12: Soluble Mediators of the Cutaneous Immune System Flashcards
1
Q
What is the role of cytokines in the hematopoietic system?
A
Cytokines are soluble polypeptide mediators that facilitate communication between cells of the hematopoietic system, influencing leukocyte function, differentiation, growth, activation, and migration, and are upregulated in response to injury.
2
Q
What is pleiotropism in cytokine biology?
A
Pleiotropism refers to cytokines having a wide range of activities, causing multiple effects in responsive cells.
3
Q
What is redundancy in cytokine biology?
A
Redundancy means that multiple cytokines can display activity in any single bioassay, such as inducing T-cell proliferation.
4
Q
What are the two major categories of soluble mediators that help regulate an effective immune response?
A
The two major categories are Cytokines and Chemokines.
5
Q
What are the primary functions of cytokines in the immune system?
A
Cytokines are involved in communication, influencing leukocyte function, upregulation in response to injury, and playing important roles in the immune system and inflammatory responses.
6
Q
What is the significance of pleiotropism and redundancy in cytokines?
A
- Pleiotropism: Cytokines have a wide range of activities, causing multiple effects in responsive cells.
- Redundancy: Different cytokines can produce similar effects.
7
Q
What roles do chemokines play in the immune response?
A
Chemokines are vital mediators of cellular trafficking, associated with recruitment of leukocyte subsets to inflammatory sites, and roles in angiogenesis, neural development, cancer metastasis, hematopoiesis, and infectious diseases.
8
Q
What are keratinocyte cytokines?
A
Keratinocyte cytokines are produced by epithelial cells and are significant in immune responses and cellular communication.
9
Q
What distinguishes Th17 cells from other T-cell subsets?
A
Th17 cells are distinguished by their production of high levels of IL-17, IL-21, and IL-22, promoting inflammation and playing critical roles in autoimmune diseases.
10
Q
How do Treg cells maintain peripheral self-tolerance?
A
Treg cells express the FoxP3 transcription factor and produce TGF-β, limiting the activity of proinflammatory T-cell subsets.
11
Q
What is the structural classification of cytokines in the four-helix bundle group?
A
Cytokines in the four-helix bundle group share a tertiary architecture of four antiparallel α-helical stretches. For example, IFN-γ is a four-helix bundle cytokine that exists as a noncovalent dimer.
12
Q
What are the main functions of Treg cells in the immune system?
A
Treg cells maintain peripheral self-tolerance by expressing FoxP3 and producing TGF-β, limiting proinflammatory T-cell activity.
13
Q
How do Th17 cells contribute to inflammation and autoimmune diseases?
A
Th17 cells produce high levels of IL-17, promoting inflammation and are critical effectors in autoimmune diseases.
14
Q
What is the role of IL-12 in T cell differentiation?
A
IL-12 promotes Th1 differentiation among T cell subsets.
15
Q
What structural classification do most cytokine ligands belong to?
A
Most cytokine ligands belong to the four-helix bundle group, which is significant for their function.
16
Q
What are the characteristics of IFN-γ and TNF-α in terms of their structure?
A
IFN-γ is a four-helix bundle cytokine that exists as a noncovalent dimer, while TNF-α and TNF-β are trimers composed of β-sheets.
17
Q
What are the major signal transduction pathways associated with the IL-1 receptor family?
A
The IL-1 receptor family leads to NF-κB activation via TRAF6.
18
Q
What is the clinical relevance of IL-6 in cutaneous biology?
A
IL-6 triggers acute-phase response and promotes immunoglobulin synthesis, and is used clinically as an anti-IL-6 treatment for rheumatoid arthritis.
19
Q
How does IL-17 contribute to autoimmune diseases?
A
IL-17, produced by activated Th17 cells, mediates autoimmune diseases and is a potential drug target.
20
Q
What is the role of TNF-α in inflammation?
A
TNF-α mediates inflammation and is targeted by anti-TNF therapies in conditions like psoriasis.
21
Q
What features of IL-2 are significant for T cell activation?
A
IL-2 acts as an autocrine factor for activated T cells, promoting their proliferation and survival.
22
Q
Describe the NF-κB pathway and its role in cytokine signaling.
A
The NF-κB pathway is activated by cytokines like IL-1 and TNF, leading to the expression of inflammation-related genes.
23
Q
What are the major signaling pathways that account for most effects attributable to cytokines?
A
The major signaling pathways are the NF-κB pathway and the JAK/STAT pathway.
24
Q
How do IL-1 and TNF relate to the NF-κB signaling pathway?
A
IL-1 and TNF activate the NF-κB transcription factor, which propagates inflammation.
25
What types of genes are encoded by NF-κB-regulated genes?
NF-κB-regulated genes encode cytokines, chemokines, adhesion molecules, nitric oxide synthase, cyclooxygenase, and phospholipase A2.
26
What is the role of the IKK complex in the NF-κB signaling pathway?
The IKK complex phosphorylates IκB proteins, leading to their degradation and allowing NF-κB to enter the nucleus.
27
What are the main stimulators of NF-κB activity?
Main stimulators include proinflammatory cytokines, bacterial products, oxidants, activators of protein kinase C, viruses, and UV radiation.
28
What is the function of TLR4 in the immune response?
TLR4 recognizes LPS and activates downstream signaling pathways upon ligand binding.
29
How do JAK kinases become activated in the JAK/STAT pathway?
JAK kinases become activated after stimulation of a cytokine receptor, leading to cross-phosphorylation.
30
What are the different adapters identified in the TLR signaling pathway?
The adapters include MyD88, TIRAP, TRIF, and TRAM.
31
How does the JAK/STAT pathway operate in cytokine signaling?
