruitment into the site of infection requires?

A

The temporary adhesion of leukocyte to the endothelial lining of blood vessels; a process that involves adhesion molecules on the surface of both the leukocytes and endothelial cells.

24
Q

Endothelial cells at sites of infection and tissue injury are activated by ________ secreted by _________, resulting in increase expression of ___________ and _________.

A

cytokines; macrophages; adhesion molecules; chemokines

25
Q

What are the three main leukocyte migration from blood to tissues? Which venule is used for each?

A
  1. Neutrophils and monocytes migrate to sites of infection and tissue injury: inflammation. POST-CAPILLARY.
  2. Native T and B cells migrate into secondary lymphoid tissues (mucosa associated too); initiation of adaptive immune responses. HIGH ENDOTHELIAL VENULE (HEV).
  3. Effector and memory T cells migrate into sites of infection and tissue injury: cell-mediated immunity. POST-CAPILLARY

*1&3 are similar and induce protective functions of eliminating infectious pathogens

26
Q

Put the sequences regarding the formation of an inflammation in the proper order.

  1. Cytokines and chemokines incude vasodilation and increased vascular permeability, causing redness, heat, and swelling.
  2. Inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain.
  3. Bacteria trigger macrophages to release cytokines and chemokines.
A
  1. Bacteria trigger macrophages to release cytokines and chemokines.
  2. Cytokines and chemokines incude vasodilation and increased vascular permeability, causing redness, heat, and swelling.
  3. Inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain.
27
Q

What happens to leukocytes in the blood vessel before and after vasodilation?

A

During normal blood flow (pre-vasodilation), leukocytes are in axial flow.

After vasodilation, leukocytes fall from axial flow and make more contact with the blood vessels, allowing for better cell adhesion.

28
Q

1) What is contraction of endothelial cells?

2) What does contraction of endothelial cells result in? What does it release?

3) How long does it last? When does it happen?

A
  1. Endothelial cells develop temporary gaps during vasodilation, resulting in contraction. This affects VENULES EXCLUSIVELY.
  2. vascular leakiness; release of histamine, bradykinin, and other chemical mediators
  3. short duration (15-30 minutes) - immediately after injury.
29
Q

(T/F) Leukocyte migration to site of inflammation involves only one step.

A

False!

Multi-steps are involved in leukocyte migration to sites of inflammation.

30
Q

__________ is important to recruit leukocytes to sites of infection of for immunosurveilence

Adhesion of the leukocytes to the endothelial lining of _____________ venules

Combination of ________ + __________ receptors on leukocytes determines cell-specific trafficking

A

Trafficking

Post-capillary

Adhesion; chemokine

31
Q

(T/F) Red blood cells and lymphocytes both express adhesion molecules and hence are so rough on the surface.

A

False! Only lymphocytes express adhesion molecules to interact with endothelial cells to go into injured tissue.

Red blood cells never interact with endothelial cells, they keep migrating

32
Q

What are the two major adhesion molecules? How are they different.

A

Selectins: induce a WEAK binding

Integrins: induce a STRONG binding

33
Q

Which one of the statements is true?

  1. Selectins bind to plasma membrane carbohydrate while integrins bind to specific ligands.
  2. Selectins are heterodimeric cell surface proteins composed of two non-covalently linked polypeptide chains
  3. Integrins mediate an initial step of low affinity adhesion of circulating leukocytes to endothelial cells lining in post-capillary venules
A

1!

For 2, INTEGRINS are heterodimeric cell surface proteins composed of two non-covalently linked polypeptide chains.

For 3, SELECTINS mediate an initial step of low affinity adhesion of circulating leukocytes to endothelial cells lining in post-capillary venules. INTEGRINS mediate adhesion of cells to other cells or to extracellular matrix.

34
Q

What is the first step of leukocyte migration? Describe it. Mention the different selectins involved.

A

TETHERING AND ROLLING.

  1. activation of endothelium by TNF-alpha or histamines induce RAPID EXTERNALIZATION of GRANULES in the cells called WEIBEL-PALADE bodies.
  2. these granules contain P-selectin, which is expressed within minutes on the endothelial cells’ surface. E-selectin appears within hours.
  3. at sites of inflammation, blood vessels dilate and blood flow slows, making leukocytes closer to blood vessels lining.
  4. ligands of P- and E- selectins (plasma membrane carbohydrate) expressed on the microvilli of the leukocytes bind to selectins on the endothelial cells.
  5. because these interactions are low affinity with a fast off rate, they are easily disrupted by blood’s force.
  6. the leukocytes repetitively detach and bind again and thus roll along the endothelial surface
35
Q

______ is retained by proteoglycans on the endothelium for presentation to chemokine receptors (GPCRs) on _______.

Chemokines (after binding to chemokine receptors on leukocytes) induce activation of ________ to capture leukocytes on endothelial cell walls (against shear force).

