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Antibodies (Basel, Switzerland) Jun 2022Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease predominantly affecting elderly patients and carries significant morbidity and mortality.... (Review)
Review
Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease predominantly affecting elderly patients and carries significant morbidity and mortality. Patients typically suffer from severe itch with eczematous lesions, urticarial plaques, and/or tense blisters. BP is characterized by the presence of circulating autoantibodies against two components of the hemidesmosome, BP180 and BP230. The transmembrane BP180, also known as type XVII collagen or BPAG2, represents the primary pathogenic autoantigen in BP, whereas the intracellular BP230 autoantigen is thought to play a minor role in disease pathogenesis. Although experimental data exist suggesting that anti-BP230 antibodies are secondarily formed following initial tissue damage mediated by antibodies targeting extracellular antigenic regions of BP180, there is emerging evidence that anti-BP230 IgG autoantibodies alone directly contribute to tissue damage. It has been further claimed that a subset of patients has a milder variant of BP driven solely by anti-BP230 autoantibodies. Furthermore, the presence of anti-BP230 autoantibodies might correlate with distinct clinical features. This review summarizes the current understanding of the role of BP230 and anti-BP230 antibodies in BP pathogenesis.
PubMed: 35892704
DOI: 10.3390/antib11030044 -
Journal of the European Academy of... Nov 2022Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two...
Serum autoantibody reactivity in bullous pemphigoid is associated with neuropsychiatric disorders and the use of antidiabetics and antipsychotics: a large, prospective cohort study.
BACKGROUND
Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed.
OBJECTIVE
To determine associations of autoantibody reactivities with comorbidities and concomitant medication.
METHODS
In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed.
RESULTS
An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine.
CONCLUSION
Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.
Topics: Antipsychotic Agents; Autoantibodies; Autoantigens; Blister; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dystonin; Humans; Hypoglycemic Agents; Immunoglobulin G; Insulins; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prospective Studies; Serum Sickness; Thyroxine
PubMed: 35796163
DOI: 10.1111/jdv.18414 -
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 -
International Journal of Molecular... May 2022Adhesion between cells and the extracellular matrix (ECM) is one of the prerequisites for multicellularity, motility, and tissue specialization. Focal adhesions (FAs)...
Adhesion between cells and the extracellular matrix (ECM) is one of the prerequisites for multicellularity, motility, and tissue specialization. Focal adhesions (FAs) are defined as protein complexes that mediate signals from the ECM to major components of the cytoskeleton (microtubules, actin, and intermediate filaments), and their mutual communication determines a variety of cellular processes. In this study, human cytoskeletal crosstalk proteins were identified by comparing datasets with experimentally determined cytoskeletal proteins. The spectraplakin dystonin was the only protein found in all datasets. Other proteins (FAK, RAC1, septin 9, MISP, and ezrin) were detected at the intersections of FAs, microtubules, and actin cytoskeleton. Homology searches for human crosstalk proteins as queries were performed against a predefined dataset of proteomes. This analysis highlighted the importance of FA communication with the actin and microtubule cytoskeleton, as these crosstalk proteins exhibit the highest degree of evolutionary conservation. Finally, phylogenetic analyses elucidated the early evolutionary history of spectraplakins and cortical microtubule stabilization complexes (CMSCs) as model representatives of the human cytoskeletal crosstalk. While spectraplakins probably arose at the onset of opisthokont evolution, the crosstalk between FAs and microtubules is associated with the emergence of metazoans. The multiprotein complexes contributing to cytoskeletal crosstalk in animals gradually gained in complexity from the onset of metazoan evolution.
Topics: Actin Cytoskeleton; Actins; Animals; Cytoskeleton; Microtubules; Phylogeny
PubMed: 35628404
DOI: 10.3390/ijms23105594 -
Journal of the American Academy of... Aug 2022Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Its presentation is polymorphic.
BACKGROUND
Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Its presentation is polymorphic.
OBJECTIVE
To investigate different clinical and biological profiles of BP.
METHODS
We conducted a retrospective 2-center study including all BP patients seen between January 1, 2015, and February 28, 2021. We performed hierarchical clustering on principal components.
