40: Eosinophilic Diseases Flashcards
(213 cards)
1
Q
What are the primary sources of eosinophilopoietic cytokines and growth factors?
A
The principal sources of eosinophilopoietic cytokines and growth factors, such as IL-3, GM-CSF, and IL-5, are activated T cells that induce eosinophil differentiation in the bone marrow.
2
Q
What is the role of IL-5 in eosinophil signaling?
A
IL-5 plays a pivotal role in immune responses involving eosinophils by binding to the α chain of the IL-5 receptor (IL-5R), which induces recruitment of the common β chain (βc) to IL-5R, activating signaling pathways essential for eosinophil function.
3
Q
Describe the four steps of signaling events in eosinophil activation.
A
The signaling events in eosinophil activation progress in four steps:
- Juxtamembranous signaling: Activation of membrane-anchored tyrosine kinases and lipid kinases.
- Signal interfacing: Transduction of juxtamembranous signals to cytosolic signals.
- Mobile signaling: Cytosolic signaling molecules translocate to other cellular compartments, including the nucleus and mitochondria.
- Transcription activation: Resulting from nuclear translocation and initiation of gene transcription.
4
Q
What is the significance of IL-5R in eosinophil development?
A
IL-5R is a prerequisite for eosinophil development, as it is necessary for the differentiation and survival of eosinophils, with IL-5 demonstrating maximum activity on the IL-5R-positive eosinophil progenitor pool.
5
Q
What are the characteristics of mature eosinophils?
A
Mature eosinophils are characterized by a diameter of 12 to 17 µm, making them slightly larger than neutrophils.
6
Q
How does IL-5 contribute to eosinophil development and activation?
A
IL-5 is the most selective eosinophil-active cytokine. It is necessary and sufficient for eosinophil differentiation, regulates their exodus from the bone marrow, and promotes survival, activation, and chemotaxis through binding to IL-5 receptors.
7
Q
What is the role of IL-5 in eosinophil development and activation?
A
IL-5 is crucial for eosinophil development as it binds to the IL-5 receptor (IL-5R), activating signaling pathways that promote eosinophil survival, activation, and chemotaxis. It is a selective eosinophil-active cytokine that demonstrates maximum activity on the IL-5R-positive eosinophil progenitor pool, which is initially expanded by earlier acting cytokines like IL-3 and GM-CSF.
8
Q
What are the implications of IL-3 and GM-CSF in eosinophil development?
A
IL-3 and GM-CSF are important pluripotent cytokines that induce eosinophil differentiation in the bone marrow. They also have effects on other hematopoietic lineages and work in conjunction with IL-5 to promote eosinophil survival, activation, and chemotaxis through their respective receptors.
9
Q
How do the JAK-STAT and Ras-mitogen-activated protein kinase pathways interact in eosinophil signaling?
A
The JAK-STAT and Ras-mitogen-activated protein kinase pathways converge at various levels in IL-5 signaling of eosinophils. Both pathways are essential for transducing signals from the IL-5 receptor, leading to gene expression that regulates eosinophil growth, development, activation, and survival.
10
Q
What are the main types of granules found in eosinophils and their characteristics?
A
Eosinophils contain several types of granules:
Granule Type | Characteristics |
|———————-|———————————————————————————|
| Primary Granules | Variable size, round, uniformly dense, present in 1 to 3 per electron microscopy cross section, more common in immature eosinophilic promyelocytes. May contain Charcot-Leyden crystal protein (galectin-10). |
| Secondary Granules | Contain highly basic proteins such as major basic protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPO). Include enzymes, cytokines, growth factors, and chemokines. |
| Small Granules | Contain acid phosphatase and arylsulfatase, present at 2-8 per electron microscopy cross section. |
| Secretory Vesicles | Small, dumbbell-shaped structures, most abundant granules in number, approximately 160 per electron microscopy cross section. |
| Non-Membrane Bound Lipid Bodies | Principal stores of arachidonic acid, contain cyclooxygenase, 5- and 15-lipoxygenase, required for synthesizing prostaglandins and leukotrienes.
11
Q
What is the role of eosinophils in immune function, particularly in relation to helminth infections?
A
Eosinophils play a crucial role in immune function, especially against helminth infections:
- Host Defense: Eosinophils are important for host defense against parasites, being cytotoxic to large nonphagocytosable organisms, such as multicellular helminthic parasites.
- Binding Mechanism: They bind to host-derived immunoglobulins and complement components on the surface of their targets, facilitating antibody- or complement-dependent cytotoxicity.
- Granule Release: Upon activation, eosinophils release their granule products, which can disrupt the integument of parasites, leading to the death of the organism.
- Cell Adhesion: Eosinophils also bind to carbohydrate ligands expressed on parasites, similar to selectins, enhancing their cytotoxic effects.
12
Q
How do eosinophils respond to tissue damage and promote tissue remodeling?
A
Eosinophils respond to tissue damage and promote tissue remodeling through several mechanisms:
- Migration: They can migrate to areas of tissue injury or necrosis, responding to signals such as the high-mobility group box-1 protein (HMGB1) released from necrotic cells.
- Repair Role: Eosinophils may play a role in the repair of gastric mucosal tissue during infections, such as those caused by Helicobacter pylori.
- Degranulation: Upon activation, eosinophils can release granule proteins that contribute to tissue remodeling and repair processes.
- Non-recirculation: Once eosinophils enter tissues, most do not recirculate, which allows them to exert localized effects in the damaged area.
13
Q
What is the function of Charcot-Leyden crystals in eosinophilic diseases?
A
Charcot-Leyden crystals, composed of galectin-10, are found in eosinophilic diseases and may contribute to inflammation by activating immune cells.
14
Q
What is the role of eosinophils in the gastrointestinal tract under normal conditions?
A
Eosinophils reside in the lamina propria of the gastrointestinal tract, where they contribute to tissue homeostasis and immune regulation.
15
Q
How do eosinophils interact with advanced glycation end products (AGEs) during tissue injury?
A
Eosinophils express receptors for AGEs, which mediate their migration to areas of tissue injury and promote tissue repair.
16
Q
What is the role of eosinophils in the repair of gastric mucosal tissue?
A
Eosinophils promote gastric mucosal repair by responding to tissue-damage signals and releasing factors like TGF-β.
17
Q
What are the primary functions of eosinophils in the immune response to helminth infections?
A
Eosinophils play a crucial role in host defense against parasites by:
- Being cytotoxic to large nonphagocytosable organisms, such as multicellular helminthic parasites.
- Binding to host-derived immunoglobulins and complement components on the surface of their targets, facilitating antibody- or complement-dependent cytotoxicity.
- Interacting with carbohydrate ligands expressed on parasites, similar to selectins, enhancing their ability to target and eliminate these organisms.
18
Q
How do eosinophils contribute to tissue remodeling and repair during inflammation?
A
Eosinophils contribute to tissue remodeling and repair by:
- Responding to tissue-damage signals and migrating to areas of tissue injury or necrosis.
- Utilizing high-mobility group box-1 protein (HMGB1) released from necrotic cells to facilitate their migration.
- Playing a role in the repair of gastric mucosal tissue during infections, such as those caused by Helicobacter pylori.
19
Q
What is the significance of eosinophil granule proteins in the context of allergic hypersensitivity?
A
Eosinophil granule proteins are significant in allergic hypersensitivity as they:
- Contribute to the inflammatory response by releasing mediators that can exacerbate allergic reactions.
- Cause tissue damage and contribute to the symptoms of allergic diseases through their cytotoxic effects on host tissues and parasites.
- Play a role in the recruitment and activation of other immune cells, further amplifying the allergic response.
20
Q
Describe the lifecycle of eosinophils from their release to their function in tissues.
A
The lifecycle of eosinophils includes:
- Release from the bone marrow into circulation as mature cells, where they are present transiently for 8-18 hours.
- Comprising a small portion (6% or less) of circulating leukocytes, they primarily dwell in tissues with an average lifespan of 2-5 days, extendable by cytokines.
