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MEDSCI 708 > TOPIC-1-LECTURE > Flashcards

TOPIC-1-LECTURE Flashcards

1
Q

What is the A subgroup of beta2 integrins?

A

This is a group of integrins made when one of the subunits, alphaL, alpha M, alpha X, alpha D and alpha E combine with the beta2 subunit to generate a leukocyte which is restricted to leukocytes

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2
Q

What is alphaL-beta2?

A

An integrin of the A subgroup of beta2 integrins, found on most leukocytes which interacts with ICAM-1,2 and 3 to play a role in transendothelial migration, recirculation, homing, localization

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3
Q

What are the key roles of alphaL-beta2?

A

Antigen presentation, T-cell co-stimulation, the cytotoxicity of T cells, delayed type hypersensitivity and endotoxin shock

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4
Q

What results in the leukocytes of mice lacking alphaL?

A

In vitro homotypic aggregation when proliferated in mixed lymphocyte reactions and in response to mitogen
In vivo experiments showed allogenic graft rejection is reduced, Neutrophils and T cells were unable to cross the endothelial monolayer
Trafficking of lymphocytes to peripheral lymph nodes, mesenteric lymphnodes and acute inflammatory sites is impaired
They also mounted normal CTL responses against system LCMV and VSV with normal ex vivo CTL function, but would not reject immunogenic tumours or a priming response against tumour-specific antigen

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5
Q

What is the conclusion reached with mouse experiments where they lacked alpha-L?

A

Alpha-L deficiency causes a selective defect in induction of peripheral immune responses, while responses to systemic infections remains normal

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6
Q

What does alphaM-beta2 interact with?

A

Alpha M-beta2 interacts with ICAM-1, iC3b, fibrinogen, serum facto X, herapin and may bind denatured proteins, deoxyoligonucleotides, elastase, high molecular weight kininogen and carbohydrate beta-glucan structures
It also interacts with the third domain on ICAM-1 –while alphaL-Beta2 interacts with the first one

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7
Q

What occurs when both alphaM-beta2 and alphaL-beta 2 are expressed at similar levels?

A

The alphaL-beta2 interaction with the first ICAM-1 domain will dominate over the alphaM-beta2 interaction with the third domain of ICAM-1

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8
Q

What does alphaX-beta2 interact with?

A

This binds to iC3b, fibrinogen and ICAM-1

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9
Q

What are the functions of alphaM-beta2 and alphaX-beta2?

A

Mediate myeloid cell adhesion to endothelium, transmigration, chemotaxis, phagocytosis of opsonized particles and respiratory burst

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10
Q

What occurs in alphaM-beta2 deficient mice?

A

Significant reductions in the numbers of mast cell resident in the peritoneal cavity, peritoneal wall and dorsal skin
These mice exhibit significantly increased mortality to acute septic peritonitis, where host resistance depends on both mast cells and complement

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11
Q

What are the functions of alphaD-beta2?

A

This binds preferentially to ICAM-3, with the subunit being more closely realted to alphaM/X than alphaL
It is expressed at moderate levels on myelomonocytic cell lines and subsets of peripheral blood leukocytes
Strongly expressed on tissue compartmentalized cells like macrophages foam cells found in aortic fatty streaks which develop into atherosclerotic lesions, as well as on eosinophils and binds VAM-1 an interaction which may play a role in chronic inflammation

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12
Q

What is the role of ICAMS?

A

These are expressed on dendritic cells, and other antigen presenting cells, delivering co-stimulatory signals via Beta-2 integrins triggering lymphocyte proliferation

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13
Q

What is the importance of the interaction between alphaE and the beta7 subunit?

A

The alphaE subunit associates with the beta7 subunit to form alphaEbeta7 activation antigen which recognizes epithelial E-cadherin. It may retain iIEL as an immune barrier against intestinal pathogens
This has a binding site within E-cadherin distinct from the homophilic binding site of E-cadherin

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14
Q

Where is alphaEbeta7 expressed?

A

On only 2% of circulating blood lymphocytes, it is upregulated by TGF-beta- which may imprint migratory gut-seeking lymphocytes to become iIELS

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15
Q

What occurs in beta-7 knockout mice?

A

These mice are viable, but have impaired gut-associated lymphoid tissue including reduced numbers of intraepithelial lymphocytes, lymphocytes found in Peyers Patches, mesenteric lymph nodes and lamina propria.

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16
Q

What occurs in alphaE knockout mice?

A

Mucosla T lymphocyte numbers are reduced, including intestinal and vaginal IEL and lamina propria, however peribronchial, intrapulmonary, peyers patch and splenic T lymphocytes were unaffected which suggests alphaE-beta 7 plays a role in generating/maintaining the gut and vaginal T lymphocytes located diffusely within the epithelium or lamina propria but not for generating the gut-associated lymphoid tissues

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17
Q

What are the alpha-4 integrins?

A

These are major immunoreceptors expressed predominately on leukocytes, playing a key role in immune response. It assmebels with bothe beta1 and beta7 subunits
These two different integrins share the ligands VCAM-1, MAdCAM-1 and FN
Both alpha 4 domains are expressed on the microvillus tips of lymphocytes and can mediate lymphocyte tethering and rolling under shear flow as well as mediating the initial attachment of eosinophils

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18
Q

What are the differences between alpha4-Beta1 and alpha4-beta7?

