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Acta Dermato-venereologica Nov 2020Pruritus is a common symptom of bullous pemphigoid (BP), but has been poorly studied. The aim of this study was to analyse the characteristics of pruritus in patients... (Observational Study)
Observational Study
Pruritus is a common symptom of bullous pemphigoid (BP), but has been poorly studied. The aim of this study was to analyse the characteristics of pruritus in patients with BP and its impact on their quality of life. A multicentre prospective observational study (in 15 French hospitals) was performed. A total of 60 patients were included, with a mean age of 77.4 years. Pruritus occurred daily in 85% of patients, with a mean pruritus intensity of 5.2/10. Tingling sensations were present in 72.4% of patients and burning sensations in 68.9%. Pruritus was exacerbated by stress, fatigue and xerosis. The mean ItchyQol score was 56.2/110 and the mean 5-D Itch Scale score was 16.5/25. The severity of pruritus was not related to age, sex, BP activity score, eosinophilia, or anti-BP230 and anti-BP180 autoantibodies. This study revealed that pruritus in BP is poorly tolerated and is an important cause of impaired quality of life.
Topics: Aged; Autoantibodies; Autoantigens; Dystonin; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prospective Studies; Pruritus; Quality of Life
PubMed: 33135772
DOI: 10.2340/00015555-3683 -
The Journal of Investigative Dermatology Nov 2011Bullous pemphigoid (BP), the most common autoimmune subepidermal bullous disease, is associated with an autoantibody response to BP180 and BP230, two components of...
Bullous pemphigoid (BP), the most common autoimmune subepidermal bullous disease, is associated with an autoantibody response to BP180 and BP230, two components of junctional adhesion complexes in human skin promoting dermo-epidermal cohesion. Retrospective analyses demonstrated that these autoantigens harbor several epitopes targeted by autoaggressive B and T cells. The aim of this prospective multicenter study was to assess the evolution of IgG autoantibodies in 35 BP patients over a 12-month observation period. Epitope-spreading (ES) events were detected in 17 of 35 BP patients (49%). They preferentially occurred in an early stage of the disease and were significantly related to disease severity at diagnosis. Moreover, in three patients, spreading of IgG reactivity to intracellular epitopes of BP180 and BP230 was preceded by recognition of the BP180 ectodomain. Finally, IgG reactivity with extracellular epitopes of BP180 and intracellular epitopes of BP230 correlated with the severity of BP in disease course. These findings support the idea that IgG recognition of the BP180 ectodomain is an early and crucial event in BP disease, followed by variable intra- and intermolecular ES events, which likely shape the individual course of BP.
Topics: Aged; Aged, 80 and over; Autoantigens; Carrier Proteins; Case-Control Studies; Cytoskeletal Proteins; Disease Progression; Dystonin; Epitopes, B-Lymphocyte; Epitopes, T-Lymphocyte; Female; Humans; Immunoglobulin G; Longitudinal Studies; Male; Membrane Glycoproteins; Middle Aged; Nerve Tissue Proteins; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prospective Studies; Severity of Illness Index; Collagen Type XVII
PubMed: 21697892
DOI: 10.1038/jid.2011.180 -
The American Journal of Pathology Dec 1995Hemidesmosomes are multiprotein structures that attach basal cells of stratified epithelia to basement membranes. Although normal human breast epithelia are not...
Hemidesmosomes are multiprotein structures that attach basal cells of stratified epithelia to basement membranes. Although normal human breast epithelia are not stratified, we observed expression of electron-dense hemidesmosomes and hemidesmosome protein components by breast epithelial and myoepithelial cells at the basal lamina in vivo. Primary cultured normal human breast epithelial cells also contained hemidesmosomes and component proteins, and could be used as a model for hemidesmosome assembly and regulation. In these cultured cells, hemidesmosome proteins were expressed and localized basally in an unvaried temporal pattern, and electron-dense hemidesmosomes were not seen until the final protein was localized to the cell base. In addition, rate of localization was influenced by confluence, doubling time, and extracellular matrix. Invasive breast cancer cells did not express hemidesmosomes or most of the component proteins in vivo. In carcinoma in situ, cells away from the basement membrane lacked hemidesmosomes and hemidesmosome proteins, and cells at the basement membrane exhibited abnormalities of hemidesmosome protein expression. Primary human malignant breast cells in culture exhibited a mix of hemidesmosome phenotypes. These data suggest that hemidesmosomes may be important subcellular structures in determining the cytoarchitecture of the breast epithelium. Further, their downregulation may influence cytoarchitecture remodeling closely linked with cell cycle, motility, and extracellular matrix interactions; and their loss in carcinoma may be associated with loss of normal cytoarchitecture.