- Entering tissues where they perform functions such as responding to tissue damage, promoting remodeling, and participating in immune responses against parasites.
21
Q
What are the roles of eosinophils in innate immunity against bacteria?
A
Eosinophils play a role in innate immunity against bacteria through the following mechanisms:
- DNA Trap: Eosinophils rapidly release mitochondrial DNA when exposed to bacteria, which traps eosinophil granule proteins (ECP and MBP) that have antimicrobial effects.
- Granule Proteins: They release granule proteins that bind and kill bacteria.
- Phagocytosis: Eosinophils can phagocytose and kill bacteria, although they are less effective when neutrophil function is deficient.
- Mucosal Epithelium: They do not undergo cell death during this process, which is important for maintaining innate immune responses, particularly in mucosal tissues.
22
Q
How do eosinophils contribute to allergic inflammation?
A
Eosinophils contribute to allergic inflammation through the following mechanisms:
- Thymic Stromal Lymphopoietin (TSLP): Eosinophils’ involvement is promoted by TSLP, a cytokine secreted by epithelial cells in response to allergens.
- T-cell Polarization: They influence T-cell polarization favoring T-helper (Th)2 responses by promoting Th1 apoptosis and influencing cytokine expression.
- Increased Numbers: Eosinophils are especially increased in lymph nodes and spleen after allergen exposure or microbial insults, enhancing the immune response.
23
Q
What are the effects of eosinophil-derived products in disease?
A
Eosinophil-derived products have several effects in disease, including:
- Cytotoxic Effects: Direct cytotoxic effects on structural cells and microbes.
- Increased Vascular Permeability: Enhances vascular permeability and procoagulant effects.
- Immune Responses: Innate immune responses to parasites, viruses, fungi, and tumor cells.
- Leukocyte Migration: Facilitates the enhancement of leukocyte migration and amplification of effector T-cell responses.
- Mammary Gland Development: Potential involvement in mammary gland development.
24
Q
What is the significance of eosinophil granule proteins in tissue damage?
A
Eosinophil granule proteins are significant in tissue damage due to the following reasons:
- Cationic Proteins: Specific granule cationic proteins (EPO, ECP, EDN, MBP-1) are among the most damaging to host tissues.
- Persistence: Once deposited, these proteins persist in tissues for extended periods (e.g., EPO for 1 week, ECP for 2 weeks, EDN for 2.5 weeks, MBP-1 for 6 weeks).
- Direct Tissue Damage: They induce direct tissue damage to host cells, including myocytes, endothelium, neurons, epithelium, and smooth muscle, as well as microbes.
- Vasodilatory Effects: They likely contribute to edema due to their vasodilatory effects, with contributions from mast cells and basophil histamine release by MBP-1.
25
What role do eosinophils play in fungal infections, and how do they interact with fungal cell walls?
Eosinophils release cytotoxic granule proteins onto fungal organisms and adhere to the fungal cell wall component β-glucan via the β2-integrin surface molecule CD11b. They kill fungi in a contact-dependent manner.
26
Describe the mechanism by which eosinophils kill bacteria using DNA traps.
Eosinophils release mitochondrial DNA traps containing granule proteins like ECP and MBP. These structures bind and kill bacteria without causing eosinophil cell death, making it an important innate immune response.
27
How do eosinophils influence T-cell responses in allergic disorders?
Eosinophils promote Th2 polarization by inducing Th1 apoptosis and releasing cytokines that favor Th2 responses.
28
How do eosinophils respond to helminth infections?
Eosinophils bind to helminths via immunoglobulins and complement, releasing granule proteins like MBP and ECP that disrupt the parasite's integument and cause death.
29
What is the role of eosinophils in bacterial infections?
Eosinophils release mitochondrial DNA traps containing granule proteins to bind and kill bacteria, especially in mucosal tissues.
30
What is the role of eosinophils in tumor immunity?
Eosinophils can have dual roles in tumor immunity, either promoting tumor destruction through cytotoxic granule proteins or contributing to tumor progression in certain cancers.
31
What role do eosinophils play in the immune response against fungal infections?
Eosinophils kill fungi in a contact-dependent manner by adhering to the fungal cell wall component, β-glucan, via the β2-integrin surface molecule CD11b. They release cytotoxic granule proteins onto fungal organisms and into the extracellular milieu, producing fragmentation and disruption of the fungal structure.
32
How do eosinophils contribute to the immune response against bacteria?
Eosinophils may have a role in innate immunity against bacteria through a unique mechanism called DNA trap, where they rapidly release mitochondrial DNA when exposed to bacteria. This traps eosinophil granule proteins, ECP and MBP, which have antimicrobial effects, forming structures that bind and kill bacteria.
33
What is the significance of eosinophils in allergic inflammation?
In allergic inflammation, eosinophils are involved in T-cell polarization favoring T-helper.
34
What is the significance of eosinophils in allergic inflammation?
In allergic inflammation, eosinophils are involved in T-cell polarization favoring T-helper (Th)2 responses by promoting Th1 apoptosis and influencing T cell-dependent responses through cytokine expression. Their involvement is promoted by thymic stromal lymphopoietin, a cytokine secreted by epithelial cells in response to allergens.
35
What are the implications of eosinophilia in cancer prognosis?
Eosinophilia is associated with certain tumors, where it can indicate a more favorable prognosis. In contrast, tumors like nodular sclerosing Hodgkin disease and Sézary syndrome may confer a poor prognosis. In Sézary syndrome, tumor cells produce IL-5, reflecting tumor burden and associated eosinophilia.
36
What are the effects of eosinophil-derived products on structural cells and microbes?
Eosinophil-derived products exert direct cytotoxic effects on structural cells and microbes, increase vascular permeability, promote procoagulant effects, and enhance innate immune responses to parasites, viruses, fungi, and tumor cells, thereby amplifying effector T-cell responses.
37
What are the clinical implications of Major Basic Protein (MBP) in eosinophil function?
- **MBP** is a major component of eosinophil granules, constituting approximately **55%** of the protein in guinea pig eosinophils.
- It has a **high isoelectric point** (>pH 11), making it strongly basic.
- MBP directly damages helminths and mammalian cells, increasing cell membrane permeability and disrupting lipid bilayers.
- It stimulates the release of **superoxide**, **lysozyme**, and **IL-8** from neutrophils.
- MBP-1 and EPO act as potent platelet agonists, promoting clotting.
38
How do Eosinophil Cationic Protein (ECP) and Eosinophil-Derived Neurotoxin (EDN) contribute to immune responses?
- **ECP** and **EDN** are homologous proteins involved in immune defense against RNA viruses.
- **EDN** enhances the migration and maturation of dendritic cells and acts as a ligand for **Toll-like receptor 2 (TLR2)**, activating myeloid dendritic cells.
- EDN functions as an **alarmin**, promoting Th2-biased immune responses and alerting the adaptive immune system.
39
What role do lipid mediators produced by eosinophils play in inflammation?
- Eosinophils store **arachidonic acids** in lipid bodies and produce various metabolites.
- They generate cysteinyl leukotrienes (LTC4, LTD4, LTE4) via the **5-lipoxygenase pathway**.
- Eosinophils also produce thromboxanes and prostaglandins (e.g., thromboxane B2, PGE2) through the **cyclooxygenase pathway**.
- These lipid mediators are crucial in modulating inflammatory responses and contributing to chronic inflammation.
40
What are the primary cytokines produced by eosinophils and their roles?
- Eosinophils produce key cytokines involved in their growth and differentiation: **IL-3**, **IL-5**, and **IL-13**.
- They also produce regulatory and proinflammatory cytokines such as **TNF-α**, **IL-1α**, **IL-4**, **IL-6**, and **GM-CSF**.
- Eosinophils release chemokines like **CXCL13** and **CCL5**, which modulate immune responses and attract other immune cells.
- These cytokines are constitutively produced in low levels and induced during inflammation, enhancing eosinophil activation.
