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Frontiers in Immunology 2021Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against...
Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against components of the basal membrane zone that lead to sub-epidermal loss of adhesion. Pruritus may be indicative of a pre-clinical stage of BP, since a subset of these patients shows serum IgG autoantibodies against BP230 and/or BP180 while chronic pruritus is increasingly common in the elderly population and is associated with a variety of dermatoses. Clinical and experimental evidence further suggests that pruritus of the elderly may be linked to autoimmunity with loss of self-tolerance against cutaneous autoantigens. Thus, the objective of this study was to determine autoreactive T cell responses against BP180 in elderly patients in comparison to patients with BP. A total of 22 elderly patients with pruritic disorders, 34 patients with bullous or non-bullous BP and 34 age-matched healthy controls were included in this study. The level of anti-BP180 and anti-BP230 IgG serum autoantibodies, Bullous Pemphigoid Disease Area Index (BPDAI), and pruritus severity were assessed for all patients and controls. For characterization of the autoreactive T cell response, peripheral blood mononuclear cells were stimulated with recombinant BP180 proteins (NH- and COOH-terminal domains) and the frequencies of BP180-specific T cells producing interferon-γ, interleukin (IL)-5 or IL-17 were subsequently determined by ELISpot assay. Patients with BP showed a mixed Th1/Th2 response against BP180 while autoreactive Th1 cells were identified in a minor subset of elderly patients with pruritic disorders. Furthermore, our T cell characterization revealed that therapeutic application of topical clobetasol propionate ointment in BP patients significantly reduced peripheral blood BP180-specific T cells, along with clinically improved symptoms, strongly suggesting a systemic immunosuppressive effect of this treatment.
Topics: Aged; Autoantibodies; Autoantigens; Autoimmunity; Clobetasol; Cohort Studies; Cytokines; Dystonin; Enzyme-Linked Immunospot Assay; Glucocorticoids; Humans; Immunoglobulin G; Non-Fibrillar Collagens; Ointments; Pemphigoid, Bullous; Pruritus; T-Lymphocytes, Helper-Inducer; Th17 Cells; Collagen Type XVII
PubMed: 33841390
DOI: 10.3389/fimmu.2021.569287 -
The Journal of Dermatology May 2021
Topics: Aged, 80 and over; Autoantibodies; Autoantigens; Contracture; Dystonin; Female; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous
PubMed: 33715202
DOI: 10.1111/1346-8138.15842 -
Pediatric Dermatology Mar 2021Epidermolysis bullosa simplex (EBS) is a heterogeneous group of inherited disorders characterized by skin fragility due to intraepidermal separation. Most cases result... (Review)
Review
BACKGROUND
Epidermolysis bullosa simplex (EBS) is a heterogeneous group of inherited disorders characterized by skin fragility due to intraepidermal separation. Most cases result from heterozygous mutations in KRT5 or KRT14; however, a minority of affected individuals carry mutations in non-keratin genes including DST encoding an epithelial isoform of dystonin. DST-associated EBS is transmitted as an autosomal recessive trait. Here, we report a series of EBS patients carrying bi-allelic DST mutations and review previously reported cases aiming to delineate phenotype-genotype correlations.
METHODS
Whole-exome and direct sequencing were used for variant analysis. Review of previously reported cases was performed.
RESULTS
Mutation analysis revealed DST mutations in five patients belonging to three families. Two variants have not been previously reported: c.7097dupA (p.Tyr2366X) and c.7429delC (p.Leu2477Serfs*13). We identified an additional six cases in the literature, bringing the total number of individuals affected with EBS due to DST variants to 11. Patients displayed distinctive phenotypes regardless of the causative variant.
CONCLUSIONS
The current study expands the clinical and genetic spectrum of DST-associated EBS subtype.
Topics: Dystonin; Epidermolysis Bullosa Simplex; Humans; Keratin-14; Keratin-5; Mutation; Phenotype
PubMed: 33471381
DOI: 10.1111/pde.14477 -
Biochemistry and Cell Biology =... Jun 2021The neuronal dystonin protein (DST-a) is a large cytoskeletal linker important for integrating the various components of the cytoskeleton. Recessive mutations lead to a...
The neuronal dystonin protein (DST-a) is a large cytoskeletal linker important for integrating the various components of the cytoskeleton. Recessive mutations lead to a sensory neuropathy in mice, known as dystonia musculorum (). The disease is characterized by ataxia, autonomic disturbances, and ultimately, death, which are associated with massive degeneration of the sensory neurons in the dorsal root ganglion (DRG). Recent investigation of sensory neurons revealed an accumulation of autophagosomes and a disruption in autophagic flux, which was believed to be due to insufficient availability of motor protein. Motor protein levels and the endolysosomal pathway were assessed in pre-symptomatic (postnatal day 5; P5) and symptomatic (P15) stage wild-type and DRGs. Levels of mRNA encoding molecular motors were reduced, although no significant reduction in the protein level was detected. An increase in lysosomal marker LAMP1 in medium-large size sensory neurons was observed, along with an accumulation of electron-light single-membraned vesicles in DRG tissue at the late stages of disease. These vesicles are likely to have been autolysosomes, and their presence in only late-stage sensory neurons is suggestive of a pathological defect in autophagy. Further investigation is necessary to confirm vesicle identity, and to determine the role of Dst-a in normal autophagic flux.