Topics: Autoantigens; Breast; Breast Neoplasms; Carcinoma; Carrier Proteins; Collagen; Cytoskeletal Proteins; Desmosomes; Dystonin; Extracellular Matrix Proteins; Female; Humans; Integrins; Intermediate Filament Proteins; Mammaplasty; Nerve Tissue Proteins; Non-Fibrillar Collagens; Tumor Cells, Cultured; Collagen Type XVII
PubMed: 7495306
DOI: No ID Found -
Genes & Development Jul 2006MACF1 (microtubule actin cross-linking factor 1) is a multidomain protein that can associate with microfilaments and microtubules. We found that MACF1 was highly...
MACF1 (microtubule actin cross-linking factor 1) is a multidomain protein that can associate with microfilaments and microtubules. We found that MACF1 was highly expressed in neuronal tissues and the foregut of embryonic day 8.5 (E8.5) embryos and the head fold and primitive streak of E7.5 embryos. MACF1(-/-) mice died at the gastrulation stage and displayed developmental retardation at E7.5 with defects in the formation of the primitive streak, node, and mesoderm. This phenotype was similar to Wnt-3(-/-) and LRP5/6 double-knockout embryos. In the absence of Wnt, MACF1 associated with a complex that contained Axin, beta-catenin, GSK3beta, and APC. Upon Wnt stimulation, MACF1 appeared to be involved in the translocation and subsequent binding of the Axin complex to LRP6 at the cell membrane. Reduction of MACF1 with small interfering RNA decreased the amount of beta-catenin in the nucleus, and led to an inhibition of Wnt-induced TCF/beta-catenin-dependent transcriptional activation. Similar results were obtained with a dominant-negative MACF1 construct that contained the Axin-binding region. Reduction of MACF1 in Wnt-1-expressing P19 cells resulted in decreased T (Brachyury) gene expression, a DNA-binding transcription factor that is a direct target of Wnt/beta-catenin signaling and required for mesoderm formation. These results suggest a new role of MACF1 in the Wnt signaling pathway.
Topics: Adenomatous Polyposis Coli Protein; Animals; Axin Protein; Base Sequence; Carrier Proteins; Cell Membrane; Cytoskeletal Proteins; Dystonin; Gene Expression Regulation, Developmental; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Mesoderm; Mice; Mice, Knockout; Microfilament Proteins; Molecular Sequence Data; Multiprotein Complexes; Nerve Tissue Proteins; Protein Structure, Tertiary; Protein Transport; Repressor Proteins; Signal Transduction; Wnt Proteins; beta Catenin
PubMed: 16815997
DOI: 10.1101/gad.1411206 -
The Journal of Biological Chemistry Apr 1993Thus far, 16 distinct vertebrate collagens (types I-XVI) have been delineated. In this study, we have cloned a mouse collagenous protein, the 180-kDa bullous pemphigoid...
Cloning of type XVII collagen. Complementary and genomic DNA sequences of mouse 180-kilodalton bullous pemphigoid antigen (BPAG2) predict an interrupted collagenous domain, a transmembrane segment, and unusual features in the 5'-end of the gene and the 3'-untranslated region of the mRNA.
Thus far, 16 distinct vertebrate collagens (types I-XVI) have been delineated. In this study, we have cloned a mouse collagenous protein, the 180-kDa bullous pemphigoid antigen (BPAG2). Isolation of over-lapping clones, together with 5' and 3' rapid amplification of cDNA ends, allowed delineation of the entire coding sequence. The 5' and 3' ends of the mRNA transcripts were confirmed by primer extension and anchored reverse transcription polymerase chain reaction analyses. The deduced polypeptide contained 1,433 amino acids, including a collagenous domain that consisted of 13 separate segments. Computer analysis of the deduced amino acid sequence demonstrated the presence of a membrane-associated segment. Examination of the 5' end of the BPAG2 gene revealed that the 295-base pair (bp) exon 1 contained two segments of (T)13AA and TT(A)11, whereas exon 2 was shown to contain the translation initiation codon. The 3' end of the mRNA transcript identified two 6-bp inverted repeat sequences that could form a stem for a 30-bp hairpin loop followed by a series of U residues. Comparison of mouse and human BPAG2 sequences demonstrated 86% homology and the unit of evolutionary period of 4.2 million years. In summary, we have cloned full-length mouse BPAG2 cDNA sequences that encode a collagenous polypeptide. We propose that this polypeptide be designated as the alpha 1-chain of type XVII collagen.
