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Frontiers in Immunology 2018Bullous pemphigoid (BP) is the most common autoimmune bullous disease and typically affects the elderly. Binding of specific autoantibodies to BP180/230 hemidesmosomal... (Clinical Trial)
Clinical Trial
Bullous pemphigoid (BP) is the most common autoimmune bullous disease and typically affects the elderly. Binding of specific autoantibodies to BP180/230 hemidesmosomal components induces an inflammatory response leading to skin blister formation. Unusual manifestations of BP include additional mucous membrane involvement, without pathophysiological knowledge associated to the formation of these lesions. We here performed a prospective study on series of consecutive BP patients with ( = 77) and without ( = 18) mucosal involvements at baseline to further investigate why some BP patients display mucosal lesion and other not. Analysis of disease activity showed that BP patients with mucosal involvement displayed a higher total BP Disease Area Index (BPDAI) score ( = 0.008), but also higher skin and blister/erosion BPDAI scores ( = 0.02 and = 0.001, respectively). By contrast, the erythema/urticaria BPDAI score was identical between the two groups of patients. The erythema/urticaria BPDAI score, but not the blister/erosion BPDAI score, was correlated with the serum concentration of anti-BP180 NC16A autoantibodies in patients with mucosal involvement. In multivariate analysis, the absence of anti-BP230 autoantibody was the only factor independently associated with mucosal involvement (OR 7.8; 95% CI, 3.1-19.6) ( < 0.0001). Analysis of the distribution of BP patients according to BPDAI scores revealed a shift toward higher blister/erosion BPDAI scores for BP patients with mucosal involvement. This study indicates that mucosal lesions are clinically mainly related to disease severity and immunologically to the absence of anti-BP230 antibodies.
Topics: Aged; Aged, 80 and over; Autoantibodies; Dystonin; Female; Humans; Immunity, Mucosal; Male; Mucous Membrane; Pemphigoid, Bullous; Severity of Illness Index
PubMed: 29662486
DOI: 10.3389/fimmu.2018.00479 -
Frontiers in Immunology 2017Regulated vascular permeability is an essential feature of normal physiology and its dysfunction is associated with major human diseases ranging from cancer to... (Review)
Review
Regulated vascular permeability is an essential feature of normal physiology and its dysfunction is associated with major human diseases ranging from cancer to inflammation and ischemic heart diseases. Integrity of endothelial cells also play a prominent role in the outcome of surgical procedures and organ transplant. Endothelial barrier function and integrity are regulated by a plethora of highly specialized transmembrane receptors, including claudin family proteins, occludin, junctional adhesion molecules (JAMs), vascular endothelial (VE)-cadherin, and the newly identified immunoglobulin (Ig) and proline-rich receptor-1 (IGPR-1) through various distinct mechanisms and signaling. On the other hand, vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2, play a central role in the destabilization of endothelial barrier function. While claudins and occludin regulate cell-cell junction recruitment of zonula occludens (ZO), cadherins catenin proteins, and JAMs ZO and afadin, IGPR-1 recruits bullous pemphigoid antigen 1 [also called dystonin (DST) and SH3 protein interacting with Nck90/WISH (SH3 protein interacting with Nck)]. Endothelial barrier function is moderated by the function of transmembrane receptors and signaling events that act to defend or destabilize it. Here, I highlight recent advances that have provided new insights into endothelial barrier function and mechanisms involved. Further investigation of these mechanisms could lead to the discovery of novel therapeutic targets for human diseases associated with endothelial dysfunction.
PubMed: 29326721
DOI: 10.3389/fimmu.2017.01847 -
JAMA Dermatology Mar 2018Enzyme-linked immunosorbent assay (ELISA) and/or chemiluminescent enzyme immunoassay (CLEIA) for BP180 noncollagenous 16A (NC16A) extracellular domain is a sensitive...
IMPORTANCE
Enzyme-linked immunosorbent assay (ELISA) and/or chemiluminescent enzyme immunoassay (CLEIA) for BP180 noncollagenous 16A (NC16A) extracellular domain is a sensitive diagnostic tool for bullous pemphigoid (BP). However, some patients with BP have negative results for these assays.
OBJECTIVE
To elucidate the clinical and immunological features of patients with BP without antibodies that react to BP180 NC16A.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective case series study included 152 patients who were diagnosed with BP and followed up at the Kurume University Hospital in Japan from 2007 to 2016. The diagnosis was made using clinical, histological, and immunological findings.
MAIN OUTCOMES AND MEASURES
Clinical and immunological features of patients with BP who had negative results for BP180 NC16A using ELISA and/or CLEIA.