Topics: Animals; Autophagosomes; Autophagy; Dystonin; Endosomes; Ganglia, Spinal; Loss of Function Mutation; Lysosomes; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons
PubMed: 33347391
DOI: 10.1139/bcb-2020-0557 -
Journal of the European Academy of... Apr 2021
Topics: Autoantibodies; Autoantigens; Dystonin; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin G; Non-Fibrillar Collagens; Pemphigoid, Bullous
PubMed: 33219610
DOI: 10.1111/jdv.17044 -
Acta Dermato-venereologica Nov 2020Pruritus is a common symptom of bullous pemphigoid (BP), but has been poorly studied. The aim of this study was to analyse the characteristics of pruritus in patients... (Observational Study)
Observational Study
Pruritus is a common symptom of bullous pemphigoid (BP), but has been poorly studied. The aim of this study was to analyse the characteristics of pruritus in patients with BP and its impact on their quality of life. A multicentre prospective observational study (in 15 French hospitals) was performed. A total of 60 patients were included, with a mean age of 77.4 years. Pruritus occurred daily in 85% of patients, with a mean pruritus intensity of 5.2/10. Tingling sensations were present in 72.4% of patients and burning sensations in 68.9%. Pruritus was exacerbated by stress, fatigue and xerosis. The mean ItchyQol score was 56.2/110 and the mean 5-D Itch Scale score was 16.5/25. The severity of pruritus was not related to age, sex, BP activity score, eosinophilia, or anti-BP230 and anti-BP180 autoantibodies. This study revealed that pruritus in BP is poorly tolerated and is an important cause of impaired quality of life.
Topics: Aged; Autoantibodies; Autoantigens; Dystonin; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prospective Studies; Pruritus; Quality of Life
PubMed: 33135772
DOI: 10.2340/00015555-3683 -
The Journal of Investigative Dermatology May 2021Bullous pemphigoid (BP) is an autoimmune blistering disease that targets the hemidesmosomal proteins BP180 and BP230/BPAG1e. Whereas the role of anti-BP180 antibodies...
Bullous pemphigoid (BP) is an autoimmune blistering disease that targets the hemidesmosomal proteins BP180 and BP230/BPAG1e. Whereas the role of anti-BP180 antibodies has been extensively characterized, the pathogenicity of anti-BPAG1e antibodies remains unclear. The purpose of this study is to elucidate the role of antibodies to BPAG1e in the experimental bullous pemphigoid models. We generated Bpag1 conditional knockout mice, where the knockout of Bpag1 is restricted to keratin 5-expressing epithelial cells. Bpag1 conditional knockout mice were immunized with the C-terminal portion of BPAG1e, and the splenocytes were injected into Rag2 mice intravenously. The recipient mice presented with erosion on the feet and tails. Microscopic examination showed subepidermal blisters and a linear deposition of IgG at the dermal-epidermal junction. To assess the potential role of trauma on BP development, we inflicted surface wounds on the dorsum of the Rag2 recipient mice after adoptive transfer. The wounded Rag2 mice had increased morbidity and severity of BP-like symptoms. Moreover, the depletion of B cells from splenocytes abolished a subepidermal blistering phenotype in vivo. These findings demonstrate that antibodies to BPAG1e might play a pathogenic role in causing subepidermal blistering, and external factors, including trauma, might be a trigger for BP development.
Topics: Animals; Autoantibodies; DNA-Binding Proteins; Disease Models, Animal; Dystonin; Immunization; Mice; Mice, Inbred C57BL; Pemphigoid, Bullous
PubMed: 33069726
DOI: 10.1016/j.jid.2020.08.031 -
The British Journal of Dermatology Jun 2021The Bullous Pemphigoid Disease Area Index (BPDAI) score has been proposed to provide an objective measure of bullous pemphigoid (BP) activity.
International validation of the Bullous Pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid.
BACKGROUND
The Bullous Pemphigoid Disease Area Index (BPDAI) score has been proposed to provide an objective measure of bullous pemphigoid (BP) activity.
OBJECTIVES
The objective of this study was to calculate BPDAI cut-off values defining mild, moderate and severe BP. We also aimed to assess the interrater reliability and correlation with the number of daily new blisters, and anti-BP180 and anti-BP230 antibodies.