Topics: Amino Acid Sequence; Animals; Autoantigens; Base Sequence; Biological Evolution; Blotting, Northern; Carrier Proteins; Cloning, Molecular; Collagen; Cytoskeletal Proteins; DNA; Dystonin; Exons; Humans; Introns; Membrane Proteins; Mice; Molecular Sequence Data; Nerve Tissue Proteins; Non-Fibrillar Collagens; Pemphigoid, Bullous; RNA, Messenger; Sequence Homology, Amino Acid; Collagen Type XVII
PubMed: 8473327
DOI: No ID Found -
Developmental Dynamics : An Official... Oct 2000Several proteins belonging to the plakin family of cytoskeletal linker proteins have recently been identified, including dystonin/Bpag1 and plectin. These proteins are...
Several proteins belonging to the plakin family of cytoskeletal linker proteins have recently been identified, including dystonin/Bpag1 and plectin. These proteins are unique in their abilities to form bridges between different cytoskeletal elements through specialized modular domains. We have previously reported the cloning and partial characterization of Acf7, a novel member of the plakin family. More recently, the full-length cDNA for mouse Acf7 has been reported. Acf7 has a hybrid composition, with extended homology to dystonin/Bpag1 and plectin in the N-terminal half, and to dystrophin in the central and C-terminal half. Recent studies have demonstrated that Acf7 has functional actin and microtubule binding domains. Here, we describe the developmental expression profile for mouse Acf7. RNA in situ hybridization experiments revealed Acf7 transcripts in the dermomyotome and neural fold of day 8.5 mouse embryos. Later in development, Acf7 expression was predominant in neural and muscle tissues and was strongly up-regulated just before birth in type II alveolar cells of the lung. Altogether, our results suggest that Acf7 functions as a versatile cytoskeletal linker protein and plays an important role in neural, muscle, and lung development.
Topics: Aging; Animals; Animals, Newborn; Brain; Embryonic and Fetal Development; Gene Expression Regulation, Developmental; Lung; Mice; Mice, Mutant Strains; Microfilament Proteins; Microtubules; Muscle Development; Muscles; Organ Specificity; Polymorphism, Restriction Fragment Length; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord
PubMed: 11002341
DOI: 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1041>3.0.CO;2-O -
Indian Journal of Dermatology,... 2012Bullous pemphigoid (BP) is an acquired autoimmune subepidermal blistering disease characterized by circulating IgG autoantibodies directed against BP180 and BP230...
BACKGROUND
Bullous pemphigoid (BP) is an acquired autoimmune subepidermal blistering disease characterized by circulating IgG autoantibodies directed against BP180 and BP230 hemidesmosomal proteins. Previous studies have demonstrated that antibodies against the NC16a domain of BP180 mediate BP pathogenesis, while antibodies against BP230 enhance the inflammatory response. Recently, commercial BP180-NC16a enzyme-linked immunosorbent assay (ELISA) and BP230 ELISA kits were developed to detect anti-BP180 and anti-BP230 autoantibodies in human BP sera.
AIMS
To evaluate the efficacy of BP180-NC16a ELISA and BP230 ELISA in the initial diagnosis of BP.
METHODS
Sera from 62 BP patients and 62 control subjects were tested by BP180-NC16a ELISA and BP230 ELISA and compared with findings from indirect immunofluorescence (IIF) and immunoblotting (IB) to determine the sensitivity and specificity of these assays.
RESULTS
The sensitivities of BP180-NC16a ELISA and BP230 ELISA were 87.1% (54/62) and 56.5% (35/62), respectively, and the specificities of both were 100% (62/62). Using both ELISAs for diagnosis increased the sensitivity to 95.2% (59/62) and was statistically comparable with IB sensitivity.