RESULTS
Of the 152 patients, 69 (45.4%) were men and 83 (54.6%) were women. The mean (SD) age of participants was 75.2 (14.4) years. Of the 152 patients with BP, 14 (9.2%) had negative results for BP180 NC16A on ELISA and/or CLEIA; most of these patients exhibited no erythema and had relatively mild phenotypes. Two (14%) of the 14 patients had positive results for intact BP180 in epidermal extracts, 10 (71%) had positive results for a 120-kD fragment of BP180 (LAD-1) and 3 (21%) had positive results for BP180 C-terminal domain. Seven (50%) patients tested positive in BP230 ELISA. Five (36%) patients did not require oral prednisolone treatment, whereas the others required a dose of prednisolone at less than 30 mg per day. Three (21%) patients were administered a dipeptidyl peptidase-4 inhibitor (DPP4i) before disease onset. This ratio was not significantly higher than that in patients with BP who tested positive for BP180 NC16A ELISA and/or CLEIA (19 [14%] of 138 patients). Our follow-up study (mean [SD], 31.9 [33.2] weeks; range, 0-108 weeks) revealed that patients with BP tested negative for BP180 NC16A ELISA and/or CLEIA during the later stages of the disease.
CONCLUSIONS AND RELEVANCE
This study indicates that patients with BP negative for BP180 NC16A ELISA and/or CLEIA had milder phenotypes, fewer erythemas, and required less extensive treatments.
Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Autoantibodies; Autoantigens; Dystonin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin G; Luminescent Measurements; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prednisolone; Retrospective Studies; Collagen Type XVII
PubMed: 29299596
DOI: 10.1001/jamadermatol.2017.5465 -
Acta Dermato-venereologica Feb 2018
Topics: Aged; Autoantibodies; Autoantigens; Biomarkers; Biopsy; Dystonin; Female; Fluorescent Antibody Technique; Humans; Immunoglobulin E; Immunologic Factors; Non-Fibrillar Collagens; Omalizumab; Pemphigoid, Bullous; Remission Induction; Severity of Illness Index; Skin; Treatment Outcome; Collagen Type XVII
PubMed: 29136264
DOI: 10.2340/00015555-2845 -
Seminars in Cell & Developmental Biology Sep 2017Spectraplakins are evolutionarily well conserved cytoskeletal linker molecules that are true members of three protein families: plakins, spectrins and Gas2-like... (Review)
Review
Spectraplakins are evolutionarily well conserved cytoskeletal linker molecules that are true members of three protein families: plakins, spectrins and Gas2-like proteins. Spectraplakin genes encode at least 7 characteristic functional domains which are combined in a modular fashion into multiple isoforms, and which are responsible for an enormous breadth of cellular functions. These functions are related to the regulation of actin, microtubules, intermediate filaments, intracellular organelles, cell adhesions and signalling processes during the development and maintenance of a wide variety of tissues. To gain a deeper understanding of this enormous functional diversity, invertebrate genetic model organisms, such as the fruit fly Drosophila, can be used to develop concepts and mechanistic paradigms that can inform the investigation in higher animals or humans. Here we provide a comprehensive overview of our current knowledge of the Drosophila spectraplakin Short stop (Shot). We describe its functional domains and isoforms and compare them with those of the mammalian spectraplakins dystonin and MACF1. We then summarise its roles during the development and maintenance of the nervous system, epithelia, oocytes and muscles, taking care to compare and contrast mechanistic insights across these functions in the fly, but especially also with related functions of dystonin and MACF1 in mostly mammalian contexts. We hope that this review will improve the wider appreciation of how work on Drosophila Shot can be used as an efficient strategy to promote the fundamental concepts and mechanisms that underpin spectraplakin functions, with important implications for biomedical research into human disease.
Topics: Animals; Axon Guidance; Drosophila Proteins; Drosophila melanogaster; Mammals; Microfilament Proteins; Sequence Homology, Amino Acid; Synapses
PubMed: 28579450
DOI: 10.1016/j.semcdb.2017.05.019 -
The Journal of Investigative Dermatology Oct 2017
Topics: Adult; DNA; DNA Mutational Analysis; Dermis; Dystonin; Epidermolysis Bullosa Simplex; Humans; Male; Microscopy, Electron, Transmission; Mutation; Pedigree; Prurigo
PubMed: 28558912
DOI: 10.1016/j.jid.2017.04.041 -
Neurology May 2017To describe a second hereditary sensory autonomic neuropathy type VI (HSAN-VI) family harboring 2 novel heterozygous mutations in the dystonin () gene and to evaluate...
OBJECTIVE
To describe a second hereditary sensory autonomic neuropathy type VI (HSAN-VI) family harboring 2 novel heterozygous mutations in the dystonin () gene and to evaluate their effect on neurons derived from induced pluripotent stem cells (iPSC).
METHODS
The family consisted of 3 affected siblings from nonconsanguineous healthy parents. All members underwent clinical and electrophysiologic evaluation and genetic analysis. Two patients underwent quantitative sensory testing (QST), cardiovascular reflexes, dynamic sweat test, and skin biopsy to evaluate somatic and autonomic cutaneous innervation and to get fibroblast cultures for developing iPSC-derived neurons.