41
A patient presents with eosinophilia and episodic angioedema. What syndrome might this indicate, and what is the underlying mechanism?
The patient might have Gleich syndrome, which is characterized by episodic angioedema with eosinophilia. The mechanism involves eosinophil activation and degranulation, leading to tissue swelling and inflammation.
42
What is the role of eosinophil-derived neurotoxin (EDN) in immune responses?
EDN induces dendritic cell migration and maturation, acts as a chemoattractant, and enhances Th2-biased immune responses by activating Toll-like receptor 2 pathways.
43
What is the function of major basic protein (MBP) in eosinophil granules?
MBP damages helminths and mammalian cells by increasing cell membrane permeability. It also stimulates histamine release from basophils and induces superoxide production in neutrophils.
44
What is the role of eosinophil peroxidase (EPO) in microbial killing?
EPO generates reactive oxidants in the presence of hydrogen peroxide and halides, killing microorganisms and potentiating phagocyte activity.
45
What is the role of arachidonic acid metabolites in eosinophil function?
Eosinophils produce arachidonic acid metabolites like leukotrienes and prostaglandins, which mediate inflammation and eosinophil trafficking.
46
How do eosinophils contribute to vascular permeability in inflammation?
Eosinophil granule proteins like MBP and ECP increase vascular permeability by disrupting endothelial cell integrity.
47
How do eosinophils interact with dendritic cells in immune responses?
Eosinophils release EDN, which induces dendritic cell migration and maturation, enhancing antigen-specific Th2 responses.
48
How do eosinophils contribute to the pathogenesis of Wells syndrome?
In Wells syndrome, eosinophils release granule proteins that cause eosinophilic cellulitis and urticaria, mimicking insect bite reactions.
49
What is the role of eosinophils in the innate immune response to viruses?
Eosinophils release EDN and ECP, which have antiviral activity and contribute to host defense against RNA viruses.
50
How do eosinophils influence platelet activation during inflammation?
Eosinophil granule proteins like MBP and EPO act as platelet agonists, promoting clotting and release of inflammatory mediators.
51
What are the clinical implications of Major Basic Protein (MBP) in eosinophil function and its effects on other immune cells?
- **MBP** is a major component of eosinophil granules, constituting approximately 55% of the protein content.
- It directly damages helminths and mammalian cells, increasing cell membrane permeability and disrupting lipid bilayers.
- MBP-1 and MBP-2 stimulate neutrophils, inducing the release of superoxide, lysozyme, and IL-8.
- They also promote the release of 5-hydroxytryptamine, enhancing clotting.
- The clinical significance lies in its role in allergic reactions and inflammation, potentially contributing to tissue damage and immune responses.
52
What is the role of eosinophils in the production of lipid mediators and their clinical significance?
- Eosinophils store **arachidonic acids** in lipid bodies and produce several metabolites through the 5-lipoxygenase and cyclooxygenase pathways.
- Key products include cysteinyl leukotrienes (LTC4, LTD4, LTE4) and thromboxanes.
- These lipid mediators are involved in inflammatory responses and can contribute to conditions such as asthma and allergic reactions.
- The clinical significance lies in their potential to exacerbate inflammation and tissue damage in eosinophilic disorders.
53
Discuss the role of cytokines produced by eosinophils in modulating immune responses and their implications in chronic inflammation.
- Eosinophils produce various **cytokines** and **chemokines** that regulate immune responses, including TNF-α, IL-1, IL-4, IL-5, and IL-6.
- These cytokines can modulate the activity of other immune cells, contributing to chronic inflammation in conditions like asthma and atopic dermatitis.
- Eosinophils also produce growth factors that induce stromal fibrosis and thickening of the basement membrane, further complicating chronic inflammatory processes.
- The implications include potential targets for therapeutic intervention in eosinophilic diseases.
54
What are the main groups of receptors found on eosinophils related to surface expression?
Eosinophil surface receptors can be grouped into the following categories:
1. **Chemotactic factor and complement receptors**
2. **Immunoglobulin supergene family member receptors**
3. **Cytokine receptors**
4. **Adhesion molecule receptors**
5. **Receptors involved in apoptosis**
6. **Miscellaneous receptors and surface factors**
These receptors play critical roles in eosinophil function and trafficking.
55
What role do chemotactic factors play in eosinophil function?
Chemotactic factors are crucial for orchestrating cellular trafficking to sites of inflammation and for physiological homing of eosinophils, such as to the gastrointestinal tract. They mediate various biological effects including:
- Cell shape change and migration
- Cell activation
- Receptor internalization
- Induction of respiratory burst with toxic oxygen metabolites
- Transient activation of integrin adhesiveness
Eosinophils have receptors for several chemotactic agents, which are important for their effector functions.
56
What is the significance of the CCR3 receptor in eosinophil-associated diseases?
The CCR3 receptor and its ligands are significant in eosinophil-associated diseases as they are critical for the cellular trafficking of eosinophils. The identification of CCR3 and its ligands has been a breakthrough in discovering eosinophil-selective chemotaxins, which are important for the recruitment of eosinophils to tissue sites during inflammation.
57
How do immunoglobulin receptors on eosinophils contribute to their function?
Among eosinophil surface receptors, the most highly expressed is **FcγRII (CD32)**, which binds aggregated IgG, particularly subclasses IgG1 and IgG3. The binding of IgG to this receptor is important for eosinophil degranulation in parasitic and allergic diseases. Eosinophils can also express other IgG receptors upon stimulation by cytokines, enhancing their functional capabilities.
58
What types of receptors are involved in eosinophil adhesion and migration?
Eosinophils express various adhesion molecule receptors that facilitate their trafficking and interactions within tissues. These include:
1. **Selectins** (e.g., L-selectin (CD62L) and P-selectin glycoprotein ligand-1 (PSGL-1, CD162))
2. **Integrins** (e.g., β1, β2, and β7 integrins)
These receptors are essential for eosinophil migration into tissues and their adhesion to extracellular matrix proteins and activated endothelium.
59
What role do chemotactic factors play in eosinophil function and how do they affect cellular trafficking?
Chemotactic factors orchestrate cellular trafficking to sites of inflammation and physiological homing, such as eosinophils migrating to the gastrointestinal tract. They mediate various biological effects including cell shape change, migration, cell activation, receptor internalization, and the induction of the respiratory burst with toxic oxygen metabolites.
60
How do eosinophils utilize immunoglobulin receptors in the context of allergic diseases?
Eosinophils express FcγRII (CD32), which binds aggregated IgG, particularly subclasses IgG1 and IgG3. This binding is crucial for eosinophil degranulation in parasitic and allergic diseases. Eosinophils can also be stimulated by cytokines to express additional IgG receptors, enhancing their functional response.
61
What is the significance of the CCR3 receptor in eosinophil trafficking and how does it relate to eosinophil-associated diseases?
The CCR3 receptor and its ligands are critical for the homeostatic and inflammation-induced recruitment of eosinophils to tissue sites. Its identification has been pivotal in understanding eosinophil-selective chemotaxis, especially in diseases characterized by tissue eosinophil infiltration with minimal neutrophil presence.
62
Describe the types of receptors expressed on eosinophils and their functional implications in cytokine signaling.
Eosinophils express low levels of cytokine receptors, including IL-3 (CD123), IL-5 (CD125), and GM-CSF (CD116), which share a common β chain (CD132). Activation of eosinophils can occur through various cytokines, indicating that these receptors may have autocrine functions, influencing eosinophil behavior in immune responses.
63
What are the different groups of adhesion molecule receptors on eosinophils and their roles in tissue migration?
Adhesion molecule receptors on eosinophils are categorized into three groups: (a) Ig superfamily, (b) selectins and their glycoprotein counterligands, and (c) integrins. These receptors facilitate eosinophil trafficking to and within tissues, with P-selectin and PSGL-1 being crucial for eosinophil migration into tissues.
64
What role do eosinophils play in apoptosis and what receptors are involved?
