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Advances in Dermatology 2007There has been a considerable progress in the understanding of the physiopathology of BP during the past 2 decades. The insights into the humoral and cellular immune... (Review)
Review
There has been a considerable progress in the understanding of the physiopathology of BP during the past 2 decades. The insights into the humoral and cellular immune response against BP180 and BP230 have increased significantly. Nevertheless, the factors underlying the initiation of the disease leading to a disruption of self-tolerance remain unclear. Clinically, the disease shows protean presentations, and diagnostic delay is common. A practical, relevant, and unresolved question is how to identify patients suffering from BP at an early stage of the disease, when direct immunofluorescence microscopy findings still may be negative. The characterization of markers allowing the differentiation of BP from other pruritic eruptions occurring in the elderly population would be extremely helpful in daily practice. Finally, despite the knowledge that potent topical steroids are efficient in controlling the disease, management of BP sometimes remains difficult and requires systemic therapies. It is hoped that a better knowledge of the regulation of the autoimmune response in BP also will facilitate the design of novel immunomodulatory therapeutic approaches devoid of the severe side effects of current immunosuppressive treatments.
Topics: Autoantibodies; Autoantigens; Carrier Proteins; Cytoskeletal Proteins; Dystonin; Hemidesmosomes; Humans; Immunologic Tests; Immunosuppressive Agents; Nerve Tissue Proteins; Non-Fibrillar Collagens; Pemphigoid, Bullous; Randomized Controlled Trials as Topic; Collagen Type XVII
PubMed: 18159905
DOI: 10.1016/j.yadr.2007.07.013 -
European Journal of Dermatology : EJD Apr 2019
Topics: Aged, 80 and over; Autoantigens; Dermatitis, Exfoliative; Dystonin; Humans; Immunoglobulin A; Immunoglobulin G; Linear IgA Bullous Dermatosis; Male; Non-Fibrillar Collagens; Collagen Type XVII
PubMed: 30973330
DOI: 10.1684/ejd.2019.3503 -
Genomics Nov 1996We have recently cloned the gene responsible for the mouse neurological disorder dystonia musculorum. The predicted product of this gene, dystonin (Dst), is a neural...
We have recently cloned the gene responsible for the mouse neurological disorder dystonia musculorum. The predicted product of this gene, dystonin (Dst), is a neural isoform of bullous pemphigoid antigen 1 (Bpag1) with an N-terminal actin binding domain. Here we report on the cloning and characterization of mouse ACF7. Sequence analysis revealed extended homology of mACF7 with both the actin binding domain (ABD) and the Bpag1 portions of dystonin. Moreover, mACF7 and Dst display similar isoform diversity and encode similar sized transcripts in the nervous system. Phylogenetic analysis of mACF7 and dystonin ABD sequences suggests a recent evolutionary origin and that these proteins form a separate novel subfamily within the beta-spectrin superfamily of actin binding proteins. Given the implication of several actin binding proteins in genetic disorders, it is important to know the pattern of mACF7 expression. mACF7 transcripts are detected principally in lung, brain, spinal cord, skeletal and cardiac muscle, and skin. Intriguingly, mACF7 expression in lung is strongly induced just before birth and is restricted to type II alveolar cells. To determine whether spontaneous mutants that may be defective in mACF7 exist, we have mapped the mACF7 gene to mouse chromosome 4.
