12 - Soluble Mediators of the Cutaneous Immune System Flashcards
Two major categories of soluble mediators that help regulate an effective immune response
Cytokines
Chemokines
Soluble polypeptide mediators that play pivotal roles in communication between cells of the hematopoietic system and other cells of the body
Cytokines
Large superfamily of small cytokines that are accepted as vital mediators of cellular trafficking
“Chemoattractant cytokine”
Chemokines
Most newly identified _____ were named according to biologic assay that was being used to isolate and characterize the active molecule
Cytokine
Many cytokines have a wide range of activities, causing multiple effects in responsive cells and a different set of effects in each type of cell capable of responding
Pleiotropism
In any single bioassay, multiple cytokines display activity. The absence of a single cytokine can often be largely or even completely compensated for by other cytokines with overlapping biologic effects
Redundancy
Assignment of T-cell derived cytokines based on the specific helper T-cell subsets that produce them
Th1
Th2
Distinguished by production of a high level of IL-17
Also secrete IL-21 and IL-22
Critical effectors in autoimmune disease
Th17
Involved in the maintenance of peripheral self-tolerance
Most distinctive features are their expression of FoxP3 transcription factor and production of transforming growth factor-beta
Regulatory T cells
Cytokine that appears to be required for Treg cells to limit the excess activity of proinflammatory T-cell subsets
Transforming growth factor-beta
Also a significant contributor to the suppressive activity of Treg cells, particularly at some mucosal interfaces
IL-10
Specialize in providing B cell help in germinal centers
Follicular helper T cells
Distinguished by high levels of IL-9 production
Function in antiparasite and antimelanoma immunity
Th9
Produce IL-22 but not other Th17-associated cytokines
Associated with skin inflammation
Th22
Key Th1-promoting factor
IL-12
Required for Th2 differentiation
IL-4
IL-6, IL-23, TGF-beta are involved in promoting _____ development
Th17
A few major signaling pathways account for most effects attributable to cytokines
Nuclear factor kappaB pathway
Janus kinase/signal transducer and activator of transcription pathway
A major mechanism contributing to the extensive overlap between the biologic activities of the primary cytokines IL-1 and TNF is the shared use of
Nuclear factor kappaB pathway
Cytokines besides IL-1 and TNF that activate NF-kappaB pathway as part of their signal transduction mechanisms include
IL-17
IL-18
Pathway shown to play a role in signaling by all cytokines that bind to members of the hematopoietin receptor family
JAK/STAT pathway
Four Janus kinases
JAK1
JAK2
JAK3
Tyrosine kinase 2
Small molecule inhibitor that targets JAK1, JAK3, and, to a lesser extent, JAK2
Has been found to be effective in the treatment of psoriasis and psoriatic arthritis
Recent reports also indicated efficacy in the treatment of alopecia areata
Tofacitinib
JAK1 and JAK2 inhibitor
Beneficial in the treatment of dermatomyositis
Ruxolitinib
Clinical trials are currently being undertaken to evaluate the clinical efficacy of JAK
inhibition in the treatment of patients with _____ with onset in infancy, an autoinflammatory disorder that targets the skin, blood vessels, and lungs
Stimulator of interferon genes (STING)-associated vasculopathy
Multimeric protein complexes that assemble in the cytosol after sensing various stimuli
Inflammasomes
Dominant form of IL-1 produced by monocytes, macrophages, Langerhans cells, dendritic cells
IL-1beta
Dominant form of IL-1 in epithelial cells, including keratinocytes
IL-1alpha
Stimulates the egress of Langerhans cells from the epidermis during the initiation of contact hypersensitivity, a pivotal event that leads to accumulation of Langerhans cells in skin-draining lymph nodes
IL-1beta
Sole signal-transducing receptor for IL-1
Type 1 IL-1 receptor or
IL-1R1
A second cell surface protein, _____, must associated with IL-1R1 for signaling to occur
IL-1R accessory protein or
IL-1RAcP
Can bind to IL-1R1 but does not induce signaling through the receptor
IL-1 receptor antagonist or
IL-1ra
IL-1ra exists in three alternatively spliced forms:
an isoform produced in _____ is the only ligand that contains a signal peptide and is secreted from cells
