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Journal of Dermatological Science May 2024Bullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the...
BACKGROUND
Bullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230 and the predominance of skin lesions. Several studies have addressed the role of anti-BP180 IgE in patients and experimental models, while data on anti-BP230 IgE are scarce.
OBJECTIVE
To assess anti-BP230 IgE level by ELISA in BP sera and to correlate it with disease severity and clinical characteristics.
METHODS
BP sera underwent anti-BP230 IgE ELISA and Western blotting against human BP230 fragments.
RESULTS
We demonstrate that 36/154 (23%) of BP sera were positive for anti-BP230 IgE. Anti-BP230 IgE levels had no correlation with clinical phenotype or disease activity per se. Interestingly, anti-BP230 IgE was significantly associated with disease activity within individuals during the course of the disease. Additionally, anti-BP230 IgE and total IgE levels showed a significant correlation. Notably, anti-BP230 IgG correlated interindividually with disease activity. By Western blotting, the C-terminal domain of BP230 fragments (C2; amino acids 2024-2349 and C3; amino acids 2326-2649), provided the best serological assay for anti-BP230 IgE detection.
CONCLUSION
As a complementary tool, IgE immunoblotting is recommended to obtain an optimal serological diagnosis, particularly in patients with severe disease without IgG reactivity by BP180- or BP230-specific ELISA. Although the detection of serum anti-BP230 IgE is not of major diagnostic significance, it may be relevant for therapeutic decisions, e.g., for anti-IgE-directed treatment, which has been successfully used in case series of BP.
Topics: Humans; Pemphigoid, Bullous; Immunoglobulin E; Autoantibodies; Male; Female; Aged; Autoantigens; Dystonin; Aged, 80 and over; Non-Fibrillar Collagens; Middle Aged; Enzyme-Linked Immunosorbent Assay; Severity of Illness Index; Immunoglobulin G; Collagen Type XVII; Adult; Blotting, Western
PubMed: 38582700
DOI: 10.1016/j.jdermsci.2024.03.009 -
The Journal of Investigative Dermatology Nov 2022
Topics: Humans; Pemphigoid, Bullous; Non-Fibrillar Collagens; Dystonin; Autoantigens; Autoantibodies; Enzyme-Linked Immunosorbent Assay
PubMed: 35671826
DOI: 10.1016/j.jid.2022.05.1084 -
Acta Dermato-venereologica Mar 2010Bullous pemphigoid is associated with antibodies to a 230 kDa and a 180 kDa protein. In a literature review we investigated the role of auto-antibodies as detected by... (Review)
Review
Bullous pemphigoid is associated with antibodies to a 230 kDa and a 180 kDa protein. In a literature review we investigated the role of auto-antibodies as detected by different serological assays. Nine reports containing data on 143 patients were analyzed. Pre-treatment data showed that indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and immunoblotting offer an 82.2% or greater probability of being positive. At the end of the study period, all patients had clinically improved, whether or not they were on therapy. Auto-antibodies were present in 29% of patients evaluated by monkey esophagus immunofluorescence and 75% of those evaluated by human skin immunofluorescence. Positive titers were also reported in 67.6% of patients evaluated by ELISA. In 100% of patients in whom immunoblotting was performed the titers became negative. In 3 patients (5.3%) using human skin immunofluorescence and in one patient (1.4%) using ELISA the titers were increased at the end of the study period. The correlation between anti-basement membrane zone antibodies and the clinical course of bullous pemphigoid requires further and long-term studies.
Topics: Aged; Aged, 80 and over; Animals; Autoantibodies; Autoantigens; Biomarkers; Carrier Proteins; Cytoskeletal Proteins; Dystonin; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Haplorhini; Humans; Immunoblotting; Immunologic Tests; Male; Middle Aged; Nerve Tissue Proteins; Non-Fibrillar Collagens; Pemphigoid, Bullous; Predictive Value of Tests; Remission Induction; Sensitivity and Specificity; Time Factors; Treatment Outcome; Collagen Type XVII
PubMed: 20169293
DOI: 10.2340/00015555-0819 -
PloS One May 2010Malignant melanoma is one of the most aggressive types of tumor. Because malignant melanoma is difficult to treat once it has metastasized, early detection and treatment...