A

Alpha4-beta1 preferentially binds VCAM-1 on activated endothelium while alpha4-beta7 preferentially binds MAdCAM1 on HEVs at sites of chronic inflammation
Alpha4-Beta1 binds IG domains 1 and 4 of VCAM while alpha4-beta7 binds to the IG 1 domain of MAdCAM-1 with assistance from domain 2
Alpha4-beta is more widely expressed found outside the leukocyte lineages on myoblasts, endothelial and melanoma cells

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19
Q

What might be the role of alpha4-beta1 on myoblasts?

A

Its interaction with VCAM-1 may allow transendothelial chemotaxis by supporting the lateral migration of attached monocytes along the endothelium

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20
Q

What might be some of the functions shared by alpha4-beta1 and alpha4-beta7?

A

The facilitating of attachment and emigration of leukocytes across the blood vessel wall, adhesion and prevention of apoptosis in B cells in germinal centres and the adhesion of lymphoid progenitors to bone marrow stroma
Production of T cells in the adult is alpha4-dependent with precursors for both T and B cells require alpha4-integrins for normal development within the bone marrow

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21
Q

What is the affect of antibodies which against alpha4-beta7 or MAdCAM1?

A

They block the binding of mesenteric lymph node lymphocytes to Peyers patches HEV in vitro, and the homing of lymphocytes to the gut and lamina propria in vivo

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22
Q

What conclusion can be drawn from studies done with antibodys against alpha4-beta7 and MAdCAM1?

A

Alpha4-beta7 is critical for the homing of lymphocytes to the gut and mucosal sites which are normally chronically inflamed. Alpha 4 integrins have the ability to compensate for the lack of LFA-1 through facilitating the migration of lymphocytes to peripheral lymph nodes in LFA-1 deficient mice
It also participates in lymphocyte recirculation through bone marrow

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23
Q

What is the link between alpha4 integrins and chronic inflammation?

A

These molecules are highly expressed on pathogenic leukocytes, and diseased sites of chronic inflammation, making them major targets for the treatment of many major chronic inflammatory diseases
The ligands VCAM-1 MAdCAM-1 are expressed on follicular dendritic cells and may deliver signals via alpha4 integrins during antigen presentation leading to co-stimulation of T cell proliferation

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24
Q

What is the other name for ICAM-1?

A

CD54

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25
Q

What is ICAM-1?

A

A single chain 80-114 kDa protein with 5 Ig like domains, a single transmembrane region and short cytoplasmic domain

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26
Q

What can ICAM-1 bind to?

A

LFA-1, Mac-1, alphaCbeta2, fibrinogen, hyaluronan and CD43

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27
Q

How is ICAM-1 expressed?

A

Resting leukocytes will express little or no ICAM-1 but expression is induced following activation
Resting endothelial cells have low levels of ICAM-1 and activation with inflammatory cytokines- IL-1, IFN-gamma, TNF-alpha- leading to increased expression and induction on epithelial cells
It is also expressed on dendritic cells where this interaction of ICAM-1 with LFA-1 is thought to be involved in the initial binding of T cells to antigen presenting cells

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28
Q

What is ICAM-2?

A

A 55-65 kDa protein with two Ig like domains its precise role is not understood but it is thought to be important for lymphocyte recirculation through uninflamed tissue endothelium

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29
Q

What is the other name for ICAM-2?

A

CD102

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30
Q

How is ICAM-2 expressed?

A

Resting lymphocytes and monocytes but not neutrophils express low levels of cell surface ICAM-2
Immunohistochemical analysis also reveals high levels of expression on endothelium and follicular Dendritic cells in germinal centres
It is not upregulated on leukocytes or endothelium upon exposure to inflammatory mediators

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31
Q

What is ICAM-3?

A

A 120-160 kDa molecule which contains 5 Ig domains constitutively expressed on high levels on leukocytes but not on endothelial cells

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32
Q

What does ICAM-3 interact with?

A

This binds LFA-1 but not Mac-1, when expressed on dendritic cells this interaction is believed to be involved in the initial binding of T cells to antigen presenting cells

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33
Q

What is the other name for ICAM-3>

A

CD50

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34
Q

What is VCAM1?

A

Vascular cell adhesion molecule, which is 110 kDa and has 7 Ig-Like domains

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35
Q

How is VCAM-1 expressed?

A

Expression is induced on endothelial cells by inflammatory mediators such as IL-1 and TNFalpha
It is also expressed on some macrophages, dendritic cells, bone marrow stromal cells, synovial cells in inflamed joints and muscle cells

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36
Q

What does VCAM-1 interact with?

A

It is recognized by the integrins alpha4-beta1, alpha4-beta7 to support the extravasation of leukocytes, particularly at sites of inflammation
It can also participate in adhesion outside the vasculature, including binding of lymphocytes to dendritic cells and bone marrow stromal cells

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37
Q

What is the other name for VCAM-1?