two other isoforms contained within _____
Monocytes
Epithelial cells
Y/N: The association of IL-1R1 with IL-1RAcP increases the affinity for IL-1alpha/beta manyfold while not affecting the affinity for IL-1ra
Yes
Y/N: A vast molar excess of IL-1ra is required to fully antagonize the effects of IL-1
Yes
A second means of antagonizing IL-1 activity occurs via expression of a
Second receptor for IL-1
IL-1R2
Serves to bind IL-1alpha/beta efficiently but not IL-1Ra
IL-1R2
Whereas soluble IL-1R2 binds to _____, cell surface IL-1R2 sequesters _____
Free IL-1
IL-1RAcP
Expression of IL-1R2 can be upregulated by a number of stimuli, including
Corticosteroids
IL-4
IL-1R2 can also be induced by inflammatory cytokines, including
IFN-gamma
IL-1
First identified based on its capacity to induce IFN-gamma
IL-18
One name initially proposed for this cytokine was IL-1gamma because of its homology with IL-1alpha and IL-1beta
IL-18
IL-18 induces proliferation, cytotoxicity, and cytokine production by Th1 and natural killer cells, mostly synergistically with
IL-12
Y/N: There is an IL-18 homolog of IL-1ra
No - no homolog
Binds to soluble mature IL-18 and prevents it from binding to the IL-18R complex
IL-18 binding protein
_____ T cells positive for cutaneous lymphocyte antigen are abundant in inflamed skin, comprising the majority of T cells present
Memory
Any injury to the skin, no matter how trivial, releases IL-1 and attracts this population of memory T cells. This has been proposed as the basis of the clinical observation of inflammation in response to trauma, knows as
Koebner reaction
Recombinant IL-1Ra
Anakinra
Antibody to IL-1beta
Canakinumab
IgG Fc fusion protein that includes the ligand binding domains of type I IL-1R and IL-1RAcP
Rilonacept or
IL-1 Trap
Biologics that act by inhibiting IL-1 function are efficacious in countering the IL-1-induced inflammation associated with a group of rare autoinflammatory diseases called
Cryopyrin-associated periodic syndrome
Anakinra was initially US FDA approved as a therapy for
Adult rheumatoid arthritis
TNF-alpha has an ability to mediate two interesting biologic effects
- Hemorrhagic necrosis of malignant tumors
2. Inflammation-associated cachexia
Metalloproteinase responsible for most TNF-alpha release by T cells and myeloid cells
TNF-alpha-converting enzyme (TACE)
TNF-beta is also known as
Lymphotoxin alpha (LT-alpha)
Other related molecules in the TNF family include
Lymphotoxin beta (LT-beta)
Fas ligand (FasL)
TNF-related apoptosis-inducing ligand (TRAIL)
Receptor activator of NF-B ligand (RANKL)
CD40 ligand (CD154)
Two receptor proteins capable of binding TNF-alpha with high afficinity
p55 receptor for TNF (TNFR1)
p75 TNF receptor (TNFR2)
Receptor responsible for most biologic activities of TNF
p55 receptor for TNF (TNFR1)
TNF-alpha evokes two types of responses in cells
- Proinflammatory effects
2. Induction of apoptotic cell death
Induction of apoptosis by signaling through TNFR1 depends on a region known as a _____ that is absent in TNFR2
Death domain
At least two TNFR family members (_____) also contribute to the normal anatomic development of the lymphoid system
TNFR1
LT-beta receptor
Important mediator of cutaneous inflammation, and its expression is induced in the course of almost all inflammatory responses in skin
TNF-alpha
One molecular mechanism that may contribute to TNF-alpha-induced migration of Langerhans cells toward lymph nodes is reduced expression of the _____ after exposure to TNF-alpha
E-cadherin adhesion molecule
Induction of _____ on both epidermal and dermal antigen-presenting cells correlates with movement into the draining lymphatics
CC chemokine receptor 7 (CCR7)
Predominant TNFR expressed by keratinocytes
TNFR1
Humanized anti-TNF-alpha antibody
Infliximab
Fully humanized anti-TNF-alpha antibody
Adalimumab
Soluble TNF receptor
Etanercept
TNF antagonists are not effective against all autoimmune diseases - _____ appears to worsen slightly after treatment with these agents
Multiple sclerosis
TNF antagonists can allow the escape of _____ from immune control
Latent mycobacterial infections
IL-17 family of cytokines includes
IL-17A through F
Have similar proinflammatory activities, bind to the same heterodimeric receptor composed of the IL-17RA and IL-17RC receptor chains, and act to promote recruitment of neutrophils and induce production of anti-microbial peptides