The pathway operates through the action of JAKs and STATs, where JAKs phosphorylate STATs that translocate to the nucleus.
32
What role do tyrosines in the cytoplasmic tail of cytokine receptors play?
Tyrosines are phosphorylated to recruit signaling proteins, facilitating the activation of STAT proteins.
33
What are the therapeutic uses of Tofacitinib and Ruxolitinib?
Tofacitinib is used for alopecia areata, psoriasis, and psoriatic arthritis, while Ruxolitinib is used for dermatomyositis.
34
What are the primary functions of the IL-1 family of cytokines?
The IL-1 family induces proinflammatory cytokines and regulates inflammatory responses.
35
How is IL-1β activated and what is its role in inflammation?
IL-1β is activated by cleavage by caspase 1 and stimulates the egress of Langerhans cells during contact hypersensitivity.
36
What is the role of IL-1 receptor antagonist (IL-1ra) in cytokine signaling?
IL-1ra acts as an antagonist of IL-1 ligand binding, regulating the inflammatory response.
37
Describe the function of IL-1R2 and its significance in inflammatory responses.
IL-1R2 binds IL-1α/β and inhibits IL-1 mediated responses, limiting inflammation.
38
What is the relationship between IL-18 and IFN-γ production?
IL-18 induces IFN-γ production and promotes Th1 and NK cell activity, often synergistically with IL-12.
39
What are the effects of IL-1 on endothelial cells and leukocyte recruitment?
IL-1 induces the expression of endothelial adhesion molecules, facilitating leukocyte recruitment to inflammation sites.
40
What is the role of IL-1β in contact hypersensitivity?
IL-1β stimulates the egress of Langerhans cells from the epidermis during contact hypersensitivity.
41
What is the role of IL-1 receptor antagonist (IL-1ra) in regulating IL-1 activity?
IL-1ra acts as an antagonist to IL-1 ligand binding, limiting the inflammatory response.
42
How does IL-18 synergize with IL-12 in immune responses?
IL-18 enhances the effects of IL-12 on Th1 and NK cells, promoting their proliferation and cytokine production.
43
Explain the role of IL-1β in the inflammasome.
IL-1β is activated by cleavage through caspase 1 in the inflammasome, initiating inflammation.
44
How does IL-1α differ from IL-1β in its activation and function?
IL-1α is active and released upon cell injury, while IL-1β requires activation by caspase 1.
45
What is the role of IL-1R2 in inhibiting IL-1 activity?
IL-1R2 serves as a decoy receptor to inhibit IL-1-mediated responses.
46
What are the two major effects mediated by TNF-α?
TNF-α mediates hemorrhagic necrosis of tumors and inflammation-associated cachexia.
47
What is the role of IL-1ra?
IL-1ra serves as a decoy receptor to inhibit IL-1-mediated responses.
48
What are the two major effects mediated by TNF-α?
TNF-α mediates (1) hemorrhagic necrosis of malignant tumors and (2) inflammation-associated cachexia.
49
What are the two biologic effects mediated by Tumor Necrosis Factor (TNF-α)?
1. Hemorrhagic necrosis of malignant tumors
2. Inflammation-associated cachexia
50
What are the two types of responses evoked by TNF-α in cells?
1. Proinflammatory effects
2. Induction of apoptotic cell death
51
What is the role of TNF-α converting enzyme (TACE) in relation to TNF-α?
TACE is a specific metalloproteinase responsible for most TNF-α release by T cells and myeloid cells.
52
What are the two receptor proteins capable of binding TNF-α with high affinity?
1. p55 receptor for TNF (TNFR1): responsible for most biologic activities of TNF
2. p75 TNF receptor (TNFR2): capable of transducing signals
53
How does TNF signaling differ from other signaling pathways?
TNF signaling does not involve the JAK/STAT pathway.
54
What are some biologics that act by inhibiting IL-1 function?
- Anakinra: recombinant IL-1Ra for adult rheumatoid arthritis
- Canakinumab: antibody to IL-1β
- Rilonacept (IL-1 Trap): an IgG Fc fusion protein that includes the ligand binding domains of type I IL-1R and IL-1RAcP
55
How does IL-17 contribute to immune defense and inflammation?
IL-17 promotes the recruitment of neutrophils and induces antimicrobial peptides, playing a role in immune defense against extracellular bacteria and fungi.
56
What are the proinflammatory effects of TNF-α?
- Upregulation of adhesion molecule expression
- Induction of secondary cytokines and chemokines through activation of NF-κB
- Can be transduced through both TNFR1 and TNFR2
57
What role does TNF-α play in autoimmune diseases?
TNF-α is a mediator of cutaneous inflammation and plays a central role in rheumatoid arthritis and psoriasis.
58
What are the TNF antagonist drugs and their uses?
1. **Infliximab**: Humanized anti-TNF-α antibody
2. **Adalimumab**: Fully human anti-TNF-α antibody
3. **Etanercept**: Soluble TNF receptor
## Footnote
Used for treatment of autoimmune and inflammatory diseases such as Crohn's disease, rheumatoid arthritis, psoriasis, and psoriatic arthritis.
59
What is the function of IL-17 in immune defense?
IL-17 (a.k.a. IL-17A) promotes recruitment of neutrophils and induces anti-microbial peptides.
60
What are the implications of mutations in STAT3 related to IL-17?
Mutations in STAT3 associated with hyper-IgE syndrome block Th17 cells, leading to recurrent skin infections with Staphylococcus aureus and recurrent infections with Candida albicans.
61
What are the biologic therapies targeting IL-17 and their application?
Anti-IL-17 biologic therapies, such as Secukinumab and Ixekizumab, are successful in treating moderate to severe chronic plaque psoriasis.