A

IL-8 (chemokine); leukocytes

Integrin

*leukocytes have chemokine receptors and integrins

36
Q

What kind of molecules induce the expression of integrin ligands on the blood vessels so leukocytes (with integrins) can bind?

A

Inflammatory cytokines such as TNF.

Upon exposure to TNF-alpha, a local expression of Intercellular Adhesion Molecule (ICAM)-1 is strongly induced on the endothelium of small vessels within the infectious focus.

37
Q

Which statement is true?

  1. during rolling, the leukocyte searches on surface of endothelium for activation signals
  2. chemokine mediated integrin activation is a “bridge between rolling and adhesion”
A

both!

38
Q

Briefly summarize chemokine-mediated integrin activation.

A

Leukocytes are activated by immobilized chemokines and integrin ligands on endothelial surface.

Chemokines bound to proteoglycans in the extracellular matrix on endothelial membrane act by signalling via the GPCRs (chemokine receptors).

The signaling induces integrin conformation changes (low affinity state to high affinitiy) and the binding of integrin to its receptor, inducing arrest of leukocytes.

39
Q

What are LFA-1 and ICAM-1?

A

LFA-1: lymphocyte function associated antigen 1 (low affinity integrin)

ICAM-1: intercellular adhesion molecule 1

Lots of ICAM-1 in the endothelium through exposure to inflammatory cytokines. High affinity integrin binds to ICAM-1.

40
Q

What is the last step of the multi-step process of leukocyte migrating into tissues?

A

Transmigration (Diapedesis)

1st step: tethering and rolling
2nd step: arrest and integrin activation, leading to stable adhesion

41
Q

In transmigration, there is interaction of ____________ molecule or ________ expressed BOTH on the leukocyte and at the __________ junctions of endothelial cells, enabling the phagocyte to squeeze between the endothelial cells.

Leukocytes penetrate the __________ membrane with the aid of ________ enzymes that break down the membrane.

The movement through the vessel wall is also known as ________, and enables phagocytes to enter the _________ tissues.

A

Platelet Endothelial Cell Adhesion Molecule (PECAM); CD31; INTERcellular

basement; proteolytic

diapedesis; subepithelial

42
Q

Which one of the statements is true?

  1. Antigens from tissues are collected to secondary lymphoid organs via lymph only.
  2. Effector lymphocytes and antibodies are delivered via blood to site of infection.
A

2!

Antigens from tissues are collected to secondary lymphoid organs via lymph AND BLOOD.

43
Q

Where does initiation of adaptive immune responses and cell-mediated immunity occur?

A

Initiation of adaptive immune responses occur at SECONDARY LYMPHOID TISSUES.

Cell-mediated immunity occurs at SITES OF INFECTION and TISSUE INJURY.

44
Q

Movement of naive T cells in the secondary lymphoid organs maximize …?

A

the chances of T cell activation and initiation of an adaptive immune response

45
Q

Fill in the blanks regarding naive T-cell migration:

  1. L-selectin on the lymphocytes bind to its carbohydrate ligand: ______.
  2. _____ and _____ (chemokines) displayed on the surface of the High Endothelial Venules (HEV) are recognized by chemokine receptor _______ on rolling lymphocytes.
  3. These chemokines activate the naive T cell integrin _______ to a ____ affinity state.
A
  1. Peripheral node addressin (PNAd)
  2. CCL19; CCL21; CCR7
  3. LFA-1; high
46
Q

What is extravasation?

A

the process of leukocytes migrating into tissues.

47
Q

Effector T cells that have been generated by antigen-induced activation exit secondary lymphoid tissues through _______ ______ and return to the ________ ______.

A

Lymphatic drainage; circulating blood

48
Q

What happens to the adhesion molecules (P-selectin) and chemokine receptors (CCR7) of naive T cells when they turn into effector cells?

What does this do?

A

There is a change in adhesion molecule (low L-selectin) and chemokine receptor expression (low CCR7).

Effector T cells match their adhesion molecules and chemokine receptors to those in Post-Capillary Venules as that is what they will use to migrate into tissues.

49
Q

Effector T cell migration is mediated by __ selectin and __ selectin, _________ and ____________ that are produced at sites of infection.

A

E;P; integrins; chemokines (CXCR3)

50
Q

(T/F) Most effector cells that enter a site of infection eventually die at these sites after performing their effector functions.

A

True!

51
Q

Cell migration is dependent on the __________ molecules on them.

A

Adhesion

MIC4125 - Immunology (13 decks)

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