RESULTS
Onset occurred in the first decade, with painless and progressive mutilating distal ulcerations leading to amputation and joint deformity. Sensation to pain, touch, and vibration was reduced. Autonomic disturbances included hypohidrosis, pupillary abnormalities, and gastrointestinal and sexual dysfunction. Nerve conduction studies showed a severe axonal sensory neuropathy. QST and autonomic functional studies were abnormal. Skin biopsy revealed a lack of sensory and autonomic nerve fibers. Genetic analysis revealed 2 pathogenic mutations in the gene affecting exclusively the DST neuronal isoform-a2. Neurons derived from iPSC showed absence or very low levels of DST protein and short and dystrophic neuritis or no projections at all.
CONCLUSIONS
Unlike the previous HSAN-VI family, our description indicates that mutations may be associated with a nonlethal and nonsyndromic phenotype. Neuronal loss affects large and small sensory nerve fibers as well as autonomic ones. Induced-PSC findings suggest that dystonin defect might alter proper development of the peripheral nerves. Dystonin-a2 plays a major role in the HSAN-VI phenotype.
Topics: Adult; Dystonin; Hereditary Sensory and Autonomic Neuropathies; Heterozygote; Humans; Induced Pluripotent Stem Cells; Male; Middle Aged; Mutation; Neurons; RNA, Messenger; Siblings
PubMed: 28468842
DOI: 10.1212/WNL.0000000000003992 -
Archives of Dermatological Research Jul 2017Bullous pemphigoid (BP) is a chronic debilitating autoimmune blistering disease that frequently occurs in the elderly population. Previous studies have suggested a high... (Meta-Analysis)
Meta-Analysis
Bullous pemphigoid (BP) is a chronic debilitating autoimmune blistering disease that frequently occurs in the elderly population. Previous studies have suggested a high morbidity and mortality associated with BP. However, relatively few studies have investigated prognostic factors of BP mortality, and they showed considerably various results. This meta-analysis aimed to quantitatively assess the association between several potential prognostic factors and risk of mortality in bullous pemphigoid. A comprehensive search was performed using Pubmed, Embase, and Cochrane Library. Cohort studies that assessed prognostic factors of BP mortality were included. Random-effects model was utilized to calculate the pooled hazard ratio (HR). Publication bias was evaluated qualitatively by constructing a funnel plot and quantitatively by conducting Egger's test. 14 studies were included comprising 2499 patients. Combined HRs suggested that advanced age (HR 1.63, 95% CI 1.34-1.97), presence of circulating antibodies (HR 1.77, 95% CI 1.20-2.62), concomitant dementia (HR 2.01, 95% CI 1.22-3.33), and concomitant stroke (HR 1.86, 95% CI 1.29-2.67) have an unfavorable impact on patient survival. Gender, disease extent, mucosal involvement, and indirect immunofluorescence result were not shown to be linked to mortality by our analysis. This study indicated that BP patients with older age, circulating antibodies, dementia, and stroke are at greater risk of mortality. Clinicians should be aware of this association and utilize this information in patient education and treatment process.
Topics: Age Factors; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Dementia; Dystonin; Female; Humans; Male; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prognosis; Risk; Stroke; Collagen Type XVII
PubMed: 28317060
DOI: 10.1007/s00403-017-1736-1 -
PloS One 2017Calgranulin B is known to be involved in tumor development, but the underlying molecular mechanism is not clear. To gain insight into possible roles of calgranulin B, we...
Calgranulin B is known to be involved in tumor development, but the underlying molecular mechanism is not clear. To gain insight into possible roles of calgranulin B, we screened for calgranulin B-interacting molecules in the SNU-484 gastric cancer and the SNU-81 colon cancer cells. Calgranulin B-interacting partners were identified by yeast two-hybrid and functional information was obtained by computational analysis. Most of the calgranulin B-interacting partners were involved in metabolic and cellular processes, and found to have molecular function of binding and catalytic activities. Interestingly, 46 molecules in the network of the calgranulin B-interacting proteins are known to be associated with cancer and FKBP2 was found to interact with calgranulin B in both SNU-484 and SNU-81 cells. Polyubiquitin-C encoded by UBC, which exhibited an interaction with calgranulin B, has been associated with various molecules of the extracellular space and plasma membrane identified in our screening, including Na-K-Cl cotransporter 1 and dystonin in SNU-484 cells, and ATPase subunit beta-1 in SNU-81 cells. Our data provide novel insight into the roles of calgranulin B of gastrointestinal cancer cells, and offer new clues suggesting calgranulin B acts as an effector molecule through which the cell can communicate with the tumor microenvironment via polyubiquitin-C.
Topics: Calgranulin B; Cell Line, Tumor; Colonic Neoplasms; HEK293 Cells; Humans; Metabolic Networks and Pathways; Neoplasm Proteins; Stomach Neoplasms; Two-Hybrid System Techniques
PubMed: 28152021
DOI: 10.1371/journal.pone.0171232 -
Acta Dermato-venereologica May 2017
Topics: Autoantigens; Codon, Nonsense; Dystonin; Epidermolysis Bullosa Simplex; Fibronectins; Homozygote; Humans; Integrin beta1; Keratinocytes; Keratins; Male; Non-Fibrillar Collagens; Protein Isoforms; RNA, Messenger; Sequence Deletion; Young Adult; Collagen Type XVII
PubMed: 28119998
DOI: 10.2340/00015555-2618