-
European Journal of Dermatology : EJD Aug 2020Autoimmune blistering diseases (AIBDs) are a group of fatal diseases with specific autoantibodies. BIOCHIP mosaic is a novel and all-in-one measure used for the rapid...
BACKGROUND
Autoimmune blistering diseases (AIBDs) are a group of fatal diseases with specific autoantibodies. BIOCHIP mosaic is a novel and all-in-one measure used for the rapid diagnosis of AIBDs.
OBJECTIVES
To evaluate the diagnostic accuracy based on BIOCHIP mosaic (FA1501-1005-60) in Chinese patients with AIBDs.
MATERIALS AND METHODS
Seventy-seven patients with AIBDs and 20 controls were enrolled. The BIOCHIP mosaic was performed using both serum and plasma samples.
RESULTS
Based on BIOCHIP mosaic, the data from paired plasma and serum samples demonstrated a high degree of concordance (Cohen's kappa = 0.896-1.000) for autoantibodies against Dsg1, Dsg3, BP180-NC16A-4X, BP230gC, prickle-cell desmosomes, and pemphigoid antigens. Moreover, BIOCHIP mosaic also demonstrated a high degree of consistency for the detection rate of anti-Dsg1, Dsg3, plakins, BP180-NC16A-4X and non-collagenous domain of type VII collagen autoantibodies for the diagnosis of pemphigus foliaceus (77.3%), pemphigus vulgaris (88.6%), paraneoplastic pemphigus (100.0%), bullous pemphigoid (92.8%) and epidermolysis bullosa acquisita (99.0%), respectively.
CONCLUSION
Using BIOCHIP mosaic, serum and plasma samples may be used interchangeably at 1/10 dilution. Overall, the BIOCHIP mosaic was shown to be a useful and accurate tool for the diagnosis of AIBDs.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asian People; Autoantibodies; Autoantigens; Autoimmune Diseases; Case-Control Studies; Desmoglein 1; Desmoglein 3; Dystonin; Fluorescent Antibody Technique, Indirect; Humans; LIM Domain Proteins; Middle Aged; Non-Fibrillar Collagens; Plakins; Predictive Value of Tests; Skin Diseases, Vesiculobullous; Tumor Suppressor Proteins; Young Adult; Collagen Type XVII
PubMed: 32969793
DOI: 10.1684/ejd.2020.3839 -
Composition of hemidesmosomes in basal keratinocytes of normal buccal mucosa and oral lichen planus.European Journal of Oral Sciences Oct 2020Oral lichen planus (OLP) is a chronic inflammatory disease displaying ultrastructural disturbances in epithelial hemidesmosomes. The expression of several key...
Oral lichen planus (OLP) is a chronic inflammatory disease displaying ultrastructural disturbances in epithelial hemidesmosomes. The expression of several key hemidesmosomal components in OLP as well as in normal buccal mucosa is, however, unknown. The aim of the study was therefore to examine intracellular and extracellular components involved in hemidesmosomal attachment, in OLP (n = 20) and in normal buccal mucosa (n = 10), by immunofluorescence. In normal buccal mucosa, laminin-α3γ2, integrin-α6β4, CD151, collagen α-1(XVII) chain, and dystonin showed linear expression along the basal membrane, indicating the presence of type I hemidesmosomes. Plectin stained most epithelial cell membranes and remained unphosphorylated at S4642. In OLP, most hemidesmosomal molecules examined showed disturbed expression consisting of discontinuous increases, apicolateral location, and/or intracellular accumulation. Plectin showed S4642-phosphorylation at the basement membrane, and deposits of laminin-α3 and laminin-γ2 were found within the connective tissue. The disturbed expression of hemidesmosomal proteins in OLP indicates deficient attachment of the basal cell layer, which can contribute to detachment and cell death of basal keratinocytes seen in the disease.