Eosinophils express several **death receptors** (e.g., Fas receptor (CD95), Siglec-8, CD30, CD45, Campath (CD52), and CD69) that are involved in apoptotic pathways. Delayed or defective apoptotic pathways can lead to the accumulation and persistence of eosinophils in blood and/or tissues, contributing to diseases characterized by eosinophilia.
65
How do eosinophils contribute to tissue trafficking during inflammation?
Eosinophils are selectively recruited to sites of inflammation through interactions with eosinophil-activating cytokines, chemokine-inducing cytokines, and endothelial-activating cytokines. They express the integrin **VLA-4**, which interacts with **VCAM-1** on endothelial cells, facilitating their movement and adhesion to extracellular matrix proteins, which prolongs their survival.
66
What are the effects of eosinophil-activating cytokines on eosinophils?
Eosinophil-activating cytokines, such as **IL-3**, **IL-5**, and **GM-CSF**, enhance chemotactic responses, promote maturation, support cell survival, and stimulate the production of leukotrienes (LT) in eosinophils. These cytokines are produced by T cells, mast cells, keratinocytes, endothelial cells, and eosinophils themselves.
67
What types of endothelial activation occur during eosinophil migration?
During eosinophil migration, three types of endothelial activation occur:
1. **Expression of P-selectin**: Initiated by Weibel-Palade bodies in endothelial cells after exposure to inflammatory mediators, facilitating leukocyte rolling.
2. **Induced by nonspecific activators**: Such as **IL-1** and **TNF-α**, stimulating expression of **E-selectin**, **ICAM-1**, and **VCAM-1** for eosinophil adhesion.
3. **Induced by IL-4 and IL-13**: These cytokines selectively induce **VCAM-1**, crucial for recruiting VLA-4-positive cells into sites of allergic inflammation.
68
What is the role of eosinophils in tissue remodeling during inflammation?
Eosinophils release TGF-β, FGF-2, and other factors that induce fibroblast proliferation and extracellular matrix production, contributing to tissue remodeling and fibrosis.
69
How do eosinophils interact with vascular endothelial cells during migration?
Eosinophils adhere to endothelial cells via integrins like VLA-4 and CD11b/CD18, which bind to VCAM-1 and ICAM-1, facilitating migration into tissues.
70
How do eosinophils contribute to fibrosis in hypereosinophilic syndrome?
Eosinophils release TGF-β and other factors that induce fibroblast proliferation and extracellular matrix production, leading to fibrosis in organs like the lungs and heart.
71
How do eosinophils contribute to nerve dysfunction in asthma?
Eosinophil granule proteins like MBP disrupt vagal muscarinic M2 receptors, contributing to nerve dysfunction in asthma.
72
How do eosinophils influence vascular endothelial growth during inflammation?
Eosinophils release vascular endothelial growth factor (VEGF), promoting angiogenesis and vascular remodeling during inflammation.
73
What role do eosinophil-activating cytokines play in the survival and function of eosinophils during inflammation?
Eosinophil-activating cytokines, such as IL-3, IL-5, and GM-CSF, enhance chemotactic responses, promote maturation, support cell survival, and facilitate the production of leukotrienes (LT) in eosinophils.
74
What is the significance of the integrin VLA-4 in eosinophil trafficking during inflammation?
VLA-4 is constitutively expressed on eosinophils and interacts with its ligand VCAM-1, which is induced on endothelial cells by Th2 cytokines (IL-4 and IL-13). This interaction is critical for the selective recruitment of eosinophils to sites of inflammation.
75
Describe the process of endothelial activation during eosinophil migration.
Endothelial activation involves: 1. P-selectin expression for leukocyte rolling. 2. Nonspecific activators like IL-1 and TNF-α stimulate E-selectin, ICAM-1, and VCAM-1 expression. 3. IL-4 and IL-13 induce VCAM-1 for recruiting VLA-4-positive cells.
76
What factors contribute to the persistence of eosinophils in tissues during eosinophilia?
Eosinophils may persist due to delayed or defective apoptotic pathways and the production of survival cytokines like IL-3, IL-5, and GM-CSF.
77
What role do CCR3 ligands play in eosinophil adherence during the inflammatory response?
CCR3 ligands significantly increase the transition from rolling to firm adherence of eosinophils to endothelial cells.
78
How do Th2 cytokines influence chemokine expression in eosinophil recruitment?
Th2 cytokines, such as IL-4 and IL-13, induce the expression of chemokines like CCL11, CCL24, and CCL26, crucial for guiding eosinophils into tissues.
79
What mechanisms do eosinophils use to release their granule contents into tissues?
Eosinophils release granule contents through piecemeal degranulation, regulated secretion, and cytolytic degranulation.
80
What are the effects of glucocorticoids on eosinophil numbers and function?
Glucocorticoids reduce eosinophil numbers and inhibit eosinophilic inflammation through sequestration, induction of apoptosis, and suppression of cytokine production.
81
What is the significance of hypodense eosinophils in allergic disease severity?
The number of hypodense eosinophils, characterized by reduced granules, is predictive of allergic disease severity.
82
What is the role of IL-33 in eosinophil activation?
IL-33 promotes eosinophil activation by inducing surface expression of CD11b and ICAM-1 and stimulating proinflammatory cytokine production.
83
How do eosinophils contribute to allergic inflammation?
Eosinophils amplify allergic inflammation by releasing cytokines like IL-4 and IL-13, which induce chemokine production and recruit more eosinophils.
84
What is the significance of CCR3 in eosinophil chemotaxis?
CCR3 is a receptor for chemokines like CCL11 and CCL24, guiding eosinophils to tissues during inflammation.
85
How do calcineurin inhibitors affect eosinophilic inflammation?
Calcineurin inhibitors like cyclosporine inhibit T-cell cytokine release, reducing eosinophilic inflammation.
86
What is the role of eosinophils in allergic skin diseases like atopic dermatitis?
Eosinophils release cytokines and chemokines like IL-4 and CCL26, correlating with disease activity in atopic dermatitis.
87
What is the role of eosinophils in eosinophilic esophagitis?
Eosinophils release CCL26 and other mediators that contribute to tissue inflammation and correlate with disease severity.
88
What is the role of eosinophils in the development of steroid resistance in asthma?
Eosinophils contribute to steroid resistance by releasing cytokines that alter the inflammatory environment.
89
What are the pharmacologic strategies to manipulate eosinophil activity in allergic diseases?
Pharmacologic strategies include glucocorticoids, calcineurin inhibitors, and other agents that reduce eosinophil numbers and inhibit inflammation.
90
What are the effects of mTOR inhibitors like rapamycin on eosinophils?
mTOR inhibitors decrease eosinophil granule protein release after IL-5 activation, but their use is limited by side effects.
91
Which myelosuppressive drug has been particularly effective in decreasing circulating eosinophil numbers?
Hydroxyurea has been particularly effective in decreasing circulating eosinophil numbers.
92
What is the role of imatinib mesylate in treating myeloproliferative hypereosinophilic syndrome?
Imatinib mesylate is a tyrosine kinase inhibitor approved for treating chronic myelogenous leukemia and hypereosinophilic syndrome.
93
How does alemtuzumab function in the treatment of eosinophil-related conditions?
Alemtuzumab is a monoclonal antibody to CD52 used to deplete CD52+ lymphocytes in chronic lymphocytic leukemia and T-cell lymphoma.
94
What is the significance of mepolizumab in eosinophil management?
Mepolizumab is the first humanized monoclonal antibody against IL-5, effective in inhibiting eosinophilia and reducing asthma exacerbation rates.
95
What distinguishes benralizumab from other eosinophil-targeting therapies?
Benralizumab is an anti-IL-5 receptor α humanized monoclonal antibody that reduces eosinophilia in a dose-dependent manner.
96
What are the therapeutic benefits of IFN-α and IFN-β in eosinophil-associated diseases?
Both may inhibit eosinophil degranulation and inflammatory mediator release, with IFN-α being better tolerated.