A

CD106

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38
Q

What is PECAM-1?

A

This is a molecule in the group known to secondarily activate integrins
It is a 130 kDa, type 1 transmembrane protein with 6 Ig domains
Most of its functions are a result of homophilic interactions allowing leukocyte extravastion, bone marrow hematopoiesis and vascular development

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39
Q

What is the other name for PECAM-1?

A

CD31

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40
Q

What is the importance of PECAM-1 to leukocyte extravastion?

A

It seems to be important during the later stages where it facilitates the binding of various leukocyte associated integrins and assists in peripheral blood leukocytes in their transit across endothelial barriers

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41
Q

What is the function of PECAM-1 on T cells?

A

Ligation of this molecule on T cells will up regulate the function of both beta1 and beta2 integrins

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42
Q

What is E-cadherin?

A

A 120 kDa cell surface glycoprotein which, when complexed with catenins, mediates Ca2+ dependent cell-cell adhesion. It forms the key functional part of adherens junctions on epithelial cells allowing the establishment and maintenance of intercellular adhesion, cell polarity and tissue architecture

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43
Q

What is the role of E-cadherin in immunity?

A

It plays a critical role in localizing intraepithelial lymphocytes to epithelial regions by binding to alphaEbeta7 this is particularly important in gut mucosal immunity

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44
Q

What are selectins?

A

This is a family of transmembrane molecules expressed on the surface of leukocytes and activated endothelial cells
They contain an N-terminal extracellular domain with structural homology to calcium-dependent lectins, followed by a domain homologous to epidermal growth factor and two nine consensus repeats similar to sequences found in complement regulatory proteins
They are all inserted via hydrophobic transmembrane domain and possess a short cytoplasmic tail

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45
Q

What are the general functions of selectins?

A

They provide the initial attachment of leukocytes during extravasation, allowing a slow downstream movement of leukocytes called rolling

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46
Q

What is L-selectin?

A

This is the smallest of the vasucalr selectins at 74-100 kDa and is constitutively expressed at the tips of microfolds on granulocytes, monocytes and a vast array of circulating lymphocytes
It is important for lymphocyte homing and adhesion to HEVs of peripheral lymph nodes
It contributes greatly to the capture of leukocytes during the early phases of extravasation, after capture this molecule is shed from leukocyte surfaces after chemoattractant stimulation

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47
Q

What does L-selectin interact with?

A

There are 4 known counter receptors, MAdCAM-1, PGlyCAM-1, P-selectin glycoprotein 1 and CD34

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48
Q

What occurs in L-selectin deficient mice?

A

Trauma-induced leukocyte rolling into mesentery or cremaster muscle venules is normal initially but will decline over time, indicating that rolling in these mice is P-selectin dependent with high velocity rolling compared to wild type
L selectin is necessary in mediating rolling after surgical trauma and is necessary for neutrophil recruitment after inflammation though basal neutrophil trafficking appears to remain normal

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49
Q

What is the effect of a loss of L-selectin on E-selectin?

A

These P-selectin dependent mice have a reduction in the efficiency of E-selectin mediated rolling, shown by a sensitivity to P-selectin antibodies
Though it is clear that P and L selectin mediate leukocyte rolling L selectin cannot assume this task at normal velocities in vivo

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50
Q

How is L-selectin expressed on T cells?

A

Levels of L selectin are higher on lymph node homing cells which may facilitate T cell accumulation at this site by enhancing binding to locally expressed ligands such as PNAd

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51
Q

What is P-selectin?

A

This is the largest known selectin at 140 kDa, containing 9 consenus repeats and is expressed on alpha-granules of activated platelets and granules of endothelial cells by inflammatory mediators such as histamine, leukotrienes, thrombin or phorbol esters

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52
Q

What does P-selectin interact with?

A

The primary ligand is PSGL-1 which is constitutively expressed on all leukocytes and rapidly released following leukocyte activation
Transient interactions between these two molecules allows leukocytes to roll along the venular endothelium

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53
Q

What is P-selectin largely responsible for?

A

The rolling phase of the leukocyte adhesion cascade, it can also mediate capture when L selectin is not present

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54
Q

What occurs in P-selectin deficient mice?

A

Trauma induced rolling is absent immediatedly but returns after 1-2 hours with this delayed rolling be L-selectin dependent
However the leukocytes roll much faster than in wild type mice suggesting that L-selectin cannot independently support rolling at typical in vivo velocities

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55
Q

What is the relationship between P and E selectin functions?

A

P and E selectin tend to have overlapping functions, In mice deficient for P-selectin, E selectin function must be blocked for a significant reduction in rolling to be seen and vice versa
While there is a lot overlap in function P selectin does appear to be responsible for early rolling while E selectin is responsible for slow rolling which generates more adhesion

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56
Q

What is E-selectin?

A

A selectin expressed on inflamed endothelial cells, with a function in leukocyte rolling which is largely redundant if P selectin is present, meaning that single knock-outs having only subtle defects such as faster rolling velocities
In addition to rolling this molecule is iomportant in the conversion of rolling to firm adhesion with deficient mice having reduced numbers of adherent leukocytes
It is expressed in skin microvessels under baseline conditions suggesting it may be important in skin inflammation as it supports the functions of skin-specific T cells

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57
Q

What are the ligands for E-selectin?