IL-17A and IL-17F
IL-17 species normally function in defense against pathogenic species of
Extracellular bacteria
Fungi
Mutations in _____ associated with hyper-IgE syndrome block development of Th17 cells, and lead to recurrent skin infections with Staphylococcus aureus and Candida albicans
STAT3
Product of Th2 cells and mast cells that signals through IL-17RB
IL-17E or
IL-25
Human monoclonal antibodies against IL-17A
Currently approved for use in moderate to severe chronic plaque psoriasis
Secukinumab
Ixekizumab
Also known as the class I cytokine receptor family
Hematopoietin receptor family
Largest of the cytokine receptor families
Hematopoietin receptor family
Five shared receptor subunits of the hematopoietin receptor family
- Common gamma chain
- Common beta chain shared between IL-2 and IL-15 receptors
- Distinct common beta chain shared between GM-CSF, IL-3, and IL-5 receptors
- IL-12Rbeta2 chain shared by the IL-12 and IL-23 receptors
- Glycoprotein 130 (gp130) molecule
Cytokines with receptors that include the common gamma chain
IL-2 IL-4 Il-7 IL-9 IL-13 IL-15 IL-21
Cytokines with receptors that include the common gamma chain that also use the IL-2Rbeta2 chain
IL-2
IL-15
Common gamma chain is physically associated with
JAK3
IL-2 is a product of activated _____ cells, and IL2R is largely restricted to _____
T
Lymphoid cells
IL-15 gene is expressed by _____, and its transcription is induced by _____ in keratinocytes and fibroblasts and _____ in monocytes and dendritic cells
Nonlymphoid tissues
UVB radiation
Lipopolysaccharide (LPS)
Y/N: The affinities of IL-2R and IL-15R for their respective ligands can be regulated, and to some extent, IL-2 and IL-15 compete with each other
Yes
Whereas (IL-2/IL-15) appears to have an important role in promoting effector functions of antigen-specific T cells, (IL-2/IL-15) is involved in reining in autoreactive T cells
IL-15
IL-2
IL-4 and IL-13 are products of activated _____ cells
Th2
A specific receptor for IL-4 which does not bind IL-13 is found on
Transmits signals via JAK1 and JAK3
T cells
NK cells
A receptor complex that can bind either IL-4 or IL-13 is found on
Transmits signals via JAK1 and JAK2
Keratinocytes
Endotheilal cells
Other nonhematopoietic cells
The genes encoding IL-4and IL-13 are located in a cluster with
IL-5
A prominent activity of IL-4 is the stimulation of
Class switching of the immunoglobulin genes of B cells
Populations of innate immune effector cells that provide an early source of IL-13 during helminth infection
Nuocytes
Natural helper cells
IL-9 is a product of activated _____ cells exposed to _____
Th2
TGF-beta
IL-9 is also produced by mast cells in response to
IL-10 or
Stem cell factor
Stimulates proliferation of T and B cells
Promotes expression of IgE by B cells
Exerts proinflammatory effects on mast cells and eosinophils
Function as effectors of allergic inflammatory processes
IL-9
IL-21 is a product made by the _____ lineages
Th2, Th17 and Tfh
Potent mitogen and survival factor for immature lymphocytes in the bone marrow and thymus
Modifier of effector cell functions in the reactive phase of certain immune response
IL-7
_____ release IL-7 in response to IFN-gamma, and _____ secrete IFN-gamma in response to IL-7
Keratinocytes
Dendritic epidermal T cells
An IL-17-related cytokine using one chain of the IL-7 receptor as part of its receptor is
Thymic stromal lymphophoietin (TSLP)
Ability to prime dendritic cells to become stronger stimulators of Th2 cells
Thymic stromal lymphophoietin (TSLP)
The receptors for IL-3, IL-5 and GM-CSF consist of unique cytokine-specific alpha chains paired with a common beta chain known as
IL-3Rbeta or
CD131
Previously known as multilineage colony-stimulating factor
Principally a product of CD4+ T cells and causes proliferation, differentiation, and colony formation of various myeloid cells from bone marrow
IL-3
IL-5 is a product of _____ cells that conveys signals to B cells and eosinophils
Th2 CD4+ cells
Activated mast cells
In conjunction with an eosinophil-attracting chemokine known as _____, IL-5 plays a central role in the accumulation of eosinophils that accompanies parasitic infections and some cutaneous inflammatory processes
CC chemokine ligand 11
Eotaxin
