-
Current Biology : CB Dec 1996The quest for the function of BPAG1, a major hemidesmosomal protein of skin keratinocytes, has led to the discovery of a group of protein isoforms derived from the same... (Review)
Review
The quest for the function of BPAG1, a major hemidesmosomal protein of skin keratinocytes, has led to the discovery of a group of protein isoforms derived from the same genomic locus that are involved in organizing and integrating cytoskeletal networks in sensory neurons.
Topics: Animals; Autoantigens; Carrier Proteins; Collagen; Cytoskeletal Proteins; Cytoskeleton; Desmoplakins; Desmosomes; Dystonia Musculorum Deformans; Dystonin; Humans; Intermediate Filament Proteins; Keratins; Nerve Tissue Proteins; Neurons, Afferent; Non-Fibrillar Collagens; Plectin; Collagen Type XVII
PubMed: 8994813
DOI: 10.1016/s0960-9822(02)70772-0 -
PloS One 2011Dystonia musculorum (dt) is a mouse inherited sensory neuropathy caused by mutations in the dystonin gene. While the primary pathology lies in the sensory neurons of dt...
Dystonia musculorum (dt) is a mouse inherited sensory neuropathy caused by mutations in the dystonin gene. While the primary pathology lies in the sensory neurons of dt mice, the overt movement disorder suggests motor neurons may also be affected. Here, we report on the contribution of motor neurons to the pathology in dt(27J) mice. Phenotypic dt(27J) mice display reduced alpha motor neuron cell number and eccentric alpha motor nuclei in the ventral horn of the lumbar L1 spinal cord region. A dramatic reduction in the total number of motor axons in the ventral root of postnatal day 15 dt(27J) mice was also evident. Moreover, analysis of the trigeminal nerve of the brainstem showed a 2.4 fold increase in number of degenerating neurons coupled with a decrease in motor neuron number relative to wild type. Aberrant phosphorylation of neurofilaments in the perikaryon region and axonal swellings within the pre-synaptic terminal region of motor neurons were observed. Furthermore, neuromuscular junction staining of dt(27J) mouse extensor digitorum longus and tibialis anterior muscle fibers showed immature endplates and a significant decrease in axon branching compared to wild type littermates. Muscle atrophy was also observed in dt(27J) muscle. Ultrastructure analysis revealed amyelinated motor axons in the ventral root of the spinal nerve, suggesting a possible defect in Schwann cells. Finally, behavioral analysis identified defective motor function in dt(27J) mice. This study reveals neuromuscular defects that likely contribute to the dt(27J) pathology and identifies a critical role for dystonin outside of sensory neurons.
Topics: Animals; Base Sequence; Brain Stem; Carrier Proteins; Cytoskeletal Proteins; DNA Primers; Dystonia Musculorum Deformans; Dystonin; Fluorescent Antibody Technique; Mice; Microscopy, Electron; Motor Neurons; Mutation; Nerve Tissue Proteins; Phosphorylation; Spinal Cord
PubMed: 21698255
DOI: 10.1371/journal.pone.0021093 -
The American Journal of Pathology Feb 2000Collagen XVII/BP180, an epidermal adhesion molecule, exists as a full-length transmembrane protein and as a soluble 120-kd ectodomain that is shed from the keratinocyte...
