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Frontiers in Immunology 2019Recent studies suggest an important role of immunoglobulin E (IgE) as an alternative pathogenic pathway in the development of bullous pemphigoid (BP), as the most...
Recent studies suggest an important role of immunoglobulin E (IgE) as an alternative pathogenic pathway in the development of bullous pemphigoid (BP), as the most frequent subepidermal blistering disease of the skin Use of IgE targeted therapies, such as omalizumab, has been shown promising in recent studies. The aim of this study was to assess the effect of omalizumab on FcεRI and IgE expression on circulating basophils and on lesional intradermal cells in BP to generate insight into the immunological effects of omalizumab in BP. We report two cases of BP patients treated with omalizumab. Efficacy of treatment was assessed clinically 4 months after initiation of the therapy. Lesional and non-lesional skin biopsies where taken before and 4 weeks after initiation of omalizumab therapy. In addition, FcεRI expression on circulating cells and IgE levels in serum and in the skin samples, as well as anti-BP180 and anti-BP230 in serum and eosinophils and basophils counts in blood were assessed before and during treatment. Both patients showed a marked improvement after 4 months, with no adverse effects. Down-regulation of FcεRI, IgE in lesional skin and on circulating basophils were observed in parallel with clinical improvement. The current case study supports the role of omalizumab in the treatment of a subset of BP patients. Our observations suggest that omalizumab represents a valuable therapeutic option in the management of BP patients. Its efficacy might be related to reduction in FcεRI+ and IgE+ basophils and intradermal cells.
Topics: Aged; Anti-Allergic Agents; Autoantibodies; Autoantigens; Basophils; Dystonin; Eosinophils; Humans; Immunoglobulin E; Leukocyte Count; Middle Aged; Non-Fibrillar Collagens; Omalizumab; Pemphigoid, Bullous; Receptors, IgE; Skin; Treatment Outcome; Collagen Type XVII
PubMed: 31474990
DOI: 10.3389/fimmu.2019.01919 -
Acta Dermato-venereologica Nov 2019
Topics: Adrenal Cortex Hormones; Autoantibodies; Drug Resistance; Drug Therapy, Combination; Dystonin; Histamine Antagonists; Humans; Immunoglobulin G; Immunosuppressive Agents; Laminin; Male; Middle Aged; Pemphigoid, Bullous; Remission Induction; Treatment Outcome
PubMed: 31449311
DOI: 10.2340/00015555-3294 -
Annals of Surgery Oct 2019To understand role of barrier molecules in melanomas.
OBJECTIVE
To understand role of barrier molecules in melanomas.
BACKGROUND
We have reported poor patient survival and low immune infiltration of melanomas that overexpress a set of genes that include filaggrin (FLG), dystonin (DST), junction plakoglobin (JUP), and plakophilin-3 (PKP3), and are involved in cell-cell adhesions. We hypothesized that these associations are causal, either by interfering with immune cell infiltration or by enhancing melanoma cell growth.
METHODS
FLG and DST were knocked out by CRISPR/Cas9 in human DM93 and murine B16-F1 melanoma cells. PKP3 and JUP were overexpressed in murine B16-AAD and human VMM39 melanoma cells by lentiviral transduction. These cell lines were evaluated in vitro for cell proliferation and in vivo for tumor burden, immune composition, cytokine expression, and vascularity.
RESULTS
Immune infiltrates were not altered by these genes. FLG/DST knockout reduced proliferation of human DM93 melanoma in vitro, and decreased B16-F1 tumor burden in vivo. Overexpression of JUP, but not PKP3, in B16-AAD significantly increased tumor burden, increased VEGF-A, reduced IL-33, and enhanced vascularity.
CONCLUSIONS
FLG and DST support melanoma cell growth in vitro and in vivo. Growth effects of JUP were only evident in vivo, and may be mediated, in part, by enhancing angiogenesis. In addition, growth-promoting effects of FLG and DST in vitro suggest that these genes may also support melanoma cell proliferation through angiogenesis-independent pathways. These findings identify FLG, DST, and JUP as novel therapeutic targets whose down-regulation may provide clinical benefit to patients with melanoma.