62
Explain the dual role of TNFR1 in TNF-α signaling.
TNFR1 mediates proinflammatory effects through NF-κB activation and induction of apoptotic cell death via recruitment of death domain-containing proteins.
63
How does TNF-α promote Langerhans cell migration?
TNF-α promotes Langerhans cell migration to draining lymph nodes by inducing CC chemokine receptor 7 (CCR7) on antigen-presenting cells.
64
What are the therapeutic applications of TNF antagonists?
TNF antagonists like infliximab, adalimumab, and etanercept are used to treat autoimmune and inflammatory diseases such as Crohn's disease, rheumatoid arthritis, psoriasis, and psoriatic arthritis.
65
Explain the role of IL-17A and IL-17F in immune defense.
IL-17A and IL-17F promote the recruitment of neutrophils and induce antimicrobial peptides.
66
What are the key characteristics of the Hematopoietin receptor family?
- Largest cytokine receptor families
- Cytoplasmic domains associate with nonreceptor tyrosine kinase molecules
- Composed of a cytokine-specific α chain subunit paired with shared receptor subunits.
67
What is the role of IL-2 and IL-15 in T cell activation?
IL-2 and IL-15 can each activate NK cells and stimulate proliferation of activated T cells.
68
How do IL-2 and IL-15 signaling pathways differ in their effects on memory CD8 T cells?
IL-2 signaling inhibits proliferation of memory CD8 T cells, while IL-15 signaling promotes their proliferation and homeostatic survival.
69
What are the receptor complexes associated with IL-4 and IL-13, and their significance?
The specific receptor for IL-4 consists of IL-4Rα and γc, transmitting signals via JAK1 and JAK3.
70
How does IL-15 differ from IL-2 in its effects on T cells?
IL-15 inhibits IL-2-mediated activation-induced cell death and stimulates growth and proliferation of memory CD8 T cells.
71
What is the significance of the γc chain in cytokine receptor signaling?
The γc chain is a shared receptor subunit used by multiple cytokine receptors and plays a critical role in transmitting signals for lymphocyte proliferation and survival.
72
How does IL-2 facilitate T-cell proliferation?
IL-2 induces the expression of IL-2Rα and IL-2Rβc, leading to vigorous T-cell proliferation.
73
What is the role of IL-15 in the survival of memory CD8 T cells?
IL-15 promotes the homeostatic survival of memory CD8 T cells and inhibits IL-2-mediated activation-induced cell death.
74
How does IL-17 contribute to the pathogenesis of psoriasis?
IL-17 promotes keratinocyte hyperplasia and neutrophil recruitment, inducing the release of proangiogenic mediators.
75
What is the primary role of the IL-4 receptor in the immune response?
The IL-4 receptor acts as a growth and differentiation factor for Th2 cells and stimulates class switching of immunoglobulin genes in B cells.
76
How does IL-9 contribute to allergic inflammatory processes?
IL-9 stimulates the proliferation of T and B cells and immunoglobulin E, playing a significant role in asthma and allergic disorders.
77
What is the significance of IL-21 in the immune system?
IL-21 is crucial for the expansion of lymphocytes and is associated with impaired Th2 responses when the IL-21 receptor is absent.
78
What role does Thymic Stromal Lymphopoietin (TSLP) play in the immune response?
TSLP acts as a growth factor for B- and T-lineage cells and primes dendritic cells to stimulate Th2 cells.
79
What are the functions of IL-3, IL-5, and GM-CSF in hematopoiesis?
1. **IL-3**: Promotes proliferation and differentiation of various myeloid cells.
2. **IL-5**: Enhances proliferation and immunoglobulin expression in B cells.
3. **GM-CSF**: Serves as a growth factor for myeloid progenitors.
80
What is the role of gp130 in cytokine signaling?
Gp130 interacts with receptors for several cytokines and is essential for signaling through these cytokine receptors.
81
Describe the role of IL-4 in Th2 cell development.
IL-4 acts as a growth and differentiation factor for Th2 cells, initiating their development and response.
82
What is the role of IL-7 in lymphocyte development?
IL-7 promotes the expansion of lymphocytes and regulates the rearrangement of their antigen receptor genes.
83
How does thymic stromal lymphopoietin (TSLP) influence allergic diseases?
TSLP primes dendritic cells to stimulate Th2 cells, fostering the development of allergic diseases.
84
What is the significance of IL-5 in eosinophil accumulation?
IL-5 plays a central role in the accumulation of eosinophils during parasitic infections.
85
How does IL-9 contribute to allergic inflammatory processes?
IL-9 stimulates the proliferation of T and B cells and immunoglobulin E production.
86
What is the role of IL-13 in helminth infections?
IL-13 contributes to the immune response by promoting Th2-mediated immunity during helminth infections.
87
What is the role of IL-4Rα in cytokine signaling?
IL-4Rα mediates IL-4 and IL-13 signaling and transmits signals via JAK1 and JAK3.
88
What is the role of IL-6 in the systemic acute-phase response?
IL-6 stimulates hepatocytes to synthesize and release acute-phase proteins.
89
Explain the therapeutic applications of IL-31 in cutaneous diseases.
IL-31 is an important mediator of cutaneous allergic diseases and atopic dermatitis, possibly through itch stimulation.
90
What are the primary functions of IL-6 in the immune response?
IL-6 stimulates immunoglobulin secretion by B cells and participates in reactive immune responses.
91
What are the two distinct signal transduction pathways of IL-6?
1. **gp130-mediated pathway**: Involves activation of JAK kinases and STAT3.
2. **Ras pathway**: Involves the mitogen-activated protein kinase cascade.