Growth factor for myeloid progenitors produced by activated T cells, phagocytes, keratinocytes, fibroblasts, and vascular endothelial cells
Role in early hematopoises
Has potent effects on macrophages and dendritic cells
GM-CSF
Receptors for IL-6, IL-11, IL-27, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1, interact with a hematopoietin receptor family member, _____
gp130
Most thoroughly characterized of the cytokines that use gp130 for signaling
IL-6
Stimulates immunoglobulin secretion by B cells and has mitogenic effects on B lineage cells and plasmacytomas
Promotes maturation of megakaryocytes and differentiation of myeloid cells
Central mediator of the systemic acute phase response
IL-6
Increases in _____ levels stimulate hepatocytes to synthesize and release acute-phase proteins
IL-6
One of several inflammatory diseases in which elevated expression of IL-6 has been described
Psoriasis
Produces a viral homolog of IL-6
Human herpesvirus 8
Inhibits production of inflammatory cytokines
Some therapeutic activity in patients with psoriasis
Has been used to treat thrombocytopenia occurring after chemotherapy
Il-11
Important mediator of cutaneous allergic diseases and atopic dermatitis, possibly through itch stimulation
Major sources are activated CD4+ T lymphocytes, in particular Th2 cells, mast cells, macrophages, and dendritic cells
IL-31
In contrast to all other IL-6 family members, _____ does not use gp130 as a receptor unit
IL-31
Serum IL-31 levels have been directly correlated with disease severity in
Atopic dermatitis
Acts directly to inhibit keratinocyte differentiation and filaggrin expression, thereby impairing skin barrier function it atopic dermatitis
IL-31
The IL-12 cytokine family includes
IL-12
IL-23
IL-27
IL-35
Different from most other cytokines in that its active from is a heterodimer of two proteins, p35 and p40
Principally a product of antigen-presenting cells, such as dendritic cells, monocytes, macrophages, and certain B cells in response to bacterial components, GM-CSF and IFN-gamma
IL-12
_____ constitutively make the p35 subunit
Expression of the p40 subunit can be induced by _____
Human keratinocytes
Stimuli including contact allergens, phorbol esters, and UV radiation
Critical immunoregulatory cytokine that is central to the initiation and maintenance of Th1 responses
IL-12
_____ signaling induces the phosphorylation of STAT1, STAT3, and STAT4
IL-12
STAT4 is essential for induction of a _____ response
Th1
Heterodimeric cytokine in the IL-12 family that consists of the p40 chain of IL-12 in association with a distinct p19 chain
IL-23
IL-23 promotes the differentiation of T cells producing
IL-17 (Th17 subset)
Also a heterodimer and consists of a subunit called p28 that is homologous to IL-12 p35 and a second subunit known as EBI3 that is homologous to IL-12 p40
Plays a role in the early induction of the Th1 response
IL-27
_____ receptor consists of a receptor called WSX-1 that associates with the shared signal-transducing molecule gp130
IL-27
Newest member of the IL-12 family
Heterodimer composed of the p35 chain of IL-12 associated with the IL-27beta chain EBI3
IL-35
IL-35 is selectively made by Treg cells, promotes the growth of Treg cells, and suppresses the activity of
Th17 cells
Antihuman p40 monoclonal antibody targeting both IL-12 and IL-23
Ustekinumab
Ustekinumab has received FDA approval for the treatment of
Psoriasis
A second major class of cytokine receptors with common features includes
Two types of receptors for IFNs, IL-10R
Receptors for additional IL-10-related cytokines, including IL-9, IL-20, IL-22, IL-24, and IL-26
IFNs were initially subdivided into three classes
- IFN-alpha (leukocyte IFNs)
- IFN-beta (fibroblast IFN)
- IFN-gamma (immune IFN)
The alpha and beta IFNs are collectively called
Type I IFNs
Type I IFNs signal through the same two-chain receptor
IFN-alphabeta receptro
The second IFN receptor is a distinct two-chain receptor specific for
IFN-gamma
Each of the chains comprising the two IFN receptors is associated with one of the JAK kinases (_____ for the IFN-alphabetaR, and _____ for the IFN-gammaR
Tyk2 and JAK1
JAK1 and JAK2
New class of IFNs known as IFN-gamma
Type III IFNs
Current members of type III IFNs
IL-28A
IL-28B
IL-29
Y/N: Although the effects of the type III IFNs are similar to those of the type I IFNs, they are more potent
No - less potent