A

These are unknown but two potential candidates are PSGL-1 and E-selectin ligand 1

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58
Q

What are Mucins?

A

These are selectin ligands, they are serine and threonine-rich which provides scaffolds for O-link glycosylation

59
Q

What is PSGL-1?

A

P-Selectin glycoprotein ligand 1 which is a 240 kDa homodimer of two peptide chains, it is constitutively expressed on all leukocytes though primarily found on the tips of the microvilli

60
Q

How does PSGL-1 interact with P selectin?

A

Psgl-1 can interact with P-selectin when decorated with the appropriate sugars, with the structure of functional PSGL-1 including the Sialyl-lewis X component, its O linked glycans must undergo two modifications in order for the molecule to correctly function, an alpha1,3 fucosylation and alpha2,3 sialylation.
This molecule can also interact with L and E selectin

61
Q

What is CD34?

A

This is a transmembrane glycoprotein constuitively expressed on endothelial cells and on hematopoietic stem cells
It is highly O-glycosylated, containing serine and threonine rich mucin-like domains which can bind to L-selectin

62
Q

What have studies suggested about CD34?

A

That it is important in lymphocyte tethering with deficient mice exhibiting no detectable abnormalities in postsurgical leukocyte rolling in cremaster venules however antibodies against CD34 resulted in reduced L-selectin function suggesting this is the major ligand for that selectin

63
Q

What is the extracellular matrix?

A

In a lot of connective tissues this is secreted by fibroblasts in the form of molecules with two major classes of macromolecules, glycosaminoglycans which are polysaccharide chains typically found covalently linked to proteins as proteoglycans. The second class is fibrous proteins, with the functional types including structural proteins such as collagen, and adhesive ones such as fibronectin and laminin

64
Q

What is the role of glycosaminoglycans in the extracellular matrix?

A

They form a highly hydrated, gel-like substance in which the members of the fibrous proteins are embedded

65
Q

What are the functions of collagen fibres to the extracellular matrix?

A

They help to strengthen and organize the matrix

66
Q

What is the function of elastin fibres to the extracellular matrix>

A

They give the matrix resilience

67
Q

What role does fibronectin play In the extracellular matrix?

A

Promoting the attachment of fibroblasts and other cells to the matrix in connective tissues via the extracellular parts of some members of the integrin family

68
Q

What is the function of laminin to the extracellular matrix?

A

Promoting of the attachment of epithelial cells to the basal lamina via the extracellular domains of some integrins

69
Q

What are the steps in the multistep process of leukocyte extravasation?

A 
Capture
Rolling
Slow Rolling
Firm adhesion
Transmigration
70
Q

What is capture in the process of leukocyte extravastion?

A

This is the first contact of a leukocyte with activated endothelium, it occurs after margination- a process which allows leukocytes to move towards the endothelium and away from central blood flow- During an inflammatory response endothelial activation is necessary for capture

71
Q

What are the molecular interactions involved in the capture phase of leukocyte extravasation?

A

P-selectin, on endothelial cells is the primary adhesion molecule for capture, with its primary ligand being PSGL-1
Many in vivo studies also indicate that L-selectin has an important role in this process with antibodies being able to inhibit rolling in models where it is P selectin dependent

72
Q

What is rolling in the process of leukocyte extravastion?

A

After capture, leukocytes transiently adhere to the venular endothelium and begin to roll at or below the velocity of freely flowing cells- a velocity known as critical velocity

73
Q

What is the most important selectin involved in rolling?

A

P-selectin as it can support both capture and rolling in the absence of L selectin
It is rapidly surface-expressed on the venular endothelium after trauma to make the endothelium sticky for leukocytes through interaction with PSGL-1 which is constitutively expressed on all leukocytes

74
Q

Where is P-selectin found?

A

It was initially found on platelets but has also been identified on Weibel-Palade bodies of human endothelial cells

75
Q

What occurs to the bonds formed between selectins and their ligands in leukocyte rolling?

A

Bonds are initially formed at the leading edge of the rolling cell, and broken at the trailing end with integrins initially remain in their resting state and endothelial IgCAMs remain at control levels

76
Q

What experiments support the critical role of P-selectin in the rolling phase of the adhesion cascade?

A

By experiments done on gene targeted mice where those lacking P-selectin did not have leukocytes roll after surgical trauma, as well as having higher number of circulating granulocytes than wild type suggesting that P-selectin is necessary to remove the leukocytes from the bloodstream
In vitro isolated human granulocytes have been shown to roll on purified P selectin

77
Q

What is the role of E and L selectins in the rolling process?

A

When P-selectin is absent, trauma induced rolling becomes L-selectin dependent but the average rolling velocity is 3 to 5 times faster suggesting L-selectin is less efficient
L-selectin is however essential for the normal inflammatory response in capturing leukocytes and initiating rolling
P and E selectin appear to act redundantly with E selectin thought to be responsible for slow rolling and possible the initiation of firm adhesion

78
Q

What is the slow rolling phase of the adhesion cascade?