Malignant melanoma is one of the most aggressive types of tumor. Because malignant melanoma is difficult to treat once it has metastasized, early detection and treatment are essential. The search for reliable biomarkers of early-stage melanoma, therefore, has received much attention. By using a novel method of screening tumor antigens and their auto-antibodies, we identified bullous pemphigoid antigen 1 (BPAG1) as a melanoma antigen recognized by its auto-antibody. BPAG1 is an auto-antigen in the skin disease bullous pemphigoid (BP) and anti-BPAG1 auto-antibodies are detectable in sera from BP patients and are used for BP diagnosis. However, BPAG1 has been viewed as predominantly a keratinocyte-associated protein and a relationship between BPAG1 expression and melanoma has not been previously reported. In the present study, we show that bpag1 is expressed in the mouse F10 melanoma cell line in vitro and F10 melanoma tumors in vivo and that BPAG1 is expressed in human melanoma cell lines (A375 and G361) and normal human melanocytes. Moreover, the levels of anti-BPAG1 auto-antibodies in the sera of melanoma patients were significantly higher than in the sera of healthy volunteers (p<0.01). Furthermore, anti-BPAG1 auto-antibodies were detected in melanoma patients at both early and advanced stages of disease. Here, we report anti-BPAG1 auto-antibodies as a promising marker for the diagnosis of melanoma, and we discuss the significance of the detection of such auto-antibodies in cancer biology and patients.
Topics: Animals; Antibodies, Anti-Idiotypic; Antigens, Neoplasm; Autoantigens; Biomarkers, Tumor; Carrier Proteins; Cell Line, Tumor; Cytoskeletal Proteins; Dystonin; Female; Gene Expression Regulation, Neoplastic; Humans; Melanocytes; Melanoma; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Non-Fibrillar Collagens; Peptide Library; Collagen Type XVII
PubMed: 20479946
DOI: 10.1371/journal.pone.0010566 -
Journal of Biomedical Science Jan 2011Dystonia musculorum (dt) is an autosomal recessive hereditary neuropathy with a characteristic uncoordinated movement and is caused by a defect in the bullous pemphigoid...
BACKGROUND
Dystonia musculorum (dt) is an autosomal recessive hereditary neuropathy with a characteristic uncoordinated movement and is caused by a defect in the bullous pemphigoid antigen 1 (BPAG1) gene. The neural isoform of BPAG1 is expressed in various neurons, including those in the central and peripheral nerve systems of mice. However, most previous studies on neuronal degeneration in BPAG1-deficient mice focused on peripheral sensory neurons and only limited investigation of the autonomic system has been conducted.
METHODS
In this study, patterns of nerve innervation in cutaneous and iridial tissues were examined using general neuronal marker protein gene product 9.5 via immunohistochemistry. To perform quantitative analysis of the autonomic neuronal number, neurons within the lumbar sympathetic and parasympathetic ciliary ganglia were calculated. In addition, autonomic neurons were cultured from embryonic dt/dt mutants to elucidate degenerative patterns in vitro. Distribution patterns of neuronal intermediate filaments in cultured autonomic neurons were thoroughly studied under immunocytochemistry and conventional electron microscopy.
RESULTS
Our immunohistochemistry results indicate that peripheral sensory nerves and autonomic innervation of sweat glands and irises dominated degeneration in dt/dt mice. Quantitative results confirmed that the number of neurons was significantly decreased in the lumbar sympathetic ganglia as well as in the parasympathetic ciliary ganglia of dt/dt mice compared with those of wild-type mice. We also observed that the neuronal intermediate filaments were aggregated abnormally in cultured autonomic neurons from dt/dt embryos.
CONCLUSIONS
These results suggest that a deficiency in the cytoskeletal linker BPAG1 is responsible for dominant sensory nerve degeneration and severe autonomic degeneration in dt/dt mice. Additionally, abnormally aggregated neuronal intermediate filaments may participate in neuronal death of cultured autonomic neurons from dt/dt mutants.
Topics: Animals; Autonomic Nervous System; Carrier Proteins; Cells, Cultured; Cytoskeletal Proteins; Dystonia Musculorum Deformans; Dystonin; Embryo, Mammalian; Humans; Mice; Mice, Mutant Strains; Nerve Tissue Proteins; Sensory Receptor Cells
PubMed: 21272373
DOI: 10.1186/1423-0127-18-9 -
Frontiers in Immunology 2019Recent studies suggest an important role of immunoglobulin E (IgE) as an alternative pathogenic pathway in the development of bullous pemphigoid (BP), as the most...