97
What is the mechanism of action of mepolizumab in treating eosinophilic diseases?
Mepolizumab is a monoclonal antibody against IL-5, inhibiting eosinophilia and reducing asthma exacerbation rates.
98
How does benralizumab differ from mepolizumab in targeting eosinophils?
Benralizumab targets the IL-5 receptor α, leading to more effective eosinophil reduction.
99
What is the mechanism of action of imatinib in hypereosinophilic syndrome?
Imatinib inhibits the FIP1L1-PDGFRA tyrosine kinase, reducing eosinophil proliferation and activity.
100
What are the potential side effects of using mTOR inhibitors like rapamycin in eosinophil-related treatments?
The use of mTOR inhibitors is limited by side effects including immunosuppression and other metabolic effects.
101
How does hydroxyurea function in the treatment of eosinophil-associated diseases?
Hydroxyurea is effective in decreasing circulating eosinophil numbers and may be used as a steroid-sparing agent.
102
What are the therapeutic implications of alemtuzumab in eosinophil-associated diseases?
Alemtuzumab depletes CD52+ lymphocytes and has been useful in treating refractory hypereosinophilic syndrome.
103
What are the key transcription factors involved in the differentiation of eosinophils from undifferentiated hematopoietic cells?
The key transcription factors involved are GATA-1, FOG-1, and PU.1.
104
What cytokines are crucial for the differentiation and survival of eosinophils?
The crucial cytokines for eosinophil differentiation and survival include IL-3, GM-CSF, and IL-5.
105
Describe the process of eosinophil transmigration through blood vessels to the skin.
The process involves rolling, adhesion, and migration through the endothelial barrier.
106
Describe the process of eosinophil transmigration through blood vessels to the skin.
The process of eosinophil transmigration involves:
1. Rolling: Interaction with selectins (L-selectin, P-selectin).
2. Adhesion: Binding to integrins (e.g., VLA-4) and ICAM-1.
3. Diapedesis: Movement through the endothelial layer into the tissue.
107
What are the main products of eosinophils and their localization in distinctive granule proteins?
The main products of eosinophils include:
| Category | Products |
|------------------------------|---------------------------------------------------------------------------------------------|
| Reactive Oxygen Intermediates | O2, H2O2, Hydroxyl radicals, Singlet oxygen |
| Enzymes | Eosinophil peroxidase (EPO), Major basic protein (MBP), Eosinophil-derived neurotoxin (EDN) |
| Lipid Mediators | Leukotriene C4, Exotoxin E4, Prostaglandin E2, Thromboxane B2 |
| Cytokines | GM-CSF, IL-1, IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, TGF-β, CCL3, CCL5, CCL11, CCL24 |
| Surface Receptors | CCR3, CD4, LTB4, PAF, CD8, CD11, CD18, VCAM-1, ICAM-1, CD25, CD26, CD69, CD80, CD86 |
108
What are the key transcription factors involved in the differentiation of eosinophils from undifferentiated hematopoietic cells in the bone marrow?
The key transcription factors involved are GATA-1, FOG-1, and PU.1.
109
Describe the process of eosinophil transmigration through blood vessels into tissue.
The process of eosinophil transmigration involves:
1. Rolling: Mediated by L-selectin and its ligands.
2. Teething: Interaction with E-selectin and ICAM-1.
3. Flattening: Eosinophils flatten against the endothelium.
4. Diapedesis: Eosinophils migrate through the endothelial barrier into the tissue.
110
What are the main products of eosinophils and their localization in distinctive granule proteins?
The main products of eosinophils include:
| Category | Products |
|------------------------------|-------------------------------------------------------------------------|
| Reactive Oxygen Intermediates | O2, H2O2, Hydroxyl radicals, Singlet oxygen |
| Enzymes | Eosinophil peroxidase (EPO), Major basic protein (MBP), Cathepsin G, etc. |
| Lipid Mediators | Leukotriene C4, Exotoxin E4, Prostaglandin E2, etc. |
| Cytokines | GM-CSF, IL-3, IL-5, IL-13, etc. |
| Surface Receptors | CCR3, CD4, LTB4, PAF, etc. |
111
What are the two major subtypes of Hypereosinophilic Syndromes (HES)?
The two major subtypes of HES are Lymphocytic HES and Myeloproliferative HES.
112
What characterizes Lymphocytic HES?
Lymphocytic HES is characterized by T-cell clones that produce IL-5.
113
What characterizes Myeloproliferative HES?
Myeloproliferative HES is associated with a deletion on chromosome 4 that produces a tyrosine kinase fusion gene.
114
What are the clinical implications of Myeloproliferative HES and Lymphocytic HES in terms of gender distribution?
Myeloproliferative HES has a gender distribution of >90% males, while Lymphocytic HES has an equal gender distribution.
115
What are the revised diagnostic criteria for Hypereosinophilic Syndromes?
The revised diagnostic criteria include blood eosinophils >1500 eosinophils/mm³ on at least 2 separate determinations or evidence of prominent tissue eosinophilia associated with symptoms and marked blood eosinophilia, and exclusion of secondary causes of eosinophilia.
116
What are the common clinical features of Hypereosinophilic Syndromes (HES)?
Common clinical features include pruritic erythematous macules, papules, plaques, wheals, or nodules in more than 50% of patients, urticaria and angioedema in all HES subtypes.
117
What complications are associated with Hypereosinophilic Syndromes (HES)?
Complications of HES can affect multiple systems: hematologic, pulmonary, cardiovascular, and neurologic.
118
What are the symptoms of Myeloproliferative HES?
Symptoms include fever, weight loss, fatigue, malaise, skin lesions, hepatosplenomegaly, mucosal ulcers, and cardiac disease.
119
What is the significance of eosinophils in Hypereosinophilic Syndromes (HES)?
Eosinophils cause most end-organ damage in all HES subtypes, and clinical improvement parallels a decrease in eosinophil count.
120
What are the characteristics of Lymphocytic HES?
Lymphocytic HES is characterized by severe pruritus, erythroderma, urticaria, angioedema, lymphadenopathy, and rare endomyocardial fibrosis.
121
What diagnostic methods are used for Lymphocytic HES?
Diagnostic methods include cytoflow of peripheral blood lymphocytes and immunophenotyping of tissue lymphocytes.
122
What is the likely diagnosis for a patient with pruritic erythematous plaques and elevated eosinophil counts?
The likely diagnosis is lymphocytic HES, associated with IL-5 secreted by abnormal T-cell clones.
123
What is the pathophysiological mechanism behind restrictive cardiomyopathy in Myeloproliferative HES?
Eosinophils adhere to the endocardium, releasing granule proteins onto endothelial cells, leading to thrombus formation and subendocardial fibrosis.
124
What cytokine is primarily involved in lymphocytic HES?
The primary cytokine involved is IL-5, secreted by abnormal T-cell clones.
125
What diagnostic tests should be performed to confirm lymphocytic HES?
Diagnostic tests include cytoflow of peripheral blood lymphocytes and immunophenotyping of tissue lymphocytes.
126
What genetic mutation is likely present in a patient with myeloproliferative HES?
The likely genetic mutation is FIP1L1-PDGFRA, and the treatment of choice is imatinib mesylate.
127
What is the hallmark clinical feature of Gleich syndrome?
The hallmark clinical feature is extreme angioedema associated with eosinophilia.
128
What cytokine is responsible for elevated serum IgE levels in lymphocytic HES?
The cytokine primarily responsible is IL-5.
129
What is the potential progression of Myeloproliferative HES with chromosomal abnormalities?
The potential progression includes transformation into aggressive myeloid malignancies.
130
What are the key characteristics of Myeloproliferative HES?
Key characteristics include increased levels of vitamin B12 and tryptase, and the presence of the FIP1L1-PDGFRA gene product.
131
What are the histopathologic features of cutaneous lesions in Myeloproliferative HES?