Stimuli that elicit release of the type I IFNs
Viruses
Double-stranded RNA
Bacterial productes
Have emerged as a particularly potent cellular source of type I IFNs
Plasmacytoid dendritic cells
Additional effects mediated through IFN-alphabetaR are increased expression of MHC class _____ molecules and stimulation of _____ cell activity
I
NK
Not only does it have well-known antiviral effects, but IFN-alpha also can modulate T-cell responses by favoring the development of a _____ type of T-cell response
Th1
Forms of _____ enjoy considerable use clinically for indications ranging from hairy cell leukemia, various cutaneous malignancies, and papillomavirus infections
IFN-alpha
Some of the same conditions that respond to therapy with _____ also respond to topical immunomodulatory agents such as imiquimod
Type I IFNs
Imiquimod is a systemic imidazoquinoline drug that is an agonist for the _____ receptor, whose natural ligand is single-stranded RNA
TLR7
Imiquimod can trigger clinically useful antiviral and tumor inhibitory effects against
Genital warts
Superficial BCC
Actinic keratoses
Synthetic compound that activates both TLR7 and TLR8
Resiquimod
Production of IFN-gamma is restricted to
NK cells
CD8 T cells
Th1 CD4 T cells
The major physiologic role is its capacity to modulate immune responses
Required for activation of macrophages to their full antimicrobial potential, enabling them to eliminate microorganisms capable of intracellular growth
Inducer of selected cytokines (CXC chemokine ligands 9 to 11) and an inducer of endothelial cell adhesion molecules
IFN-gamma
Comes the closest of the T-cell cytokines to behaving as a primary cytokine
IFN-gamma
Exert regulatory rather than stimulatory effects on immune responses
Produced by Th2 T cells that inhibited cytokine production after activation of T cells by antigen and antigen-presenting cells
IL-10
The ligand-binding chain of the IL-10 receptor is homologous to the receptors of
IFN-alpha/beta
IFN-gamma
IL-10 binding to its receptor activates _____ and leads to the activation of _____
JAK1 and Tyk2 kinases
STAT 1 and STAT3
A major source of IL-10 within skin is
Epidermal keratinocytes
Immunosuppressive effects that occur after UV light exposure are the result of the liberation of keratinocyte-derived _____ into the systemic circulation
IL-10
Novel IL-10-related cytokines
IL-19 IL-20 IL-22 IL-24 IL-26
Increased expression of novel IL-10-related cytokines and their receptors is associated with
Psoriasis
Has structural properties uniquely reminiscent of anti-microbial peptides
IL-26
TGF-beta family of cytokines can be grouped into
Prototypic TGF-beta (TGF-beta 1 to 3)
Bone morphogenetic proteins
Growth and differentiation factors
Activins
The _____ name for this family of molecules is somewhat a misnomer because _____ has antiproliferative rather than proliferative effects on most cell types
TGF
TGF-beta
Y/N: TGF-beta family members are made as precursor proteins that are biologically inactive until a large prodomain is cleaved
Yes
Enhances production of collagen and other ECM proteins
Inhibits the production of metalloproteinases by fibroblasts and stimulates the production of inhibitors of the same metalloproteinases
May contribute to the immunopathology of sleroderma through its profibrogenic effects
TGF-beta
TNF-alpha blockade adverse events
Risk of serious infections (e.g., tuberculosis)
Potential for increased risk of malignancies or major adverse cardiovascular events
Human IgG2 monoclonal antibody that binds to and blocks the IL-17 receptor
Brodalumab
Inhibitor of phosphodiesterase 4 that has been recently approved for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis
Apremilast
Causes degradation of the secondary messenger cyclic AMP, leading to increased production of proinflammatory soluble mediators
PD-4
Monoclonal antibody directed against the alpha-subunit of the IL-4 receptor, and through this effect blocks IL-4 and IL-13, the drivers of Th2-mediated inflammation responsible for the hallmark symptoms of atopic dermatitis
Dupilumab
Large superfamily of small cytokines with two major specialized functions:
Guide leukocytes via chemotactic gradients in tissue
Capacity to increase the binding of leukocytes via their integrins to ligands at the endothelial cell surface
Chemokines
Chemokines are grouped into four subfamilies based on the spacing of amino acids between the first two cysteines
