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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 -
Progress in Neuro-psychopharmacology &... Dec 2019DISC1 was discovered as a gene disrupted by a balanced translocation in a large pedigree that segregated with major mental disorders, including schizophrenia. Further...
DISC1 was discovered as a gene disrupted by a balanced translocation in a large pedigree that segregated with major mental disorders, including schizophrenia. Further attempts to find genetic association with schizophrenia were inconclusive. Most of the biology of DISC1 was inferred from the functionality of its protein partners. Recently, a gene set constituted by DISC1 and several of its partners has been associated with cognitive performance during development, a well-known schizophrenia endophenotype, by means of burden test of rare disruptive variants. Here, we performed a gene set analysis using common variants from the largest schizophrenia genome-wide association study of the Psychiatric Genomics Consortium to test if this gene set is associated with schizophrenia. The main test was based on the MAGMA software. Several additional tests were performed to analyze the robustness of the main findings. The DISC1 interactome gene set was associated with schizophrenia (P = .0056), confirmed by an additional method (INRICH). This association was robust to removal of the major histocompatibility complex region, different definitions of gene boundaries, or different statistical gene models. Conditional analysis revealed that the association was not solely explained by higher expression in brain. Three genes from the gene set, CLIC1, DST, and PDE4B, were associated with schizophrenia at the gene level. Consideration of other DISC1 interactome gene sets revealed the importance of gene set definition. Therefore, we present the first evidence from genome-wide association studies of the role of DISC1 and interacting partners in schizophrenia susceptibility, reconciling genetic and molecular biology data.
Topics: Alleles; Chloride Channels; Cyclic Nucleotide Phosphodiesterases, Type 4; Dystonin; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Schizophrenia
PubMed: 31398428
DOI: 10.1016/j.pnpbp.2019.109729 -
Journal of the American Academy of... Nov 2019
Topics: Autoantibodies; Dystonin; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prognosis; Pruritus
PubMed: 31374311
DOI: 10.1016/j.jaad.2019.06.1314 -
Journal of the American Academy of... Nov 2019
Topics: Autoantibodies; Dystonin; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous; Prognosis; Pruritus
PubMed: 31369772
DOI: 10.1016/j.jaad.2019.07.078 -
The British Journal of Dermatology Jan 2020
Topics: Autoantibodies; Autoantigens; Dystonin; Enzyme-Linked Immunosorbent Assay; Humans; Non-Fibrillar Collagens; Pemphigoid, Bullous
PubMed: 31301230
DOI: 10.1111/bjd.18343 -
Journal of the European Academy of... Jan 2020The BIOCHIP is a novel multiplex indirect immunofluorescence technique used in the serological diagnosis of bullous pemphigoid and pemphigus. The BIOCHIP method combines...
BACKGROUND
The BIOCHIP is a novel multiplex indirect immunofluorescence technique used in the serological diagnosis of bullous pemphigoid and pemphigus. The BIOCHIP method combines the screening of autoantibodies and target antigen-specific substrates in a single miniature incubation field.
OBJECTIVE
To evaluate the diagnostic accuracy of the new immunofluorescence BIOCHIP multiplex tool in pemphigus and bullous pemphigoid.
METHODS
For the validation of the BIOCHIP, sera from patients with BP (n = 38), PF (n = 8) and pemphigus vulgaris (PV) (n = 23) were used. In addition, sera from disease control patients (n = 63) and healthy volunteers (n = 39) were used. The multiplex BIOCHIP and direct immunofluorescence (DIF) were performed for all BP, PF and PV patients. Additional indirect immunofluorescence (IIF) was performed on patients with BP, and ELISA was performed on patients with pemphigus.
RESULTS
The BIOCHIP mosaic showed a sensitivity of 86.8% and specificity of 85% for BP180 or BP230 being positive in BP. It demonstrated a sensitivity of 75% and specificity of 97.7% for Dsg1 in PF. The BIOCHIP was found to have a sensitivity of 60.9% and specificity of 73.6% for Dsg3 in PV.
CONCLUSION
The BIOCHIP mosaic-based immunofluorescence test is potentially a simple, time and effort saving test that can aid in the diagnosis and screening of BP, PV and PF. However, there is potential for interpretation bias and a learning curve that needs to be taken into consideration.
Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Desmoglein 1; Desmoglein 3; Diagnosis, Differential; Dystonin; Female; Fluorescent Antibody Technique, Indirect; Humans; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Pemphigus; Sensitivity and Specificity; Collagen Type XVII
PubMed: 31260565
DOI: 10.1111/jdv.15770 -
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 -
The British Journal of Dermatology Sep 2019
Topics: Autoantibodies; Autoantigens; Complement Activation; Complement C5a; Complement Fixation Tests; Dystonin; Humans; Non-Fibrillar Collagens; Off-Label Use; Pemphigoid, Bullous; Skin; Tinzaparin; Collagen Type XVII
PubMed: 31124130
DOI: 10.1111/bjd.18156