Topics: Animals; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Cytokines; Dystonin; Filaggrin Proteins; Flow Cytometry; Fluorescent Antibody Technique; Humans; Intermediate Filament Proteins; Melanoma; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; gamma Catenin
PubMed: 31425296
DOI: 10.1097/SLA.0000000000003522 -
Frontiers in Immunology 2019There are several lines of evidence indicating that the physiopathological bases of bullous pemphigoid (BP), the most common subepidermal autoimmune bullous disease, are... (Review)
Review
There are several lines of evidence indicating that the physiopathological bases of bullous pemphigoid (BP), the most common subepidermal autoimmune bullous disease, are hallmarked by the production of autoantibodies directed against the hemidesmosomal anchoring proteins BP180 and BP230. In contrast to the robustness of the latter assumption, the multifaceted complexity of upstream and downstream mechanisms implied in the pathogenesis of BP remains an area of intense speculation. So far, an imbalance between T regulatory cells and autoreactive T helper (Th) cells has been regarded as the main pathogenic factor triggering the autoimmune response in BP patients. However, the contributory role of signaling pathways fostering the B cell stimulation, such as Toll-like receptor activation, as well as that of ancillary inflammatory mechanisms responsible for blister formation, such as Th17 axis stimulation and the activation of the coagulation cascade, are still a matter of debate. In the same way, the pathomechanisms implied in the loss of dermal-epidermal adhesion secondary to autoantibodies binding are not fully understood. Herein, we review in detail the current concepts and controversies on the complex pathogenesis of BP, shedding light on the most recent theories emerging from the literature.
Topics: Autoantibodies; Autoantigens; Autoimmunity; Blood Coagulation; Comorbidity; Complement Activation; Dystonin; Humans; Leukocytes; Neurodegenerative Diseases; Non-Fibrillar Collagens; Pemphigoid, Bullous; Pinocytosis; Thrombosis; Vitamin D Deficiency; Collagen Type XVII
PubMed: 31312206
DOI: 10.3389/fimmu.2019.01506 -
The Journal of Investigative Dermatology Dec 2019Deposition of autoantibodies (α-BP180 and BP230) and complement along the dermal-epidermal-junction is a hallmark of bullous pemphigoid and was shown to be important... (Randomized Controlled Trial)
Randomized Controlled Trial
Deposition of autoantibodies (α-BP180 and BP230) and complement along the dermal-epidermal-junction is a hallmark of bullous pemphigoid and was shown to be important for pathogenesis. Given the adverse effects of standard treatment (glucocorticoids, immunosuppressants), there is an unmet need for safe and effective therapies. In this phase 1 trial, we evaluated the safety and activity of BIVV009 (sutimlimab, previously TNT009), a targeted C1s inhibitor, in 10 subjects with active or past bullous pemphigoid (NCT02502903). Four weekly 60 mg/kg infusions of BIVV009 proved sufficient for inhibition of the classical complement pathway in all patients, as measured by CH50. C3c deposition along the dermal-epidermal junction was partially or completely abrogated in 4 of 5 patients, where it was present at baseline. BIVV009 was found to be safe and tolerable in this elderly population, with only mild to moderate adverse events reported (e.g., headache, fatigue). One serious adverse event (i.e., fatal cardiac decompensation) occurred at the end of the post-treatment observation period in an 84-year-old patient with a history of diabetes and heart failure, but was deemed unlikely to be related to the study drug. This trial provides the first results with a complement-targeting therapy in bullous pemphigoid, to our knowledge, and supports further studies on BIVV009's efficacy and safety in this population.
Topics: Aged; Aged, 80 and over; Autoantigens; Complement C3; Complement Pathway, Classical; Dermis; Dystonin; Epidermis; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 31229501
DOI: 10.1016/j.jid.2019.04.025 -
Frontiers in Immunology 2019Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies target the hemidesmosomal components BP180 and/or BP230 in basal keratinocytes....
Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies target the hemidesmosomal components BP180 and/or BP230 in basal keratinocytes. In BP, 80 to 90% of autoantibodies target the juxtamembranous extracellular non-collagenous 16th A (NC16A) domain of BP180. Recently, the administration of dipeptidyl peptidase-IV inhibitors (DPP4i), which are widely used as antihyperglycemic drugs, has been recognized to be a causative factor for BP. DPP4i-associated BP (DPP4i-BP) autoantibodies tend to target epitopes on non-NC16A regions of BP180, and the pathomechanism for the development of the unique autoantibodies remains unknown. To address the characteristics of DPP4i-BP autoantibodies in detail, we performed epitope analysis of 18 DPP4i-BP autoantibodies targeting the non-NC16A domains of BP180 using various domain-specific as well as plasmin-digested polypeptides derived from recombinant BP180. Firstly, Western blotting showed that only one DPP4i-BP serum reacted with the epitopes on the intracellular domain of BP180, and no sera reacted with the C-terminal domain of the molecule. In addition, only 2 DPP4i-BP sera reacted with BP230 as determined by enzyme-linked immunosorbent assay. Thus, DPP4i-BP autoantibodies were found to mainly target the non-NC16A mid-portion of the extracellular domain of BP. Interestingly, Western blotting using plasmin-digested BP180 as a substrate revealed that all of the DPP4i-BP sera reacted more intensively with the 97-kDa processed extracellular domain of BP180, which is known as the LABD97 autoantigen, than full-length BP180 did. All of the DPP4i-BP autoantibodies targeting the LABD97 autoantigen were IgG1, and IgG4 was observed to react with the molecule in only 7 cases (38.9%). In summary, the present study suggests that IgG1-class autoantibodies targeting epitopes on the processed extracellular domain of BP180, i.e., LABD97, are the major autoantibodies in DPP4i-BP.
Topics: Aged; Aged, 80 and over; Antibody Specificity; Autoantibodies; Autoantigens; Blotting, Western; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dystonin; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Fibrinolysin; Humans; Immunoglobulin G; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Peptide Fragments; Protein Domains; Recombinant Proteins; Collagen Type XVII
PubMed: 31191560
DOI: 10.3389/fimmu.2019.01224 -
Structure (London, England : 1993) Jun 2019Mechanical stability of epithelia requires firm attachment to the basement membrane via hemidesmosomes. Dysfunction of hemidesmosomal proteins causes severe...
Mechanical stability of epithelia requires firm attachment to the basement membrane via hemidesmosomes. Dysfunction of hemidesmosomal proteins causes severe skin-blistering diseases. Two plakins, plectin and BP230 (BPAG1e), link the integrin α6β4 to intermediate filaments in epidermal hemidesmosomes. Here, we show that a linear sequence within the isoform-specific N-terminal region of BP230 binds to the third and fourth FnIII domains of β4. The crystal structure of the complex and mutagenesis analysis revealed that BP230 binds between the two domains of β4. BP230 induces closing of the two FnIII domains that are locked in place by an interdomain ionic clasp required for binding. Disruption of BP230-β4 binding prevents recruitment of BP230 to hemidesmosomes in human keratinocytes, revealing a key role of this interaction for hemidesmosome assembly. Phosphomimetic substitutions in β4 and BP230 destabilize the complex. Thus, our study provides insights into the architecture of hemidesmosomes and potential mechanisms of regulation.
Topics: Amino Acid Sequence; Basement Membrane; Binding Sites; Crystallography, X-Ray; Dystonin; Hemidesmosomes; Humans; Integrin alpha6beta4; Keratinocytes; Models, Molecular; Mutagenesis; Pemphigoid, Bullous; Protein Binding; Protein Domains; Sequence Homology, Amino Acid
PubMed: 31006587
DOI: 10.1016/j.str.2019.03.016 -
The Journal of Investigative Dermatology Sep 2019Bullous pemphigoid (BP) is an autoantibody-mediated blistering disease that is often associated with neurologic disease. BP antibodies target two epidermal adhesion...
