15: Epidermal and Dermal Adhesion Flashcards
What is the primary function of desmosomes in epithelial tissues?
Desmosomes, also known as Macula Adherens, serve as major cell adhesion junctions in the epidermis, providing structural integrity and mechanical strength to epithelial tissues by anchoring adjacent cells together.
What are the three major categories of desmosomal proteins?
The three major categories of desmosomal proteins are:
-
Desmosomal cadherins
- Desmogleins
- Desmocollins
-
Armadillo family proteins
- Plakoglobin
- Plakophilins
-
Plakins
- Desmoplakin
- Envoplakin
- Periplakin
How do desmosomal cadherins contribute to epithelial adhesion?
Desmosomal cadherins mediate calcium-dependent adhesion in various epithelial tissues and are crucial for maintaining the structural integrity of the epidermis. They are also known to act as autoantigens in conditions like pemphigus.
What is the significance of heterophilic interactions between desmosomal cadherins?
Heterophilic interactions between desmosomal cadherins (Dsg-Dsc) are significant as they likely form the basis of epidermal intercellular adhesion, enhancing the stability and integrity of epithelial layers.
What are the clinical implications of desmoglein 1 in skin diseases?
Desmoglein 1 is targeted in several skin diseases, including:
- Bullous Impetigo
- Staphylococcal Scalded Skin Syndrome (SSSS)
- Inherited ichthyosis in Netherton Syndrome
Pathogenic autoantibodies to Dsg1 are associated with conditions like pemphigus foliaceus and mucocutaneous pemphigus vulgaris.
A patient with pemphigus foliaceus has autoantibodies targeting which desmosomal cadherin?
Pemphigus foliaceus involves autoantibodies targeting Desmoglein 1 (Dsg1).
A patient has a mutation in Desmoglein 1. What conditions might this lead to?
Mutations in Desmoglein 1 can lead to palmoplantar keratoderma (PPK), bullous impetigo, or inherited ichthyosis in Netherton syndrome.
A patient with inherited ichthyosis in Netherton syndrome has a mutation in which desmosomal cadherin?
Inherited ichthyosis in Netherton syndrome is associated with mutations in Desmoglein 1 (Dsg1).
A patient with palmoplantar keratoderma (PPK) has a mutation in which desmosomal cadherin?
Palmoplantar keratoderma (PPK) is associated with mutations in Desmoglein 1 (Dsg1).
A patient with bullous impetigo has a mutation in which desmosomal cadherin?
Bullous impetigo is associated with mutations in Desmoglein 1 (Dsg1).
What are the three major categories of desmosomal proteins and their roles in epithelial tissues?
The three major categories of desmosomal proteins are:
-
Desmosomal cadherins
- Include desmogleins and desmocollins.
- Mediate calcium-dependent adhesion in epithelial tissues.
- Known as autoantigens in diseases like pemphigus.
-
Armadillo family proteins
- Include plakoglobin and plakophilins.
- Play a role in the structural integrity of desmosomes.
-
Plakins
- Include desmoplakin, envoplakin, and periplakin.
- Connect desmosomes to the cytoskeleton, providing mechanical stability.
How do desmosomal cadherins contribute to intercellular adhesion in epithelial tissues?
Desmosomal cadherins contribute to intercellular adhesion through:
- Homophilic interactions (Dsg-Dsg or Dsc-Dsc) which promote adhesion between similar types of cells.
- Heterophilic interactions (Dsg-Dsc) which likely form the basis of epidermal intercellular adhesion, allowing different cell types to adhere to one another effectively.
What are the clinical implications of desmoglein 1 in autoimmune diseases?
Desmoglein 1 is clinically significant due to its role in:
- Being a target in Bullous Impetigo, SSSS, and Inherited ichthyosis in Netherton Syndrome.
- Cleavage by staphylococcal exfoliative toxin, which disrupts adhesion between cells.