The cutaneous histopathologic features include urticarial lesions characterized by mild, nonspecific perivascular and interstitial infiltration of lymphocytes, eosinophils, and occasionally neutrophils.
132
What immunostaining findings are associated with Myeloproliferative HES?
Immunostaining shows extensive deposition of eosinophil granule proteins and absence of intact eosinophils.
133
What are the differential diagnoses for Hypereosinophilic Syndrome (HES)?
Differential diagnoses include parasitic infection, ectopic infection, urticaria, hereditary angioedema, drug reaction, and others.
134
What clinical features are associated with hereditary angioedema in the context of HES?
Hereditary angioedema is characterized by family history, episodic angioedema, and markedly elevated eosinophil counts.
135
What diagnostic tests should be performed for a patient with eosinophilia and travel history to endemic areas?
Diagnostic tests should include examination of stool samples for ova and parasites and serologic testing for Strongyloides antibodies.
136
What additional test can confirm the diagnosis of Myeloproliferative HES?
The Chic2 fluorescent in situ hybridization assay or polymerase chain reaction assay can confirm the diagnosis.
137
How is HES distinguished from hereditary angioedema?
HES is distinguished by the absence of complement abnormalities and the presence of markedly elevated eosinophil counts.
138
What are the common clinical features of pruritic eczematous lesions in lymphocytic HES?
Common clinical features resemble atopic dermatitis, contact dermatitis, drug reactions, and fungal infections.
139
What is the overall 5-year survival rate for patients with hypereosinophilic syndromes (HES)?
The overall 5-year survival rate for patients with hypereosinophilic syndromes (HES) is 80%.
140
What are the common clinical features of pruritic eczematous lesions in lymphocytic HES?
Common clinical features resemble:
- Atopic dermatitis
- Contact dermatitis
- Drug reactions
- Fungal infections
- T-cell lymphoma
141
What are the major causes of death in patients with hypereosinophilic syndromes (HES)?
The major causes of death are:
1. Congestive heart failure from the restrictive cardiomyopathy of eosinophilic endomyocardial disease.
2. Sepsis.
142
What is the goal of treatment for hypereosinophilic syndromes (HES)?
The goals of treatment are to:
- Relieve symptoms
- Improve organ function
- Keep peripheral blood eosinophils at 1000 to 2000/mm³
- Minimize treatment side effects
143
What is the first-line therapy for patients with lymphocytic hypereosinophilic syndrome (HES) without gene mutation?
The first-line therapy is corticosteroids. Patients with elevated thymus and activation-regulated chemokine (TARC) may show a favorable response.
144
What treatment options are available for refractory hypereosinophilic syndromes (HES)?
Treatment options include:
- Infliximab (anti-TNF-α)
- Alemtuzumab (anti-CD52)
- Bone marrow and peripheral blood stem cell allogeneic transplantation
145
What are the potential improvements seen with imatinib therapy in myeloproliferative hypereosinophilic syndrome (HES)?
Imatinib therapy can lead to improvements in:
- Cardiac involvement with endocarditis
- Myelofibrosis
- Skin disease with bullous pemphigoid
146
What are the two monoclonal antibodies used in the treatment of lymphocytic hypereosinophilic syndrome (HES)?
The two monoclonal antibodies are:
- Mepolizumab
- Reslizumab
147
What is the most appropriate first-line treatment for a patient with FIP1L1-PDGFRA gene mutation?
The most appropriate first-line treatment is imatinib mesylate. Troponin levels should be monitored before and during therapy.
148
What is the primary treatment approach for eosinophilic granulomatosis with polyangiitis?
The primary treatment approach involves systemic glucocorticoids and immunosuppressive agents.
149
What complication should be closely monitored during the initial days of imatinib treatment?
Endomyocardial disease may worsen, so close monitoring is required.
150
What is the long-term risk for a patient with stable T-cell clones in lymphocytic HES?
The long-term risk is evolution into lymphoma, especially in CD3-CD4+ T-cell populations.
151
What is the underlying cause of peripheral neuropathy in eosinophilic granulomatosis with polyangiitis?
The underlying cause is vasculitis involving small to medium-sized blood vessels.
152
What are the two main forms of Hypereosinophilic Syndrome (HES) based on FIP1L1-PDGFRA gene mutation status?
The two main forms are:
1. Myeloproliferative forms (Positive for FIP1L1-PDGFRA gene mutation)
2. Lymphocytic forms (Negative for FIP1L1-PDGFRA gene mutation)
153
What are the treatment options for patients with myeloproliferative HES who are positive for the FIP1L1-PDGFRA gene mutation?
Treatment options include:
1. Imatinib alone (100-400 mg/day) or with glucocorticoids if cardiac involvement is present.
2. Other tyrosine kinase inhibitors.
3. Systemic glucocorticoids (0.5-1 mg/kg/day).
4. Interferon-α.
154
What is the clinical significance of monitoring T-cell clone development in undefined or overlap forms of HES?
Monitoring for T-cell clone development is crucial as it can indicate progression to a more severe form of the disease.
155
What are the characteristics of the lymphocytic forms of Hypereosinophilic Syndrome (HES)?
The lymphocytic forms are characterized by:
- Undefined: Benign, no organ involvement.
- Overlap: Associated with other organ-restricted eosinophilic disorders.
156
What is the recommended approach for treating lymphocytic forms of hypereosinophilic syndrome (HES) associated with other organ-restricted eosinophilic disorders?
The recommended approach includes:
- Monitoring for T-cell clone development.
- Systemic glucocorticoids (0.5-1 mg/kg/day).
- Consideration of imatinib therapy.
157
What are the common clinical features of Wells syndrome?
Common clinical features include:
- Cutaneous edema
- Prodromal symptoms of burning or itching
- Lesions with erythema and edema, evolving into large edematous plaques with violaceous borders.
158
What is the etiology and pathogenesis of Wells syndrome?
The etiology is unclear and considered a nonspecific hypersensitivity reaction to stimuli, with common triggers being insect bites, infections, drugs, and vaccines.
159
How is Wells syndrome diagnosed?
Diagnosis is characterized by peripheral blood eosinophilia and histopathological examination showing diffuse dermal infiltration with eosinophils and flame figures.
160
What are the differential diagnoses associated with Wells syndrome?
Differential diagnoses include:
- Arthropod bite
- Eosinophilic fasciitis
- Drug reaction
- Eosinophilic granulomatosis with polyangiitis
161
What histological hallmark is associated with Wells syndrome?
The histological hallmark is the presence of flame figures, which are areas of amorphous and granular material associated with connective tissue fibers.
162
What is the most frequent systemic complaint associated with Wells syndrome?
The most frequent systemic complaint is malaise.
163
What is the typical appearance of Wells syndrome lesions over time?
Lesions typically evolve from bright red to brown-red to blue-gray or greenish-gray, resembling morphea.
164
What are the common clinical features of Angiolymphoid Hyperplasia with Eosinophilia (ALHE)?
ALHE lesions tend to be smaller, superficial, and more numerous than those of Kimura Disease (KD). Symptoms may include pruritus.
165
What are the early clinical features of Angiolymphoid Hyperplasia with Eosinophilia (ALHE)?
Lesions with erythema and edema, may include blisters.
166
What are the late clinical features of Angiolymphoid Hyperplasia with Eosinophilia (ALHE)?
Lesions resembling morphea, with possible pigmentation changes.
167
What are the common clinical features of Angiolymphoid Hyperplasia with Eosinophilia (ALHE)?
- ALHE lesions tend to be smaller, superficial, and more numerous than those of Kimura Disease (KD).
- Symptoms may include pruritus, pain, and pulsation.
- Lesions are typically located on the head and neck region.
- Peripheral blood eosinophilia is present in both diseases, but increased IgE levels are found only in KD.
168
What is the management approach for Angiolymphoid Hyperplasia with Eosinophilia?
1. **Initial treatment**: Systemic glucocorticoids, tapering the dose over 1 month.