A

The expression of E-selectin on endothelial cells and CD18 integrins on the rolling leukocytes
This process is not based on a unique property of E-selectin, however the expression of E-selectin and its ligands seems to sufficiently high in vivo for the support of slow rolling
The contact time of the leukocyte in close proximity with the endothelium is a key factor in the successfulness of this step, with transit time being linked to chemokines which are presented on the endothelial surface

79
Q

What have tracking studies shown about the slow rolling phase of the adhesion cascade?

A

Individual leukocytes were found to slow down systematically before becoming firmly adherent, with rolling leukocytes being likely to be activated by surface bound chemo-attractants and adhesion molecule-based signalling
Velocity of the rolling may have an effect independent of transit time as secondary binding events may not be able to form unless the leukocyte spends a certain amount of time in a position favourable for bond formation

80
Q

Is slow rolling required for leukocyte recruitment?

A

No as high concentrations of chemoattractants can also arrest fast moving leukocytes, however it does make the process much more efficient

81
Q

What is the role of chemokines in slow rolling?

A

They activate integrins resulting in the firm adhesion of leukocytes to the vascular wall, with integrins contributing to the rolling process through transient binding to their ligands

82
Q

What is the firm adhesion phase of the adhesion cascade?

A

This phase is believed to only be possible for most ,if not all, leukocytes after rolling/ slow rolling has occurred with E-selectin participating in the transition from rolling to adhesion

83
Q

What is the result of interfering with the CD18 integrin?

A

This is one of the most efficient ways to curb leukocyte recruitment in experimental inflammation, despite the drastic reduction in response to exogenous chemo attractants, CD18 deficient mice still have robust inflammatory responses suggesting these integrins participate in arrest but are not always required –potentially due to alternative pathways like alpha4beta1 on neutrophils.
Deficient mice do however have sever inflammatory defects including skin ulceration, elevated neutrophil counts and Ig levels, increased susceptibility to streptococcus pneumonia and a severe defect in leukocyte adhesion and T-cell activation

84
Q

What occurs in patients lacking CD18?

A

These individuals suffer from leukocyte adhesion deficiency type1, a serious disease which can lead to early lethality patients develop severe infections, periodontitis, and skin infections. S. Aureus and gram negative enteric organisms are common along with fungal infections

85
Q

What is the role of ICAM-1 in the firm adhesion phase of the adhesion cascade?

A

Leukocytes rolling in resting inflamed venules require this molecule to stop in response to chemoattractant, but not required after activation with inflammatory cytokines

86
Q

What is the role of alpha4beta1 in the firm adhesion phase of the adhesion cascade/

A

This molecule is expressed on monocytes, eosinophils and many lymphocytes, when no other molecules are represent this can mediate both rolling and firm adhesion through VCAM-1 interaction

87
Q

What does intravital microscopic evidence reveal about the role of alpha4beta1 in firm adhesion?

A

That most binding is VCAM-1 dependent as antibodies to the molecule will stop the adhesion cascade

88
Q

What is the transmigration phase of the adhesion cascade?

A

Leukocyte migrate across resting epithelium if an exogenous chemoattractant is present via leukocyte driven transmigration

89
Q

What is the pathophysiological hallmark of established inflammatory transmigration?

A

Endothelial activation, which is an event which requires transcription and protein synthesis resulting in upregulation of adhesion molecules production of inflammatory mediators and secretion of chemoattractants

90
Q

What is the role of endothelial chemokines in transmigration?

A

These are critical for this process and contain heparin binding sites allowing them to bind to proteoglycans on the vascular endothelium which positions them to activate integrins
Cells upon activation by integrins release heparin binding protein which causes increases in vascular permeability which allows for leukocyte transmigration

91
Q

What are some to the adhesion molecules which have been implicated in transmigration?

A

PECAM-1, ICAM-1, VE-cadherin, CD11a/CD18 (LFA-1), IAP(CD47) and VLA-4(alpha4beta1 integrin)

92
Q

What occurs in in vivo studies with ICAM-1 knockout mice?

A

Significantly impaired neutrophil migration into inflamed peritoneum, this combined with ICAM-1 antibody studies show reduction in acute and chronic inflammation in animal models as well as reducing cytokine-activated transmigration of neutrophils in vitro by 85% and chemotactic transmigration by 55%

93
Q

What is the role of PECAM-1 in transmigration?

A

It is critical in passage through the junction in cytokine-activated transmigration with antibodies to this molecule reducing monocyte transmigration through resting endothelium and both neutrophil and monocyte transmigration through activated endothelium, without affecting the ability of leukocytes to bind to the endothelium

94
Q

How does the alphaVbeta3 integrin interact with PECAM-1 during transmigration?

A

This molecule can be a ligand for PECAM-1, with monocytes which lack the beta 3 integrin transmigrating poorly, though this is largely believed to be due to modulation of CD11a/CD18 rather than interaction with PECAM-1

95
Q

What have studies with PECAM-1 antibodies shown?

A

They do not decrease chemotactic transmigration in vivo or decrease transmigration triggered by thrombin, there is also significant residual transmigration after PECAM-1 inhibition

96
Q

How significant is the involvement of VLA-4 in transmigration?