Collagen XVII/BP180, an epidermal adhesion molecule, exists as a full-length transmembrane protein and as a soluble 120-kd ectodomain that is shed from the keratinocyte surface by furin-mediated proteolysis. Despite a number of studies on autoantibody targets in blistering skin diseases, it has remained unclear whether the physiologically shed ectodomain of collagen XVII plays a role as an autoantigen. Here we isolated the authentic, soluble form of human collagen XVII and showed that it is an autoantigen recognized by IgG and IgA autoantibodies in different blistering skin diseases and is, in some cases, the preferential target. The ectodomain was isolated from the epidermis, keratinocyte media, amniotic fluid, and pemphigoid blister fluid, and autoantibodies affinity-purified with this ectodomain bound to the proximal surface of the epidermis in normal skin but not in collagen XVII-deficient skin. The antibody reactivity was not dependent on the native conformation or the N-glycosylation of the soluble ectodomain, but was abolished by collagenase treatment. Sera of 81 patients with a clinically active blistering skin disease were reacted with full-length collagen XVII, the authentic soluble ectodomain, and recombinant fragments. In bullous and cicatricial pemphigoid, IgG reactive with full-length collagen XVII also recognized the soluble ectodomain. In linear IgA dermatosis and chronic bullous dermatosis of childhood, IgA targeted the soluble ectodomain more efficiently than the full-length protein. The use of recombinant fragments demonstrated that epitopes were present in several noncollagenous and collagenous subdomains of the molecule, and that a significant portion of the sera targeted Col15 domain, a hitherto unrecognized epitope region.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Carrier Proteins; Child; Child, Preschool; Collagen; Cytoskeletal Proteins; Dystonin; Female; Humans; Immunoglobulin A; Immunoglobulin G; Immunosorbent Techniques; Male; Middle Aged; Nerve Tissue Proteins; Non-Fibrillar Collagens; Peptide Fragments; Recombinant Proteins; Skin Diseases, Vesiculobullous; Solubility; Collagen Type XVII
PubMed: 10666397
DOI: 10.1016/S0002-9440(10)64772-4 -
Cell & Bioscience 2015Under inflammatory conditions or during tumor progression macrophages acquire distinct phenotypes, with factors of the microenvironment such as hypoxia and transforming...
BACKGROUND
Under inflammatory conditions or during tumor progression macrophages acquire distinct phenotypes, with factors of the microenvironment such as hypoxia and transforming growth factor β (TGFβ) shaping their functional plasticity. TGFβ is among the factors causing alternative macrophage activation, which contributes to tissue regeneration and thus, resolution of inflammation but may also provoke tumor progression. However, the signal crosstalk between TGFβ and hypoxia is ill defined.
RESULTS
Exposing human primary macrophages to TGFβ elicited a rapid SMAD2/SMAD3 phosphorylation. This early TGFβ-signaling remained unaffected by hypoxia. However, with prolonged exposure periods to TGFβ/hypoxia the expression of SMAD2 declined because of decreased protein stability. In parallel, hypoxia increased mRNA and protein amount of the calpain regulatory subunit, with the further notion that TGFβ/hypoxia elicited calpain activation. The dual specific proteasome/calpain inhibitor MG132 and the specific calpain inhibitor 1 rescued SMAD2 degradation, substantiating the ability of calpain to degrade SMAD2. Decreased SMAD2 expression reduced TGFβ transcriptional activity of its target genes thrombospondin 1, dystonin, and matrix metalloproteinase 2.
CONCLUSIONS
Hypoxia interferes with TGFβ signaling in macrophages by calpain-mediated proteolysis of the central signaling component SMAD2.
PubMed: 26146544
DOI: 10.1186/s13578-015-0026-x -
Archives of Dermatological Research Jul 2017Bullous pemphigoid (BP) is a chronic debilitating autoimmune blistering disease that frequently occurs in the elderly population. Previous studies have suggested a high... (Meta-Analysis)
Meta-Analysis
Bullous pemphigoid (BP) is a chronic debilitating autoimmune blistering disease that frequently occurs in the elderly population. Previous studies have suggested a high morbidity and mortality associated with BP. However, relatively few studies have investigated prognostic factors of BP mortality, and they showed considerably various results. This meta-analysis aimed to quantitatively assess the association between several potential prognostic factors and risk of mortality in bullous pemphigoid. A comprehensive search was performed using Pubmed, Embase, and Cochrane Library. Cohort studies that assessed prognostic factors of BP mortality were included. Random-effects model was utilized to calculate the pooled hazard ratio (HR). Publication bias was evaluated qualitatively by constructing a funnel plot and quantitatively by conducting Egger's test. 14 studies were included comprising 2499 patients. Combined HRs suggested that advanced age (HR 1.63, 95% CI 1.34-1.97), presence of circulating antibodies (HR 1.77, 95% CI 1.20-2.62), concomitant dementia (HR 2.01, 95% CI 1.22-3.33), and concomitant stroke (HR 1.86, 95% CI 1.29-2.67) have an unfavorable impact on patient survival. Gender, disease extent, mucosal involvement, and indirect immunofluorescence result were not shown to be linked to mortality by our analysis. This study indicated that BP patients with older age, circulating antibodies, dementia, and stroke are at greater risk of mortality. Clinicians should be aware of this association and utilize this information in patient education and treatment process.