2. **For recurrences or persistent cases**: Maintain with low-dose (5 mg) alternate-day prednisone.
3. **If treatment fails or relapses**: Consider other options such as:
- Minocycline
- Dapsone
- Griseofulvin
- Antihistamines
- Cyclosporine
- IFN-α
4. **For mild disease**: Use topical glucocorticoids.
169
How do Angiolymphoid Hyperplasia with Eosinophilia and Kimura Disease differ in terms of symptoms and demographics?
| Feature | Angiolymphoid Hyperplasia with Eosinophilia (ALHE) | Kimura Disease (KD) |
|---------|--------------------------------------------------|--------------------|
| Gender | Typically middle-aged females | Predominantly young adult Asian males |
| Symptoms| Pruritus, pain, pulsation | Asymptomatic |
| Lesion Type | Small and superficial, with overlying erythema | Large, mainly subcutaneous, may involve regional lymph nodes and salivary glands |
| Fibrosis | Absent or limited | Prominent |
170
What alternative treatments can be considered for a patient with Wells syndrome who has recurrent lesions despite systemic glucocorticoid therapy?
Alternative treatments include minocycline, dapsone, griseofulvin, antihistamines, cyclosporine, and IFN-α.
171
What histological feature distinguishes Angiolymphoid Hyperplasia with Eosinophilia?
Histological features include blood vessels with prominent 'hobnail' endothelial cells that protrude into the vascular lumina.
172
What is the typical clinical course of Wells syndrome?
The typical clinical course involves resolution without scarring within weeks to months, although multiple recurrences are common.
173
What is the next step in management for a patient with Wells syndrome whose lesions fail to respond to systemic glucocorticoids?
The next step in management includes alternative treatments such as minocycline, dapsone, or cyclosporine.
174
What are the common clinical features and management strategies for Angiolymphoid Hyperplasia with Eosinophilia (ALHE)?
- **Clinical Features**:
- Lesions are small, superficial, and often located on the head and neck.
- Symptoms may include pruritus, pain, and pulsation.
- Multiple recurrences are common.
- **Management Strategies**:
1. **Initial Treatment**: Systemic glucocorticoids with tapering over 1 month.
2. **Maintenance**: Low-dose (5 mg) alternate-day prednisone.
3. **If Relapse Occurs**: Consider minocycline, dapsone, griseofulvin, antihistamines, cyclosporine, or IFN-α.
4. **For Mild Disease**: Topical glucocorticoids may be used.
175
How do the clinical features of Angiolymphoid Hyperplasia with Eosinophilia (ALHE) compare to those of Kimura Disease (KD)?
| Feature | Angiolymphoid Hyperplasia with Eosinophilia (ALHE) | Kimura Disease (KD) |
|---------|--------------------------------------------------|---------------------|
| Gender | Typically middle-aged females | Predominantly young adult Asian males |
| Symptoms | Pruritus, pain, pulsation; lesions are small and superficial | Generally asymptomatic; large lesions primarily in the head and neck |
| Lesion Type | Small, superficial lesions with overlying erythema | Large, subcutaneous lesions; may involve lymph nodes and salivary glands |
| Lymphoid Follicles | Uncommon | Prominent with germinal centers |
| Vascular Proliferation | Prominent with large epithelioid/histiocytoid endothelial cells | Some stromal vascularity with unremarkable endothelial cells |
| Fibrosis | Absent or limited | Prominent |
| Serum Immunoglobulin | Normal | Increased |
| Nephropathy | Absent | Present in up to 20% of patients |
176
What are the clinical features of Granuloma Faciale?
- Solitary papules, plaques, or nodules
- Asymptomatic red, brown, or violaceous plaques that are soft, smooth, and well circumscribed, often showing follicular accentuation and telangiectasia
- 'Peau d’orange' appearance: prominent follicular openings
- Affects the face: nose, preauricular area, cheeks, forehead, eyelids, ears
- Extrafacial lesions are rare; may occur on trunk or extremities
- May have tenderness, burning, or pruritus
- Photoexacerbation reported
- Rarely associated with systemic disease
177
What is the etiology and pathogenesis of Granuloma Faciale?
- Etiology: Unknown
- Localized chronic fibrosing vasculitis
- Immunofluorescence shows deposition of immunoglobulins and complement factors in the vessel walls (superficial and deep blood vessels)
- Type III immunologic response
- Other tests show negative results with immunofluorescence
178
What is the significance of the histologic examination in diagnosing Papulerythroderma of Ofuji?
- Histologic examination reveals:
- Epidermis: normal-appearing, may be separated from the underlying inflammatory infiltrate by a narrow grenz zone
- Dermis: dense and diffuse infiltrate of lymphocytes, plasma cells, eosinophils, and neutrophils
- Leukocytoclasis
- Inflammatory infiltrate surrounds blood vessels, showing evidence of fibrin deposition
- In later stages, perivascular fibrin deposition becomes extensive and dominates the histologic picture
- Deposition of hemosiderin (brown color)
179
What are the characteristics of Eosinophilic Pustular Folliculitis?
- Three clinical types characterized by follicular papules and pustules, potentially involving the head, trunk, and extremities.
- Classic type occurs in Japanese patients with chronic, recurrent follicular pustules, often forming circinate plaques in a seborrheic distribution.
- Associated with immunosuppression and peripheral blood eosinophilia.
- Tendency for recurrences and chronicity, except in cases of eosinophilic pustular folliculitis of infancy.
180
What is the diagnosis and distinguishing histological feature for a patient with solitary violaceous plaques on the face showing a 'peau d’orange' appearance?
The diagnosis is granuloma faciale. A distinguishing histological feature is the presence of a grenz zone of normal collagen beneath the epidermis.
181
What is the most likely histological finding in a patient with eosinophilic pustular folliculitis presenting with pruritic papules on the face?
The most likely histological finding is an eosinophilic infiltrate around hair follicles.
182
What is the recommended diagnostic procedure for a patient with granuloma faciale who has a dense dermal infiltrate of eosinophils and neutrophils?
The recommended diagnostic procedure is a punch biopsy that includes the full thickness of the dermis.
183
What is the most likely etiology of eosinophilic pustular folliculitis in a patient with pruritic papules on the trunk?
The most likely etiology is an eosinophilic infiltrate around hair follicles.
184
What are the clinical features of Granuloma Faciale and how do they differ from Eosinophilic Pustular Folliculitis?
Granuloma Faciale presents with:
- Solitary papules, plaques, or nodules
- Asymptomatic red, brown, or violaceous plaques that are soft, smooth, and well circumscribed, often showing follicular accentuation and telangiectasia
- 'Peau d’orange' appearance with prominent follicular openings
- Commonly affects the face (nose, preauricular area, cheeks, forehead, eyelids, ears)
- Rarely associated with systemic disease
In contrast, Eosinophilic Pustular Folliculitis typically involves:
- Follicular papules and pustules, often in a seborrheic distribution
- Tendency for recurrences and chronicity, especially in immunocompromised patients.
185
Discuss the etiology and pathogenesis of Granuloma Faciale and its clinical implications.
The etiology of Granuloma Faciale is unknown, but it is characterized by:
- Localized chronic fibrosing vasculitis
- Immunofluorescence shows deposition of immunoglobulins and complement factors in the vessel walls (both superficial and deep blood vessels)
- Type III immunologic response is noted, with negative results in others.
Clinical implications include the need for biopsy to confirm diagnosis and the potential for misdiagnosis due to its asymptomatic nature and resemblance to other skin conditions.
186
What is the significance of the histologic examination findings in Papulerythroderma of Ofuji?
Histologic examination in Papulerythroderma of Ofuji reveals:
- Normal-appearing epidermis, which may be separated from the underlying inflammatory infiltrate by a narrow grenz zone.
- Dense and diffuse infiltrate of lymphocytes, plasma cells, eosinophils, and neutrophils in the dermis, indicating leukocytoclasis.
- Inflammatory infiltrate surrounding blood vessels shows evidence of fibrin deposition, which becomes extensive in later stages, dominating the histologic picture.