RESULTS
Three clusters were identified. Patients in cluster 1 (n = 155) were older than those in clusters 2 (n = 89) and 3 (n = 35; P < .0001), more frequently presented pauci-bullous BP (n = 63 [41%] vs 14 [16%] and 2 [6%], respectively; P < .0001) and had anti-BP230 antibodies in 87% of cases. More than 100 blisters were observed in 14 patients (40%) from cluster 3, versus 3 (2%) from cluster 1 and 0 (0%) from cluster 2 (P < .0001). Frequency of mucosal involvement was higher in cluster 3 (n = 32 [91%, including epiglottis in 40%] vs 11 [7%] and 34 [38%]; P < .0001). In clusters 2 and 3, 70% and 74% of patients had antibodies targeting only BP180. Those in cluster 3 received more lines of systemic treatment and experienced more relapses.
LIMITATIONS
Retrospective study without immunoelectron microscopy.
CONCLUSION
We identified 3 different BP clusters, including one corresponding to severe BP180 BP230 BP with features common to mucous membrane pemphigoid.
Topics: Autoantibodies; Autoantigens; Blister; Dystonin; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous; Retrospective Studies
PubMed: 35483492
DOI: 10.1016/j.jaad.2022.04.029 -
Experimental Dermatology Jun 2022DST encodes bullous pemphigoid antigen-1 (BPAG1), a protein with eight tissue-specific isoforms expressed in the skin, muscle, brain and nerves. Accordingly, mutations...
DST encodes bullous pemphigoid antigen-1 (BPAG1), a protein with eight tissue-specific isoforms expressed in the skin, muscle, brain and nerves. Accordingly, mutations in this gene are associated with epidermolysis bullosa simplex (EBS) and hereditary sensory and autonomic neuropathy type 6 (HSAN-VI). The genotypic spectrum is attested to by 19 distinct mutations but genotype-phenotype correlation for both disorders is not well established. In this study, we performed next-generation sequencing (NGS) on two families with different phenotypic presentations, one foetus (P1) with musculoskeletal and neurological malformations established by prenatal ultrasound and family history, and a 15-year-old female patient (P2) with skin blistering. P1 had a novel homozygous nonsense mutation, DST: NM_001144769, c.3805C>T, p.R1269* within a region of genetic homozygosity (ROH). This mutation resides within the plakin domain of BPAG1 and ablates all isoforms of this protein, leading to novel extracutaneous phenotypes consistent with HSAN-VI in P1. P2 had a recurrent homozygous mutation DST: NM_001723.7, c.3370C>T, p.Gln1124* that presented with giant, trauma-induced skin blisters without extracutaneous involvement. This mutation is located within the coiled-coil domain present in the skin isoform of DST, BPGA1-e, associated with EBS. In summary, we report two families with pathogenic DST variants and expand the spectrum of DST genotype and phenotypes.
Topics: Dystonin; Epidermolysis Bullosa Simplex; Female; Hereditary Sensory and Autonomic Neuropathies; Homozygote; Humans; Mutation; Phenotype; Protein Isoforms
PubMed: 35276021
DOI: 10.1111/exd.14562 -
Molecular Biology of the Cell May 2022The spectraplakin family of proteins includes ACF7/MACF1 and BPAG1/dystonin in mammals, VAB-10 in in zebrafish, and Short stop (Shot), the sole member. Spectraplakins...
The spectraplakin family of proteins includes ACF7/MACF1 and BPAG1/dystonin in mammals, VAB-10 in in zebrafish, and Short stop (Shot), the sole member. Spectraplakins are giant cytoskeletal proteins that cross-link actin, microtubules, and intermediate filaments, coordinating the activity of the entire cytoskeleton. We examined the role of Shot during cell migration using two systems: the in vitro migration of tissue culture cells and in vivo through border cell migration. RNA interference (RNAi) depletion of Shot increases the rate of random cell migration in tissue culture cells as well as the rate of wound closure during scratch-wound assays. This increase in cell migration prompted us to analyze focal adhesion dynamics. We found that the rates of focal adhesion assembly and disassembly were faster in Shot-depleted cells, leading to faster adhesion turnover that could underlie the increased migration speeds. This regulation of focal adhesion dynamics may be dependent on Shot being in an open confirmation. Using border cells as an in vivo model for cell migration, we found that RNAi depletion led to precocious border cell migration. Collectively, these results suggest that spectraplakins not only function to cross-link the cytoskeleton but may regulate cell-matrix adhesion.
Topics: Actins; Animals; Cell Movement; Cytoskeletal Proteins; Drosophila; Drosophila Proteins; Focal Adhesions; Mammals; Microfilament Proteins; Microtubules; Zebrafish
PubMed: 35235367
DOI: 10.1091/mbc.E21-09-0434 -
Scientific Reports Jan 2022The adaptation of vertebrates to different environments was associated with changes in the molecular composition and regulation of epithelia. Whales and dolphins,...