92
How does IL-31 relate to atopic dermatitis?
IL-31 levels correlate with the severity of atopic dermatitis and inhibit keratinocyte differentiation.
93
What role does IL-11 play in inflammatory responses?
IL-11 inhibits the production of inflammatory cytokines and stimulates platelet production.
94
What is the significance of elevated IL-6 levels in psoriasis?
Elevated IL-6 levels indicate its role in skin health and may contribute to the pathogenesis of psoriasis.
95
How does IL-31 contribute to atopic dermatitis?
IL-31 inhibits keratinocyte differentiation and filaggrin expression, impairing skin barrier function.
96
What are the main cell types involved in the pathogenesis of psoriasis?
Keratinocytes, fibroblasts, and vascular endothelial cells are involved. IL-6 stimulates the proliferation of keratinocytes, suggesting its role in psoriasis.
## Footnote
IL-6 may contribute to the pathogenesis of psoriasis and other skin conditions.
97
How does IL-31 contribute to atopic dermatitis?
IL-31 inhibits keratinocyte differentiation and filaggrin expression, impairing skin barrier function. It is produced by activated CD4+ T lymphocytes, particularly Th2 cells.
## Footnote
Serum levels of IL-31 correlate with the severity of atopic dermatitis.
98
What is the role of gp130 in cytokine signaling?
Gp130 is a member of the hematopoietin receptor family that interacts with receptors for cytokines like IL-6, IL-11, and leukemia inhibitory factor. It mediates signal transduction through pathways involving STAT3 activation and the Ras/MAPK cascade.
99
Explain the therapeutic use of IL-11 in psoriasis.
IL-11 inhibits the production of inflammatory cytokines and has shown therapeutic activity in patients with psoriasis. It also stimulates platelet production and is used to treat thrombocytopenia after chemotherapy.
100
How does IL-6 contribute to the pathogenesis of psoriasis?
IL-6 promotes keratinocyte proliferation and is elevated in psoriasis. It acts as a central mediator of the systemic acute-phase response and stimulates the production of acute-phase proteins by hepatocytes.
101
Describe the dual signaling pathways of IL-6 through gp130.
IL-6 signals through gp130 via two pathways: (1) activation of STAT3 through JAK kinases and gp130 dimerization, and (2) the Ras/MAPK cascade, resulting in the activation of nuclear factor of IL-6.
102
How does IL-31RA contribute to IL-31 signaling?
IL-31RA, along with OSMRβ, forms the receptor complex for IL-31. This complex mediates IL-31's effects on keratinocyte differentiation and skin barrier function, contributing to atopic dermatitis.
103
What is the role of IL-6 in Kaposi sarcoma?
Human herpesvirus 8 (HHV8) produces a viral homolog of IL-6, which may contribute to the pathogenesis of Kaposi sarcoma by mimicking IL-6's effects on cell proliferation and inflammation.
104
What are the two major types of receptors for the second class of cytokine receptors?
The two major types of receptors are for:
- Interferons
- IL-10
- IL-10-related cytokines (IL-19, 20, 22, 24, 26)
105
What is the prototype of cytokines signaling through the JAK/STAT pathway?
Interferons are the prototype of cytokines signaling through the JAK/STAT pathway.
106
What are the effects of type I interferons (IFNs)?
The effects of type I IFNs (α and β) include:
- Increased host resistance to viral infections
- Increased expression of MHC class I molecules
- Stimulation of NK cell activity
- Modulation of T-cell responses, promoting a TH1 type response
- Inhibition of proliferation of various cell types, which is useful in cancer treatment.
107
What is the major source of IL-10 within the skin and what stimuli can lead to its production?
The major source of IL-10 within the skin is epidermal keratinocytes, and it can be stimulated by UV radiation, leading to local and systemic effects on immunity.
108
What are the effects of IL-10 on antigen-presenting cells (APCs)?
The effects of IL-10 on APCs include:
- Inhibition of expression of class II MHC and costimulatory molecules
- Decreased production of T cell-stimulating cytokines (IL-1, 6, 12)
109
What are the novel IL-10-related cytokines and their associated receptors?
The novel IL-10-related cytokines and their receptors are:
| Cytokine | Receptors |
|----------|----------|
| IL-19, 20, 24, 26 | IL-20Rα and IL-20Rβ |
| IL-22 | IL-22R and IL-10Rβ |
110
Describe the role of Type I interferons (IFNs) in the immune response and their therapeutic applications.
Type I IFNs (α and β) increase host resistance to viral infections, enhance MHC class I molecule expression, stimulate NK cell activity, and modulate T-cell responses towards a TH1 type. They also inhibit cell proliferation, which is why IFN-α is used to treat hairy cell leukemia, cutaneous malignancies, and HPV infections.
111
Explain the mechanism of action of imiquimod in treating genital warts and superficial BCC.
Imiquimod stimulates TLR7 receptors, leading to the local release of large amounts of Type I IFNs. This triggers antiviral and tumor-inhibitory effects, making it effective against genital warts and superficial basal cell carcinoma (BCC).
112
How does UV radiation influence IL-10 production in the skin?
UV radiation stimulates epidermal keratinocytes to produce IL-10, leading to local and systemic immunosuppressive effects, such as reduced contact sensitivity responses.
113
How does IL-10 contribute to UV-induced immunosuppression?
IL-10, produced by keratinocytes after UV exposure, suppresses immune responses locally and systemically.
114
How does IL-10 influence keratinocyte function?
IL-10 dampens keratinocyte-mediated immune responses, reducing inflammation and sensitivity.
115
What are the primary roles of type I interferons in immune response modulation?