Topics: Basement Membrane; Hemidesmosomes; Humans; Keratinocytes; Lichen Planus, Oral; Mouth Mucosa
PubMed: 32870574
DOI: 10.1111/eos.12732 -
Journal of Dermatological Science Oct 2020Regulatory T (Treg) cells play an essential role in peripheral immune tolerance. Bullous pemphigoid (BP) is the most common blistering disease and is caused by... (Observational Study)
Observational Study
BACKGROUND
Regulatory T (Treg) cells play an essential role in peripheral immune tolerance. Bullous pemphigoid (BP) is the most common blistering disease and is caused by autoantibodies to two BP antigens: type XVII collagen and BP230. Recently, we reported that Treg cell dysfunction may cause the production of autoantibodies to BP antigens. Several studies have suggested an association between Treg cells and BP pathogenesis. However, Treg cells are heterogeneous in humans, leading to inconsistent results in previous studies.
OBJECTIVE
To assess functional Treg subsets in BP.
METHODS
We examined three distinct Treg subsets in conventional BP (cBP) patients before versus after systemic corticosteroid treatment, dipeptidyl peptidase-4 inhibitor-associated BP (DPP-4i-BP) patients, younger controls and older controls.
RESULTS
We found that total Treg cells and all Treg cell subsets were increased in cBP patients before treatment and decreased by systemic corticosteroid treatment. In contrast, neither total Treg cells nor all Treg subsets were increased in DPP-4i-BP. Notably, CD45RA Foxp3 effector Treg cells positively correlated with disease severity in cBP, whereas CD45RAFoxp3 naïve Treg cells positively correlated with the disease severity in DPP-4i-BP.
CONCLUSION
These findings suggest that Treg cells are differently involved in the pathogeneses of cBP and DPP-4i-BP.
Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; CD4 Lymphocyte Count; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dystonin; Female; Glucocorticoids; Healthy Volunteers; Humans; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Severity of Illness Index; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Collagen Type XVII
PubMed: 32843228
DOI: 10.1016/j.jdermsci.2020.08.004 -
Neurology. Genetics Oct 2020To determine the genetic cause of axonal Charcot-Marie-Tooth disease in a small family with 2 affected siblings, one of whom had cerebellar features on examination.
OBJECTIVE
To determine the genetic cause of axonal Charcot-Marie-Tooth disease in a small family with 2 affected siblings, one of whom had cerebellar features on examination.
METHODS
Whole-exome sequencing of genomic DNA and analysis for recessively inherited mutations; PCR-based messenger RNA/complementary DNA analysis of transcripts to characterize the effects of variants identified by exome sequencing.
RESULTS
We identified compound heterozygous mutations in dystonin (), which is alternatively spliced to create many plakin family linker proteins (named the bullous pemphigoid antigen 1 [BPAG1] proteins) that function to bridge cytoskeletal filament networks. One mutation (c.250C>T) is predicted to cause a nonsense mutation (p.R84X) that only affects isoform 2 variants, which have an N-terminal transmembrane domain; the other (c.8283+1G>A) mutates a consensus splice donor site and results in a 22 amino acid in-frame deletion in the spectrin repeat domain of all BPAG1a and BPAG1b isoforms.
CONCLUSIONS
These findings introduce a novel human phenotype, axonal Charcot-Marie-Tooth, of recessive mutations, and provide further evidence that BPAG1 plays an essential role in axonal health.
PubMed: 32802955
DOI: 10.1212/NXG.0000000000000496 -
Immunological Medicine Mar 2021Bullous pemphigoid (BP) is a cutaneous autoimmune blistering disorder. Recently, it has been reported that dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with...
Bullous pemphigoid (BP) is a cutaneous autoimmune blistering disorder. Recently, it has been reported that dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with the development of BP (DPP4i-BP). Patients with DPP4i-BP have autoantibodies (autoAbs) preferentially targeting full-length BP180, but not the BP180NC16a domain. In this report, we described a case of anti-BP230 antibody (Ab)-positive BP receiving DPP4i. A 78-year-old male with a medical history of type 2 diabetes receiving vildagliptin at 100 mg daily for 38 months was referred to our hospital with itching blisters on his body and extremities. Skin biopsy showed subepidermal bulla with eosinophil infiltration. Direct immunofluorescence staining revealed a linear staining pattern with complement C3 and IgG at the subepidermal basement membrane zone. By laboratory testing, autoAbs against BP180NC16a and full-length BP180 were negative by enzyme-linked immunosorbent assay (ELISA); however, anti-BP230 Abs were positive by ELISA (index: 123.91). His HLA genotype was DQB1*04:01 and 05:01. Based on these results, we diagnosed the patient with anti-BP230 Abs-positive BP associated with DPP4i. To the best of our knowledge, this is the first case of DPP4i-BP with only anti-BP230 Abs. Further accumulation of DPP4i-BP cases is needed to clarify the relationship between overall features of DPP4i-BP and anti-BP230 Abs.