A

It is variable in vitro, possibly reflecting redundancy with beta2 integrins as well as the degree of VCAM-1 expression on endothelium which in turn reflects the state of endothelial cell activation
It appears to be unimportant in neutrophil and activated T cell transmigration in vitro while resting T-cell and NK-cell cytokine activated transmigration are reduced by 40% and 30%

97
Q

What are ectoenzymes?

A

Membrane proteins which have their active site outside the cell, they include proteases, nucleotidases and oxidases and are capable of regulating leukocyte transmigration

98
Q

What is the impact of ATP on the immune system?

A

It is proinflammatory, binding to purigenic receptors of the P2X and P2Y families inducing proliferation by inducing cytokine expression and activating dendritic cells

99
Q

What is adenosine’s effect on the immune system?

A

It inhibits neutrophil adhesion to the microvascular endothelium through activating the adenosine receptors A(2A)R and A(2B)R on neutrophils
It prevents leukocyte activation by inhibiting L-selectin and expression of CD18 integrins by leukocytes and down-regulates VCAM-1 and cytokine expression by endothelial cells

100
Q

What is CD73?

A

A glycosylphosphatidylinositol linked cell surface molecule expressed by vascular endothelial cells and up to 15% of lymphocytes
It catalyses the dephosphorylation of AMP to adenosine, indicating it has anti-inflammatory properties. It is increased in expression at sites of inflammation by IFNalpha with mice defieicnet in CD73 hain=ving increased leukocyte attachment to the endothelium and leukocyte migration

101
Q

What is CD39?

A

This converts extracellular ATP to AMP suggesting it has anti-inflammatory properties, it is expressed by many different types of leukocytes and by vascular endothelial cells. Mice deficient in this molecule display exacerbated skin inflammation by irritants

102
Q

How do leukocytes use ATP to manipulate the inflammatory status of the local microenvironment?

A

Both ATP-generating and consuming pathways exist on the surface of leukocytes and endothelial cells with their balance regulating the levels of ATP and adenosine and therefore the levels of inflammation

103
Q

How is ATP metabolized on the surface of leukocytes?

A

It can be dephosphorylated by CD39 on resting endothelium to the AMP which can be further dephosphorylated by CD73 to adenosine
The activity of CD73 is inhibited when lymphocytes attach to the endothelium, leading to a reduction in adenosine production and a resultant increase in migration

104
Q

What is the role of ADP-ribosyltransferases in immunity?

A

Enzymes such as ART2 can transfer the ADP-ribose molecule from NAD(P) to an acceptor which may result in covalent modifications and inactivation of several surface proteins including alphaLbeta2
The homing of NAD(P) treated cells to lymph nodes decreases T cell homing

105
Q

Why is B cell homing unaffected by ADP-ribosyltransferases?

A

Alpha4beta1 is not ADP ribosylated, and B cells do not express ART3

106
Q

How do ectopeptidases regulate chemokines?

A

CD26 is an ectoenzyme which leaves N-terminal dipeptides containing either proline or alanine residues from polypeptides, this molecule is expressed de novo on T cells, B cells, NK cells and endothelial cells
Numerous bioactive peptides are cleaved by CD26 including chemokines which results in a reduction of their ability to bind to and activate receptors while enhancing their ability to act as chemoattractants

107
Q

What occurs in rodents deficient in CD26?

A

There is increased infiltration of leukocytes into the lung and joints in models of asthma and arthritis, suggesting CD26 plays a role in inhibiting inflammation

108
Q

What are sheddases?

A

CD156b is a sheddase which cleaves L-selectin from the surface of thymocytes with other sheddases laso being involved.
L-selectin is shed from lymphocytes to prevent re-entry of activated T cells to secondary lymphoid organs

109
Q

What is the role of ectoenzymes in the control of leukocyte traffic?

A

The nucleotidases CD39 and CD73 regulate the balance of ATP and adenosine and the activation of leukocyte integrins and vascular cell adhesion molecules
CD26 proteolytically modifies the activities of chemokines, wheras sheddases cleave leukocyte cell adhesion molecules such as L-selectin, ADP ribosyltransferases such as ART2 modify and inactivate adhesion molecules

110
Q

What might be the purpose of tissue-restricted recirculation of memory and effector lymphocytes?

A

It may increase the efficiency of regional immune responses and allow functional immune specialization of particular tissues
Differences in chemokine receptor, integrin or selectin expression plays a major role as they serve as attractants for inflammatory leukocytes, control leukocyte/integrin activation and control microenvironmental segregation within lymphoid organs

111
Q

How do dendritic cells control the entry of the lymphocytes to lymph nodes?

A

Through modulating the phenotype of HEVs with deletion in DCs resulting in a reduction in size and cellularity of peripheral and mucosal lymphnodes
DCs directly affect HEVs via lymphotoxin stimulation of the lymphotoxin-beta receptor

112
Q

What are HEVs (High endothelial venules)?