Type I interferons (IFN-α and IFN-β) play several critical roles in immune response modulation:
1. Increased host resistance to the spread of viral infections.
2. Enhanced expression of MHC class I molecules.
3. Stimulation of NK cell activity.
4. Modulation of T-cell responses, promoting a TH1 type of T-cell response.
5. Inhibition of cell proliferation, which is relevant for cancer treatment.
116
How does interleukin-10 (IL-10) influence antigen-presenting cells (APCs) and T-cell responses?
Interleukin-10 (IL-10) exerts several effects on antigen-presenting cells (APCs) and T-cell responses:
- Inhibition of class II MHC expression and costimulatory molecules on APCs.
- Decreased production of T-cell stimulating cytokines such as IL-1, IL-6, and IL-12.
- Regulatory effects that can dampen immune responses, potentially leading to increased susceptibility to irritant and contact sensitivity.
117
What are the implications of IL-10's role in the skin, particularly in response to UV radiation?
IL-10 plays a significant role in the skin, particularly in response to UV radiation:
- Major source of IL-10 in the skin is epidermal keratinocytes.
- Stimulated by UV radiation, leading to both local and systemic effects on immunity.
- Immunosuppressive effects following UV exposure are attributed to keratinocyte-derived IL-10 entering systemic circulation, which can dampen cutaneous immune responses.
118
What are the shared receptor complexes for novel IL-10-related cytokines and their significance?
Novel IL-10-related cytokines (IL-19, 20, 22, 24, 26) engage several receptor complexes with shared chains:
| Cytokine | Receptors |
|----------|------------------------|
| IL-19, 20, 24, 26 | IL-20Rα and IL-20Rβ |
| IL-22 | IL-22R and IL-10Rβ |
- These receptors are preferentially expressed on epithelial cells, including keratinocytes, indicating their role in modulating epithelial immune responses.
119
What role does IL-22 play in psoriasis and keratinocyte behavior?
IL-22 promotes keratinocyte proliferation and epidermal acanthosis, contributing to the epidermal changes associated with psoriasis.
120
What are the therapeutic implications of targeting TNF-α in psoriasis treatment?
Targeting TNF-α can inhibit Th17 cells and is achieved through agents like Infliximab, Adalimumab, and Etanercept. These agents interrupt TNF-α mediated inflammatory pathways but require monitoring for serious infections and increased risk of malignancies.
121
How does the TGF-β family influence cell differentiation?
The TGF-β family influences the differentiation of uncommitted cells into specific lineages by binding to type II receptors, which phosphorylate and activate type I receptors, leading to downstream signaling that regulates transcription of target genes.
122
What is the significance of IL-17 in psoriasis pathogenesis?
IL-17 is a key cytokine in the pathogenesis of psoriasis at the keratinocyte level, and monoclonal antibodies like Secukinumab and Ixekizumab target IL-17A to treat the condition.
123
What are the advantages and disadvantages of using cytokine antagonists in treatment?
Advantages include a more targeted treatment approach, while disadvantages involve immunosuppressive properties that may increase the risk of infections and malignancies.
124
What is the role of chemokines in leukocyte mobilization?
Chemokines are secondary cytokines that are central to leukocyte mobilization, playing a crucial role in the immune response and inflammation.
125
What is the role of IL-22 in psoriasis?
IL-22 promotes keratinocyte proliferation and epidermal acanthosis, contributing to the epidermal changes associated with cutaneous inflammation in psoriasis.
126
How does TGF-β influence fibroblast activity and its implications in scleroderma?
TGF-β enhances fibroblast production of collagen and extracellular matrix molecules, inhibits metalloproteinase production, and stimulates their inhibitors. These profibrogenic effects contribute to the immunopathology of scleroderma.
127
What are the therapeutic implications of TNF-α blockade in psoriasis?
TNF-α inhibitors like infliximab, adalimumab, and etanercept interrupt TNF-α-mediated inflammatory pathways, reducing Th17 cell activity. However, they increase the risk of infections, malignancies, and cardiovascular events.
128
Describe the mechanism of action of ustekinumab in treating psoriasis.
Ustekinumab is a monoclonal antibody targeting the p40 subunit shared by IL-12 and IL-23, reducing Th17 cytokines and their effects in psoriatic skin.
129
What are the therapeutic applications of JAK inhibitors like tofacitinib?
Tofacitinib inhibits JAK1 and JAK3, altering lymphocyte function. It is being investigated for treating psoriasis, alopecia areata, and dermatomyositis.
130
How does IL-26 contribute to inflammatory diseases?
IL-26 mediates proinflammatory signals in diseases like inflammatory bowel disease and rheumatoid arthritis. Its cationic and amphipathic nature allows it to kill select bacteria.
131
What are the effects of IL-17A in psoriasis?
IL-17A, produced by Th17 cells, is a key cytokine in psoriasis pathogenesis, promoting keratinocyte inflammation and proliferation.
132
Describe the therapeutic potential of IL-22 blockade in skin diseases.
Blocking the IL-22–IL-22R axis may treat atopic dermatitis and psoriasis by reducing keratinocyte proliferation and inflammation.
133
How does TGF-β regulate immune responses?
TGF-β influences T-cell differentiation, enhances regulatory T-cell development, and inhibits immune responses.
134
What is the role of Smad proteins in TGF-β signaling?
Smad proteins mediate downstream signaling from TGF-β receptors to the nucleus, regulating gene transcription.
135
What is the role of IL-17 receptor blockers in psoriasis?
IL-17 receptor blockers like brodalumab inhibit IL-17 signaling, reducing keratinocyte inflammation and proliferation in psoriasis.
136
What is the role of phosphodiesterase-4 inhibitors in psoriasis?