METHODS
Severity scores were recorded by two blinded investigators. Anti-BP180 and anti-BP230 antibodies were measured using an enzyme-linked immunosorbent assay (ELISA). Cut-off values defining mild, moderate and severe subgroups were calculated based on the 25th and 75th percentiles of the BPDAI score.
RESULTS
In total, 285 patients with BP were enrolled from 50 dermatology departments in Europe. Median BPDAI activity was 37·5 points (range 0-164). Cut-off values corresponding to the first and third quartiles of the BPDAI score were 20 and 57, respectively; thus, these values were used to define mild (≤ 19), moderate (≥ 20 and ≤ 56) and severe (≥ 57) BP. The median BPDAI score for patients with ≤ 10 daily new blisters was 26 [interquartile range (IQR) 17-45], and for patients with > 10 daily new blisters the median score was 55 (IQR 39-82). The BPDAI intraclass correlation coefficient measured at baseline was 0·97 and remained higher than 0·90 up to month 6. The improvement in the BPDAI score was correlated with the absolute decrease in anti-BP180 ELISA value (Spearman's rank r = 0·34, P < 0·004), but not with anti-BP230 antibodies (r = 0·17, P = 0·15).
CONCLUSIONS
This study suggests cut-off values of 20-57 for BPDAI to distinguish mild, moderate and severe BP, and confirms that it is a robust tool to assess BP severity precisely.
Topics: Autoantibodies; Autoantigens; Dystonin; Enzyme-Linked Immunosorbent Assay; Europe; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous; Reproducibility of Results; Severity of Illness Index
PubMed: 33067805
DOI: 10.1111/bjd.19611 -
American Journal of Clinical Dermatology Jan 2021The clinical and immunological profile of patients with dipeptidyl peptidase-4 inhibitor (DPP4i)-associated bullous pemphigoid (BP) is inconsistent in the current...
More Severe Erosive Phenotype Despite Lower Circulating Autoantibody Levels in Dipeptidyl Peptidase-4 Inhibitor (DPP4i)-Associated Bullous Pemphigoid: A Retrospective Cohort Study.
BACKGROUND
The clinical and immunological profile of patients with dipeptidyl peptidase-4 inhibitor (DPP4i)-associated bullous pemphigoid (BP) is inconsistent in the current literature.
OBJECTIVES
The aims were to investigate the clinical and immunological features of patients with DPP4i-associated BP and to examine whether there are intraclass differences between different DPP4i agents.
METHODS
A retrospective cohort study was conducted, including all consecutive patients diagnosed with BP throughout the years 2009-2019 in a tertiary referral center.
RESULTS
The study encompassed 273 patients with BP (mean age at diagnosis 79.1 ± 9.9 years), of whom 24 (8.8%) were associated with DPP4i. Sitagliptin was the prescribed agent for 17 patients (70.8%), and vildagliptin was prescribed in seven patients (29.2%). Relative to other patients with BP, patients with DPP4i-associated BP had more prominent truncal involvement (95.8% vs. 73.9%; P = 0.017), greater erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) subscore (29.8 ± 17.4 vs. 20.6 ± 14.4; P = 0.018), and lower levels of anti-BP180 NC16A (279.2 ± 346.1 vs. 572.2 ± 1352.0 U/ml; P = 0.009) and anti-BP230 (25.5 ± 47.8 vs. 128.6 ± 302.9 U/ml; P = 0.009) antibodies. Relative to patients with sitagliptin-associated BP, those with vildagliptin-associated BP had a lower seropositivity rate (57.1% vs. 94.1%, P = 0.031) and lower levels (96.7 ± 139.0 vs. 354.5 ± 376.5; P = 0.023) of anti-BP180 NC16A antibodies, and tended to present with higher erosion/blister BPDAI subscore (36.3 ± 9.6 vs. 25.8 ± 19.7; P = 0.095).
CONCLUSIONS
DPP4i-associated BP is characterized by a more severe blistering and erosive presentation despite lower levels of typically pathogenic antibodies.
Topics: Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Dipeptidyl-Peptidase IV Inhibitors; Dystonin; Female; Humans; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Retrospective Studies; Severity of Illness Index; Sitagliptin Phosphate; Skin; Vildagliptin; Collagen Type XVII
PubMed: 33026629
DOI: 10.1007/s40257-020-00563-7 -
International Journal of Dermatology Mar 2021
Topics: Autoantibodies; Autoantigens; Dystonin; Enzyme-Linked Immunosorbent Assay; Humans; Mucous Membrane; Non-Fibrillar Collagens; Pemphigoid, Benign Mucous Membrane; Pemphigoid, Bullous
PubMed: 32970829
DOI: 10.1111/ijd.15195