- The presence of pathogenic autoantibodies in conditions like Pemphigus foliaceus and mucocutaneous pemphigus vulgaris, leading to blistering skin diseases.
- Autosomal dominant mutations causing haploinsufficiency of Dsg1, resulting in palmoplantar keratoderma (PPK).
What is the role of Desmoglein 2 in arrhythmogenic right ventricular cardiomyopathy (ARVC)?
Desmoglein 2 causes autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) and is not required for epidermal adhesion.
What are the clinical implications of mutations in Desmoglein 4?
Mutations in Desmoglein 4 cause rare autosomal recessive forms of hypotrichosis and monilethrix, indicating its role in hair follicle integrity.
How does Plakophilin contribute to desmosomal stability?
Plakophilin directly binds to desmoplakin and aids in clustering and lateral stability of the desmosomal plaque, which is crucial for cell adhesion.
What is the significance of Plakoglobin in epidermal keratinocytes?
Plakoglobin, also known as γ-catenin, binds to the cytoplasmic tails of desmogleins and desmocollins, playing a key role in adherens junctions in epidermal keratinocytes.
What are the functions of Desmoplakin in desmosomal function?
Desmoplakin provides a major link between keratin filaments and the desmosomal plaque, existing in two RNA splice variants, with Desmoplakin I being required for normal desmosomal function.
What are the consequences of mutations in Plakophilin 2?
Mutations in Plakophilin 2 are the most common cause of autosomal dominant ARVC, highlighting its critical role in cardiac and epidermal integrity.
What is the role of Envoplakin and Periplakin in the epidermis?
Envoplakin and Periplakin are expressed in the superficial layers of the epidermis, contributing to the structural integrity of the skin.
A patient presents with a rare autosomal recessive form of hypotrichosis. Which desmosomal cadherin mutation is most likely responsible?
The mutation in Desmoglein 4 (Dsg4) is most likely responsible for the rare autosomal recessive form of hypotrichosis.
A patient with pemphigus vulgaris has autoantibodies targeting a specific desmosomal cadherin. Which one is it?
The autoantibodies in pemphigus vulgaris target Desmoglein 3 (Dsg3).
A patient with Naxos disease has a mutation in which protein, and what are the associated symptoms?
Naxos disease is caused by a mutation in Plakoglobin (γ-catenin). Symptoms include diffuse palmoplantar keratoderma (PPK), wooly hair, and arrhythmogenic right ventricular cardiomyopathy (ARVC).
A patient with arrhythmogenic right ventricular cardiomyopathy (ARVC) has a mutation in which desmosomal cadherin?
ARVC is associated with mutations in Desmoglein 2 (Dsg2).
A patient has a mutation in Plakophilin 1. What syndrome does this cause, and what are its symptoms?
A mutation in Plakophilin 1 causes ectodermal dysplasia-skin fragility syndrome, characterized by skin fragility and ectodermal dysplasia.
A patient with subcorneal pustular dermatosis-type IgA pemphigus has autoantibodies targeting which desmosomal protein?
Subcorneal pustular dermatosis-type IgA pemphigus involves autoantibodies targeting Desmocollin 1 (Dsc1).
A patient has a mutation in Desmoplakin I. What is the role of this protein in desmosomes?
Desmoplakin I provides a major link between keratin filaments and the desmosomal plaque, and is required for normal desmosomal function.
A patient with pemphigus vulgaris (vegetative type) has autoantibodies targeting which desmosomal protein?
Pemphigus vulgaris (vegetative type) involves autoantibodies targeting Desmocollin 3 (Dsc3).
A patient with severe skin fragility has a mutation in which Plakin protein?
Severe skin fragility can result from a mutation in Plakophilin 1.
A patient with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) has a mutation in which Plakophilin protein?
Autosomal dominant ARVC is most commonly caused by mutations in Plakophilin 2.
A patient with pemphigus vulgaris has autoantibodies targeting which desmosomal cadherin?