CONCLUSIONS
ELISA is a convenient, effective, and reliable method for serodiagnosis of BP, and combined use of BP180-NC16a ELISA and BP230 ELISA can increase the sensitivity of this diagnostic approach.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies; Autoantigens; Carrier Proteins; Case-Control Studies; Child; Child, Preschool; Cytoskeletal Proteins; Dystonin; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Humans; Immunoblotting; Male; Membrane Glycoproteins; Middle Aged; Nerve Tissue Proteins; Non-Fibrillar Collagens; Pemphigoid, Bullous; Sensitivity and Specificity; Young Adult; Collagen Type XVII
PubMed: 23075641
DOI: 10.4103/0378-6323.102364 -
American Journal of Transplantation :... Mar 2008Donor-reactive memory T cells undermine the survival of transplanted organs through multiple pathways. We have previously reported that memory CD4 T cells resist...
Donor-reactive memory T cells undermine the survival of transplanted organs through multiple pathways. We have previously reported that memory CD4 T cells resist treatment with anti-CD154 antibody and donor-specific transfusion (DST/MR1) and promote cardiac allograft rejection via generation of effector CD4 T cells and alloantibody. We hypothesized that the helper functions of memory CD4 T cells are independent of T-cell costimulation through CD154 but instead are regulated by alternative costimulatory pathways. This study investigated how blocking ICOS/B7RP-1 interactions affects functions of donor-reactive memory CD4 T cells. Treatment with blocking anti-ICOS mAb synergized with DST/MR1 and prolonged mouse cardiac allograft survival despite the presence of donor-reactive memory CD4 T cells. While blocking ICOS did not diminish the expansion of preexisting memory CD4 T cells or the induction of allospecific effector T cells, it did inhibit recruitment of the activated memory and effector T cells into the graft. In addition, anti-ICOS mAb treatment in combination with DST/MR1 prevented help provided by memory CD4 T cells for production of donor-specific IgG antibody. These results demonstrate the potential efficacy of ICOS blockade in sensitized transplant patients and provide the foundation for rational use of ICOS blockade in combination with other graft-prolonging strategies.
Topics: Animals; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; B7-1 Antigen; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Carrier Proteins; Cytoskeletal Proteins; Dystonin; Female; Graft Rejection; Graft Survival; Heart Transplantation; Histocompatibility Antigens Class I; Immunoglobulin Switch Region; Immunologic Memory; Inducible T-Cell Co-Stimulator Ligand; Inducible T-Cell Co-Stimulator Protein; Male; Mice; Mice, Inbred Strains; Minor Histocompatibility Antigens; Nerve Tissue Proteins
PubMed: 18294146
DOI: 10.1111/j.1600-6143.2007.02096.x -
The Journal of Investigative Dermatology Mar 2022
Topics: Autoantibodies; Autoantigens; Dystonin; Enzyme-Linked Immunosorbent Assay; Fractures, Bone; Humans; Non-Fibrillar Collagens
PubMed: 34883045
DOI: 10.1016/j.jid.2021.11.028 -
The Journal of Biological Chemistry Feb 2000Collagen XVII is a hemidesmosomal transmembrane molecule important for epithelial adhesion in the skin. It exists in two forms, as a full-length protein and as a soluble...
Collagen XVII is a hemidesmosomal transmembrane molecule important for epithelial adhesion in the skin. It exists in two forms, as a full-length protein and as a soluble ectodomain that is shed from the keratinocyte surface by furin-mediated proteolysis. To obtain information on the conformation and the functions of this unusual collagen, its largest collagenous domain, Col15, was expressed in a eukaryotic episomal expression system and purified by DEAE and fast protein liquid- Mono S chromatography. The protein was triple-helical (T(m) of 26.5 degrees C) when produced in cultures containing ascorbic acid. When the vitamin supply was limited, the 4-hydroxyproline content was reduced from 74 to 9%, which, in turn, resulted in a drastic reduction of the stability of the triple helix. The glycine substitution mutation G627V associated with junctional epidermolysis bullosa, a human blistering skin disease, also had a striking effect on thermal stability of rCol15 causing partial unfolding already at 4 degrees C. Col15 promoted cell adhesion of epithelial and fibroblastic cell lines with a beta1 integrin-mediated mechanism. In concert with this, in acquired autoimmune blistering skin diseases, circulating IgG and IgA autoantibodies were found to target rCol15r.
Topics: Amino Acid Substitution; Autoantigens; Carrier Proteins; Cell Adhesion; Circular Dichroism; Collagen; Cytoskeletal Proteins; Dystonin; Glycine; Humans; Nerve Tissue Proteins; Non-Fibrillar Collagens; Point Mutation; Protein Conformation; Structure-Activity Relationship; Collagen Type XVII
PubMed: 10652291
DOI: 10.1074/jbc.275.5.3093