Topics: Amino Acid Sequence; Animals; Base Sequence; Carrier Proteins; Chromosome Mapping; Cloning, Molecular; Cytoskeletal Proteins; DNA, Complementary; Dystonin; Male; Mice; Mice, Inbred BALB C; Microfilament Proteins; Molecular Sequence Data; Nerve Tissue Proteins; RNA, Messenger
PubMed: 8954775
DOI: 10.1006/geno.1996.0587 -
Journal of Dermatological Science Apr 2015Bullous pemphigoid (BP) is a common autoimmune blistering skin disease in which two hemidesmosomal components--the transmembrane collagen XVII (BP180 or BPAG2) and the... (Review)
Review
Bullous pemphigoid (BP) is a common autoimmune blistering skin disease in which two hemidesmosomal components--the transmembrane collagen XVII (BP180 or BPAG2) and the plakin family protein BP230 (BPAG1)--are targeted by autoimmunity. Of these, collagen XVII (COL17) is thought to be a major autoantigen, and vital roles of IgG autoantibodies in blister formation have been elucidated. However, BP shows distinct features, including pruritic urticarial erythema and eosinophilic infiltration, which may be independent of IgG-mediated autoimmunity. Recently, it has been revealed that sera from certain patients with BP contain IgE autoantibodies to COL17 and that IgE autoantibodies bind to peri-lesional dermal-epidermal junctions. Mouse models have demonstrated that IgE antibodies to COL17 induce erythema and eosinophilic infiltration in skin. In addition, the successful treatment of severe BP with omalizumab, a humanized monoclonal antibody targeting IgE, has been reported. These findings suggest that both IgG and IgE autoantibodies to COL17 may be involved in the BP pathogenesis. This article summarizes IgE-mediated autoimmunity to COL17 in BP.
Topics: Animals; Anti-Allergic Agents; Autoantibodies; Autoantigens; Autoimmunity; Carrier Proteins; Cytoskeletal Proteins; Disease Models, Animal; Dystonin; Humans; Immunoglobulin E; Nerve Tissue Proteins; Non-Fibrillar Collagens; Omalizumab; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 25797172
DOI: 10.1016/j.jdermsci.2015.03.002 -
Experimental Dermatology Dec 2017The dermal-epidermal junction consists of a network of several interacting structural proteins that strengthen adhesion and mediate signalling events. This structural... (Review)
Review
The dermal-epidermal junction consists of a network of several interacting structural proteins that strengthen adhesion and mediate signalling events. This structural network consists of hemidesmosomal-anchoring filament complexes connecting the basal keratinocytes to the basement membrane. The anchoring filaments in turn interact with the anchoring fibrils to attach the basement membrane to the underlying dermis. Several of these structural proteins are recognized by autoantibodies in pemphigoid diseases, a heterogeneous group of clinically and immunopathologically diverse entities. Targeted proteins include the two intracellular plakins, plectin isoform 1a and BP230 (also called bullous pemphigoid antigen (BPAG) 1 isoform e (BPAG1e)). Plectin 1a and BP230 are connected to the intermediate filaments and to the cell surface receptor α6β4 integrin, which in turn is connected to laminin 332, a component of the anchoring filaments. Further essential adhesion proteins are BP180, a transmembrane protein, laminin γ1 and type VII collagen. Latter protein is the major constituent of the anchoring fibrils. Mutations in the corresponding genes of these adhesion molecules lead to inherited epidermolysis bullosa emphasizing the importance of these proteins for the integrity of the dermal-epidermal junction. This review will provide an overview on the structure and function of the proteins situated in the dermal-epidermal junction targeted by autoantibodies.