Topics: Aged; Autoantibodies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dystonin; Humans; Male; Pemphigoid, Bullous; Time Factors; Vildagliptin
PubMed: 32634333
DOI: 10.1080/25785826.2020.1787584 -
Frontiers in Genetics 2020Hereditary sensory and autonomic neuropathies (HSANs) are a rare and severe group of sensory axonal neuropathies. HSANs have been classified into eight groups based on...
Hereditary sensory and autonomic neuropathies (HSANs) are a rare and severe group of sensory axonal neuropathies. HSANs have been classified into eight groups based on mode of inheritance, clinical features, and the involved genes. HSAN-VI, perhaps the most notable type, is an autosomal recessive disease, which manifests as the severely impaired pain sensitivity, autonomic disturbances, distal myopathy, spontaneous or surgical amputations, and sometimes early death. Mutations in have been identified as the cause of HSAN-VI. encodes dystonin, a member of the plakin protein family that is involved in cytoskeletal filament networks. Dystonin has seven major isoforms in nerve, muscle, and epithelium. The present study investigated a Chinese family with HSAN and explored potential pathogenic variants using whole-exome sequencing (WES). Variants were screened and filtered through bioinformatics analysis and prediction of variant pathogenicity. Co-segregation analysis was subsequently conducted. We identified compound heterozygous variants of (c.3304G>A, p.V1102I and c.13796G>A, p.R4599H) in two patients. We reported on a Chinese family with HSAN-VI family and detected the disease-causing variants. Our description expands the spectrum of known variants and contributes to the clinical diagnosis of HSAN-VI.
PubMed: 32528525
DOI: 10.3389/fgene.2020.00492 -
Disease Models & Mechanisms May 2020Loss-of-function mutations in dystonin () can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently,...
Loss-of-function mutations in dystonin () can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently, -related diseases were recognized to be more complex than previously thought because a patient exhibited both neurological and skin manifestations, whereas others display only one or the other. A single locus produces at least three major isoforms: (neuronal isoform), (muscular isoform) and (epithelial isoform). () mice, which have mutations in , were originally identified as spontaneous mutants displaying neurological phenotypes. To reveal the mechanisms underlying the phenotypic heterogeneity of -related diseases, we investigated two mutant strains with different mutations: a spontaneous mutant ( mice) and a gene-trap mutant ( mice). The allele possesses a nonsense mutation in an exon shared by all isoforms. The allele is predicted to inactivate and isoforms but not There was a decrease in the levels of mRNA in the neural tissue of both and homozygotes. Loss of sensory and autonomic nerve ends in the skin was observed in both and mice at postnatal stages. In contrast, mRNA expression was reduced in the skin of mice but not in mice. Expression levels of Dst proteins in neural and cutaneous tissues correlated with mRNAs. Because encodes a structural protein in hemidesmosomes (HDs), we performed transmission electron microscopy. Lack of inner plaques and loss of keratin filament invasions underneath the HDs were observed in the basal keratinocytes of mice but not in those of mice; thus, the distinct phenotype of the skin of mice could be because of failure of Dst-e expression. These results indicate that distinct mutations within the locus can cause different loss-of-function patterns among isoforms, which accounts for the heterogeneous neural and skin phenotypes in mice and -related diseases.
Topics: Animals; Desmosomes; Disease Models, Animal; Dystonic Disorders; Dystonin; Gene Expression Regulation; Homozygote; Mice; Mutation; Neurons; Phenotype; Protein Isoforms; RNA, Messenger; Skin
PubMed: 32482619
DOI: 10.1242/dmm.041608 -
Glia Nov 2020Dystonin (Dst) is a causative gene for Dystonia musculorum (dt) mice, which is an inherited disorder exhibiting dystonia-like movement and ataxia with sensory...