Topics: Age Factors; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Dementia; Dystonin; Female; Humans; Male; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prognosis; Risk; Stroke; Collagen Type XVII
PubMed: 28317060
DOI: 10.1007/s00403-017-1736-1 -
The Journal of Investigative Dermatology May 1991In order to determine the kinetics of epidermo-dermal junction (EDJ) regeneration during would healing, we studied the regeneration of five EDJ components during...
In order to determine the kinetics of epidermo-dermal junction (EDJ) regeneration during would healing, we studied the regeneration of five EDJ components during reepidermization. Cutaneous wounds (50-mm length, 2-mm width, and 5-mm depth) were produced on the flank area of two pigs and left unsutured. Daily biopsies from day 1 to day 20 were studied by light microscopy on paraffin-embedded sections and by indirect immunofluorescence on cryostat sections using human sera to bullous pemphigoid antigen (BPA) with specificity previously confirmed by indirect immuno-electron microscopy, rabbit antisera to type IV collagen (Coll IV) and to fibronectin, and the monoclonal antibodies (MoAb) 4C 12-8 to laminin and NP-76 to type VII collagen (Coll VII). Histologically, reepidermization started from day 1 and progressed unidirectionally and exclusively from the wound edges. Up to day 9, the distal tips of the neo-epidermal tongues generally extended between the crust and the granulation tissue (GT). They fused on day 10, restoring epidermal continuity. For each EDJ component, the date of appearance (emergence), the spreading under the neo-epidermis tongue (expression), and the morphologic aspect of the labeling were studied. BPA and Coll IV were detected from day 1 to day 20 and found to be expressed all along the neo-EDJ. Fibronectin and laminin were detected from day 1, were present in the proximal and median zones of the neo-EDJ before day 7, up to the distal tip from day 7 to day 9 and were all along the neo-EDJ from day 10 to day 20. Coll VII was only detected from day 3. It was present in the proximal zone on day 3 and day 4, in the proximal and median zones on day 5 and day 6, than all along the neo-EDJ from day 7 to day 20. From day 10, all the labeling characteristics of the five components were found to be similar in the neo-EDJ and in the normal EDJ. With regard to the neo-epidermis progression, we found a synchronism of emergence and expression for BPA and Coll IV, a synchronism of emergence but a delay of expression for fibronectin and laminin and lastly, a delay of emergence and expression for Coll VII. We concluded that BPA and Coll IV could constitute the framework on which the neo-EDJ is progressively built by adjunction of the other components, restitution being obtained just after epidermal continuity is restored.
Topics: Animals; Autoantigens; Carrier Proteins; Collagen; Cytoskeletal Proteins; Dystonin; Epidermis; Female; Fibronectins; Fluorescent Antibody Technique; Immunohistochemistry; Laminin; Microscopy, Immunoelectron; Nerve Tissue Proteins; Non-Fibrillar Collagens; Regeneration; Skin; Skin Physiological Phenomena; Swine; Wound Healing; Collagen Type XVII
PubMed: 2022886
DOI: 10.1111/1523-1747.ep12471745 -
The Journal of Investigative Dermatology Mar 2014Bullous pemphigoid antigen 1 (BPAG1-e, also known as BP230) is a member of the plakin family of hemidesmosome cytoskeletal linker proteins that is encoded by an isoform...