Topics: Animals; Autoantibodies; Autoantigens; Collagen Type VII; Dystonin; Humans; Integrin alpha6beta4; Laminin; Non-Fibrillar Collagens; Plectin; Skin Diseases, Vesiculobullous; Collagen Type XVII
PubMed: 28887824
DOI: 10.1111/exd.13446 -
Experimental Dermatology Dec 2017In elderly patients, bullous pemphigoid (BP) is associated with several comorbidities; the strongest association occurs between BP and neurological diseases. Different... (Review)
Review
In elderly patients, bullous pemphigoid (BP) is associated with several comorbidities; the strongest association occurs between BP and neurological diseases. Different types of dementia, Parkinson's disease, cerebrovascular disorders and epilepsy all have a significant association with BP, but patients with multiple sclerosis have the highest risk of BP. An existing neurological disorder appears to increase the risk for subsequent BP, but an increased risk for developing some neurological diseases has also been reported following BP diagnosis. BP seems to be associated with several psychiatric diseases such as schizophrenia, uni- and bipolar disorder, schizotypal and delusional disorders, and personality disorders, but the risk ratios are usually lower than with neurological diseases. In addition to the skin, the BP autoantigens BP180 and BP230 are expressed in the central nervous system. This finding together with the strong epidemiological association between neurological disorders and BP has led to an assumption that neurodegeneration or neuroinflammation could lead to a cross-reactive immunoresponse between neural and cutaneous antigens and the failure of self-tolerance. A subpopulation of patients with Alzheimer's disease or Parkinson's disease have circulating IgG autoantibodies against BP180, but currently their significance for the development of BP is unclear, because these antineural BP180 antibodies neither bind to the cutaneous basement membrane nor cause BP-like symptoms. Further studies analysing large and well-characterized populations of neurological and psychiatric patients are required to understand better the role of autoimmunization against neural BP autoantigens in the pathogenesis of BP.
Topics: Autoantigens; Dystonin; Humans; Mental Disorders; Nervous System Diseases; Non-Fibrillar Collagens; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 28677172
DOI: 10.1111/exd.13401 -
Brain Research Aug 2008The trigeminal ganglion (TG) and mesencephalic trigeminal tract nucleus (Mes5) were investigated in wild type and dystonia musculorum (dt) mice to study the effect of...
The number of nociceptors in the trigeminal ganglion but not proprioceptors in the mesencephalic trigeminal tract nucleus is reduced in dystonin deficient dystonia musculorum mice.
The trigeminal ganglion (TG) and mesencephalic trigeminal tract nucleus (Mes5) were investigated in wild type and dystonia musculorum (dt) mice to study the effect of dystonin deficiency on primary sensory neurons in the trigeminal nervous system. At postnatal day 14, the number of TG neurons was markedly decreased in dt mice when compared to wild type mice (43.1% reduction). In addition, dystonin disruption decreased the number of sensory neurons which bound to isolectin B4, and contained calcitonin gene-related peptide or high-affinity nerve growth factor receptor TrkA. Immunohistochemistry for caspase-3 demonstrated that dystonin deficiency induced excess cell death of TG neurons during the early postnatal period. In contrast, Mes5 neurons were barely affected in dt mice. These data together suggest that dystonin is necessary for survival of nociceptors but not proprioceptors in the trigeminal nervous system.
Topics: Animals; Carrier Proteins; Caspase 3; Cytoskeletal Proteins; Dystonin; Gene Expression Regulation; Lectins; Mice; Mice, Knockout; Nerve Tissue Proteins; Nociceptors; Receptor, trkA; Sensory Receptor Cells; Trigeminal Ganglion; Trigeminal Nuclei
PubMed: 18619576
DOI: 10.1016/j.brainres.2008.05.063 -
Current Opinion in Genetics &... Jun 1997Desmoplakin, plectin, bullous pemphigoid antigen 1 and envoplakin are four sequence-related proteins--recently named the plakin family--that localize to intermediate... (Review)
Review
Desmoplakin, plectin, bullous pemphigoid antigen 1 and envoplakin are four sequence-related proteins--recently named the plakin family--that localize to intermediate filaments and filament attachment sites at the plasma membrane. New interest in the plakins has been stimulated by the discoveries that they can link different cytoskeletal elements together and that loss of plakin function can cause diseases of the skin and other tissues.