Recent studies suggest an important role of immunoglobulin E (IgE) as an alternative pathogenic pathway in the development of bullous pemphigoid (BP), as the most frequent subepidermal blistering disease of the skin Use of IgE targeted therapies, such as omalizumab, has been shown promising in recent studies. The aim of this study was to assess the effect of omalizumab on FcεRI and IgE expression on circulating basophils and on lesional intradermal cells in BP to generate insight into the immunological effects of omalizumab in BP. We report two cases of BP patients treated with omalizumab. Efficacy of treatment was assessed clinically 4 months after initiation of the therapy. Lesional and non-lesional skin biopsies where taken before and 4 weeks after initiation of omalizumab therapy. In addition, FcεRI expression on circulating cells and IgE levels in serum and in the skin samples, as well as anti-BP180 and anti-BP230 in serum and eosinophils and basophils counts in blood were assessed before and during treatment. Both patients showed a marked improvement after 4 months, with no adverse effects. Down-regulation of FcεRI, IgE in lesional skin and on circulating basophils were observed in parallel with clinical improvement. The current case study supports the role of omalizumab in the treatment of a subset of BP patients. Our observations suggest that omalizumab represents a valuable therapeutic option in the management of BP patients. Its efficacy might be related to reduction in FcεRI+ and IgE+ basophils and intradermal cells.
Topics: Aged; Anti-Allergic Agents; Autoantibodies; Autoantigens; Basophils; Dystonin; Eosinophils; Humans; Immunoglobulin E; Leukocyte Count; Middle Aged; Non-Fibrillar Collagens; Omalizumab; Pemphigoid, Bullous; Receptors, IgE; Skin; Treatment Outcome; Collagen Type XVII
PubMed: 31474990
DOI: 10.3389/fimmu.2019.01919 -
The Journal of Cell Biology Feb 1999The dystonia musculorum (dt) mouse suffers from severe degeneration of primary sensory neurons. The mutated gene product is named dystonin and is identical to the...
The dystonia musculorum (dt) mouse suffers from severe degeneration of primary sensory neurons. The mutated gene product is named dystonin and is identical to the neuronal isoform of bullous pemphigoid antigen 1 (BPAG1-n). BPAG1-n contains an actin-binding domain at its NH2 terminus and a putative intermediate filament-binding domain at its COOH terminus. Because the degenerating sensory neurons of dt mice display abnormal accumulations of intermediate filaments in the axons, BPAG1-n has been postulated to organize the neuronal cytoskeleton by interacting with both the neurofilament triplet proteins (NFTPs) and microfilaments. In this paper we show by a variety of methods that the COOH-terminal tail domain of mouse BPAG1 interacts specifically with peripherin, but in contrast to a previous study (Yang, Y., J. Dowling, Q.C. Yu, P. Kouklis, D.W. Cleveland, and E. Fuchs. 1996. Cell. 86:655-665), mouse BPAG1 fails to associate with full-length NFTPs. The tail domains interfered with the association of the NFTPs with BPAG1. In dt mice, peripherin is present in axonal swellings of degenerating sensory neurons in the dorsal root ganglia and is downregulated even in other neural regions, which have no obvious signs of pathology. Since peripherin and BPAG1-n also display similar expression patterns in the nervous system, we suggest that peripherin is the specific interaction partner of BPAG1-n in vivo.
Topics: Animals; Autoantigens; Base Sequence; Binding Sites; Carrier Proteins; Cloning, Molecular; Collagen; Cytoskeletal Proteins; DNA Primers; DNA, Complementary; Disease Models, Animal; Dystonia; Dystonin; Intermediate Filament Proteins; Membrane Glycoproteins; Mice; Mice, Neurologic Mutants; Nerve Tissue Proteins; Neurofilament Proteins; Neurons; Non-Fibrillar Collagens; Peripherins; Protein Binding; Saccharomyces cerevisiae; Transfection; Collagen Type XVII
PubMed: 9971739
DOI: 10.1083/jcb.144.3.435 -
The Journal of Investigative Dermatology Jun 2010Epidermolysis bullosa (EB) is a group of autosomal dominant and recessive blistering skin diseases in which pathogenic mutations have been reported in 13 different genes...
A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex.