Pemphigus vulgaris involves autoantibodies targeting Desmoglein 3 (Dsg3).
A patient with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) has a mutation in which desmosomal cadherin?
Autosomal dominant ARVC is associated with mutations in Desmoglein 2 (Dsg2).
A patient with autosomal recessive wooly hair has a mutation in which desmosomal protein?
Autosomal recessive wooly hair is associated with mutations in Plakoglobin (γ-catenin).
What is the role of Desmoglein 2 in arrhythmogenic right ventricular cardiomyopathy (ARVC) and its requirement for epidermal adhesion?
Desmoglein 2 (Dsg2) causes autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) but is not required for epidermal adhesion.
How do mutations in Plakophilin contribute to skin conditions, and what are the specific conditions associated with its mutations?
Mutations in Plakophilin can lead to various skin conditions:
- Plakophilin 1 - associated with ectodermal dysplasia-skin fragility syndrome.
- Plakophilin 2 - the most common cause of autosomal dominant ARVC.
- Plakophilin 3 - currently has no known human disease associated with it.
What is the significance of Desmoplakin in desmosomal function and its relationship with keratin filaments?
Desmoplakin provides a major link between keratin filaments and the desmosomal plaque. It exists in two RNA splice variants, Desmoplakin I and II, where Desmoplakin I is required for normal desmosomal function, while Desmoplakin II is not sufficient to restore this function in the epidermis.
What are the implications of mutations in Plakoglobin, and what condition is associated with these mutations?
Mutations in Plakoglobin, also known as γ-catenin, can result in Naxos disease, which is an autosomal recessive syndrome characterized by diffuse palmoplantar keratoderma (PPK), woolly hair, and arrhythmogenic right ventricular cardiomyopathy (ARVC).
What are the major functions of basement membranes?
- Scaffold for tissue organization and template for tissue repair
- Selective permeability barrier
- Physical barrier between different types of cells or between cells and their underlying matrix
- Links epithelium to its underlying matrix or to another cell
- Regulates cellular functions
What is the significance of the absence of distinguishable basement membranes in tumor biopsies?
The absence of distinguishable basement membranes in tumor biopsies is used as an indicator of malignancy, as malignant cells can migrate through basement membranes while nonmalignant cells seldom cross them.
What are the three distinct zones of the dermal-epidermal junction (DEJ)?
-
Keratin filament-hemidesmosome complex of the basal cells
- Extends through the lamina lucida to the lamina densa
- Hemidesmosomes are electron-dense plates located in the plasma membranes of the basal cells in this region
-
Lamina densa
- Structural scaffold for the attachment of the epidermal cells at one surface, secured by anchoring filaments extending from the lamina densa to the hemidesmosomes
- Contains collagen IV, nidogens, perlecan, laminins
-
Sublamina densa
- Contains 2 microfibrillar structures: anchoring fibrils (aggregates of Collagen VII) and fibrillin-containing microfibrils that merge with the elastic fibers of the dermis to form a plexus parallel to the DEJ.
What are the basic constituents of basement membranes?
- Collagen IV
- Laminins
- Nidogens
- Heparan sulfate proteoglycans
What role does corneodesmosin play in the hair follicle?
Corneodesmosin is expressed in the inner root sheath of the hair follicle and heterozygous mutations are associated with autosomal dominant hypotrichosis simplex of the scalp.
A biopsy reveals the absence of a distinguishable basement membrane in a tumor. What does this indicate about the tumor’s malignancy?
The absence of a distinguishable basement membrane in a tumor biopsy is an indicator of malignancy, as malignant cells migrate through basement membranes.
A patient with autosomal recessive hypotrichosis simplex of the scalp has a mutation in which desmosomal protein?
Autosomal recessive hypotrichosis simplex of the scalp is associated with mutations in Corneodesmosin.
What are the major functions of basement membranes in the context of epidermal-dermal adhesion?