A

These are the portal by which lymphocytes circulating in the blood directly enter a lymph node. They have a plump walled structure and phenotype which allows increased extravasation of lymphocytes into lymphnodes with their numbers are increased at sites of inflammation

113
Q

How are Naïve T cells homed to lymph nodes?

A

They interact with HEVs via L-seceltin binding to PNAd and LFA-1 binding to ICAM-1 with interactions stimulated by the chemokine SLC which interacts with CCR7 on the T cell

114
Q

How is positional localization of naïve T cells within lymph nodes controlled?

A

By the production of MIP-3beta within the T cell zone, thus the development of lymph nodes is reduced in L-selectin deficient mice which results in few B and T cells

115
Q

What occurs in the plt mutant mouse?

A

This mutant is deficient in SLC has lymph nodes deficient in T cells but not B cells, showing that B cells are not dependent on SLC for recruitment to the lymph node via HEVs this is further evidenced by the fact that injected normal T cells fail to homing to the lymph nodes as well while injection of SLC restores normal homing

116
Q

What is SLC?

A

A molecule only prominently expressed in the T cell zone of lymph nodes, it can trigger integrin-dependent arrest of CCR7 bearing T cells.

117
Q

What are the differences between Th1 and Th2 cells with regards to homing into specialized regions of the lymph node?

A

Th1 and Th2 cells may home to different regions within the lymph node with CCR7 being more prominent expressed on Th1 cells

118
Q

What is the role of MIP-3beta in T cell homing in the lymph node?

A

MIP-3beta is not found on HEV but is rather present in the T cell area, thought to play a role in positional localization rather than capture

119
Q

How are memory cells different to naïve cells with regard to lymphnode recruitment?

A

They lack CCR7 and therefore can’t enter lymphnodes instead they home to inflammatory sites in non-lymphoid organs where they play a role in antigen specific immune responses

120
Q

How are Naïve B cells recruited to the lymph node/

A

CXCR5 is a ligand for the chemokine BLC is found predominantly on naïve B cells. BLC has been localized to B cell follicles of lymph nodes, the spleen and peyer’s patches.

121
Q

What occurs in mice deficient in CXCR5?

A

They have diminished development ot of B cell follicles. Ectopic expression of BLC in pancreatic islets in mice results in local B cell accumulation.

122
Q

Why don’t granulocytes home to lymphnodes?

A

Presumably because they lack CCR7 and CXCR5

123
Q

How do T cells which do not encounter their antigen in the lymph node leave?

A

The chemoattractant S1P is present in blood and lymph, this causes the egress of T cells which don’t find antigen upon entering lymph nodesnm

124
Q

How are B cells able to move from the B cell zone to the T cell zone?

A

After B cells bind antigen, they move to the boundry of the two zones allowing them to interact with T helper cells. This may be a result of antigen-engaged B cells having increased expression of CCR7 exhibiting increased responsiveness to the T cell zone chemokines MIP3beta and SLC, however antigen-stimulated B cells will respond less strongly to these signals excluding them form the central T cell zone
However CXCR5 overexpression is sufficient to overcome antigen induced B cell movement to the T cell zone so a careful balance of cytokines is required

125
Q

What subpopulation of cells does the marker CD45RO identify?

A

Memory T cells which can enter any inflamed tissue to perform antigen-specific immunosurveillance, they are specifically recruited after allergen challenge in the skin

126
Q

What is CLA?

A

This is a specialized form of PSGL-1 and a ligand for E selectin only found on activated memory skin homing T cells. E selectin is induced de novov on inflamed post capillary endothelium especially in the skin

127
Q

What does recruitmemt of CLA+ T cells require?

A

Interactions between CLA and E selectin, LFA-1 to ICAM-1, VLA-4 to VCAM-1 these are stimulated by TARC binding to CCR4 on leukocytes
There may then be subsequent localization controlled by local production of other chemokines such as MDC binding to CCR4 and CTACK binding to CCR10 by VLA-1 andVLA-2

128
Q

What is the impact of LAD-1 (leukocyte adhesion deficiency-1) on skin infections?

A

Due to these patients loss of beta2 subunit have frequent skin infections with the skin being devoid of neutrophils and reduced numbers of other leukocytes

129
Q

What is the relationship between CLA+ T memory cells and CCR4?

A

CCR4 is highly expressed on these cells and its ligand, TARC is present in the venules of inflamed skin, as TAARC is expressed by endothelial cells and stimulates T cell adhesion to ICAM-1. CTACK preferentially activates homing of the CLA+ skin homing memory cells And is produced by keratinocytes within the skin, activating cells via CCR10

130
Q

How does eosinophil recruitment to the skin occur?

A

Migration of these cells to the skin during allergic inflammation involves P-selectin binding to PSGL-1, LFA-1 binding to ICAM-1 and VLA-4 binding to VCAM-1, this is probably stimulated by eotaxin and eotaxin-3 binding to CCR3

131
Q

What is the role of CCR3 in eosinophil recruitment to the skin during allergic inflammation?

A

It may mediate subsequent localization, after the cells have been recruited to the skin through the CCR3- active chemokines and by VLA-4 and VLA-6
Human eosinophils also express high levels of PSGL-1 and L-selectin, CCR3 active chemokines such as RANTES, eotaxin, eotaxin-2 and MCP-4 are implicated in eosionphil accumulation in the skin

132
Q

What is the role of sunshine in getting T cells to migrate to the peodremis of the skin?