CXC (alpha-chemokines)
CC (beta-chemokines)
C
CXXXC (or CX3C)
Represented by lymphotactin
C subfamily
Fractalkine is the only member of the
CXXXC subfamily
Common structural features of chemokines
Disordered amino terminus followed by three conserved antiparallel beta-pleated sheets
Unique in that the chemokine domain sits atop a mucin-like stalk tethered to the plasma membrane via a transmembrane domain and short cytoplasmic tail
Fractalkine
Because most chemokines have a net (positive/negative) charge, these proteins tend to bind to (positively/negatively) charged carbohydrates present on GAGs
Positive
Negatively
Chemokine receptors are seven transmembrane spanning membrane proteins that couple to intracellular heterotrimeric G-proteins containing alpha, beta, and gamma subunits. They represent a part of a large family of
G protein-coupled receptors
Normally G proteins are (active/inactive) when guanosine diphosphate is bound, but they are (activated/inactivated) when the GDP is exchanged for guanosine triphosphate
Inactive
Activated
Commonly used inhibitor of GPCR that irreversibly ADP-ribosylates Galpha subunits of the alphai class and subsequently prevents most chemokine receptor-mediated signaling
Pertussis toxin
After chemokine receptors are exposed to appropriate ligands, they are frequently internalized, leading to an inability of the chemokine receptor to mediate further signaling. This has been termed
Desensitization
Occurs because of Ser/Thr residues in the C-terminal tail by proteins termed GPCR kinases
Important mechanism for regulating the function of chemokine receptors by inhibiting cell migration as leukocytes arrive at the primary site of inflammation
Desensitization
Homologous adhesion molecules that mediates the transient attachment or “rolling” of leukocytes on endothelial cells
Selectins
Set of adhesions molecules and their receptors (immunoglobulin superfamily members) that mediates stronger binding (ie, arrest) and transmigration of leukocytes
Integrins
Members of a larger family of carbohydrate-binding proteins termed lectins
Selectins (E-, L-, and P-selectins)
The skin-associated vascular selectin known as _____ is upregulated on endothelial cells by inflammatory cytokines such as TNF-alpha and binds to sialyl Lewis x-based carbohydrates
E-selectin
Although E-selectin is likely to be an important component of skin-selective homing, there is also evidence to suggest that _____ is involved in T-cell migration to skin
L-selectin
Must be “turned on” or activated from their resting state to bind their counter receptors such as ICAM-1 that are expressed by endothelial cells
Integrins
High-affinity and -avidity binding of integrins to endothelial cell intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecule-1 (VCAM-1) in a step termed
Firm adhesion
Multistep model of leukocytes recruitment
- Rolling
- Integrin activation
- Firm adhesion
Antigen-inexperienced T cells are termed naive can be identified by expressing three cell surface protines
- CD45RA (an isoform of the pan-leukocyte marker)
- L-selectin
- Chemokine receptor CCR7
After being activated by dendritic cells presenting antigen, T cells then express CD45RO, are termed
“Memory” T cells
A specific subset of CCR7– L-selectin memory T cells has been proposed to represent _____ that is ready for rapid deployment at peripheral sites in therms of their cytotoxic activity and ability to mobilize cytokines
Effector memory T-cell subset
When expressed on T cells, _____ is capable of mediating arrest of memory T cells on activated endothelial cells
CXCR3
____ are associated with Th2 cells in vitro, and Th1 cells are associated with _____
CCR4 and CCR3
CCR5 and CXCR3
Marker for a newly characterized T-helper subset, expressing the hallmark effector cytokines IL-17 and IL-22
CCR6
Keratinoyctes derived from patients with _____ synthesized mRNA for RANTES at considerably earlier time points in response to IL-4 and IFN-alpha
Atopic dermatitis
Keratinocytes derived from _____ synthesized higher levels of IP-10 with cytokine stimulation as well as higher constitutive levels of IL-8, a chemokine known to recruit neutrophils
Psoriatic patients
IP-10 may serve to recruit activated T cells of the Th1 helper phenotype to the epidermis and has been postulated to have a role in the recruitment of malignant T cells to the skin in