The major functions of basement membranes include:
- Scaffold for tissue organization and template for tissue repair
- Selective permeability barrier
- Physical barrier between different types of cells or between cells and their underlying matrix.
What mutation is associated with autosomal recessive hypotrichosis simplex of the scalp?
Autosomal recessive hypotrichosis simplex of the scalp is associated with mutations in Corneodesmosin.
What are the major functions of basement membranes in the context of epidermal-dermal adhesion?
The major functions of basement membranes include:
- Scaffold for tissue organization and template for tissue repair
- Selective permeability barrier
- Physical barrier between different types of cells or between cells and their underlying matrix
- Links epithelium to its underlying matrix or to another cell
- Regulates cellular functions
How does the absence of distinguishable basement membranes in tumor biopsies relate to malignancy?
The absence of distinguishable basement membranes in tumor biopsies is used as an indicator of malignancy because:
- Nonmalignant cells seldom cross a basement membrane.
- Malignant cells can migrate through basement membranes, indicating a loss of structural integrity and potential for invasion.
Describe the structural composition of the dermal-epidermal junction (DEJ) and its significance in cellular attachment.
The dermal-epidermal junction (DEJ) consists of:
- Keratin filament-hemidesmosome complex of the basal cells, which extends through the lamina lucida to the lamina densa.
- Lamina densa, which serves as a structural scaffold for the attachment of epidermal cells, containing collagen IV, nidogens, perlecan, and laminins.
-
Sublamina densa, which contains microfibrillar structures including:
- Anchoring fibrils (aggregates of Collagen VII)
- Fibrillin-containing microfibrils that merge with the elastic fibers of the dermis.
This complex structure is crucial for maintaining the integrity and stability of the epidermal-dermal interface.
What is the biochemical composition of the basement membrane, and what role do collagens play in it?
The biochemical composition of the basement membrane includes:
- Collagen IV
- Laminins
- Nidogens
- Heparan sulfate proteoglycans
Collagens account for 40-65% of the total protein in the basement membrane, providing structural support and playing a critical role in maintaining the integrity and function of the membrane.
What are the major components of basement membranes?
- Collagen IV: Dominant in the DEJ (dermal-epidermal junction).
- Laminins: Laminin 332 is the major laminin of the epidermal BM.
- Nidogens: Connect elements between collagen IV and laminin networks.
- Heparan sulfate proteoglycans.
- Fibulins: Genetic defects in fibulin 4 and 5 lead to cutis laxa.
What are the components of hemidesmosomes?
- Bullous pemphigoid antigen 1 (BPAG1 or BP230): Major component of the hemidesmosomal inner dense plaque.
- Bullous pemphigoid antigen 2 (BPAG2 or BP180): Also known as collagen XVII; mutations cause junctional epidermolysis bullosa.
- Plectin: Mutations result in epidermolysis bullosa simplex (EBS) with progressive mucosal dystrophy and EBS with pyloric atresia.
- Integrin α6β4: Has high affinity for laminin 332.
- CD151: Forms complexes with α3β1 and α6β4 integrins; plays a role in the assembly of the BM in various tissues.
What is the role of laminin 332 in anchoring filaments?
- Laminin 332 is essential in keratinocyte adhesion.
- Mutations in laminin 332 can result in severe junctional epidermolysis bullosa.
What is the significance of collagen VII in anchoring fibrils?
- Collagen VII is the major component of anchoring fibrils.
- The NC-1 domain of collagen VII binds to laminin 332 and collagen IV within the lamina densa.
- It extends perpendicularly from the lamina densa, either looping back into the lamina densa or inserting into the dermis, thus entraps dermal fibrils through covalent crosslinks with collagen I.
What are the clinical implications of mutations in the COL7A1 gene?
- Mutations in the COL7A1 gene, which encodes collagen VII, result in dystrophic epidermolysis bullosa.