Dystonin (Dst) is a causative gene for Dystonia musculorum (dt) mice, which is an inherited disorder exhibiting dystonia-like movement and ataxia with sensory degeneration. Dst is expressed in a variety of tissues, including the central nervous system and the peripheral nervous system (PNS), muscles, and skin. However, the Dst-expressing cell type(s) for dt phenotypes have not been well characterized. To address the questions whether the disruption of Dst in Schwann cells induces movement disorders and how much impact does it have on dt phenotypes, we generated Dst conditional knockout (cKO) mice using P0-Cre transgenic mice and Dst gene trap mice. First, we assessed the P0-Cre transgene-dependent Cre recombination using tdTomato reporter mice and then confirmed the preferential tdTomato expression in Schwann cells. In the Dst cKO mice, Dst mRNA expression was significantly decreased in Schwann cells, but it was intact in most of the sensory neurons in the dorsal root ganglion. Next, we analyzed the phenotype of Dst cKO mice. They exhibited a normal motor phenotype during juvenile periods, and thereafter, started exhibiting an ataxia. Behavioral tests and electrophysiological analyses demonstrated impaired motor abilities and slowed motor nerve conduction velocity in Dst cKO mice, but these mice did not manifest dystonic movements. Electron microscopic observation of the PNS of Dst cKO mice revealed significant numbers of hypomyelinated axons and numerous infiltrating macrophages engulfing myelin debris. These results indicate that Dst is important for normal PNS myelin organization and Dst disruption in Schwann cells induces late-onset neuropathy and sensory ataxia. MAIN POINTS: Dystonin (Dst) disruption in Schwann cells results in late-onset neuropathy and sensory ataxia. Dst in Schwann cells is important for normal myelin organization in the peripheral nervous system.
Topics: Animals; Ataxia; Dystonia; Dystonic Disorders; Dystonin; Mice; Mice, Transgenic; Schwann Cells
PubMed: 32445516
DOI: 10.1002/glia.23843 -
Disease Markers 2020Bullous pemphigoid (BP) is a common T helper 2- (Th2-) dominated autoimmune blistering skin disease with significant mortality. MicroRNAs (miRNAs), which are endogenous...
BACKGROUND
Bullous pemphigoid (BP) is a common T helper 2- (Th2-) dominated autoimmune blistering skin disease with significant mortality. MicroRNAs (miRNAs), which are endogenous noncoding RNA molecules, have been reported to be potential biomarkers for some autoimmune diseases; however, to date, there exist no reports on serum expression profiles of miRNAs in BP patients.
METHODS
A RNA quantitative PCR- (qPCR-) based array was conducted on sera from 20 active BP patients and 20 healthy controls for screening of miRNAs. Significantly dysregulated miRNAs were validated with use of qPCR as performed on sera samples of 45 active BP patients and 60 healthy controls. Serum CCL17, anti-BP180, and anti-BP230 levels were measured with use of ELISA.
RESULTS
Relative baseline expression levels of serum miR-1291 were significantly upregulated in the 45 BP patients as compared with the 60 healthy controls ( < 0.001) and significantly decreased in the disease control stage ( = 13, = 0.006). In addition, these baseline miR-1291 levels showed a significant positive correlation with the baseline levels of serum CCL17 ( < 0.001) and anti-BP180 ( = 38, = 0.024). Like that observed for miR-1291, baseline levels of serum CCL17 were also significantly elevated in the 45 BP patients compared with the 60 healthy controls ( < 0.001) and significantly decreased in the disease control stage ( = 13, = 0.002). However, for anti-BP180, baseline serum levels were significantly elevated in only 38 of the 45 BP patients and significantly decreased in the disease control stage ( = 10, = 0.004).
CONCLUSIONS
Relative expression levels of serum miR-1291 can reflect disease activity of BP. miR-1291 may function as an important new serum biomarker for BP.
Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Biomarkers; Case-Control Studies; Chemokine CCL17; Dystonin; Female; Humans; Male; MicroRNAs; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Skin; Th2 Cells; Collagen Type XVII
PubMed: 32399091
DOI: 10.1155/2020/9505312 -
The Journal of Dermatology Jul 2020
Topics: Autoantibodies; Autoantigens; Disease Progression; Dystonin; Enzyme-Linked Immunosorbent Assay; Epitopes; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous
PubMed: 32343019
DOI: 10.1111/1346-8138.15362