Epidermolysis bullosa (EB) is a group of autosomal dominant and recessive blistering skin diseases in which pathogenic mutations have been reported in 13 different genes encoding structural proteins involved in keratinocyte integrity, as well as cell-matrix or cell-cell adhesion. We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1, BPAG1-e (also known as BP230). The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen. The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles. In addition, he experiences episodic numbness in his limbs, which started at the age of 37 years. These neurological symptoms may also be due to DST gene mutation, although he has a concomitant diagnosis of CADASIL (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy), a cerebral small-vessel arteriopathy, which thus complicates the genotype-phenotype interpretation. With regard to skin blistering, the clinicopathological findings expand the molecular basis of EB by identifying BPAG1-e pathology in a new form of autosomal recessive EB simplex.
Topics: Adult; Blister; Carrier Proteins; Codon, Nonsense; Collagen Type VII; Cytoskeletal Proteins; Dystonin; Epidermolysis Bullosa Simplex; Hemidesmosomes; Homozygote; Humans; Integrin beta4; Male; Nerve Tissue Proteins; Plectin; Protein Isoforms; Skin
PubMed: 20164846
DOI: 10.1038/jid.2010.19 -
Molecular Biology of the Cell May 2003The bullous pemphigoid antigen 1 (BP230) and desmoplakin (DP) are members of the plakin protein family of cytolinkers. Despite their homology, their COOH termini...
The bullous pemphigoid antigen 1 (BP230) and desmoplakin (DP) are members of the plakin protein family of cytolinkers. Despite their homology, their COOH termini selectively bind distinct intermediate filaments (IFs). We studied sequences within their COOH termini required for their interaction with the epidermal keratins K5/K14, the simple epithelial keratins K8/K18, and type III IF vimentin by yeast three-hybrid, cell transfection, and overlay assays. The results indicate that BP230 interacts with K5/K14 but not with K8/K18 or vimentin via a region encompassing both the B and C subdomains and the COOH extremity, including a COOH-terminal eight-amino-acid stretch. In contrast, the C subdomain with the COOH-terminal extremity of DP interacts with K5/K14 and K8/K18, and its linker region is able to associate with K8/K18 and vimentin. Furthermore, the potential of DP to interact with IF proteins in yeast seems to be regulated by phosphorylation of Ser 2849 within its COOH terminus. Strikingly, BP230 and DP interacted with cytokeratins only when both type I and type II keratins were present. The head and tail domains of K5/K14 keratins were dispensable for their interaction with BP230 or DP. On the basis of our findings, we postulate that (1) the binding specificity of plakins for various IF proteins depends on their linker region between the highly homologous B and C subdomains and their COOH extremity and (2) the association of DP and BP230 with both epidermal and simple keratins is critically affected by the tertiary structure induced by heterodimerization and involves recognition sites located primarily in the rod domain of these keratins.
Topics: Amino Acid Sequence; Animals; Autoantigens; COS Cells; Carrier Proteins; Collagen; Cytoskeletal Proteins; Desmoplakins; Dimerization; Dystonin; Immunoblotting; Intermediate Filaments; Keratin-14; Keratin-15; Keratin-5; Keratins; Molecular Sequence Data; Nerve Tissue Proteins; Non-Fibrillar Collagens; Serine; Two-Hybrid System Techniques; Collagen Type XVII
PubMed: 12802069
DOI: 10.1091/mbc.e02-08-0548 -
Current Biology : CB Nov 1999A new isoform of the actin-neurofilament linker protein BPAG has been found that binds to and stabilizes axonal microtubules. This and other newly identified... (Review)
Review
A new isoform of the actin-neurofilament linker protein BPAG has been found that binds to and stabilizes axonal microtubules. This and other newly identified microtubule-associated proteins are likely to be just the tip of an iceberg of multifunctional proteins that stabilize and crosslink cytoskeletal filament networks.
Topics: Actin Cytoskeleton; Actins; Alternative Splicing; Animals; Autoantigens; Carrier Proteins; Collagen; Cytoskeletal Proteins; Dystonin; Eukaryotic Cells; Intermediate Filament Proteins; Macromolecular Substances; Mice; Mice, Knockout; Microtubule-Associated Proteins; Models, Molecular; Nerve Tissue Proteins; Non-Fibrillar Collagens; Plectin; Protein Isoforms; Research Design; Structure-Activity Relationship; Collagen Type XVII
PubMed: 10574751
DOI: 10.1016/s0960-9822(00)80048-2