Bullous pemphigoid antigen 1 (BPAG1-e, also known as BP230) is a member of the plakin family of hemidesmosome cytoskeletal linker proteins that is encoded by an isoform of the dystonin (DST) gene. Recently, we reported two unrelated families with homozygous nonsense mutations in this DST isoform that led to ultrastructural loss of hemidesmosomal inner plaques and clinical features of trauma-induced skin fragility. We now demonstrate that keratinocytes isolated from these individuals have significant defects in adhesion, as well as increased cell spreading and migration. These mutant keratinocytes also display reduced levels of β4 integrins at the cell surface but increased total protein levels of keratin-14 and β1 integrins. These alterations in cell behavior and protein expression were not seen in control keratinocytes in which BPAG1-e expression had been silenced by stable expression of short hairpin RNA to target DST. The failure of knockdown approaches to recapitulate the changes in morphology, adhesion, and migration seen in patient cells therefore suggests such approaches are not appropriate to study loss of this protein in vivo. The contrasting findings in keratinocytes harboring naturally occurring mutations, however, demonstrate a previously unappreciated key role for BPAG1-e in regulating keratinocyte adhesion and migration and suggest a requirement for this protein in controlling functional switching between integrin types in epithelial cells.
Topics: Breast; Carrier Proteins; Cell Adhesion; Cell Line; Cell Movement; Cytoskeletal Proteins; Desmosomes; Dystonin; Female; Humans; Integrin beta1; Integrin beta4; Keratin-14; Keratinocytes; Middle Aged; Mutation; Nerve Tissue Proteins
PubMed: 24025550
DOI: 10.1038/jid.2013.382 -
Iranian Journal of Allergy, Asthma, and... Feb 2020No Abstract.
No Abstract.
Topics: Aged; Anti-Inflammatory Agents; Autoantigens; Dystonin; Female; Humans; Interleukin-10; Interleukin-18; Iran; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 32245316
DOI: 10.18502/ijaai.v19i1.2423 -
Frontiers in Immunology 2021Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against...
Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against components of the basal membrane zone that lead to sub-epidermal loss of adhesion. Pruritus may be indicative of a pre-clinical stage of BP, since a subset of these patients shows serum IgG autoantibodies against BP230 and/or BP180 while chronic pruritus is increasingly common in the elderly population and is associated with a variety of dermatoses. Clinical and experimental evidence further suggests that pruritus of the elderly may be linked to autoimmunity with loss of self-tolerance against cutaneous autoantigens. Thus, the objective of this study was to determine autoreactive T cell responses against BP180 in elderly patients in comparison to patients with BP. A total of 22 elderly patients with pruritic disorders, 34 patients with bullous or non-bullous BP and 34 age-matched healthy controls were included in this study. The level of anti-BP180 and anti-BP230 IgG serum autoantibodies, Bullous Pemphigoid Disease Area Index (BPDAI), and pruritus severity were assessed for all patients and controls. For characterization of the autoreactive T cell response, peripheral blood mononuclear cells were stimulated with recombinant BP180 proteins (NH- and COOH-terminal domains) and the frequencies of BP180-specific T cells producing interferon-γ, interleukin (IL)-5 or IL-17 were subsequently determined by ELISpot assay. Patients with BP showed a mixed Th1/Th2 response against BP180 while autoreactive Th1 cells were identified in a minor subset of elderly patients with pruritic disorders. Furthermore, our T cell characterization revealed that therapeutic application of topical clobetasol propionate ointment in BP patients significantly reduced peripheral blood BP180-specific T cells, along with clinically improved symptoms, strongly suggesting a systemic immunosuppressive effect of this treatment.
Topics: Aged; Autoantibodies; Autoantigens; Autoimmunity; Clobetasol; Cohort Studies; Cytokines; Dystonin; Enzyme-Linked Immunospot Assay; Glucocorticoids; Humans; Immunoglobulin G; Non-Fibrillar Collagens; Ointments; Pemphigoid, Bullous; Pruritus; T-Lymphocytes, Helper-Inducer; Th17 Cells; Collagen Type XVII
PubMed: 33841390
DOI: 10.3389/fimmu.2021.569287 -
PloS One 2023Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur...
Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an 'EB related gene', Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known 'EB related genes', with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.
Topics: Animals; Mice; Epidermolysis Bullosa, Junctional; Skin; Blister; Epidermis; Quantitative Trait Loci
PubMed: 37437067
DOI: 10.1371/journal.pone.0288263