- Deposition of hemosiderin, which gives a brown color, is also noted.
These findings are crucial for diagnosis and understanding the disease's progression.
187
What are the key histological findings in Granuloma Faciale as observed through electron microscopy and DIF?
- **Electron microscopy**: Extensive eosinophilic infiltrate with Charcot–Leyden crystals and numerous histiocytes filled with lysosomal vesicles.
- **DIF**: Immunoglobulins, fibrin, and complement deposited along the dermal–epidermal junction in a granular pattern and around blood vessels.
188
What is the clinical course and management of Granuloma Faciale?
- **Clinical course**: Chronic condition that rarely resolves spontaneously, may last weeks or months, resistant to treatment, and has a tendency to relapse after treatment.
- **Management options** include:
- **Topical treatments**: Corticosteroids, tacrolimus ointment.
- **Physical treatments**: Cryotherapy, intralesional steroids, pulsed-dye laser.
- **Systemic treatments**: Dapsone (50-100 mg/day).
189
What are the characteristic clinical features of Eosinophilic Fasciitis?
- **Symptoms**: Pain, erythema, edema, and induration of the extremities.
- **Laboratory findings**: Peripheral blood eosinophilia and hypergammaglobulinemia.
- **Physical findings**: Contractures and rippling of the skin, and the **Groove sign**, which is a depression along the course of the superficial veins that is more marked upon elevation of the affected limb.
190
What are the clinical features and implications of Eosinophilia-Myalgia Syndrome?
- **Etiology**: Ingestion of L-tryptophan.
- **Symptoms**: Marked peripheral eosinophilia, disabling generalized myalgias, pneumonitis, myocarditis, neuropathy, encephalopathy, and fibrosis.
- **Cutaneous abnormalities**: Edema, pruritus, faint erythematous rash, hair loss, and peau d’orange or morphea-like skin lesions.
- **Histological findings**: Prominent inflammatory infiltrate in the perimysium and fascia, with eosinophil granule protein deposition in skin and around muscle bundles.
191
What is the characteristic physical finding in a patient with eosinophilic fasciitis presenting with pain, erythema, and induration of the extremities?
The characteristic physical finding is the groove sign, which is a depression along the course of superficial veins that becomes more marked upon elevation of the affected limb. It indicates thickening of the fascia.
192
What is the underlying histological finding in a patient with eosinophilic fasciitis who has rippling of the skin?
The underlying histological finding is infiltration of lymphocytes, plasma cells, mast cells, and eosinophils, with increased thickness of the fascia.
193
What is the primary treatment option for a patient with granuloma faciale who has recurrent lesions on the face?
The primary treatment option includes pulsed-dye lasers or topical tacrolimus ointment.
194
What is the most likely trigger for eosinophilia-myalgia syndrome in a patient with encephalopathy and fibrosis?
The most likely trigger is the ingestion of L-tryptophan.
195
What is the likely cause of eosinophilia-myalgia syndrome in a patient presenting with disabling myalgias and pneumonitis?
The likely cause of eosinophilia-myalgia syndrome is the ingestion of L-tryptophan.
196
What is the underlying histological finding in a patient with eosinophilic fasciitis who has contractures and rippling of the skin?
The underlying histological finding is infiltration of lymphocytes, plasma cells, mast cells, and eosinophils, with increased thickness of the fascia.
197
What is the characteristic physical finding associated with eosinophilic fasciitis in a patient with hypergammaglobulinemia?
The characteristic physical finding is the groove sign, a depression along the course of superficial veins.
198
What is the primary treatment approach for a patient with eosinophilic fasciitis who has a prominent inflammatory infiltrate in the fascia?
The primary treatment approach involves systemic glucocorticoids.
199
What characterizes Granuloma Faciale?
Granuloma Faciale is characterized by chronic nature and resistance to treatment.
## Footnote
Chronic nature: Rarely resolves spontaneously, often lasting weeks to months. Resistance to treatment: Patients may experience relapse after treatment.
200
What are the management options for Granuloma Faciale?
Management options include topical treatments, physical treatments, and surgical options.
## Footnote
Topical treatments: Corticosteroids, tacrolimus ointment. Physical treatments: Cryotherapy, intralesional steroids, pulsed-dye laser. Surgical options: Surgical excision may be considered.
201
What are the characteristic clinical features of Eosinophilic Fasciitis?
Eosinophilic Fasciitis is characterized by symptoms, laboratory findings, physical findings, and histological findings.
## Footnote
Symptoms: Pain, erythema, edema, and induration of the extremities. Laboratory findings: Peripheral blood eosinophilia and hypergammaglobulinemia. Physical findings: Contractures and rippling of the skin, with a characteristic 'Groove sign'. Histological findings: Infiltration of lymphocytes, plasma cells, mast cells, and eosinophils.
202
What are the clinical manifestations of Eosinophilia-Myalgia Syndrome?
Eosinophilia-Myalgia Syndrome presents with symptoms, cutaneous abnormalities, and histological findings.
## Footnote
Symptoms: Marked peripheral eosinophilia, disabling generalized myalgias, pneumonitis, myocarditis, neuropathy, encephalopathy, and fibrosis. Cutaneous abnormalities: Edema, pruritus, faint erythematous rash, hair loss, and peau d’orange or morphea-like skin lesions. Histological findings: Prominent inflammatory infiltrate in the perimysium and fascia.
203
Describe the revised criteria for hypereosinophilic syndromes.
204
What is the diagnosis?
Wells syndrome
205
Course, prognosis and management of Wells syndrome?
206
Differentiate angiolymphoid hyperplasia with eosinophilia (ALHE) and Kimura disease in terms of
1. demographic affected
2. symptoms
3. lesion type and location
4. lymphoid follicles
5. vascular proliferation
6. fibrosis
7. serum IgE level
8. nephropathy
207
- 3 clinical types characterized by follicular papules and
pustules, and may involve the head, trunk, and extremities (1. classic type with circinate plaques in a seborrheic distribution, 2. associated with HIV, 3. associated with infants/neonates)
- Tendency for recurrences and chronicity (except disease in infancy)
- Characterized by follicular and perifollicular eosinophil infiltration
- Associated with peripheral blood eosinophilia.
What is the diagnosis?
What is the course, prognosis and management of this disease?
Eosinophilic pustular folliculitis
208
What is the diagnosis?
Papuloerythroderma of Ofuji
209
- an uncommon inflammatory dermatosis characterized clinically by asymptomatic reddish-brown papules and plaques primarily involving the face.
- “peau d’orange” appearance: prominent follicular openings
- rarely associated with systemic disease
- changes of a chronic leukocytoclastic vasculitis with a mixed infiltrate containing eosinophils, extensive perivascular fibrin deposition, and dermal fibrosis.
What is the diagnosis?
What is the course, prognosis, and the 1st/2nd line topical, physical, and systemic management of this disease?
210
- Pain, erythema, edema, and induration of the extremities, peripheral blood eosinophilia, hypergammaglobulinemia
- Contractures and rippling of the skin
- Groove sign: characteristic finding of depression along the course of the superficial veins that is more marked
upon elevation of the affected limb
- infiltration of lymphocytes, plasma cells, mast cells, and eosinophils; increased thickness of the fascia
What is the diagnosis?
Eosinophilic Fasciitis / Schulman Disease
211
- Ingestion of L-tryptophan
- Marked peripheral eosinophilia, disabling generalized myalgias, pneumonitis, myocarditis, neuropathy, encephalopathy, fibrosis
- Edema, pruritus, faint erythematous rash, hair loss, and peau d’orange or morphea-like skin lesions
- Prominent inflammatory infiltrate in the perimysium and fascia; eosinophil granule protein deposition in the skin and around muscle bundles
Eosinophilia-myalgia syndrome
212
What diagnoses are most likely, to consider, and always ruled out when considering granuloma faciale?
213
What are conditions associated with flame figures and/or Wells syndrome?