- Autoantibodies targeting the NC-1 domain of collagen VII can lead to acquired forms of epidermolysis bullosa, epidermolysis bullosa acquisita, and bullous systemic lupus erythematosus (SLE).
A patient has a mutation in COL7A1. What condition might this lead to, and what is the role of the affected protein?
A mutation in COL7A1, which encodes Collagen VII, can lead to dystrophic epidermolysis bullosa. Collagen VII is the major component of anchoring fibrils that secure the lamina densa to the dermis.
A patient presents with epidermolysis bullosa simplex. Which hemidesmosomal protein mutation is likely involved?
Epidermolysis bullosa simplex is associated with mutations in Plectin, a hemidesmosomal protein.
A patient has a mutation in Laminin 332. What condition might this cause, and why is Laminin 332 important?
A mutation in Laminin 332 can cause severe junctional epidermolysis bullosa. Laminin 332 is essential for keratinocyte adhesion.
A patient with bullous pemphigoid has autoantibodies targeting which hemidesmosomal proteins?
Bullous pemphigoid involves autoantibodies targeting BPAG1 (BP230) and BPAG2 (BP180, also known as Collagen XVII).
A patient has autoantibodies targeting the NC-1 domain of Collagen VII. What conditions might this lead to?
Autoantibodies targeting the NC-1 domain of Collagen VII can lead to acquired epidermolysis bullosa, epidermolysis bullosa acquisita, or bullous systemic lupus erythematosus (SLE).
A patient has a mutation in Fibulin 4 or 5. What condition might this cause?
Mutations in Fibulin 4 or 5 can cause cutis laxa.
A patient with progressive mucosal dystrophy has a mutation in which hemidesmosomal protein?
Progressive mucosal dystrophy is associated with mutations in Plectin.
A patient with junctional epidermolysis bullosa has a mutation in which hemidesmosomal protein?
Junctional epidermolysis bullosa is caused by mutations in Collagen XVII (BPAG2).
A patient with dystrophic epidermolysis bullosa has a mutation in which gene?
Dystrophic epidermolysis bullosa is caused by mutations in the COL7A1 gene, which encodes Collagen VII.
A patient with bullous systemic lupus erythematosus (SLE) has autoantibodies targeting which domain of Collagen VII?
Bullous SLE involves autoantibodies targeting the NC-1 domain of Collagen VII.
A patient with cutis laxa has a mutation in which basement membrane component?
Cutis laxa is caused by mutations in Fibulin 4 or 5.
A patient with severe junctional epidermolysis bullosa has a mutation in which hemidesmosomal protein?
Severe junctional epidermolysis bullosa is caused by mutations in Laminin 332.
What are the major components of hemidesmosomes and their associated conditions?
The major components of hemidesmosomes include:
- Bullous pemphigoid antigen 1 (BPAG1 or BP230): Major component of the hemidesmosomal inner dense plaque.
- Bullous pemphigoid antigen 2 (BPAG2 or BP180): Also known as collagen XVII; mutations cause junctional epidermolysis bullosa.
- Plectin: Mutations result in epidermolysis bullosa simplex (EBS) with progressive mucosal dystrophy and EBS with pyloric atresia.
- Integrin α6β4: Has high affinity for laminin 332.
- CD151: Forms complexes with α3β1 and α6β4 integrins; plays a role in the assembly of the BM in various tissues.
How does laminin 332 contribute to keratinocyte adhesion and what are the implications of its mutations?
Laminin 332 is essential for keratinocyte adhesion. Mutations in laminin 332 can lead to severe conditions such as junctional epidermolysis bullosa, which is characterized by skin fragility and blistering due to impaired adhesion between the epidermis and dermis.
What is the role of collagen VII in the structure of anchoring fibrils and its clinical significance?
Collagen VII is a major component of anchoring fibrils, which:
- Bind to laminin 332 and collagen IV within the lamina densa.
- Extend perpendicularly from the lamina densa, looping back into the lamina densa or inserting into the dermis.