A

v=The upper layer of the skin generates vitamin D3 in response to YVBH rays, this can be metabolized by dendritic cells to the active from of the vitamin, this active form will then stimulate memory and effector T cells to express CCR10 which responds to the epidermal chemokine CCL27 expressed by keratinocytes

133
Q

How are Skin DCs guided to lymph nodes?

A

They are guided to lymphatic vessels via haptotaxis on a gradient of the chemokine SLC immobilized to herapin sulfates, they then migrate to peripheral lymph nodes where they might imprint naïve T cells with a skin homing phenotype

134
Q

How are lymphocytes homed to Peyer’s patches and the lamina propria?

A

This involves interactions between LFA-1 and ICAM-1, alpha4bet7 and MAdCAM-1, MAdCAM-1 and L-selectin, these are probably stimulated by TECK binding to CCR9 or SLC bidning to CCR7
Chemokines such as IP-10, RANTES, MIP-1alpha and MIP-1beta may influence lymphocyte accumulation within the lamina proprira under both inflamed and uninflamed conditions

135
Q

What is the significance of a subset of gut homing T cells expressing CCR5, CXCR3 and alphaEbeta7?

A

They can migrate to the gut epithelium where they interact with E-cadherin, for B cells local production of Peyer’s patches of BLC may be important

136
Q

How do accumulation of eosinophils in the gut occur?

A

It involves LFA-1/ICAM-1, VLA-4/VCAM1 and alpha4beta7/MAdCAM-1/L-selectin and is perhaps influenced by eotaxin produced by mononuclear cells

137
Q

What occurs to leukocyte homing to the gut in animals deficient in beta7?

A

They fail to accumulate T cells I nthe gastrointestinal tract, and peyers patches because alpha4beta7 is missing, SLC stimulates this integrin to cause lymphocytes to become adherent to MAdCAM-1
Defects in SLC or CCR7 result in mice with reduced T cell counts in secondary lymphoid organs

138
Q

How does Vitamin A play a role in the imprinting of T and B cells to migrate to the small intestine?

A

The small intestine absorbs vitamin A as retinol, at processes it to retinoic acid which is present at high concentrations in the gut wall, luminal antigens in the gut are internalized by M cells and processed by Dendritic cells in the lamina propria, these DCs are then induced by TGF-beta to express alphaEbeta7 and express the enzymes required to process retinol to retinoic acid
These DCs then activate naïve B and T cells in the mesenteric lymphnodes to express alpha4beta7 and CCR9 imprinitng them with intestine homing properties

139
Q

How are regulatory T cells homed to the large intestine (colon) lamina propria?

A

GPR15 is a G-protein-coupled cell surfaced chemokine receptor whose ligand is unknown, in mice it is preferentially expressed by Treg cells in the lamina propria of the large intestine and controls the homing of T cells, particularly Treg cells to this region. TGFbeta, expressed in the colon, increases this GPR15 expression may help to maintain this population while retoonic acid was noted to have no effect

140
Q

What si the role of GPR15 in humans?

A

While it plays a role in homing of Tregs to the lamina propria of the large intestine in mice, in humans it performs a similar function with T effector cells suggesting a species difference

141
Q

How are neutrophils guided to sites of sterile inflammation?

A

ATP is released from necrotic cells at the wound site, this activates the NLRP3 inflammasome via the P2X7 receptor in inflammatory cells resulting in the release of IL-1beta
IL-1beta then upregulates ICAM-1 on the vascular endothelium leading to the alphaMbeta2 integrin mediated adhesion of neutrophils to microvascular endothelia near the wound site within 30-60 minutes of injury
The chemokine MIP-2 released at the wound site forms a chemoattractant gradient which surrounds but does not completely reach the injured area with it being maximal at 100-150 micrometeres from the injury border
Neutrophils migrate via an intravascular route to the site of injury
MIP-2 attracts neutrophils up to the injury border
Necrotic cells release mitochondria derived formylated peptides which over-ride MIP2 and guide neutrophils directly into the injury site via formyl peptide receptor-1 signalling focusing the innate immune response on sites of damage rather than healthy tissue

142
Q

How do commensal bacteria influence skin immunity?

A

S. epidermidus induces IL-17A+CD8+T cells that home to the epidermis and enhance innate barrier immunity and limit pathogen invasion, skin resident CD103+ DC acquire commensals, or commensal derived antigens in the skin, priming CD8+ T cells in the lymph node which migrate to the skin and are locally tuned to produce more IL-17A by IL-1 produced CD11b DCs
Commensal-specific CD8 T cells enhance antimicrobial defense of keratinocytes in an IL-17 dependent non-inflammatory manner
This mechanism may be an evolutionary means through which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide protection against invasive pathogens

143
Q

What experimental evidence has suggested that commensals improve skin immunity?

A

Topically applied S. epidermidis experimentally improved innate protection against C. albicans applied to sandpaper-scraped skin of mice

MEDSCI 708 (7 decks)

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