Phosphodiesterase-4 inhibitors like apremilast reduce proinflammatory cytokine production, treating moderate to severe psoriasis.
137
How does TGF-β contribute to fibrosis?
TGF-β stimulates fibroblasts to produce collagen and extracellular matrix, contributing to fibrotic diseases like scleroderma.
138
What are the roles of IL-22 and IL-26 in psoriasis and related conditions?
IL-22 promotes keratinocyte proliferation and epidermal acanthosis, contributing to the epidermal changes associated with psoriasis. IL-26 mediates proinflammatory signals in inflammatory bowel disease and rheumatoid arthritis, and has antimicrobial properties that allow it to kill select gram-negative and gram-positive bacteria.
139
How does the TGF-β family influence cell differentiation and development?
The TGF-β family, consisting of approximately 30 additional cytokines, plays a crucial role in development by influencing the differentiation of uncommitted cells into specific lineages. Binding to type II receptors leads to the formation of complexes that activate downstream signaling pathways, which regulate the transcription of target genes essential for cell development.
140
What are the therapeutic implications of targeting TNF-α in the treatment of psoriasis?
Targeting TNF-α with inhibitors such as Infliximab and Adalimumab can effectively treat plaque psoriasis by inhibiting Th17 cells and interrupting TNF-α mediated inflammatory pathways. However, patients must be monitored closely for serious infections and increased risk of malignancies or major adverse cardiovascular events.
141
What is the significance of IL-17 in the pathogenesis of psoriasis and how is it targeted therapeutically?
IL-17 is a key cytokine in the pathogenesis of psoriasis at the keratinocyte level. Therapeutic agents like Secukinumab and ixekizumab target IL-17A, while Brodalumab blocks the IL-17 receptor, aiming to reduce the inflammatory response associated with psoriasis.
142
What are the advantages and disadvantages of using cytokine antagonists in therapy?
Advantages: Cytokine antagonists offer a more targeted treatment approach for inflammatory conditions. Disadvantages: They may have immunosuppressive properties, increasing the risk of infections and malignancies, necessitating careful patient monitoring during treatment.
143
What are the special functions of chemokines in the immune system?
- Guide leukocytes via chemotactic gradients in tissue to bring effector cells to required locations.
- Increase the binding of leukocytes via their integrins to ligands at the endothelial cell surface, facilitating firm adhesion and extravasation of leukocytes in tissue.
- Play an important role in skin development, immunity, inflammation, and cancer.
144
How are chemokines classified based on their structure?
Chemokines are grouped into 4 subfamilies based on the spacing of amino acids between the first 2 cysteines:
| Subfamily | Description |
|-----------|-------------|
| CXC | α-chemokines; one non-conserved AA between the 2 cysteines |
| CC | β-chemokines; lacks the additional AA |
| C | Only member is lymphotactin |
| CXXXC or CX3C | Only member is fractalkine |
145
What is the role of chemokine receptors in signal transduction?
- Chemokine receptors are seven transmembrane spanning membrane proteins that couple to intracellular G proteins containing α, β, and γ subunits.
- These receptors are part of a large family of G protein-coupled receptors (GPCR).
- The G protein subtypes and their subunit subtypes may account for specificity in the action of certain chemokine receptors.
- G proteins are inactive when GDP is bound and activated when GDP is exchanged for GTP, leading to receptor association with G-proteins and increased exchange of GTP and GDP.
146
What is the role of chemokines in leukocyte mobilization?
Chemokines guide leukocytes via chemotactic gradients, increase leukocyte binding to endothelial cells, and facilitate firm adhesion and extravasation into tissues.
147
How do chemokine receptors mediate intracellular signaling?
Chemokine receptors, part of the GPCR family, activate G proteins upon ligand binding. This leads to cytoskeletal changes, gene transcription, chemotaxis, and cell adhesion.
148
What are the special functions of chemokines in the immune response?
- Guide leukocytes via chemotactic gradients in tissue to bring effector cells to required locations.
- Increase binding of leukocytes via their integrins to ligands at the endothelial cell surface, facilitating firm adhesion and extravasation of leukocytes in tissue.
- Play an important role in skin development, immunity, inflammation, and cancer.
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How are chemokines classified into subfamilies and what are the characteristics of each?
Chemokines are grouped into 4 subfamilies based on the spacing of amino acids between the first 2 cysteines:
| Subfamily | Characteristics |
|-----------|----------------|
| CXC | α-chemokines; one non-conserved AA between the 2 cysteines |
| CC | β-chemokines; lacks the additional AA |
| C | Only member is lymphotactin |
| CXXXC or CX3C | Only member is fractalkine |
150
What is the significance of the positive charge of most chemokines in their function?
Most chemokines have a net positive charge, allowing them to bind to negatively charged carbohydrates (glycosaminoglycans) on the luminal surface of blood vessels. This binding helps chemokines to preferentially associate with the blood vessel surface, counteracting the shear forces that would otherwise wash them away, thus enhancing their effectiveness in guiding leukocytes.
151
What is lymphotactin?
Lymphotactin is a chemokine, specifically the only member of the CXXXC or CX3C family, known as fractalkine.
152
What is the significance of the positive charge of most chemokines in their function?
Most chemokines have a net positive charge, allowing them to bind to negatively charged carbohydrates (glycosaminoglycans) on the luminal surface of blood vessels. This binding helps chemokines to preferentially associate with the blood vessel surface, counteracting shear forces that would otherwise wash them away, thus enhancing their effectiveness in guiding leukocytes.
153
Describe the structure and function of chemokine receptors in signal transduction.