- Are crucial for maintaining the structural integrity of the basement membrane.
Mutations in the gene encoding collagen VII (COL7A1) can result in dystrophic epidermolysis bullosa, a condition marked by severe skin blistering and scarring.
What is the most abundant protein in the dermis and what percentage of its dry weight does it constitute?
Collagen is the most abundant protein in the dermis, constituting 75% of its dry weight and 20-30% of its volume.
What are the main components of elastic fibers in the dermis?
The main components of elastic fibers in the dermis are:
- Elastin (90%)
-
Microfibrils - which extend from the basement membrane into the papillary dermis and merge with the elastic fiber plexus.
- Fibrillin is a major component of the microfibrils.
What role do glycosaminoglycans play in the dermis?
Glycosaminoglycans are negatively charged polysaccharides that bind to different proteins to form proteoglycans. They include:
- Chondroitin sulfate
- Dermatan sulfate
- Keratan sulfate
- Heparan sulfate
What is the function of syndecans in the dermis?
Syndecans are heparan sulfate proteoglycans that control cell adhesion to the matrix and interact with extracellular proteins.
What is the significance of collagen XVII in the skin?
Collagen XVII is a transmembrane collagen that plays a crucial role in the dermal-epidermal junction. It is associated with bullous pemphigoid and is involved in binding to intracellular ligands like plectin and BP230, as well as extracellular ligands such as laminin 332.
How do desmosomal proteins vary in expression across different layers of the epidermis?
Desmosomal proteins exhibit distinct expression patterns in the epidermis:
- Dsg3 is strongly expressed in stratified squamous epithelia and squamous cell carcinomas.
- Dsg2 is the major isoform in simple and transitional epithelia.
- Dsg4 is prominent in hair follicles, testis, and prostate.
- Dsc1 is limited to skin and oral epithelia, while Dsc2 is more widely expressed in desmosome-containing epithelia.
What are the main components of elastic fibers in the dermis and their significance?
The main components of elastic fibers in the dermis are:
- Elastin (90%) - Provides elasticity to the skin.
-
Microfibrils - Extend from the basement membrane into the papillary dermis, merging with the elastic fiber plexus.
- Fibrillin is a major component of the microfibrils, crucial for the structural integrity of elastic fibers.
How do glycosaminoglycans contribute to the structure of the dermis?
Glycosaminoglycans (GAGs) are negatively charged polysaccharides that bind to different proteins to form proteoglycans. The four main types of GAGs in the dermis include:
- Chondroitin sulfate
- Dermatan sulfate
- Keratan sulfate
- Heparan sulfate
These GAGs play a vital role in maintaining hydration and structural integrity of the dermis by forming large complexes with proteins such as hyaluronic acid.
What is the role of collagen XVIII in the dermis?
Collagen XVIII is a hybrid collagen/proteoglycan found in the epidermal and vascular basement membrane in the skin. It plays a significant role in maintaining the structural integrity of the basement membrane and is involved in cell adhesion processes.
Describe the function of syndecans in the dermis.
Syndecans are heparan sulfate proteoglycans that control cell adhesion to the extracellular matrix. They interact with extracellular proteins, facilitating communication between the cell and the matrix, which is essential for maintaining tissue structure and function.
What are the expression patterns of desmosomal proteins in normal human epidermis?
Desmosomal proteins exhibit specific expression patterns in the layers of normal human epidermis:
These proteins are crucial for maintaining cell adhesion and structural integrity of the epidermis.
Layer | Desmosomal Proteins |
|———————-|—————————|
| Stratum Corneum (SC) | Dsg1, PKP1 |
| Stratum Granulosum (SG) | Dsg2, PKP1, Dsg4 |
| Stratum Spinosum (SS) | Dsg3, Dsc3, PKP2 |
| Stratum Basale (SB) | Dsg2, Dsc2, PKP3 |