Cutaneous T-cell lymphomas
Skin-resident dendritic cells are initially derived from hematopoietic bone marrow progenitors and migrate to skin during the _____ periods of life
Late prenatal and newborn
Under resting (steady-state) conditions, homeostatic production by keratinocytes of _____ may be involved in attracting CD14+ dendritic cell precursors to the basal layer of the epidermis. Similarly, Langerhans cells as well as CD1c+ Langerhans cell precursors are strongly chemoattracted to keratinocyte-derived _____
CXCL14
CCL20
Under inflammatory conditions, when skin-resident dendritic cells and Langerhans cells leave the skin in large numbers, keratinocytes release a variety of chemokines, including _____ (via CCR2) and _____ (via CCR6), which may attract monocyte-like dendritic cell precursors to the epidermis to replenish the Langerhans cell population
CCL2 and CCL7
CCL20
Activated dendritic cell specifically upregulate expression of _____, which binds to seconday lymphoid tissue chemokine (SLC/CCL21), a chemokine expressed constitutively by lymphatic endothelial cells
CCR7
Naive T cells also strongly express _____ and this receptor to arrest on high endothelial venules
CCR7
CCR7 and its ligands facilitate the recruitment of at least two different kinds of cells - _____ - to the lymph nodes through two different routes under both inflammatory and resting conditions
Naive T cells
Dedritic cells
After dendritic cells reach the lymph nodes, they must interact with T cells to form a so-called “_____” that is critical for T-cell activation
Immunologic synapse
Activated dendritic cells secrete a number of chemokines, including _____, which attracts T cells to the vicinity of dendritic cells and promotes adhesion between the two cell types
Macrophage-derived chemokine
_____ (via CCL3/4) has been identified as mediating recruitment of naive CD8+ T cells to aggregates of antigen-specific CD4+ T cells and dendritic cells
CCR5
The roles of CCR4 and CCR10 in _____ have been particularly well documented
Atopic dermatitis
Serum levels of TARC/CCL17 and CTACK/CCL27 in _____ patients were significantly higher than concentrations found in healthy or psoriatic control participants and correlated with disease severity
Atopic dermatitis
CCL18, whose receptor is currently unknown, has been reported to be expressed at higher levels in skin of patients with _____ compared with psoriasis
Atopic dermatitis
CCL18, and another chemokine, _____ (produced by mast cells and endothelial cells), are elicited in volunteer skin after topical challenge with dust mite allergen and Staphylococcal superantigen
CCL1
Binds primarily to CCR3, a receptor expressed by eosinophils, basophils, and Th2 cells
Eotaxin/CCL11
Expression of eotaxin (and RANTES) by dermal endothelial cells has been correlated with the appearance of eosinophils in the dermis in patients with _____ that experience allergic reactions after treatment with ivermectin
Onchocerciasis
Production of _____ may contribute to the recruitment of eosinophils and Th2 lymphocytes in addition to stimulating keratinocyte proliferation
Eotaxin
CCR3
The inflammatory infiltrate of _____ skin is predominantly composed of Th1- and Th17-polarized memory T cells, as well as neutrophils, macrophages, and increased numbers of dendritic cells
Psoriatic
In _____, chemokines, including CCL20 and CCL17, mediate the arrest of effector memory T cells on endothelial cells that synthesize these chemokines. Both CCL17 and CCL20 can be synthesized by keratinocytes, possibly by contributing to T-cell migration to the epidermis
Psoriasis
Accumulating evidence strongly implicates pathogenetic _____ cells, which strongly express CCR6 in the pathogenesis of psoriasis. _____ cells, their signature effector cytokines IL-17 and IL-22, as well as high levels of IL-23, a major growth differentiation factor for _____ cells, are abundant in psoriatic lesions
Th17
Neutrophils found in the epidermis of psoriatic skin are probably attracted there by high levels of _____, which would act via CXCR1 and CXCR2
IL-8
In addition to attracting neutrophils, _____ is an ELR+ CXC chemokine that is known to be angiogenic, and may also attract endothelial cells
IL-8