Chemokine receptors are seven transmembrane spanning membrane proteins that couple to intracellular G proteins containing α, β, and γ subunits. They are part of a large family of G protein-coupled receptors (GPCR). The specificity of chemokine receptors is influenced by the G protein subtypes and their subunit combinations.
154
What are the roles of chemokines in the recruitment of host defense cells to sites of inflammation?
1. Provide signals required for leukocytes to come to a complete stop in blood vessels at inflamed sites.
2. Transmigration of leukocytes from the luminal side to the abluminal side of blood vessels.
3. Attract leukocytes to sites of inflammation in the dermis or epidermis following transmigration.
155
How do selectins and integrins function in leukocyte adhesion during inflammation?
- **Selectins**: Mediate transient attachment (rolling) of leukocytes to endothelial cells.
- E-selectin: Skin-associated vascular selectin.
- L-selectin: Involved in T-cell migration to skin.
- **Integrins**: Provide stronger binding and transmigration.
- Must be activated from resting state to bind to counter receptors like ICAM-1 expressed by endothelial cells.
- Binding of chemokines to leukocyte chemokine receptors activates β1 and β2 integrins, increasing affinity and avidity of individual leukocyte integrins.
156
What is the significance of G protein activation in chemokine receptor signaling?
- Activation of G protein leads to dissociation of the Gα and Gβγ subunits.
- Gα activates protein tyrosine kinases (PTK) and mitogen-activated protein kinases (MaPK), resulting in cytoskeletal changes and gene transcription.
- Gβγ initiates events that lead to chemotaxis and cell adhesion, and activates phospholipase C, forming diacylglycerol (DAG) and inositol triphosphate, which stimulate calcium entry into the cytosol.
157
What happens to chemokine receptors after they are exposed to appropriate ligands?
After chemokine receptors are exposed to appropriate ligands, they are frequently internalized, leading to the inability of the receptor to mediate further signaling, a process known as **desensitization**.
158
Explain the role of chemokines in leukocyte recruitment during inflammation.
Chemokines provide signals for leukocytes to stop in blood vessels, transmigrate to the abluminal side, and move to inflamed dermis or epidermis.
159
What is the multistep model of leukocyte recruitment?
Leukocytes adhere to endothelial cells via selectins for rolling, followed by integrin activation for firm adhesion and transmigration, facilitated by chemokines.
160
What is the role of chemokines in dendritic cell migration?
Chemokines facilitate dendritic cell emigration from the skin to lymph nodes, essential for acquired immune responses.
161
How do chemokines mediate leukocyte adhesion?
Chemokines activate leukocyte integrins, increasing their affinity for endothelial receptors like ICAM-1, facilitating firm adhesion.
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How do chemokines facilitate leukocyte transmigration?
Chemokines guide leukocytes across the endothelium to inflamed tissues, aiding in immune response.
163
What are the roles of chemokines in the recruitment of leukocytes to sites of inflammation?
Chemokines play three critical roles in leukocyte recruitment:
1. **Provide signals** required for leukocytes to come to a complete stop in blood vessels at inflamed sites.
2. **Transmigration** of leukocytes from the luminal side to the abluminal side of blood vessels.
3. **Attract leukocytes** to sites of inflammation in the dermis or epidermis following transmigration.
164
How do selectins and integrins contribute to leukocyte adhesion and migration during inflammation?
Selectins and integrins are adhesion molecules that facilitate leukocyte adhesion and migration:
- **Selectins** mediate transient attachment (rolling) of leukocytes to endothelial cells:
- E-selectin: skin-associated vascular selectin.
- L-selectin: involved in T-cell migration to skin.
- **Integrins** and their receptors (Ig superfamily) provide stronger binding and transmigration:
- Must be activated from resting state to bind to counter receptors like ICAM-1 on endothelial cells.
- Binding of chemokines to leukocyte chemokine receptors activates β1 and β2 integrins, increasing their affinity and avidity for binding.
165
What is the significance of G protein activation in chemokine receptor signaling?
Activation of G proteins in chemokine receptor signaling leads to several important cellular events:
- **Dissociation of Gα and Gβγ subunits** initiates signaling pathways.
- Gα activates protein tyrosine kinases (PTK) and mitogen-activated protein kinases (MaPK), resulting in **cytoskeletal changes** and **gene transcription**.
- Gβγ initiates events that lead to **chemotaxis** and **cell adhesion**.
- Gβγ activates phospholipase C, leading to the formation of **diacylglycerol (DAG)** and inositol triphosphate, which stimulate calcium entry into the cytosol, further influencing cellular responses.
166
What happens to chemokine receptors after they are exposed to appropriate ligands, and what is the clinical significance of this process?
After chemokine receptors are exposed to appropriate ligands, they undergo **internalization**, leading to an **inability of the receptor to mediate further signaling**, a process known as **desensitization**. This is clinically significant as it regulates the duration and intensity of the immune response, preventing overactivation that could lead to tissue damage or chronic inflammation.
167
What are the associated chemokine receptors involved in Atopic Dermatitis and their roles?
The associated chemokine receptors in Atopic Dermatitis are **CCR4** and **CCR10**.
- **CCR4** and its ligand **TARC/CCL17** recruit T cells to atopic skin.
- **CLA+ CCR4+ CCR10+ lymphocytes** are increased in peripheral blood and lesional skin of atopic patients.
- **Eotaxin** and **CCR3** are responsible for the recruitment of eosinophils.
168
What characterizes the inflammatory infiltrate in Psoriasis?
The inflammatory infiltrate in Psoriasis is characterized by:
- Hyperplasia of the epidermis with prominent dermal and epidermal inflammatory infiltrate.
- Composition of **Th1** and **Th17** polarized memory T cells, neutrophils, macrophages, and dendritic cells.