Topics: Alternative Splicing; Animals; Autoantigens; Carrier Proteins; Collagen; Cytoskeletal Proteins; Desmoplakins; Dystonin; Humans; Intermediate Filament Proteins; Membrane Proteins; Nerve Tissue Proteins; Non-Fibrillar Collagens; Plectin; Protein Conformation; Protein Precursors; Skin Diseases; Collagen Type XVII
PubMed: 9229116
DOI: 10.1016/s0959-437x(97)80154-2 -
The 'spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families.Journal of Cell Science Nov 2002Recent studies have characterised a family of giant cytoskeletal crosslinkers encoded by the short stop gene in Drosophila and the dystonin/BPAG1 and MACF1 genes in... (Review)
Review
Recent studies have characterised a family of giant cytoskeletal crosslinkers encoded by the short stop gene in Drosophila and the dystonin/BPAG1 and MACF1 genes in mammals. We refer to the products of these genes as spectraplakins to highlight the fact that they share features with both the spectrin and plakin superfamilies. These genes produce a variety of large proteins, up to almost 9000 residues long, which can potentially extend 0.4 micro m across a cell. Spectraplakins can interact with all three elements of the cytoskeleton: actin, microtubules and intermediate filaments. The analysis of mutant phenotypes in BPAG1 in mouse and short stop in Drosophila demonstrates that spectraplakins have diverse roles. These include linking the plasma membrane and the cytoskeleton, linking together different elements of the cytoskeleton and organising membrane domains.
Topics: Actins; Animals; Autoantigens; Carrier Proteins; Cell Membrane; Collagen; Cytoskeletal Proteins; Drosophila Proteins; Dystonin; Eukaryotic Cells; Humans; Intermediate Filaments; Microfilament Proteins; Microtubules; Nerve Tissue Proteins; Non-Fibrillar Collagens; Spectrin; Collagen Type XVII
PubMed: 12376554
DOI: 10.1242/jcs.00157 -
Acta Odontologica Scandinavica Aug 2001Pemphigus and pemphigoid are two of a group of bullous diseases affecting oral mucosa and skin. Mucous membrane pemphigoid (MMP) comprises a heterogeneous group of... (Review)
Review
Pemphigus and pemphigoid are two of a group of bullous diseases affecting oral mucosa and skin. Mucous membrane pemphigoid (MMP) comprises a heterogeneous group of disorders characterized by subepithelial separation and the deposition of immunoglobulins and complement along the basement membrane zone (BMZ). The target antigens in the epithelium and BMZ determine the nature of the condition, and recently there have been considerable improvements in our understanding of the BMZ antigenic composition. Pemphigus vulgaris (PV) is characterized by autoantibodies of the IgG isotype to the desmosomal glycoprotein desmoglein (Dsg) 3, whereas pemphigus foliaccus targets Dsg1, although at least 50% of PV patients have additional autoantibodies to Dsg1. The clinical phenotype appears to be determined by the relative amounts of Dsg1 and Dsg3. Patients with oral or mucosal PV have predominantly Dsg3 autoantibodies. The most frequently targeted antigen in MMP is bullous pemphigoid antigen 180 (BP180), although bullous pemphigoid antigen 230 (BP230), laminin 5, and beta 4 integrin are also involved. Circulating IgG and IgA antibodies may bind to different epitopes of BP180 namely the NC 16A domain or COOH -terminal domain. Pure ocular disease has been associated with IgA antibodies to a 45-kDa antigen and IgG antibodies to the 205-kDa antigen b4 integrin. The use of salt-split skin substrate enables differentiation between epidermal and dermal 'binders'. Since both the specificity and the antibody titer appear to have direct relationships with the disease severity, and a combination of clinical score and antibody titer provides valuable prognostic data, these investigations should be carried out on a more routine basis.
Topics: Autoantigens; Basement Membrane; Carrier Proteins; Cell Adhesion Molecules; Cytoskeletal Proteins; Desmoglein 1; Desmogleins; Desmoplakins; Desmosomes; Diagnosis, Differential; Dystonin; Humans; Immunologic Tests; Mouth Diseases; Nerve Tissue Proteins; Non-Fibrillar Collagens; Pemphigoid, Bullous; Pemphigus; Collagen Type XVII
PubMed: 11570526
DOI: 10.1080/00016350152509256