An IL-8/CXCL8-producing population of memory T cells that express _____ has been isolated from patients with AGEP, a condition most commonly induced by drugs (eg, aminopenicillins). Similar T cells have been isolated from patients with _____
CCR6
Behcet disease and pustular psoriasis
CXC chemokines that express a three-amino-acid motif consisting of glu-leu-arg (ELR) immediately preceeding the CXC signature are (angiogenic/angiostatic), but most non-ELR CXC chemokines, except SDF-1, are (angiogenic/angiostatic)
Angiogenic
Angiostatic
_____, a prototypical ELR+ chemokine, can be secreted by melanoma cells and has been detected in conjunction with metastatic dissemination of this cancer
IL-8
Breast cancers are known to secrete _____, a chemokine that attracts macrophages through CCR2
MCP-1
Y/N: Although chemokines secreted by tumor cells do lead to recruitment of immune cells, this does not necessarily to increased clearance of the tumor
Yes
MCP-1 may increase expression of macrophage _____ through an autocrine feedback loop and possibly skew the immune response from Th1 to Th2
IL-4
MCP-1-deficient mice show markedly reduced dermal fibrosis after dermal challenge with bleomycin, a finding of possible relevance to the pathogenesis of conditions such as
Scleroderma
ELR- CXCR3 ligands such as IP-10 are potently (antiangiogenic/antiangiostatic) and may act as downstream effectors of IL-12 induced, NK cell-dependent (angiogenesis/angiostasis)
Antiangiogenic
Angiostasis
Some cancer cells can synthesize _____, attracting immature dendritic cells that express CCR6.
LARC
Chemokines produced by tumor cells may attract _____ that suppress host antitumor cytolytic T cells
CD4+CD25+ Tregs
Human breast cancer and melanoma lines express the chemokine receptors _____, but normal breast epithelial and melanocytes do not appear to express these receptors
CXCR4 and CCR7
_____ is expressed in more than 23 different solid and hematopoietic cancers. Broad expression of this receptor may be due to its regulation by hypoxia, a condition common to growing tumors, via the hypoxia inducible factor-1alpha transcription factor
CXCR4
Stromal fibroblasts within human cancers express the CXCR4 ligand, _____, which stimulates tumor growth as well as angiogenesis
CXCL12
_____ may play a role in melanoma metastasis to the small bowel, which shows high expression of _____ ligand, CCL25
CCR9
CCR10 is highly expressed by _____ and is correlated with nodal metastasis
Melanoma primary tumors
Engagement of _____ by CTACK results in activation (via phosphorylation) of the phosphatidylinositol 3-kinase (PI3K) and Akt signaling pathways, leading to antiapoptitic effecs in melanoma cells
CCR10
Because _____ is constitutively produced by keratinocytes, it may act as a survival factor for both pimary as well as secondary (metastatic) melanoma tumors that express CCR10
CTACK
_____-activated melanoma cells become resistant to killing by melanoma antigen-specific T cells
CCR10
Have been implicated in the trafficking or survival of malignant T- (lymphoma) cells to skin
CCR4
CXCR4
CCR10
A variety of microorganisms express chemokine receptors, including _____ by cytomegalovirus and _____ by Kaposi sarcoma
US28
Kaposi sarcoma herpes virus (or HHV-8) GPCR
Primary fusion receptor for all strains of HIV-1
CD4
CD4 binds to HIV-1 proteins
gp120 and gp41
DIfferent strains of HIV-1 have emerged that preferentially use _____ (T-tropic) or _____ (M-tropic) or either chemokine receptor as a coreceptor for entry
CXCR4
CCR5
A 32-base pair deletion (D32) in _____ in some individuals leads to low levels of _____ expression in T cells and dendritic cells and correlates with a dramatic resistance to HIV-1 infection
CCR5
The frequency of D32 mutations in humans is surprisingly high, and the complete absence of CCR5 in homozygotes has been associated with a more clinically severe form of
Sarcoidosis
Association of (more/less) severe autoimmune diseases in patients with D32 mutations
Less
Small molecule inhibitor of CCR5
Maraviroc
Autosomal dominant genetic syndrome composed of warts (HPV associated), hypogammaglobulinemia, infections, and myelokathexis (WHIM) is the result of an activating mutation in the cytoplasmic tail of the _____ receptor or in yet unidentified downstream regulators of _____ fuction
CXCR4
_____ infections are common because myelokathexis is associated with neutrophenia and abnormal neutrophil morphology
Bacterial