- High levels of **IL-17**, **IL-22**, and **IL-23** in psoriatic skin lesions.
- **Th17 cells** express **CCR6**, which mediates psoriasis along with its ligand **CCL20**.
169
How do chemokines play a role in cancer, particularly in melanoma?
Chemokines play a significant role in cancer by:
- Controlling **angiogenesis** (via ELR chemokines).
- Inducing **tumor immune responses**.
- **IL-8** is a prototypical ELR+ chemokine secreted by melanoma cells, detected in metastatic dissemination, and may attract circulating tumor cells to primary tumors.
- Tumors secrete chemokines that attract various leukocytes, which can aid in tumor progression rather than being deleterious.
170
What is the significance of chemokines in infectious diseases such as Kaposi sarcoma and AIDS?
In infectious diseases, chemokines and their receptors have evolved as a host response:
- In **Kaposi sarcoma**, the Kaposi sarcoma herpes virus GPCR can promiscuously bind several chemokines, potentially acting as a growth promoter.
- In **AIDS**, **CD4** serves as the primary fusion receptor for HIV-1, while **CXCR4** or **CCR5** act as coreceptors for entry of other strains of HIV-1.
171
What therapeutic implications arise from the imbalance of cytokines and chemokines?
The imbalance of cytokines and chemokines may lead to chronic disease, highlighting the importance of understanding the underlying biology of soluble mediators. Currently, chemokines and cytokines are being clinically targeted to help treat patients, indicating their potential role in therapeutic applications.
172
What is the role of chemokines in atopic dermatitis?
In atopic dermatitis, chemokines like TARC/CCL17 and CTACK/CCL27 recruit T cells to atopic skin, while eotaxin and CCR3 recruit eosinophils. Their levels correlate with disease severity.
173
How do Th17 cells contribute to psoriasis pathogenesis?
Th17 cells produce IL-17 and IL-22, which promote keratinocyte proliferation and inflammation. They also express CCR6, which interacts with CCL20 to mediate T-cell migration to psoriatic lesions.
174
What is the role of IL-8 in cancer progression?
IL-8 acts as an autocrine growth factor for melanoma and other cancers, promotes angiogenesis, and attracts circulating tumor cells to primary tumors.
175
How do chemokines influence HIV-1 infection?
HIV-1 uses CD4 as its primary fusion receptor and CXCR4 or CCR5 as coreceptors for entry into host cells.
176
What is the role of CXCR4 in cancer metastasis?
CXCR4 aids in cancer metastasis to distant organs, while CCR7 is critical for lymphatic invasion and lymph node metastasis.
177
How do chemokines contribute to Kaposi sarcoma?
Kaposi sarcoma herpesvirus encodes a GPCR that binds chemokines, promoting tumor growth.
178
How do chemokines influence angiogenesis in cancer?
ELR+ chemokines like IL-8 control angiogenesis, aiding tumor growth and metastasis.
179
What is the role of CCR4 and CCR10 in atopic dermatitis?
CCR4 and CCR10, along with their ligands, recruit T cells to atopic skin, contributing to inflammation.
180
What is the role of IL-23 in psoriasis?
IL-23 promotes Th17 cell differentiation and cytokine production, contributing to psoriatic inflammation.
181
What is the role of CCR6 in psoriasis?
CCR6, expressed by Th17 cells, interacts with CCL20 to mediate T-cell migration to psoriatic lesions.
182
How does IL-8 mediate neutrophil recruitment in psoriasis?
IL-8 attracts neutrophils via CXCR1 and CXCR2, contributing to psoriatic inflammation.
183
What is the role of chemokines in infectious diseases?
Chemokines and their receptors may be exploited by pathogens like HIV and Kaposi sarcoma herpesvirus to promote infection and growth.
184
What is the role of chemokines in Th2-mediated diseases?
Chemokines like TARC/CCL17 recruit Th2 cells to inflamed tissues, driving diseases like atopic dermatitis.
185
What role do chemokines play in the pathogenesis of Atopic Dermatitis?
Chemokines such as **CCR4** and **CCR10** are associated with Atopic Dermatitis. They recruit T cells to atopic skin, while **Eotaxin** and **CCR3** are responsible for the recruitment of eosinophils. Increased levels of **TARC/CCR17** and **CTACK/CCL27** correlate with disease severity.
186
How do Th17 cells contribute to the inflammatory response in Psoriasis?
Th17 cells express **CCR6**, which mediates psoriasis along with its ligand **CCL20**. They secrete cytokines such as **IL-17** and **IL-22**, and high levels of **IL-23** are found in psoriatic lesions. Neutrophils are attracted by high levels of **IL-8** acting via **CXCR1** and **CXCR2**.
187
What is the significance of IL-8 in cancer, particularly in melanoma?
**IL-8** is a prototypical **ELR+** chemokine secreted by melanoma cells. It is associated with metastatic dissemination and may attract circulating tumor cells to primary tumors, influencing leukocyte and endothelial cell recruitment. It acts as an autocrine growth factor for melanoma and other cancers.
188
In what way do chemokines and their receptors interact with infectious diseases like AIDS?
In AIDS, **CD4** serves as the primary fusion receptor for all strains of HIV-1, binding to HIV-1 proteins. Additionally, **CXCR4** or **CCR5** act as coreceptors for entry of other strains of HIV-1, highlighting the role of chemokine receptors in viral pathogenesis.
189
What therapeutic implications arise from the imbalance of cytokines and chemokines in chronic diseases?
An imbalance of cytokines and chemokines can lead to chronic diseases. Understanding the biology of soluble mediators is crucial for developing therapeutic strategies, as chemokines and cytokines are currently being targeted clinically to treat patients effectively.