Bullous pemphigoid (BP) is an autoantibody-mediated blistering disease that is often associated with neurologic disease. BP antibodies target two epidermal adhesion molecules, known as BP180 and BP230. Homologues to these proteins are found in the brain, and it is hypothesized that neurologic disease leads to the production of autoantibodies that can cross-react with their cutaneous forms. To better understand the link between BP and neurologic disease, we evaluated primary demographic features (age, sex, race, ethnicity, and elapsed time between onset of skin symptoms and BP diagnosis), severity of BP, and IgG and IgE autoantibody levels in BP control individuals and patients with BP with preceding Parkinson disease, dementia, and stroke. The main findings of this study are that patients with BP with preceding neurologic disease have a shorter elapsed time between onset of skin disease and BP diagnosis and that patients with preceding Parkinson disease or dementia, but not stroke, are significantly older than patients with BP without neurologic disease. However, no significant differences in clinical presentation, BP severity scores, or autoantibody (IgG and IgE) responses were observed among the groups. These findings suggest that, despite the age difference, the clinical phenotype of BP is not affected by preceding neurologic disease.
Topics: Age Factors; Age of Onset; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Comorbidity; Dementia; Dystonin; Female; Humans; Incidence; Male; Middle Aged; Non-Fibrillar Collagens; Parkinson Disease; Pemphigoid, Bullous; Risk Factors; Severity of Illness Index; Sex Factors; Stroke; Time Factors; Collagen Type XVII
PubMed: 30876802
DOI: 10.1016/j.jid.2019.01.034 -
Anti-BP180 Autoantibodies Are Present in Stroke and Recognize Human Cutaneous BP180 and BP180-NC16A.Frontiers in Immunology 2019Current evidence has revealed a significant association between bullous pemphigoid (BP) and neurological diseases (ND), including stroke, but the incidence of BP...
Current evidence has revealed a significant association between bullous pemphigoid (BP) and neurological diseases (ND), including stroke, but the incidence of BP autoantibodies in patients with stroke has not previously been investigated. Our study aimed to assess BP antigen-specific antibodies in stroke patients. One hundred patients with stroke and 100 matched healthy controls were randomly selected for measurement of anti-BP180/BP230 IgG autoantibodies by enzyme-linked immunosorbent assay (ELISA), salt-split indirect immunofluorescence (IIF), and immunoblotting against human cutaneous BP180 and BP180-NC16A. Anti-BP180 autoantibodies were found in 14 (14.0%) patients with stroke and 5 (5.0%) of controls by ELISA ( < 0.05). Sera from 13 (13.0%) patients with stroke and 3 (3.0%) controls reacted with 180-kDa proteins from human epidermal extract ( < 0.05). 11 (11.0%) of stroke and 2 (2.0%) of control sera recognized the human recombinant full length BP180 and NC16A ( < 0.05). The anti-BP180-positive patients were significantly younger than the negative patients at the time of stroke ( < 0.001). Development of anti-BP180 autoantibodies occurs at a higher frequency after stroke, suggesting BP180 as a relatively common autoantigen after stroke and providing novel insights into BP pathogenesis in aging.
Topics: Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Chromatography, Affinity; Dystonin; Female; Fluorescent Antibody Technique, Indirect; Humans; Immunoglobulin G; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Skin; Stroke; Collagen Type XVII
PubMed: 30863396
DOI: 10.3389/fimmu.2019.00236 -
Dermatology Online Journal Aug 2018Enzyme-linked immunosorbent assay is a sensitive and specific method for the detection of circulating autoantibodies in pemphigus vulgaris and foliaceus. Herein,...
Enzyme-linked immunosorbent assay is a sensitive and specific method for the detection of circulating autoantibodies in pemphigus vulgaris and foliaceus. Herein, pemphigus erythematosus with equivocal immunofluorescence and non-diagnostic histology, but confirmed by enzyme-linked immunosorbent assay, is described. As a non-invasive, sensitive, and specific assay with additional utility for monitoring disease activity, this case adds to growing evidence supporting ELISA as the diagnostic method of choice for common and less common variants of pemphigus.
Topics: Aged; Autoantibodies; Autoantigens; Desmoglein 1; Desmoglein 3; Dystonin; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Humans; Non-Fibrillar Collagens; Pemphigus; Sensitivity and Specificity; Collagen Type XVII
PubMed: 30677852
DOI: No ID Found