The adaptation of vertebrates to different environments was associated with changes in the molecular composition and regulation of epithelia. Whales and dolphins, together forming the clade cetaceans, have lost multiple epithelial keratins during or after their evolutionary transition from life on land to life in water. It is unknown whether the changes in keratins were accompanied by gain or loss of cytoskeletal adapter proteins of the plakin family. Here we investigated whether plakin proteins are conserved in cetaceans and other vertebrates. Comparative analysis of genome sequences showed conservation of dystonin, microtubule actin crosslinking factor 1 (MACF1), plectin, desmoplakin, periplakin and envoplakin in cetaceans. By contrast, EPPK1 (epiplakin) was disrupted by inactivating mutations in all cetaceans investigated. Orthologs of EPPK1 are present in bony and cartilaginous fishes and tetrapods, indicating an evolutionary origin of EPPK1 in a common ancestor of jawed vertebrates (Gnathostomes). In many vertebrates, EPPK1 is flanked by an as-yet uncharacterized gene that encodes protein domains homologous to the carboxy-terminal segment of MACF1. We conclude that epiplakin, unlike other plakins, was lost in cetaceans.
Topics: Animals; Autoantigens; Cetacea; Datasets as Topic; Evolution, Molecular; Genomics; Loss of Function Mutation
PubMed: 35064199
DOI: 10.1038/s41598-022-05087-0 -
Journal of Dermatological Science Feb 2022Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP is characterized by the development of tense blisters induced by tissue-bound specific... (Review)
Review
Bullous pemphigoid (BP) patients with selective IgG autoreactivity against BP230: Review of a rare but valuable cohort with impact on the comprehension of the pathogenesis of BP.
Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP is characterized by the development of tense blisters induced by tissue-bound specific autoantibodies directed against the major autoantigens bullous pemphigoid autoantigen 180 (BP180, also called BPAG2 or Collagen XVII) and bullous pemphigoid autoantigen 230 (BP230, also called BPAG1 or dystonin). The vast majority of BP patients have autoantibodies targeting BP180, or both, BP180 and BP230. The hemidesmosomal protein BP180 is regarded as the main autoantigen, whereas the pathophysiologic relevance of intracellularly-located BP230 is controversial. A small subpopulation of BP patients selectively reveals autoantibodies against BP230 (BP230 patients) strongly supporting that BP230 autoantibodies might be sufficient to induce skin pathology. In line, BP animal models have been developed, which successfully mimic a human BP phenotype by targeting BP230. In this context, our group has recently shown that a murine autoantibody targeting BP230 induces subepidermal blisters in vivo. This finding suggests that blister formation in the population of patients with selective autoreactivity against BP230 may share pathophysiologic features of pathogenic anti-BP230 autoantibodies in our murine model. This review summarizes the clinical features of BP patients with selective autoreactivity against BP230, enlightens the currently available BP mouse models targeting BP230 and discusses the potential pathophysiological mechanism of BP230 autoantibodies.
Topics: Animals; Autoantibodies; Autoantigens; Comprehension; Dystonin; Humans; Immunoglobulin G; Mice; Non-Fibrillar Collagens; Pemphigoid, Bullous; Skin
PubMed: 34930674
DOI: 10.1016/j.jdermsci.2021.11.011 -
American Journal of Medical Genetics.... Apr 2022The DST gene is located on chromosome 6p and encodes for a large protein. Alternative splicing of this protein produces the neuronal (a1-a3), muscular (b1-b3), and... (Review)
Review
The DST gene is located on chromosome 6p and encodes for a large protein. Alternative splicing of this protein produces the neuronal (a1-a3), muscular (b1-b3), and epithelial (e) isoforms. Hereditary sensory and autonomic neuropathy (HSAN) type VI is a rare autosomal recessive disorder due to mutations affecting the a2 isoform. We present a case of HSAN-VI in a male neonate born to consanguineous parents. Genome sequencing revealed a novel homozygous variant (DST_c.1118C > T; p.Pro373Leu) inherited from both parents. This case further expands the phenotype and genotype of this rare syndrome.
Topics: Dystonin; Hereditary Sensory and Autonomic Neuropathies; Humans; Infant; Male; Neurons; Phenotype; Protein Isoforms
PubMed: 34897952
DOI: 10.1002/ajmg.a.62609