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
